BuzzSugar

TV Tonight: The Next Great American Band

BuzzSugar — Fri, 19 Oct 2007 07:30:00 -0700

There are two key ingredients to the basic American Idol recipe: there's music, and the audience picks the winner. Idol is the biggest thing on TV, but Fox's attempts at separating the two elements that make it so successful haven't worked out so well - On the Lot, all voting and no music, limped to a finish, while Nashville, all music and no voting, was the first of the fall's new shows to be pulled.

But both parts of the Idol formula will be in full effect tonight during the premiere of The Next Great American Band, essentially a large-scale battle of the bands. Like Idol, the show is starting with several two-hour audition episodes that will narrow the field to 12 finalists. And, also like Idol, the audience will eventually have a say in which band wins. There's one key difference from Idol, and it's the thing I think could make the show kind of cool: The bands are playing their own music or selecting their own cover tunes, not using songs or genres chosen by producers. I'm hoping that carries through all the way to the finals, because I never want to hear a band called Zombie Bazooka Patrol take on Whitney Houston ballads.

I still don't know how smart it is to put a show that relies on audience participation on a Friday - and it's hard for me to imagine that Fox has much faith in it when, as of this writing, the network still hasn't built the show a proper Web site. (Update: A real site is finally up.) What do you think? Are you willing to give The Next American Band a shot? To watch a preview clip, just read more

Photo and video courtesy of Fox

Fox Picks Its Host, Judges for "American Band"

BuzzSugar — Mon, 27 Aug 2007 11:33:28 -0700

After "On the Lot," I'm a little wary of Fox dipping its toes into any new reality markets. But so far, it sounds like "The Next Great American Band," the "American Idol" crew's search for a new group to rule the airwaves, is keeping it all in the "Idol" family with its host and judges.

Host Dominic Bowden may be a newcomer to American TV, but he's well-known in New Zealand for hosting "New Zealand Idol." And judge Ian "Dicko" Dickson has pretty good music bonafides (he worked in promotions for Oasis and LL Cool J), but he's made his mark as the outlandish, Simon Cowell-esque judge on "Australian Idol." Joining Dicko at the judges' panel will be Goo Goo Dolls singer/songwriter John Rzeznik and Prince protege Sheila E. It may not be the strongest group ever, but really, if you'd heard back in 2002 that Randy Jackson and Paula Abdul were judging a reality show, wouldn't you have thought that would be dead in the water, too?

Here's how the show will work: After auditions, the judges will pick 10 semifinalists to perform weekly in front of a live audience. The competition will include both original music from the bands and covers of various styles. Voting will start at the end of each show, and the eliminated band will be announced at the start of the following week's episode.

Given that the show's airing on Fridays at 8 p.m., I can't imagine it would be as popular as an "Idol" or even a "So You Think You Can Dance." Are any of you curious to check it out?

Source

Cirrhosis

FitSugar — Wed, 08 Oct 2008 17:35:41 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

In 2007, the Food and Drug Administration approved HepaGram B, an injectable immune globulin that can help prevent recurrence of hepatitis B following liver transplantation.

Primary Biliary Cirrhosis

Primary biliary cirrhosis is an autoimmune liver disease that increases the risk for liver cancer. According to a 2007 study, specific risk factors may help predict which patients with primary biliary cirrhosis are at particularly high risk of developing liver cancer. These risk factors include older age, being male, history of blood transfusion, and any signs of portal hypertension (high pressure of the blood in the portal vein, which leads to the liver) or cirrhosis.

Hepatitis C and Cirrhosis

Patients with cirrhosis who are infected with a particular hepatitis C genotype (1b) have a high risk of developing liver cancer, indicates a 2007 study. These patients should receive regular monitoring so that liver cancer can be detected in its earliest stages.
Interferon drug therapy can help reduce -- but not entirely eliminate -- the risk of liver cancer developing in patients with hepatitis C-related cirrhosis.

Hemochromatosis

Hemochromatosis, also called “iron overload,” is an iron disorder that increases the risk for cirrhosis. Hereditary hemochromatosis is one of the most common genetic diseases in the United States, and experts have debated whether all people should get screened for it. In 2006, the U.S. Preventive Services Task Force (USPSTF) released updated guidelines concerning hemochromatosis screening. The USPSTF does not recommend routine screening in the general population. However, people who have family histories of hemochromatosis, or who show signs or symptoms of this disorder, should get tested.

Encephalopathy

Lactulose, a drug that helps remove ammonia from the body, can help improve cognitive function and quality of life for people with hepatic encephalopathy, suggests a 2007 study. Hepatic encephalopathy, a complication of liver disease, affects the brain and nervous system.

Introduction

Cirrhosis is an irreversible result of various disorders that damage liver cells over time. Eventually, damage becomes so extensive that the normal structure of the liver is distorted and its function is impaired.

Cirrhosis is a chronic liver disease that causes damage to liver tissue, scarring of the liver (fibrosis - nodular regeneration), progressive decrease in liver function, excessive fluid in the abdomen (ascites), bleeding disorders (coagulopathy), increased pressure in the blood vessels (portal hypertension), and brain function disorders (hepatic encephalopathy). Excessive alcohol use is the leading cause of cirrhosis.

The disease process often takes the following path:

Scarring. The main damage in cirrhosis is triggered by scarring (fibrosis) that occurs from injuries due to alcohol, viruses, or other assaults. Normal clumps and form nodules around the scarred areas. The scar tissue and regenerated nodules act like small dams and alter the flow of blood and bile in and out of the liver.

Altered Blood and Bile Flow. The changes in blood and bile flow have significant consequences, with both the liver and other organs responding to the altered flow:

The spleen overproduces nitric oxide, a gas that causes blood vessels in the spleen to relax and open.
The small blood vessels and bile ducts in the liver itself, however, narrow (constrict). (Blood vessels in other organs, including the kidney, also narrow.)
Blood flow coming from the intestine into the liver is slowed by the narrow blood vessels. It backs up through the portal vein and seeks other routes.
New, abnormally twisted and swollen veins called varices form in the stomach and lower part of the esophagus in order to compensate for the backup blood.
Bile also builds up in the bloodstream, resulting in high levels of bilirubin, which causes a yellowish cast in the skin called jaundice.
Fluid buildup also occurs in the abdomen (called ascites), and swelling in the arms and legs is common.

Changes in Liver Size. The liver enlarges in the first phases of the disease. In advanced stages, the liver sometimes shrinks, a condition called postnecrotic cirrhosis.

The liver is the largest organ in the body. In the healthy adult, it weighs about 3 pounds. The liver is wedge-shaped, with the top part wider than the bottom. It is located immediately below the diaphragm and occupies the entire upper right quadrant of the abdomen.

Vital Functions. The liver performs over 500 vital functions. Damage to the liver can impair these and many other processes. Among them are the following:

Processing Healthful Nutrients. It processes all of the nutrients the body requires, including proteins, glucose, vitamins, and fats.

Bile Production. The liver produces bile, a green-colored fluid that helps the body absorb fats and fat-soluble vitamins. Bile is formed from bilirubin, a yellow-green pigment produced from the breakdown of hemoglobin, the oxygen-carrying component in red blood cells. Bile contains bile salts, fatty acids, cholesterol, and other substances. Bile travels from the liver to the gallbladder, where it is stored until after a meal. It is then secreted into the intestines where it helps digest fat.

Eliminating Toxins. One of the liver's major functions is to render harmless potentially toxic substances, including alcohol, ammonia, nicotine, drugs, and harmful by-products of digestion.

Recycling Blood. The liver and spleen removes old red blood cells from the blood. The iron contained in them is recycled in the bone marrow to make new red blood cells.

The Liver's Architecture. The vital processes the liver performs rely on well-organized liver architecture.

The Building Blocks. The basic building blocks of the liver are the following structures:

Bile ducts
Blood vessels
Working liver tissue (called the parenchyma)
Supportive (connective) tissue

The Architecture. The liver is a built on a framework of lobes:

The lobes. The liver is divided into two major lobes, a right and a smaller left, that are separated by tough, fibrous connective tissue.
The lobules. The liver's two major lobes contain about 100,000 smaller lobes, called lobules. Each lobule contains microscopic columns of liver cells and blood vessels. Bracing the corners of each lobule column are an artery and a vein that carry blood and a bile duct that drains bile.
The arteries and veins. The arteries bring oxygen-rich blood to nourish the liver cells. The veins supply the liver cells with blood containing the nutrients and toxins that the liver cells process. A central vein runs through each column and collects the processed blood from both sources. These veins join to form the hepatic vein.
The bile ducts. The bile ducts in the column corners collect bile draining from tiny canals around the liver cells. These ducts eventually join to form the large common bile duct that leads from the liver to the gallbladder.

The Liver's Blood Supply. The liver is rich in blood. It holds about a pint, or 13% of the body's supply. It is furnished with blood from two large vessels, the hepatic artery and the portal vein, and is drained of blood by the hepatic vein. (The word "hepatic" derives from the Latin word for liver.)

The hepatic artery. This artery supplies blood from the heart directly to the liver. This blood nourishes the liver.

The portal vein. The portal vein carries to the liver blood that has been circulating through the stomach, spleen, and intestine. The liver processes this blood, extracting nutrients and toxins.

The hepatic vein. This vein carries blood from the liver and connects to the inferior vena cava, a large vein that carries blood back to the heart.

Click the icon to see an image of the liver.

Causes

Several processes can lead to cirrhosis.

Alcoholism particularly endangers the liver. Alcoholic cirrhosis (also sometimes referred to as portal, Laennec's, nutritional, or micronodular cirrhosis) is the primary cause of cirrhosis in the U.S. It is estimated to be responsible for 44% of deaths from cirrhosis in North America. Some experts believe this estimate is low. One Canadian study found alcohol to be the major contributor in 80% of all cirrhosis deaths.

The relationship between alcohol and cirrhosis is generally as follows:

Alcohol is absorbed from the small intestine, and the blood carries it directly into the liver, where it becomes the preferred energy source.
In the liver, alcohol converts to toxic chemicals, such as acetaldehyde (AcH), which trigger the production of powerful immune factors called cytokines. These molecules in large amounts can cause inflammation and tissue injury. They are proving to be major culprits in the destructive process in the liver. AcH is particularly being researched because it plays a role in most actions of alcohol, including damaging effects on the liver that may lead to cirrhosis.
The injured liver eventually is unable to break down fatty acids, compounds that make up fat. Over time, then, fat accumulates, further impairing the liver's ability to absorb oxygen and increasing its susceptibility to injury. During the initial phase, the fat-laden liver becomes greatly enlarged, but it eventually shrinks as cirrhosis develops.

Chronic hepatitis, both hepatitis B and hepatitis C, is the second leading cause of cirrhosis. Chronic hepatitis C is the more dangerous form and accounts for one-third of all cirrhosis cases. About 5 - 20% of patients with chronic hepatitis C, and 5 - 10% of patients with chronic hepatitis B, eventually develop cirrhosis over the course of several decades. The longer a patient has had chronic hepatitis, the greater the risk for eventually developing cirrhosis. A 2005 study indicated that cirrhosis develops in 70% of patients who have had hepatitis C for more than 60 years.

The hepatitis virus can produce inflammation in liver cells, causing injury or destruction. If the condition is severe enough, the cell damage becomes progressive, building a layer of scar tissue over the liver. In advanced cases, as with alcoholic cirrhosis, the liver shrivels in size, a condition called postnecrotic or posthepatic cirrhosis.

Hepatitis C is a virus-caused liver inflammation which may lead to jaundice, fever, and cirrhosis. The people most at risk for contracting and spreading hepatitis C are those who share needles for injecting drugs and health care workers or emergency workers who may be exposed to contaminated blood.

Autoimmune liver diseases include autoimmune hepatitis and primary biliary cirrhosis. Like other autoimmune disorders, these conditions most likely develop because a genetically defective immune system attacks the body's own cells and organs. People who have one of these liver diseases also often have other autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, scleroderma, inflammatory bowel disease, glomerulonephritis, and hemolytic anemia.

Autoimmune Hepatitis. Autoimmune chronic hepatitis occurs when an abnormal immune response causes an attack on the liver cells. It accounts for about 20% of all chronic hepatitis cases. Autoimmune chronic hepatitis typically occurs in women age 20 - 40 who have other autoimmune diseases. Some research indicates that the postmenopausal period may be another peak in incidence of AIH among women. About 30% of patients are men, however, and in both genders there is often no relationship to another autoimmune disease. In general, no major risk factors have been discovered for this condition.

Suspects for triggering this hepatitis include the measles virus, a hepatitis virus, or the Epstein-Barr virus, which causes mononucleosis. It is also possible that a reaction to a drug or other toxin that affects the liver also triggers an autoimmune response in some people.

Click the icon to see an image of mononucleosis.

Primary Biliary Cirrhosis. Up to 95% of primary biliary cirrhosis (PBC) cases occur in women, usually around age 50. In people with PBC, the immune system attacks and destroys cells in the liver’s bile ducts. Like many autoimmune disorders, the causes of PBC are unknown. Recent research indicates the following risk factors:

Family history of PBC
Family history of Sjögren syndrome (another autoimmune disorder)
Individual history of urinary tract infections (UTI)
History of smoking
History of nail polish use
Hormone replacement therapy
Exposure to toxins from hazardous waste sites

This research suggests that environmental factors (chemicals, cigarette smoke) or infectious organisms (bacteria that causes UTI) may trigger PBC in patients who are genetically susceptible to the disease. Women who have never been pregnant appear less likely to develop PBC.

Nonalcoholic fatty liver disease (NAFLD) resembles alcoholic liver disease, but it occurs in people who do not drink a lot of alcohol. Obesity and type 2 diabetes are the two main causes of a fatty liver. Some evidence suggests that insulin resistance (the primary problem in type 2 diabetes) is a major factor in development of a fatty liver. A diet high in fatty foods may also be a risk factor, as dietary fat accumulates in the liver. Due to the recent rise in childhood obesity, NAFLD is increasingly occurring in children. In fact, NAFLD is now the most common liver disease in American children.

Nonalcoholic fatty liver disease can lead to nonalcoholic steatohepatitis (NASH). Liver inflammation and injury, as well as a fatty liver, characterize NASH. NASH occurs in about half of people with diabetes and up to 75% of obese people.

Nonalcoholic fatty liver disease is usually benign and very slowly progressive. But, in certain patients it can lead to cirrhosis, liver failure, or liver cancer. About 8 - 20% of people with nonalcoholic steatohepatitis go on to develop cirrhosis. A 2006 study indicated that NASH-related cirrhosis causes fewer deaths than cirrhosis that is caused by chronic hepatitis C. However, many patients with NASH have coronary artery disease and heart failure and have a high risk of dying from heart disease.

Weight reduction and diabetes and cholesterol management are the primary approaches to controlling these diseases.

Hemochromatosis is a disorder of iron metabolism. This disease interferes with the way the body normally gets rid of iron. People with hemochromatosis absorb too much more iron from the food that they eat. The iron overload accumulates in organs in the body. When excess iron deposits accumulate in the liver, they can cause cirrhosis.

There are two main forms of hemochromatosis:

Primary hemochromatosis, also called hereditary hemochromatosis, is an inherited genetic disease.
Secondary hemochromatosis results from other conditions, such as anemia and alcoholism.

Hereditary hemochromatosis is one of the most common genetic diseases, especially among Caucasians. About 1 in every 200 Americans carries the gene that causes this disease. Although experts do not recommend that everyone get screened for hemochromatosis, people who have a family history of this disease, or who show symptoms (joint pain, fatigue, abdominal pain), should get tested. Left untreated, hemochromatosis can lead to serious damage of the liver, heart, and pancreas.

Hemochromatosis is treated with phlebotomy, a procedure that involves removing about a pint of blood once or twice a week. Starting phlebotomy treatment before organ damage occurs can help prevent cirrhosis. If, however, cirrhosis has already developed, patients have a high risk for developing liver cancer even if iron levels are normalized.

Inherited Diseases. Cirrhosis can be caused by several inherited diseases, including:

Cystic fibrosis
Alpha-1 antitrypsin deficiency
Galactosemia
Glycogen storage diseases
Wilson's disease

Other Rare Causes. Rare causes of cirrhosis include:

Schistosomiasis, caused by a parasite found in the Far East, Africa, and South America.
Small intestine bypass surgery (rarely, if ever, performed anymore).
Long-term or high level exposure to certain chemicals and drugs can cause cirrhosis, including arsenic, methotrexate, and toxic doses of vitamin A.

Cancers that have metastasized to the liver, blood clots in the hepatic or portal vein, or obstructions in the bile duct can cause changes that resemble cirrhosis.

Risk Factors

Cirrhosis affects about 3 million Americans a year. However, because about 2.7 - 4 million people harbor hepatitis C, the rates of cirrhosis could dramatically increase over the next few years.

Only 10% of heavy drinkers develop advanced liver disease. Not eating when drinking and consuming a variety of alcoholic beverages are factors that increase the risk for liver damage. Still, the amount of alcohol consumed and the patterns of drinking are only weak predictions of risk. Other risk factors have been identified that may increase the danger to the liver:

Obesity is a major factor for all stages of liver disease.
Women develop liver disease at lower quantities of alcohol intake than men. The reason for this may be due to women's inability to metabolize alcohol as quickly as men, so it stays in the bloodstream longer.
Genetic factors that regulate the immune responses in the intestine also play a role in increasing the risk for liver injury from alcoholism.

Risk Factors for Developing Cirrhosis from Hepatitis C. Overall, between 10 - 15% of patients with chronic hepatitis C develop cirrhosis. The risk varies widely, however. The following conditions put people with hepatitis C at higher risk for liver damage:

Overall the risk for progression is highest in men -- particularly African-Americans -- who were older at the time of infection. The risk is much lower in women and children (2 - 4%).
Moderate-to-heavy alcohol users. (Even one or two alcoholic drinks a day increase the risk for liver injury in hepatitis C patients.)
Having a specific genetic type of the virus. There are six main genetic types and more than 90 subtypes, which can differ significantly in their effects and response to treatment. Genotype 1 is the most serious and is the cause of up to three quarters of the cases in the U.S. The other common forms are types 2 (15%) and 3 (7%), which pose less danger.
Co-infection with hepatitis B. Co-infection with B significantly affects the outcome of these patients and may be more common than previously believed. This co-condition may cause superinfections with very serious consequences, reduce these patients' responses to interferon therapy, and increase their risk of liver cancer. Patients with hepatitis C should be immunized against hepatitis B.
Co-infection with HIV.
A history of transfusions. (In one report, the risk in middle-aged patients with a history of transfusions was 20 - 30%).
Being diabetic and overweight, particularly if fat is distributed in the abdomen (an apple-shape). This condition poses a higher risk for nonalcoholic fatty liver disease (NASH), which in turn is apt to become scarred and cirrhotic.

Weight gain in the area of and above the waist (apple type) is more dangerous than weight gained around the hips and flank area (pear type). Fat cells in the upper body have different qualities than those found in hips and thighs.

Having large iron stores in the liver.
High exposure to toxic chemicals or environmental contaminants.

Because there are millions of Americans now infected with chronic hepatitis C, doctors have been justifiably concerned that there will be a significant number of cases of liver failure and liver cancer in the coming years. Computer analyses have suggested that mortality rates from hepatitis C-related cirrhosis or liver cancer will double or triple over the next 20 years. Fortunately, improved therapies may significantly reduce these discouraging estimates.

Researchers are working on developing a genetic test to identify patients with chronic hepatitis C who are most at risk of developing cirrhosis. In 2007, scientists announced they had made progress on a test that measures variations in seven genes to calculate a “Cirrhosis Risk Score.” The researchers hope that this experimental test may eventually help doctors decide which patients should receive early treatment with alpha-interferon and ribavirin.

Risk Factors for Developing Cirrhosis from Hepatitis B. The great majority of people with chronic persistent hepatitis B have a good long-term outlook. Between 5 - 10%, however, become carriers of the virus, and 5 - 10% of these individuals eventually develop cirrhosis. The addition of hepatitis D is a particular danger and increases the risk for cirrhosis. Seven genetic types of hepatitis B virus (designated A to G) have now been identified, which may help researchers determine the patients who may have a better outlook than others. Genotype C is the most common form and is more aggressive than genotype B, which also responds better to treatment.

Primary biliary cirrhosis accounts for only 0.6 - 2% of deaths from cirrhosis. In patients with chronic persistent autoimmune hepatitis, the outlook is very favorable, and survival rates are equal to the general population. If it becomes active, it must be treated. Left untreated, the 5-year survival rates of primary biliary cirrhosis are 50%.

Obesity increases the risk for nonalcoholic fatty liver disease (NAFLD), a condition that can lead to nonalcoholic steatohepatitis (NASH). Studies estimate that 8 - 20% of people with NASH eventually develop cirrhosis. A 2006 study found that people with NAFLD and elevated liver enzymes have a high risk of developing end-stage liver disease. People with NASH had an especially poor prognosis for survival. Losing weight is important for overweight people with NASH and may help to delay disease progression. A 2003 study of more than 11,000 patients indicated that obesity increases the risk of death from cirrhosis in people who drink little or no alcohol, but not among those who drink alcohol.

Symptoms

Many people experience few symptoms at the onset of cirrhosis.

Early symptoms include:

Fatigue and loss of energy.
Loss of appetite and nausea.
Spider angiomas may develop on the skin. These are pinhead-sized red spots from which tiny blood vessels radiate.

Patients in later stages may develop the following symptoms:

Jaundice. This yellowish cast to the skin and eyes occurs because the liver cannot process bilirubin for elimination from the body.

Jaundice is a condition produced when excess amounts of bilirubin circulating in the bloodstream dissolve in the subcutaneous fat (the layer of fat just beneath the skin), causing a yellowish appearance of the skin and the whites of the eyes. With the exception of normal newborn jaundice in the first week of life, all other jaundice indicates overload or damage to the liver, or inability to move bilirubin from the liver through the biliary tract to the gut.

The palms of the hands may be reddish and blotchy, a condition known as palmar erythema.
Loss of body hair.
Abnormalities in hormone-affected organs. In men with alcoholic cirrhosis, the testicles may atrophy, and their breasts may become swollen, sometimes painfully.
Ascites. A swollen belly is a sign of ascites, the most common major complication of cirrhosis, which occurs when fluid accumulates in the abdomen. Fever, abdominal pain, and tenderness when the belly is pressed indicate that the fluid is infected, but infection can occur without any symptoms.
Fluid buildup and swelling (edema) in legs.

People with primary biliary cirrhosis may have severe generalized itching and often develop small fatty yellow lumps called xanthomas on the eyelids, hands, and elbows. They may have an unpleasant condition called steatorrhea, in which the feces contain excessive fat, causing them to float and to be very foul smelling.

Click the icon to see an image of a xanthoma.

Complications

Cirrhosis is the eleventh leading cause of death by disease in the United States, killing more than 25,000 people each year. A damaged liver affects almost every bodily process, including the functions of the digestive, hormonal, and circulatory systems. The most serious complications are those associated with so-called decompensation, which occur when cirrhosis progresses. They include the following:

Bleeding and fluid buildup (ascites).
Infections.
Damage to the brain (encephalopathy). Impaired brain function occurs when the liver cannot detoxify harmful substances.

Liver cancer is also a long-term risk with cirrhosis.

Cirrhosis is irreversible, but the rate of progression can be very slow, depending on its cause and other factors. Five-year survival rates are about 85% and can be lower or higher depending on severity.

For example, alcoholics with cirrhosis who abstain can have a 5-year or more survival rate of as high as 85%. For those who continue drinking, the chance for living beyond 5 years is no higher than 60%.
In patients with hepatitis B or C, the 5-year survival rate after a diagnosis of cirrhosis is 71 - 85%.
About two-thirds of patients with primary biliary cirrhosis never develop symptoms and can have a normal lifespan. Once symptoms of liver damage, such as jaundice, occur, however, the average survival time declines. In one study of women diagnosed with primary biliary cirrhosis, about 36% developed symptoms over an 11-year period, and 11% either died or required liver transplantation.

Unfortunately, doctors are usually unable to determine when cirrhosis first occurred, which makes it difficult to determine prognosis.

In cirrhosis, liver cell damage slows down blood flow. This causes a backup of blood through the portal vein, a condition called portal hypertension. The effects of portal hypertension can be widespread and serious, including fluid buildup and bleeding.

Ascites and Fluid Buildup. Ascites is fluid buildup in the abdomen. It is uncomfortable and can reduce breathing function and urination. Ascites is usually caused by portal hypertension, but it can result from other conditions. Swelling can also occur in the arms, legs, and spleen. Although ascites itself is not fatal, it is a marker for severe progression. Once ascites occurs, only half of patients survive after 2 years. Some doctors refer to the phases of cirrhosis as preascitic and ascitic. Some doctors even believe that ascites signals the need for liver transplantation, particularly in alcoholic cirrhosis.

Variceal Bleeding. One of the most serious repercussions of portal hypertension is the development of varices, blood vessels that enlarge to provide an alternative pathway for blood diverted from the liver. In about two-thirds of patients, they form in esophagus. Varices pose a high risk for rupture and bleeding because of the following characteristics:

They are thin-walled.
They are often twisted.
They are subject to high pressure.
Internal bleeding from these varices (variceal bleeding) occurs in 20 - 30% of patients with cirrhosis. The risk of death from a single episode can reach 70%.

Bleeding commonly recurs within 2 weeks of the first episode, but after 6 weeks, the risk for recurrence is the same as for patients who have not had a bleeding event.

Factors that predict variceal bleeding include:

Ascites
Encephalopathy
Large veins

Factors that can increase the danger for a bleeding episode in high-risk individuals include the following:

Moderate-to-intense exercise
Bacterial infection
Certain times of the day. Eating increases portal pressure, and there is a greater risk for bleeding in the evening. A lesser but still significant risk occurs in the early morning.

It is important for patients to be screened for esophageal varices and treated with preventive beta blockers if they show signs of risk. Between 30 - 40% of patients with cirrhosis have bleeding. The risk of dying from this complication is 20 - 35%. Some doctors recommend that all newly diagnosed patients be screened using endoscopy. Screening should also be considered for all previously diagnosed patients who have not been screened but would benefit from preventive treatments.

Portal hypertension can cause several secondary complications, including kidney failure. Non-steroidal anti-inflammatory drugs, such as naproxen, may increase the risk for kidney failure.

Gastrointestinal bleeding can occur from abnormal blood clotting, which can be a result of a combination of complications associated with cirrhosis. They include vitamin K deficiencies and thrombocytopenia -- a drop in platelets (the blood cells that normally initiate the clotting process). Some research now suggests that thrombocytopenia itself may be associated with more advanced liver failure.

Bacterial infections are very common in advanced cirrhosis, and may even increase the risk for bleeding. Most bacterial infections, including those in the urinary, respiratory, or gastrointestinal tracts, develop when patients are in the hospital. Abdominal infections are a particular problem in cirrhosis and occur in up to 25% of patients with cirrhosis within a year of diagnosis.

Mental impairment is a common event in advanced cirrhosis. In severe cases, the disease causes encephalopathy (damage to the brain), with mental symptoms that range from confusion to coma and death. A combination of conditions associated with cirrhosis causes this serious complication:

Buildup in the blood of harmful intestinal toxins, particularly ammonia.
An imbalance of amino acids that affect the central nervous system.

Encephalopathy is often triggered by certain conditions, including:

Gastrointestinal bleeding
Constipation
Excessive dietary protein
Infection
Surgery
Dehydration

Alcoholics with cirrhosis are believed to be at higher risk for this complication than are nonalcoholic cirrhosis, but one study suggested that alcoholics simply tend to have more severe cirrhosis. Even minimal hepatic encephalopathy (MHE) can have detrimental effects on functional ability. One study suggested that MHE impairs the ability to safely drive a car, and that all patients with cirrhosis be tested for MHE.

Symptoms of Encephalopathy. Early symptoms of hepatic encephalopathy include forgetfulness, unresponsiveness, and trouble concentrating. Sudden changes in the patient's mental state, including agitation or confusion, may indicate an emergency condition. Other symptoms include bad fruity-smelling breath and tremor. Late stage symptoms of encephalopathy are stupor and eventually coma.

Hepatorenal syndrome occurs if the kidneys drastically reduce their own blood flow in response to the altered blood flow in the liver. It is a life-threatening complication of late-stage liver disease that occurs in patients with ascites. Symptoms include dark colored urine and a reduction in volume, yellowish skin, abdominal swelling, mental changes (delirium, confusion), jerking or coarse muscle movement, nausea, and vomiting.

People with cirrhosis have an increased risk for liver cancer. Hepatitis B and C themselves increase the risk for liver cancer, regardless of the presence of cirrhosis. Hepatitis B infection is the leading cause of liver cancer.

For hepatitis C-related cirrhosis, a 2007 study indicated that patients with cirrhosis who are infected with genotype 1b hepatitis C have a greater risk of developing liver cancer than patients infected with other types of hepatitis C genotypes. (Genotype 1 is the most common type of hepatitis C in the United States.)

People with primary biliary cirrhosis also face a high risk of liver cancer. According to a 2007 study, several factors can indicate the increased likelihood of developing liver cancer. These factors include older age, male gender, history of blood transfusion, and signs of portal hypertension or cirrhosis.

About 30% of patients with chronic liver disease develop osteoporosis (loss of bone density), which is twice the usual incidence. Patients with primary biliary cirrhosis have a particularly high risk for osteoporosis. Treating osteoporosis in patients with cirrhosis can be complicated. One study found that calcitriol (a form of vitamin D) is especially helpful in preventing bone loss in patients with cirrhosis.

Osteoporosis is a condition characterized by progressive loss of bone density, thinning of bone tissue, and increased vulnerability to fractures. Osteoporosis may result from disease, dietary or hormonal deficiency, or advanced age. Regular exercise and vitamin and mineral supplements may reduce and even reverse loss of bone density.

Nearly all patients with cirrhosis are insulin resistant. Insulin resistance is a primary feature in type 2 diabetes and occurs when the body is unable to use insulin. This hormone is important for delivering blood sugar and amino acids into cells and helps determine whether these nutrients will be burned for energy or stored for future use.

One study reported that nearly a quarter of patients with cirrhosis had gallstones.

Click the icon to see an image of gallstones.

They may also face a higher than average risk for certain abnormal heart rhythms. Peptic ulcers, sleep disorders, and respiratory problems are also more common in people with cirrhosis than in the general population.

Diagnosis

A physical examination may reveal the following in a patient with cirrhosis:

The cirrhotic liver is firm and often enlarged. The liver may feel rock-hard. (In advanced stages of cirrhosis, the liver may become small and shriveled.)
The left side can often be felt by the doctor when pressing on the abdomen.

If the abdomen is swollen, the doctor will check for ascites by tapping the flanks and listening for a dull thud and feeling the abdomen for a shifting wave of fluid.

Measuring Liver Enzymes (Aminotransferases). Enzymes known as aminotransferases, including aspartate (AST) and alanine (ALT), are released when the liver is damaged. Measurements of these enzymes, particularly ALT, are the least expensive and most noninvasive tests for determining severity of the underlying liver disease and monitoring treatment effectiveness. Enzyme levels vary, however, and are not always an accurate indicator of disease activity. (For example, they are not useful in detecting progression to cirrhosis.)

Radioimmunoassays. To identify a particular virus that may be causing hepatitis, blood tests called radioimmunoassays are performed. Typically, radioimmunoassays identify particular antibodies, which are molecules in the immune system that attack specific antigens. (Antigens are any molecules that the body considers threatening or dangerous, and can be targeted by antibodies.)

An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

Some of these tests can pinpoint hepatitis antigens directly. These tests, however, have limitations:

There may not be enough antibodies for blood tests to detect for up to weeks or months after hepatitis develops. Blood tests that are taken too early, then, may miss these signs of infection.
Antibodies also persist after patients recover, so a positive antibody test can indicate a previous infection but does not necessarily determine if the infection is active.

The assays for individual hepatitis viruses may differ.

Polymerase Chain Reaction. In some cases of hepatitis C, a polymerase chain reaction (PCR), may be performed. A PCR is able to make multiple copies of the genetic material (the RNA) of the virus to the point where it is detectable.

Screening for Hepatitis C Virus. In 2004, the U.S. Preventive Services Task Force (USPSTF) recommended against routine screening for the hepatitis C infection in the general population due to low prevalence of the disease. In addition, it "found no evidence that screening for HCV infection in adults at high risk leads to improved long-term health outcomes" and found insufficient evidence to recommend for or against such screening. However, the USPSTF did advise testing in those with signs or symptoms of liver disease. The failure to recommend testing in the high-risk population goes against current recommendations made by the Centers for Disease Control and Prevention, the National Institutes of Health, and other professional organizations. In response to the study, published in the Annals of Internal Medicine, the American Association for the Study of Liver Diseases issued a statement saying that halting such screening would be a "terrible mistake with grave consequences," pointing out that the study itself underscored some key infection-related data that strongly emphasizes the need for screening in high-risk populations.

A liver biopsy is the only definite method for diagnosing cirrhosis. It also helps determine its cause, treatment possibilities, the extent of damage, and the long-term outlook. For example, hepatitis C patients who show no significant liver scarring when biopsied appear to have a low risk for cirrhosis.

The biopsy may be performed using various approaches, including:

Percutaneous Liver Biopsy. This approach uses a needle inserted through the abdomen to obtain a tissue sample from the liver. Various forms of needles are used, including those that use suction or those that cut out the tissue. If cirrhosis is suspected, a cutting needle is the better tool. This approach should not be used in patients with bleeding problems, and it must be used with caution in patients with ascites or severe obesity.

Click the icon to see an image of liver biopsy.

Transjugular Liver Biopsy. This approach uses a catheter (a thin tube) that is inserted in the jugular vein in the neck and threaded through the hepatic vein (which leads to the liver). A needle is passed through the tube, and a suction device collects liver samples. This procedure is risky but may be used for patients with severe ascites.
Laparoscopy. This procedure requires a small abdominal incision through which the doctor inserts a thin tube that contains small surgical instruments and a tiny camera to view the surface of the liver. This is generally reserved for staging cancer or for ascites with unknown causes.

Biopsies can be dangerous, so they cannot be performed on patients who have test results that indicate clotting problems, on those who have had previous liver biopsies, or who have ascites.

Certain blood tests are used to determine liver function. They include the following:

Serum albumin concentration. Serum albumin measures protein in the blood (low levels indicate poor liver function).
Prothrombin time (PT). The PT test measures in seconds the time it takes for blood clots to form (the longer it takes the greater the risk for bleeding).
Bilirubin. One of the most important factors indicative of liver damage is bilirubin, a red-yellow pigment that is normally metabolized in the liver and then excreted in the urine. In patients with hepatitis, the liver cannot process bilirubin, and blood levels of this substance rise, sometimes causing jaundice.

The results of these tests along with the presence of specific complications (ascites and encephalopathy) are used for calculating the Child-Pugh Classification. This is a staging system (A to C) that helps doctors determine the severity of cirrhosis.

Very high levels of serum alkaline phosphatase, an enzyme produced in the liver, and high levels of immune factors called mitochondrial antibodies are usually present in blood tests of patients with primary biliary blood cirrhosis. Bilirubin measurements appear to be important factors in determining its severity.

Fatty liver is suspected when a patient has elevated liver enzymes. The doctor will take imaging tests of the liver using ultrasound, computed tomography, or magnetic resonance imaging. A liver biopsy is the standard test for confirming a diagnosis of fatty liver disease and for distinguishing NAFLD from nonalcoholic steatohepatitis (NASH). Several studies in 2006 and 2007 suggested that a blood test for cytokeratin-18 (CK-18), a protein found in liver cells, may be an effective noninvasive approach for diagnosing NASH. Doctors hope that this simple blood test may eventually be able to replace liver biopsy.

Several imaging tests can be used to diagnose cirrhosis and its complications.

Imaging Techniques. Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound are all imaging techniques that are useful in detecting and defining the extent of cirrhosis. Such tests can reveal ascites, an enlarged spleen, an irregular liver surface, reversed portal vein blood flow, and liver cancer. Sometimes they can even detect abnormally large blood vessels in the liver. In some cases, images from ultrasound and CT can be misinterpreted as cancer. MRI is most useful for ruling out or confirming cancer.

Click the icon to see an image of an MRI scan.

Click the icon to see an image of a CT scan.

Liver Scans. Sometimes liver scans are performed using a small radioactive tracer and a special camera that records information provided by the tracer as it passes through the liver:

Arteriography uses dye injected into the hepatic arteries that show up on x-ray.
Splenoportography uses dye injected into the spleen, which allows the doctor to measure portal vein pressure. This procedure is risky.

Hepatic vein wedge pressure involves insertion of a catheter into the hepatic veins. The blood pressure in the veins of the liver is then measured. The result is an indicator of portal vein pressure. If pressure is high, cirrhosis is likely. A low measurement is a favorable sign.

Endoscopy. Some doctors recommend endoscopy for patients newly diagnosed with mild-to-moderate cirrhosis in order to screen for esophageal varices. (These are abnormal blood vessels in the esophagus that increase the risk for bleeding). In this test, a fiber optic tube is inserted down the throat. The tube contains tiny cameras to view the inside of the esophagus, where varices are most likely to develop. Endoscopy is the only procedure for detecting varices, but it is not clear if screening for varices in patients without severe cirrhosis is any more beneficial than simply putting them immediately on preventive drugs -- whether or not varices have been identified.

Paracentesis. If ascites is present, paracentesis is performed to determine its cause. This procedure involves using a thin needle to withdraw fluid from the abdomen. The fluid is tested for different factors to determine the cause of ascites:

Bacteria cultures and white blood cell counts. (These are used to determine the presence of infection.)
Protein levels. Low levels of protein in the fluid plus a low white blood cell count suggest that cirrhosis is the cause of the ascites.

The appearance of the fluid is helpful in determining problems:

A cloudy fluid plus a high white blood cell count means an infection is present.
Bloody fluid suggests the presence of a tumor.

Screening for Liver Cancer. Patients with cirrhosis are usually screened for liver cancer using ultrasound and tests for a substance called alpha-fetoprotein (AFP). It is not known whether such screening has much impact on survival, because it is not very sensitive and has a high rate of false positives (suggesting the presence of cancer when it is not actually present). Screening is not necessary in patients without cirrhosis.

Treatment

The only treatment for alcoholic cirrhosis is to stop drinking. Individuals with alcoholic cirrhosis are typically malnourished and require increased calories and rigorous nutritional support, which can improve survival rates.

Interferons Alone and in Combination with Ribavirin. Pegylated interferon combined with ribavirin is the gold standard treatment for chronic hepatitis C in both adults and children. It achieves response rates of up to 50% for patients infected with HCV genotype 1 (the most common genotype form in the U.S.) and up to 80% for patients infected with genotypes 2 or 3. Interferon alone is usually reserved for patients who cannot tolerate ribavarin.

A 2005 clinical trial of patients with chronic hepatitis C and cirrhosis found that interferon treatment reduced the risk of liver cancer and significantly improved chance of survival. The study emphasizes the importance and substantial benefits of interferon therapy. A 2007 study of patients with hepatitis C-related cirrhosis also indicated that interferon therapy can help reduce the risk of liver cancer and overall risk of death from liver disease.

A number of natural and synthetic interferons are available:

Natural interferons include interferon alfa-2a (Intron) and interferon alfa-2b (Roferon).
Pegylated interferons (PegINF) are long-acting formulations of interferon. They include alfa-2b (Peg-Intron) or alfa-2a (Pegasys). These drugs are used in combination with ribavarin (Copegus, Rebetol).
Alfacon-1 (Infergen), also called consensus interferon, is a genetically modified interferon. A combination of alfacon-1 with ribavirin is proving to help some patients who had been resistant to ribavirin with interferon.

A 2005 study suggested that some patients with hepatitis C genotypes 2 or 3 may be able to benefit from a shorter course of combination treatment (12 weeks) than the standard 24-week treatment duration. A shorter treatment time may reduce the risk of side effects. However, a 2007 study in the New England Journal of Medicine found that 16 weeks of combination therapy in patients with these genotypes did not work as well as the 24-week regimen. Given the significant side effects associated with combination pegylated interferon and ribavarin treatment, particularly anemia, researchers are actively investigating how to identify which patients may be able to succeed with shorter treatment duration.

PegINF combinations are proving to slow progression of scarring, and have even achieved improvement in some patients who already have cirrhosis. Whether the combination treatment protects against future liver cancer is still unclear. (A higher total dose, rather than a longer duration of treatment, may be the critical factor for protection.)

Side Effects of Combination Treatment. The side effects of the combination include those of both interferon and ribavirin. Interferon side effects may occur more often in the combination treatment. Combination treatment side effects may include:

Anemia occurs in about 22% of patients who take combination treatment versus 1% who take interferon alone. This complication is reversible and usually stabilizes after 1 - 2 months of treatment. However, some patients may become so anemic that they have to stop the medication. Since anemia can worsen heart disease, patients with a history of significant heart problems should not be treated with ribavirin. Other nucleoside analogues are being investigated that may have a lower risk for anemia than ribavirin.
Flu-like symptoms, such as fever, headaches, and muscle aches, are the most common side effect.
Reduced white blood cell count.
Skin disorders, such as dry skin and rash.
Coughing and shortness of breath.
Gastrointestinal symptoms (nausea, indigestion, lack of appetite).
Emotional and psychological symptoms, such as severe sleep disturbances, depression, irritability, and anxiety.
Combination treatment in pregnant women poses a very high risk for birth defects.

The current drugs used for hepatitis C still do not meet the needs of all patients. They are expensive, have significant side effects, do not work in half the patients who take them, and are unsuitable in many others. Investigation is ongoing to find better solutions. Drugs showing promise include:

Albinterferon alfa-2b (Albuferon). This long-acting form of interferon-alfa may have fewer side effects and require less dosing than pegylated interferons. It is currently being tested in combination with ribavarin in Phase II trials for patients with genotype 1 chronic hepatitis C.
Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a peptide derived from the thymus gland (which is responsible for maturation of immune factors called T-cells). It is being used for hepatitis B and is under investigation for hepatitis C in combination with interferon.
Celgosivir. Celgosivir is a new type of antiviral drug, which blocks alpha-glucosidase, an enzyme involved in viral replication. Celgosivir is being studied in combination with pegylated interferon alfa-2b and ribavirin. The drug is derived from the Australian chestnut tree.
Eltrombopag (Revolade). Thrombocytopenia, reduced production of blood platelets, is a condition that affects patients with hepatitis C and cirrhosis. Patients with thrombocytopenia cannot tolerate standard antiviral therapy. Researchers hope that eltrombopag, a drug that stimulates platelet production, may help normalize platelet levels so that they can start antiviral drug treatment.
Statins. Statin drugs are used for the treatment and management of cholesterol. Researchers are studying whether they may help improve liver enzyme levels in patients with hepatitis C.

Of interest are studies using phlebotomy (which is simply drawing blood) to reduce iron levels. In one study, maintenance therapy with this procedure reduced liver inflammation and possibly slowed progression of cirrhosis.

An ounce of prevention is worth a pound of cure, and the phrase resoundingly holds true in the case of hepatitis B. Today, a vaccine against hepatitis B is available. It can prevent hepatitis B and, therefore, also prevent liver cancer. The American Academy of Pediatrics and the Centers for Disease Control and Prevention currently recommend that all babies born in the United States receive a hepatitis B vaccine at birth.

Six drugs are currently approved in the United States for treatment of chronic hepatitis B:

Peginterferon alfa-2a (Pegasys)
Interferon-alfa-2b (Intron)
Adefovir (Hepsera)
Lamivudine (Epivir)
Entecavir (Baraclude)
Telbivudine (Tyzeka)

These drugs block the replication of hepatitis B in the body. Some also help boost the immune system. A doctor will decide which drug to prescribe based on a patient’s age, disease severity, and other factors. Each drug has various advantages and disadvantages in terms of cost, efficacy, side effects, and likelihood of drug resistance. A combination of drugs may also be prescribed.

Peginterferon alfa-2a. Peginterferon alfa-2a (Pegasys) was approved in 2005 for treatment of chronic hepatitis B. (Peginterferon is also called pegylated interferon.) The drug was previously approved in 2002 for treatment of chronic hepatitis C. Pegasys prevents the hepatitis B virus from replicating and also helps boost the immune system. It is given as a weekly injection. Peginterferon is sometimes prescribed in combination with lamivudine (Epivir).

Interferon Alpha. For many years, interferon alfa-2b (Intron) was the standard drug for hepatitis B. The drug is usually taken by injection every day for 16 weeks. (It does not appear to help hepatitis D.) Unfortunately, even in hepatitis B, the virus recurs in almost all cases, although this recurring mutation may be weaker than the original strain. Administering the drug for longer periods may produce sustained remission in more patients while still being safe. Interferon is also effective in eligible children, although long-term effects are unclear.

Lamivudine, Entecavir, and Telbivudine. These drugs are classified as nucleoside analogs. Lamivudine (Epivir or 3TC) is an antiretroviral drug that is used to treat human immunodeficiency virus (HIV) as well as hepatitis B. Studies suggest that lamivudine reduces viral count in over half of hepatitis B patients who take it as sole therapy for about a year. It is less expensive than interferon-alfa and has fewer side effects, but may not work as well as interferon-alfa for long-term therapy. A major problem with lamivudine is the development of mutated viral strains that become resistant to the drug, particularly in areas where the virus is common. About 20% of patients who take lamivudine develop drug resistance.

In 2005, the Food and Drug Administration (FDA) approved entecavir (Baraclude) for treatment of adults with chronic hepatitis B. In clinical trials, entecavir worked better than lamivudine for treating hepatitis B. Entecavir appears to have less risk of drug resistance than lamivudine. Studies also suggest that it may be a good alternative treatment for patients who have developed resistance to lamivudine. Questions have been raised about the drug’s possible cancer risks. Ongoing studies are evaluating this risk.

In 2006, the FDA approved telbivudine (Tyzeka), the newest nucleoside analog drug, for treatment of chronic hepatitis B.

Adefovir. Adefovir (Hepsera) belongs to a class of antiviral drugs called nucleotide analogs. (Nucleotides are related to nucleosides but have a slightly different chemical structure.) Nucleotide analogs block an enzyme involved in the replication of viruses. Adefovir costs more than lamivudine, but may be effective against lamivudine-resistant strains of hepatitis B. The drug must be taken on a long-term basis. A 2006 study indicated that when patients stopped taking adefovir after 48 weeks, the hepitatis B virus resumed replication. Patients who took the drug for a longer period (144 weeks) continued to benefit from treatment. Another 2006 study indicated that for some patients, adefovir remains effective for up to 5 years, although resistance occurs in about 20% of patients.

Drug Warnings. In 2004, the FDA issued two drug warnings for patients with hepatitis B. The HIV drug tenofovir (Viread) should not be used to treat patients with HIV who are co-infected with hepatitis Bas the drug may increase hepatitis severity. The lymphoma drug rituximab (Rituxan) may reactivate hepatitis B. Patients with lymphoma should be screened for hepatitis B. In 2007, the FDA revised the label for entecavir (Baraclude); patients who are co-infected with hepatitis Band HIV should take entecavir only if they are also taking antiviral HIV drugs.

Emtricitabine is a nucleoside analog drug used to treat HIV and AIDS. It is being investigated for chronic hepatitis B.
Pegylated interferon alfa-2b (Peg-Intron) and alfa-2a (Pegasys) are approved for treatment of chronic hepatitis C. They are being investigated alone and in combination with other drugs, such as ribavirin (Copegus, Rebetol), for treatment of hepatitis B. The combination of pegylated interferon and ribavirin is the standard treatment for hepatitis C.
Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a substance derived from the thymus gland (which is responsible for maturation of immune factors called T-cells). It appears to be safe for hepatitis B patients when used alone or in combination with interferon. It is approved in many countries, but not the United States.

Ursodeoxycholic Acid (UDCA) and Drugs Used to Slow Progression. At this time no medication can cure primary biliary cirrhosis. Ursodiol, ursodeoxycholic acid (Actigall), or UDCA has been the standard drug used for primary biliary cirrhosis. Several studies have reported that it slows progression and helps prevent the need for liver transplantation.

It has no effect on symptoms, including itching and fatigue. Some drugs, such as colchicine, corticosteroids, or immunosuppressants, are being investigated for use in combination with UDCA. Long-term controlled trials are needed to determine the value of UDCA alone or with other drugs.

Drugs for Itching. Itching is a major problem with this disease. Cholestyramine, taken with meals, is the first choice for relieving itching. Several other drugs have been used or investigated, including low doses of the drug naltrexone and phototherapy.

Drugs for Impaired Fat Absorption. Because primary biliary cirrhosis affects fat absorption, patients may need high doses or injections of important fat-soluble vitamins, including K, D, A, and E.

Treatment of Nonalcoholic Fatty Liver Disease. Weight loss is the most important method for managing nonalcoholic fatty liver disease (NAFLD) and preventing progression to nonalcoholic steatohepatitis (NASH) and, eventually, cirrhosis. Diabetes and cholesterol control are also important. Investigators are studying whether various drugs used to treat type 2 diabetes may help treat NAFLD and NASH.

Other research is focusing on antioxidant vitamins, such as vitamin E.

In 2005, the National Institutes of Health launched two trials to study treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitisin adults and children. Children with NAFLD will receive vitamin E, metformin, or placebo. In the adult trial, patients with NASH will receive vitamin E, pioglitazone, or placebo.

Secondary Biliary Cirrhosis. Secondary biliary cirrhosis caused by blockage in the bile ducts can be relieved by surgery.

Autoimmune Hepatitis. Autoimmune hepatitis is treated with the corticosteroid prednisone and also sometimes immunosuppressants, such as azathioprine (Imuran).

Hemochromatosis. For hemochromatosis, weekly bleedings (phlebotomies) may be performed until iron levels are normal, then repeated as needed. If treatment is given before cirrhosis develops, life expectancy may be normal.

Wilson's Disease. D-penicillamine is the drug most used for Wilson's disease.

There are no current safe and effective therapies for liver scarring (fibrosis). However, recent insights into the cellular and molecular mechanisms responsible for scarring have led to the development of specific, antifibrotic drugs that target the primary injury and inhibit abnormal cell mechanisms. Such drugs, now in very early testing, could one day help prevent or reduce the progression of liver scarring or the progression to liver cancer.

Liver transplantation may be indicated for the following:

Patients who have developed life-threatening cirrhosis and who have a life expectancy of more than 12 years.
Patients with liver cancer that has not spread beyond the liver.

Survival rates after transplantation are similar among those who have hepatitis B, hepatitis C, or alcoholic liver disease. Current 5-year survival rates after liver transplantation are about 75%. Patients also report improved quality of life and mental functioning after liver transplantation. Patients should seek medical centers that perform more than 50 transplants per year and produce better-than-average results.

Unfortunately, there are many more patients waiting for liver transplants than there are available organs. Fortunately, more procedures are now being performed using liver tissue from a living donor. In these cases, surgeons replace the patient’s diseased liver with a part of the liver taken from a donor. The donor’s liver regenerates to full size within a few weeks of surgery, and the recipient’s liver also regrows.

Transplantation surgery generally takes 4 - 12 hours to perform, and patients stay in the hospital for up to 3 weeks after the surgery. Most patients return to normal or near-normal activities 6 - 12 months following the transplant. For the rest of their lives, patients need to take immunosuppressive medication to prevent rejection.

Liver Transplantation in Patients with Hepatitis. One of the primary problems with many hepatitis patients is recurrence of the virus after transplantation.

One study of patients with hepatitis C reported 5-year risks of 80% for viral recurrence and 10% for cirrhosis. A 2004 study found that the hepatitis C virus recurs with more severity with liver donations from living donors than livers taken from cadavers.
Viral recurrence is also high in patients with hepatitis B. In 2007, the FDA approved HepaGram B, an immune globulin, to prevent recurrence of hepatitis B after transplantation. Patients need to receive HepaGram B injections on a lifelong basis.

Liver Transplantation in Autoimmune Liver Diseases. Patients who require transplantation for primary biliary cirrhosis are those who develop major complications of portal hypertension and liver failure or who have poor quality of life and short survival without the procedure. Survival rates after transplantation are excellent.

The outlook is also good for patients who have autoimmune hepatitis who require a transplant. Survival rates are about 90% after 1 year, and 70 - 80% after 5 years. Rejection usually occurs in those patients whose immune systems are very compromised.

Liver Transplantation in Alcoholism. There is considerable controversy over whether liver transplantation should be performed in alcoholics with cirrhosis who are unlikely to abstain. One French study reported no differences in survival, transplant rejection, and other indicators of success and failure after transplantation between alcoholics and non-alcoholics and between alcoholics who abstained and those who relapsed after the procedure.

Click the icon to see an illustrated series detailing a liver transplant.

Lifestyle Changes

A healthy lifestyle is particularly important for people with cirrhosis.

Healthy Foods. Because important antioxidant vitamins are depleted in the cirrhotic liver, patients should maintain a diet rich in fresh fruits, vegetables, and whole grains.

Coffee and Tea. Coffee appears to help lower the risk of cirrhosis, especially among heavy drinkers. A 2006 study indicated that people who drank 1 - 3 cups of coffee a day reduced their risk of alcoholic cirrhosis by 40%. Those who drank 4 or more cups reduced their risk by 80%. Researchers think that there is some ingredient in coffee (other than caffeine) that is responsible for this apparent protection. Studies on tea have been mixed. Some studies report that tea also lowers the risk of chronic liver disease, while others have found no effect.

Antioxidant Supplements. There is some preliminary laboratory evidence that various antioxidant supplements -- including vitamin E, selenium, and S-adenosylmethionine (SAMe) -- may help protect against liver damage and cirrhosis. Supplements, however, are not recommended for people with liver disease except with the advice of a doctor. Some vitamins, such as vitamins D and A, are metabolized in the liver and can be toxic.

Iron Restrictions. Elevated iron levels have been associated with cirrhosis from many causes. Patients should avoid iron-rich foods, such as red meats, liver, and iron-fortified cereals, and should avoid cooking with iron-coated cookware and utensils.

Supplemental Nutritional Products. Supplemental nutritional beverages may be helpful, particularly for patients with both alcoholism and cirrhosis. In one study, patients with both alcoholism and cirrhosis drank Ensure every day as a supplement to their regular diet. After 6 months they showed significant improvement in many signs of overall health compared to those who did not consume the beverage.

Vitamin B1 (Thiamine). Thiamine binds to iron and helps reduce iron load in the liver. One small study suggested it may be helpful for patients with chronic hepatitis B. It is not known if it has any benefit for cirrhosis. Pork is high in the vitamin, but more healthful sources include dried fortified cereals, oatmeal, corn, nuts, cauliflower, sunflower seeds and vitamin pills.

Like most vitamins, vitamin B1 may be obtained in the recommended amount with a well-balanced diet, including some enriched or fortified foods.

Omega-3 Fatty Acids. Some research suggests that supplements of omega-3 fatty acids (found in fish oil and evening primrose oil) may help protect the diseased liver.

Click the icon to see an image of omega-3 fatty acids.

Protein and Soy. High-quality dietary protein may be especially helpful for patients with ascites and for repairing muscle mass, but excessive protein loads may trigger encephalopathy. Protein solutions have been devised that provide beneficial amino acids without including those that increase this risk. There is no limit on vegetable proteins, such as those from soy.

Salt Restriction. Restricting salt consumption to less than 2,000 mg a day is particularly important for patients with ascites. The less salt the better.

Zinc. In some studies, taking zinc supplements have lowered ammonia levels in some patients who were zinc-deficient, a common problem in cirrhosis. Zinc replacement may reduce frequency and severity of muscle cramps and may even help protect against encephalopathy.

Fluid restriction is not usually necessary, but patients with severe ascites should discuss limiting fluid with their doctors.

Exercise increases the risk for portal pressure and variceal bleeding. One study reported that taking a beta-blocker may reduce this risk, although patients should discuss this with their doctor.

Infections can have a severe impact on the liver. Although most respiratory infections generally affect only the lungs, one small study suggested influenza may directly affect the liver in patients with cirrhosis and exacerbate the disease process. Researchers in the study advise annual flu shots for people with cirrhosis.

Patients should be aware that manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been several reported cases of serious and even lethal side effects from herbal products. Patients should always check with their doctors before using any herbal remedies or dietary supplements.

Among the natural substances being investigated for liver disease are ginseng, glycyrrhizin (a compound in licorice), catechin (found in green tea), SAMe, and silymarin (found in milk thistle).

Silymarin. Silymarin is a chemical found in the milk thistle herb. It is one of the most popular, and most studied, herbal remedies for liver disease. Some studies have indicated that silymarin may help improve liver enzyme levels. However, a 2005 review found that milk thistle did not help reduce deaths from liver disease caused by alcohol or hepatitis.

S-adenosylmethionine. S-adenosylmethionine (SAMe) is a chemical found in all parts of the body, which declines with age. It has been investigated for years in Europe for arthritis, depression, and liver disease. Some preliminary studies suggest it may provide some protection against liver damage and scarring and may improve survival rates in alcoholic patients with cirrhosis. It is very expensive, however, and as with all unregulated products, long-term side effects, drug interactions, and other factors are not fully known.

The following warnings are of particular importance for people with liver disease:

Kava kava (an herb used for anxiety and tension) can be toxic to the liver and cause severe hepatitis and even liver failure if taken excessively.

Abdominal Infections

Antibiotics are administered when fluid examination and tests for ascites indicate infection. For a first episode, the antibiotic cefotaxime is typically administered intravenously, requiring hospitalization. Treatment usually lasts 10 days, but research indicates that 5 days may be sufficient for certain patients. Some research indicates that the oral antibiotic ofloxacin may work as well with fewer complications, allowing patients to be treated at home.

In advanced cirrhosis, the risk for serious abdominal infection is high, and the antibiotic norfloxacin is often prescribed preventively against specific organisms that infect the abdominal cavity. One study reported, however, that patients who took norfloxacin became susceptible to Staphylococcal infections. Long-term treatments with norfloxacin or similar antibiotics may increase the risk for fungal infections after liver transplantation.

Encephalopathy

The first step in managing encephalopathy (damage to the brain) is to treat any precipitating cause, such as:

High ammonia levels
Bleeding
Low oxygen
Dehydration
Infection
Use of sedatives

Some studies indicate that manganese poisoning may be partially responsible for encephalopathy in cirrhosis. Studies are needed to determine if drugs that remove manganese improve this complication.

Ammonia is the leading toxin in causing encephalopathy related to cirrhosis. Mild encephalopathy is managed by directing therapy toward eliminating ammonia in the intestine:

The first step is to restrict animal protein, substituting meats and dairy products with vegetable protein, such as soy, and amino acid supplements.
Enemas, which clean out the intestine, may be effective.
Lactulose (Cephulac, Chronulac, Constulose, Duphalac, Enulose) and lactitol, known as disaccharides, help lower blood ammonia levels and have been shown to be effective in improving cognitive function and quality of life in people with mild encephalopathy.
Antibiotics, such as metronidazole, rifamycin, or neomycin, are effective in reducing levels of ammonia-producing bacteria in the intestine, although long-term use of these drugs can cause toxic side effects. Rifaximin (Xifaxan), another antibiotic, was approved in 2005 for treatment of hepatic encephalopathy.
L. acidophilus is the probiotic found in live culture yogurt. Researchers are studying whether L. acidophilus food or supplements can aid in improving liver and cognitive functions.
Researchers are investigating whether exercise can help remove ammonia from the body and improve encephalopathy.

Investigational Drugs. Certain drugs, such as rifaximin (Xifaxan) and flumazenil (Mazicon, Romazicon), are under investigation for treating encephalopathy. Flumazenil is typically administered to counteract the effects of sedatives.

Ascites

Nearly all patients with ascites (fluid accumulation in the abdomen) can benefit from the following measures:

Abstaining from alcohol. (Sometimes abstaining from alcohol is enough to improve this complication.)
Restricting salt.
Taking diuretics, usually spironolactone (Aldactone) and furosemide (Lasix). Previously, spironolactone was usually given alone, but experts now use it by itself only in patients with minimal fluid buildup. Patients should be monitored carefully for excessive and too-fluid loss, which can set off complications, including hypokalemia (dangerously low potassium levels), kidney failure, or encephalopathy. Weight loss from diuretics usually should not exceed 1 - 2 pounds per day, but there is no limit for patients with massive swelling.

Doctors often recommend bed rest for patients with ascites, but studies do not support its benefits. Restricting fluid is not usually necessary unless sodium levels in the blood are very low.

Patients with recurring ascites, or ascites that does not respond to standard diuretics after a month (refractory ascites), may require procedures to reduce fluid.

Large-Volume Paracentesis. Large-volume paracentesis is the current standard procedure and involves the following:

Large volumes of fluid are removed through a tube in the abdomen. Research indicates that 4 - 6 liters are usually effective and safe.
Albumin (protein) may be administered intravenously. This helps prevent a sudden drop in blood flow in the arteries. One study suggested that terlipressin, a drug that constricts blood vessels, may be as effective.
If the ascites does not respond to treatments, the patient may need paracentesis every 2 weeks or more frequently, and up to 10 liters may need to be removed.

Patients who need this procedure are probably not complying with dietary requirements.

Transjugular Intrahepatic Portosystemic Shunt. Studies have been mixed on whether transjugular intrahepatic portosystemic shunt (TIPS) improves survival without transplantation compared to large-volume paracentesis. An important 2003 study reported that although TIPS reduced the number of paracenteses, there was no improvement in survival rates. In addition, patients who were given TIPS had a higher risk for encephalopathy than those given large-volume paracentesis. In general, TIPS should be a second-line option for ascites that does not respond to diuretics.

Peritoneovenous Shunting. Peritoneovenous shunting is an older, more invasive, procedure involving insertion of a tube, or shunt, under the skin that routes the fluid from the abdomen into the jugular vein. The procedure can have serious complications, including infection, blood clots, encephalopathy, and rupture of blood vessels in the esophagus. It is now generally reserved for patients who are not candidates for repeat paracentesis or liver transplantation.

Hepatorenal syndrome can occur in patients with ascites. This is a life-threatening condition in which the kidneys fail in trying to compensate for altered blood flow in the liver. Studies suggest that terlipressin may be an effective treatment in combination with albumin for hepatorenal syndrome.

Researchers are testing certain drugs that may correct the imbalances in circulation that lead to portal hypertension and ascites. Of particular interest are drugs called nonpeptide vasopressin antagonists, also referred to as aquaretics. They may reverse the dilation in blood vessels that lead to salt and fluid retention.

The prognosis for patients with ascites is poor, even with intensive procedures. Liver transplantation should be considered for patients when ascites does not respond to treatments and when poor liver function or other complications, such as peritonitis or kidney failure, are present.

Bleeding Episodes

Preventing an Initial Bleeding Episode. About half of patients with mild-to-moderate cirrhosis have esophageal varices (enlarged veins in the esophagus). In such patients, the risk for bleeding within 2 years is as high as 35%. Bleeding is fatal in half of these patients. In general, experts recommend preventive drugs for such patients, even if they have not been screened with endoscopy -- the procedure needed to actually detect varices. Beta-blockers are the only medications to date that have some preventive effects, but others are under investigation.

Guidelines for Treating Bleeding Episodes. The doctor should first be certain that bleeding is caused by portal hypertension and ruptured varices and not by other conditions. For example, patients with cirrhosis are also at higher than average risk for bleeding peptic ulcers.

Saline or Ringers solution (a fluid and electrolyte replenisher) followed by red blood cells and plasma is administered immediately to replace lost blood.

The next step is to immediately achieve normal blood clotting (hemostasis) in order to stop the current bleeding episode and prevent early recurrence, which typically occurs 3 - 5 days after a bleeding episode.

In general it is a two-pronged approach using drugs and endoscopy procedures.

Drugs. Either octreotide or vasopressin are typically used to reduce portal pressure and blood flow.
Endoscopy. Endoscopy involves insertion of a thin tube containing a tiny camera followed by surgery to make repairs. Endoscopic sclerotherapy is the most common procedure. Emergency sclerotherapy is often used as first-line therapy for variceal bleeding, but a major 2002 analysis suggested that it is no more effective than drugs for stopping bleeding, and it has potentially serious adverse effects.

A combination of drugs and endoscopy is the best approach for stopping bleeding compared to endoscopy alone. It is not clear if there is any difference in long-term survival, however.

Prevent Bleeding Recurrence. Rebleeding is common after an episode. Beta-blocker drugs are typically used, although they are not effective for many patients.

Preventing Complications. The patient who is experiencing a bleeding episode is at high risk for other complications, including pneumonia, bacterial infections, and hepatic encephalopathy. Bacterial infections can also impair blood clotting. Preventive oral antibiotics are often problematic in these patients. One study suggested that intravenous ciprofloxacin may be helpful.

Beta-Blockers. Beta-blockers, typically propranolol (Inderal) or nadolol (Corgard), reduce the heart rate and can lower portal vein pressure in many patients and so reduce variceal bleeding. Carvedilol (Coreg), a newer drug, may be even more effective, but more research is needed. Beta-blockers are also used as a primary approach for prevention of recurring bleeding. Nevertheless, they fail to reduce portal pressure in nearly 40% of patients with cirrhosis. They may not be appropriate for patients with type 1 diabetes, asthma, emphysema, and chronic bronchitis. They must be taken for at least 2 years and most likely longer to sustain a survival advantage.

Other Drugs. Other drugs are being used or investigated, mostly in combination with beta-blockers, to reduce recurrence rates.

Isosorbide mononitrate is a nitrate, a type of drug commonly used for angina. Combinations with beta-blockers appear to prevent rebleeding more effectively than beta-blockers alone. It is not clear if the combination improves any other aspects of the disease. The nitrate may also be an alternative drug for patients who cannot tolerate beta-blockers. Studies have failed to show any survival advantage, however, when isosorbide mononitrate is used alone.
The diuretic spironolactone may be helpful in combination with a beta-blocker for reducing both ascites and rebleeding after an initial episode.
Angiotensin II receptor antagonists, including losartan (Cozaar), are being studied for lowering portal pressure.

Somatostatinand Similar Drugs. Somatostatin is a natural hormone that constricts blood vessels. This drug or synthetic derivatives (octreotide and vapreotide) may be more effective than the common procedure, endoscopic sclerotherapy, for controlling bleeding. No single drug is more effective than another. Their benefits for improving overall survival, however, are still uncertain, and a major analysis of current studies found no effects on survival rates with either octreotide or somatostatin.

Somatostatin, the natural hormone, controlled variceal bleeding in 87% of patients in one study, but it is short acting.
Octreotide (Sandostatin) is a derivative of somatostatin and is longer acting. It has largely replaced the older drug. It is very safe, even for heart patients, and has few serious side effects.
Vapreotide (Octastatin) also resembles somatostatin. One study concluded that a combination of vapreotide and endoscopic treatment is more effective than endoscopic treatment alone for controlling bleeding, but the combination therapy did not improve mortality rates at 42 days. The study suggested that these drugs should be taken for 5 days.

Vasoconstrictors. Vasoconstrictors narrow the blood vessels and reduce flow in the spleen. They are particularly effective when used with nitroglycerin.

Vasopressin (Pitressin) is the most commonly used vasoconstrictor. It poses a risk to the heart, however, and it is not clear whether it is actually helpful.
Terlipressin is a synthetic version of vasopressin that is proving to be as effective as sclerotherapy in controlling bleeding. It also lacks vasopressin's side effects and may prove to prolong survival and serve as a bridge for patients waiting for liver transplantation.

Endoscopic procedures use a tube inserted down through the esophagus, containing microcameras and tiny instruments. Endoscopy is used both to diagnose the disease and stop bleeding. The two standard procedures are band ligation and sclerotherapy. In general, a combination of drug therapies and an endoscopic procedure is the usual approach for preventing a bleeding recurrence.

Endoscopic Band Ligation. In endoscopic band ligation, latex bands are wrapped around the bleeding varices, shutting off the blood supply. It is the method of choice to control of bleeding and, in weekly sessions, to prevent rebleeding, because it has a lower risk for complications than sclerotherapy. Recurrence rates are higher with band ligation, however. Studies are mixed on whether weekly treatments with band ligation are any more effective in preventing rebleeding than beta-blockers plus isosorbide mononitrate. A combination of medications plus band ligation is under investigation.

Investigators are studying argon plasma coagulation (APC) after band ligation to prevent variceal recurrence and rebleeding. This procedure uses argon gas to deliver electric currents that coagulate and stop bleeding.

Endoscopic Sclerotherapy. Endoscopic sclerotherapy is only effective against bleeding in the esophagus. The endoscopic tube is inserted through the mouth. A sclerosant (a solution that toughens the tissue around the variceal blood vessels) is injected to stop the bleeding. The procedure is repeated over a period of 2 - 3 months. Repeat treatments appear to reduce rebleeding and death. Minor complications (usually ulcers in the mucus membranes) are common, and serious complications can occur (narrowing or perforation of the esophagus and leakage at the injection site.)

Balloon tamponade has been available for years, but it is now used only for bleeding that cannot be controlled by drugs or endoscopy. It uses a tube inserted through the nose and down through the esophagus until it reaches the upper part of the stomach. A balloon at the tube's end is inflated and positioned tightly against the esophageal wall. It is usually deflated in about 24 hours. Serious complications can occur, the most dangerous being rupture of the esophagus. Recurrence of bleeding is common.

Shunts are used for patients who are still bleeding in the esophagus after endoscopic sclerotherapy or who are bleeding in the stomach. Choices include the following:

Transjugular intrahepatic portosystemic shunt (TIPS)
A surgical shunt

Shunt operations usually eliminate variceal bleeding, but encephalopathy and shunt failure are frequent complications. Doctors do not recommend shunts as elective surgery for high-risk patients who are candidates for liver transplantation, since shunts make this operation more difficult.

Transjugular Intrahepatic Portosystemic Shunt.A transjugular intrahepatic portosystemic (or portal-systemic) shunt (TIPS) involves the following:

The patient only requires a local anesthetic and a sedative.
A long needle is inserted into the jugular vein in the neck and passed down through the vena cava, a large vein that conducts blood back to the heart. This serves to widen the vein.
The surgeon makes an incision in the hepatic vein in the liver and creates a connection to the portal vein.
A cylindrical wire-mesh stent is inserted into this connecting vein.
The stent now acts as a shunt, which reroutes blood around the scarred liver.

TIPS is a good choice for bleeding that is not controlled by endoscopy, particularly when it is performed shortly after a bleeding episode. It also reduces ascites.

It is not useful as the first choice for stopping an initial bleeding episode or for preventing rebleeding, however, since it poses a high risk for encephalopathy. This complication outweighs its benefits compared to endoscopy for initial treatment and to beta-blockers for preventing recurrence. Blockage or closure of the shunt can develop over time.

TIPS is generally recommended for only patients who:

Cannot tolerate sclerotherapy
Are unlikely or unable to comply with the repeated procedures necessary for sclerotherapy
Have poor blood circulation

Surgical Shunts. There are two types of surgical shunts:

A portal shunt, or portal systemic shunt. It was introduced in 1945 and was the first significant treatment for bleeding varices. It relieves pressure in the portal vein by surgically joining it to the inferior vena cava, a large vein that conducts blood back to the heart. It poses a high risk for encephalopathy and does not appear to improve survival, so is not used often.
A variation called the H-graft portacaval shunt is a partial shunt that is proving to be effective for treating bleeding. It controls bleeding in 90% of patients and has a lower encephalopathy rate than the complete portal shunt or TIPS. In fact, early studies report that it may have lower rates for transplantation and death than TIPS.
A distal splenorenal shunt (DSRS) preserves blood flow through the portal vein while relieving pressure on the varices by joining the left kidney vein to the splenic vein. (The splenic vein returns blood from the spleen and is one of two veins that form the portal vein.) Studies show that DSRS has similar mortality rates compared to the portal shunt but lower rates of encephalopathy afterwards. Patients with alcoholic cirrhosis fare worse with DSRS than nonalcoholic patients. It is probably best used as an elective operation in patients with good liver function who continue to bleed in spite of endoscopy.

Resources

www2.niddk.nih.gov -- National Institute of Diabetes and Digestive and Kidney Diseases
www.aasld.org -- American Association for the Study of Liver Diseases
www.liverfoundation.org -- American Liver Foundation
www.gastro.org -- American Gastrointestinal Association
www.cdc.gov/ncidod/diseases/hepatitis -- Centers for Disease Control and Prevention, Hepatitis
www.hepfi.org -- Hepatitis Foundation International
www.pbcers.org -- Primary Biliary Cirrhosis Organization
www.organdonor.org -- National Transplant Society
www.unos.org -- United Network for Organ Sharing
www.organdonor.gov -- US government organ donor site

References

Bruno S, Crosignani A, Maisonneuve P, Rossi S, Silini E, Mondelli MU. Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: A seventeen-year prospective cohort study. Hepatology. 2007 Aug 6; [Epub ahead of print]

Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L, Mazzella G, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology. 2007 Mar;45(3):579-87.

Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006 Oct;44(4):865-73.

Huang H, Shiffman ML, Friedman S, Venkatesh R, Bzowej N, Abar OT, et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology. 2007 Aug;46(2):297-306.

Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life inpatients with cirrhosis who have minimal hepatic encephalopathy. Hepatology. 2007 Mar;45(3):549-59.

Suzuki A, Lymp J, Donlinger J, Mendes F, Angulo P, Lindor K. Clinical predictors for hepatocellular carcinoma in patients with primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007 Feb;5(2):259-64. Epub 2006 Dec 15.

U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006 Aug 1;145(3):204-8.

Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2006 Aug 1;145(3):209-23.

Review Date:
8/31/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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A.D.A.M. Copyright

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2009 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

adam.com

Gallstones and gallbladder disease

FitSugar — Wed, 08 Oct 2008 17:35:38 -0700

In This Report

Highlights
Introduction
Symptoms
Prognosis
Risk Factors
Prevention
Diagnosis
Treatment
Surgery
Lithotripsy and Dissolution...
Managing Common Bile Duct S...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Connection to endometrial cancer

Excess estrogen appears to play a role in the development of both gallstones and endometrial cancer. One study found that women who had undergone cholecystectomy (surgery to remove the gallbladder) had a 50% increased risk of developing endometrial cancer. The connection was weaker in women who developed asymptomatic gallstones.

Diet

Men who consume a diet high in foods containing heme iron, such as meat and seafood, are at increased risk for developing gallstones. Gallstones are not associated with diets high in non-heme iron sources, such as beans, lentils, and enriched grains.

Fruits and vegetables appear to substantially reduce the risk of symptomatic gallstone formation. The effect holds true regardless of which fruits or vegetables are consumed. Risk drops in proportion to the percentage of fruits and vegetables in the diet.

Genetics

Studies of twins and families indicate a genetic connection to gallstone formation, but until recently, the mechanism has eluded researchers. Defects in proteins involved in biliary lipid secretion have been identified as a factor predisposing men and women to gallstone disease. But not everyone with these genes develops gallstones. The disease appears to result from the interaction between genetic and environmental factors, with immune and inflammatory mediators possibly playing key roles.

Bariatric Surgery

Patients who undergo bariatric surgery are at increased risk for gallstones and are often required to have their gallbladders removed (cholecystectomy) before their bariatric surgery is performed. Recent studies indicate this practice may not be necessary. In one study, only 8% of patients who did not undergo cholecystectomy before a Roux-en-Y procedure developed symptomatic gallstones. In another study, only 3% of those who underwent lap banding developed symptomatic gallstones.

Prolonged Intravenous Feeding

People who must rely on intravenous nutrition (home parenteral nutrition or total parenteral nutrition) are at greatly increased risk of developing gallstones, possibly due to lack of intestinal stimulation that decreases the flow of bile. However, gallstones in these patients are easily treated and have a low risk of complications.

Introduction

Gallstones are small, hard pellets that can form in the gallbladder, a sac-like organ that lies under the liver on the right side of the abdomen. Most people with gallstones don't even know they have them. But in some cases a stone may cause the gallbladder to become inflamed, resulting in pain, infection, or other serious complication.

The formation of gallstones is a complex process that starts with bile, a fluid composed mostly of water, bile salts, lecithin (a fat known as a phospholipid), and cholesterol. Most gallstones are formed from cholesterol.

Bile is important for the digestion of fat. It is first produced by the liver and then secreted through tiny channels that eventually lead into a larger tube called the common bile duct, which leads to the small intestine.

Only a small amount of bile drains directly into the small intestine, however. Most flows into the gallbladder through the cystic duct, which is a side extension off the common bile duct. This system of ducts through which bile flows is called the biliary tree.

Click the icon to see an image of the biliary tree.

The gallbladder is a 4-inch sac with a muscular wall that is located under the liver. Here, most of the bile fluid (about 2 - 5 cups a day) is removed, leaving a few tablespoons of concentrated bile.
The gallbladder serves as a reservoir until bile is needed in the small intestine to digest fats. This need is triggered by a hormone called cholecystokinin, which is released when food enters the small intestine.
Cholecystokinin signals the gallbladder to contract and deliver bile into the intestine. The force of the contraction propels the bile down the common bile duct and into the small intestine, where it emulsifies (breaks down) fatty molecules.
This part of the digestive process enables the emulsified fat along with important fat-absorbable nutrients (e.g., vitamins A, D, E, and K) to pass through the intestinal lining and enter the blood stream.

Gallstones can range from a few millimeters to several centimeters in diameter. Most are formed from cholesterol. Pigment stones are the second most common type of gallstones (approximately 15% of stones are pigment stones). Patients can also have a mixture of the two. Pigment stones are formed from a brown-colored substance called calcium bilirubinate.

Cholesterol Stones. Although cholesterol makes up only 5% of bile, about three-fourths of the gallstones found in the US population are formed from cholesterol. Cholesterol gallstones typically form in the following way:

Cholesterol is not very soluble, so in order to remain suspended in fluid it must be transported within clusters of bile salts called micelles. If there is an imbalance between these bile salts and cholesterol, then the bile fluid turns to sludge. This thickened fluid consists of a mucus gel containing cholesterol and calcium bilirubinate.
If the imbalance worsens, cholesterol crystals form (a condition called supersaturation), which can eventually form gallstones.
This process of gallstone formation is referred to as cholelithiasis. It is very slow and most often painless.

Click the icon to see an image of gallstones.

Supersaturation and cholelithiasis can occur as a result of various abnormalities, although the cause is not entirely clear. There are many events that may promote cholelithiasis:

The liver secretes too much cholesterol into the bile.
The gallbladder may not be able to empty normally, so bile becomes stagnant.
The cells lining the gallbladder may not be able to efficiently absorb cholesterol and fat from bile.
High levels of bilirubin have been observed in patients with gallstones. Bilirubin is a substance normally formed by the breakdown of hemoglobin in the blood and is excreted in bile. Some experts believe it may play an important role in the formation of cholesterol gallstones.

Pigment Stones. Pigment stones are composed of calcium bilirubinate, or calcified bilirubin. Pigment stones can be black or brown.

Black stones form in the gallbladder and are the more common type. They represent 20% of all gallstones in the US. They are more likely to develop in people with hemolytic anemia (a relatively rare anemia where red blood cells are destroyed) or cirrhosis (scarred liver).
Brown pigment stones are more common in Asian populations. They contain more cholesterol and calcium than black pigment stones and are more likely to occur in the bile ducts. Infection plays a role in the development of these stones. One report suggested that bacteria or other microorganisms may trigger oxidation (a damaging chemical process in the body) which, in this case, can cause changes that lead to pigment stone formation.

Gallstones can also be present in the common bile duct. This is called choledocholithiasis.

Click the icon to see an image of gallstone obstruction.

Secondary Common Bile Duct Stones. In most cases, common bile duct stones originally form in the gallbladder and pass into the common duct (called secondary stones). Choledocholithiasis occurs in about 10% of patients with gallstones.

Primary Common Bile Duct Stones. In less common cases, the stones form in the common duct itself (called primary stones). Primary common duct stones are usually of the brown pigment type and are more likely to cause infection than secondary common duct stones.

Gallbladder disease can occur without stones, a condition called acalculous gallbladder disease. It can be acute (arising suddenly) or chronic (persistent).

Acute acalculous gallbladder disease usually occurs in patients who are very ill from other disorders. In such cases, inflammation occurs in the gallbladder, usually from a diminished blood supply or an impaired ability to contract and empty its bile.
Chronic acalculous gallbladder disease (also called biliary dyskinesia) appears to be caused by muscle defects or other problems in the gallbladder that cause impaired motility.

Diagnosing Acute Acalculous Gallbladder Disease. Symptoms are similar to those of acute cholecystitis with gallstones, but they may be obscured by other medical conditions, since patients with this condition are often critically ill with other illnesses.

Diagnosing Chronic Acalculous Gallbladder Disease. Chronic acalculous gallbladder disease is usually diagnosed when a patient complains of gallbladder symptoms, but no evidence of stones is seen using standard imaging techniques. More than half of patients initially diagnosed with this disease, however, are eventually shown to have small stones or gallbladder sludge. The patient is given the hormone cholecystokinin octapeptide (CCK), which induces gallbladder contraction, followed by a radioisotope scan to determine whether the gallbladder is emptying correctly. If the gallbladder demonstrates difficulty releasing bile, doctors usually consider the diagnosis confirmed.

Treatment for Acute Acalculous Gallbladder Disease. Acute acalculous gallbladder disease has a very high rate of serious complications (gangrene, perforation, and pus in the gallbladder), so emergency removal of the gallbladder is warranted.

Treatment for Chronic Acalculous Gallbladder Disease. Most patients (75 - 90%) diagnosed with chronic acalculous gallbladder disease are relieved of their symptoms by cholecystectomy (removal of the gallbladder). Between 10 - 23%, however, still experience pain. Surgery is most warranted in these patients when the symptoms are caused by impaired emptying of the gallbladder.

Symptoms

About 90% of gallstones provoke no symptoms at all. If problems do develop, the chance of developing pain is about 2% per year for the first 10 years after stone formation. After this, the chance for developing symptoms declines. On average, symptoms take about 8 years to develop. The reason for the decline in incidence after 10 years is not known, although some doctors suggest that "younger," smaller stones may be more likely to cause symptoms than larger, older ones.

The mildest and most common symptom of gallbladder disease is intermittent pain called biliary colic, which occurs either in the mid- or the right portion of the upper abdomen. A typical attack has several features:

The primary symptom is typically a steady gripping or gnawing pain in the upper right abdomen near the rib cage, which can be quite severe and can radiate to the upper back. Some patients with biliary colic experience the pain behind the breast bone.
Nausea or vomiting may occur.
Changes in position, over-the-counter pain relievers, and passage of gas do not relieve the symptoms.
Biliary colic typically disappears after 1 to several hours. If it persists beyond this point, acute cholecystitis or more serious conditions may be present.
The episodes typically occur at the same time of day, but less frequently than once a week. Large or fatty meals can precipitate the pain, but it usually occurs several hours after eating and often awakens the patient during the night.
Recurrence is common, but attacks can be years apart. In one study, for example, 30% of people who had had 1- 2 attacks experienced no further biliary pain over the next 10 years.

Digestive complaints such as belching, feeling unduly full after meals, bloating, heartburn (burning feeling behind the breast bone), or regurgitation (acid back-up in the food pipe) are not likely to be caused by gallbladder disease. Conditions that may cause these symptoms include peptic ulcer, gastroesophageal reflux disease, or indigestion of unknown cause. [See In-Depth Report #19 Peptic Ulcers and In-Depth Report #85 Gastroesophageal Reflux Disease.]

Between 1 - 3% of people with symptomatic gallstones develop inflammation in the gallbladder (acute cholecystitis), which occurs when stones or sludge obstruct the duct. The symptoms are similar to those of biliary colic but are more persistent and severe. They include the following:

Pain in the upper right abdomen is severe and constant and can last for days. Pain frequently increases when drawing a breath.
Pain also may radiate to the back or occur under the shoulder blades, behind the breast bone, or on the left side.
About a third of patients have fever and chills.
Nausea and vomiting may occur.

Anyone who experiences such symptoms should seek medical attention. Infection develops in about 20% of these cases, which increases the danger. Acute cholecystitis can progress to gangrene or perforation of the gallbladder if left untreated. People with diabetes are at particular risk for serious complications.

Chronic gallbladder disease (chronic cholecystitis) is marked by gallstones and low-grade inflammation. In such cases the gallbladder may become scarred and stiff. Symptoms of chronic gallbladder disease include the following:

Complaints of gas, nausea, and abdominal discomfort after meals are the most common, but they may be vague and indistinguishable from similar complaints in people without gallbladder disease.
Chronic diarrhea (4 - 10 bowel movements every day for at least 3 months) may be a common symptom of gallbladder dysfunction.

Stones lodged in the common bile duct (choledocholithiasis) can cause symptoms that are similar to those produced by stones that lodge in the gallbladder, but they may also cause the following symptoms:

Jaundice (yellowish skin)
Dark urine, lighter stools, or both
Heartbeat may become rapid and blood pressure may drop abruptly
Fever, chills, nausea and vomiting, and severe pain in the upper right abdomen. These symptoms suggest an infection in the bile duct (called cholangitis).

As in acute cholecystitis, patients who have these symptoms should seek medical help immediately. They may require emergency treatment.

Prognosis

Asymptomatic gallstones seldom lead to problems. Death, even from symptomatic gallstones, is very rare, accounting for only 0.2% of annual deaths in the United States. Serious complications are rare. If they do occur, complications usually develop from stones in the bile duct or after surgery.

Gallstones, however, can cause obstruction at any point along the ducts that carry bile and, in such cases, symptoms can develop.

In most cases of obstruction, the stones block the cystic duct, which leads from the gallbladder to the common bile duct. This can cause pain (biliary colic), infection and inflammation (acute cholecystitis), or both.
About 10% of patients with symptomatic gallstones also have stones that pass into and obstruct the common bile duct (called choledocholithiasis).

The most serious complication of acute cholecystitis is infection, which develops in about 20% of cases. It is extremely dangerous and life-threatening if it spreads to other parts of the body (septicemia), and surgery is often required. Symptoms include fever, rapid heartbeat, fast breathing, and mental confusion. Among the conditions that can lead to septicemia are the following:

Gangrene or Abscesses. If acute cholecystitis is untreated and becomes very severe, inflammation can cause abscesses or destroy enough tissue in the gallbladder ( necrosis) to lead to gangrene. Studies have reported this complication in between 2 - 30% of cases. The highest risk is in men over 50 with a history of heart disease who have high levels of infection.
Perforated Gallbladder. An estimated 10% of acute cholecystitis cases result in a perforated gallbladder, which is a life-threatening condition. In general, this occurs in people who wait too long to seek help or who do not respond to treatment. This condition is most common in people with diabetes. The risk for perforation increases with a condition called emphysematous cholecystitis, in which gas forms in the gallbladder. Once the gallbladder has been perforated, pain may temporarily decrease. This is a dangerous and misleading event, however, since peritonitis (widespread abdominal infection) develops afterward.
Empyema. Pus in the gallbladder (empyema) occurs in 2 - 3% of patients with acute cholecystitis. Patients usually experience severe abdominal pain for more than 7 days. The physical exam often fails to reveal the underlying cause. The condition can be life-threatening, particularly if infection spreads to other parts of the body.
Fistula. In some cases, the inflamed gallbladder adheres to and perforates nearby organs, such as the small intestine. In such cases a fistula (channel) between the organs develops. Sometimes, in these cases, gallstones can actually pass into the small intestine, which can be very serious and requires immediate surgery.
Gallstone Ileus. A gallstone blocking the intestine is known as gallstone ileus. It primarily occurs in patients over age 65, and can sometimes be fatal. Depending on where the stone is located, surgery to remove the stone may be required.

When gallstones lodge in the common bile duct (choledocholithiasis) instead of the gallbladder, serious complications can occur.

Infection in the Common Bile Duct (Cholangitis). Infection in the common bile duct (cholangitis) from obstruction is common and serious. Those at highest risk for a poor outlook also have one or more of the following conditions:

Kidney failure
Liver abscess
Cirrhosis
Being over 50 years

If antibiotics are administered immediately, the infection clears up in 75% of patients. If cholangitis does not improve, the infection may spread and become life-threatening. Either surgery or a procedure known as endoscopic sphincterotomy is required to open and drain the ducts.

Pancreatitis. Choledocholithiasis is responsible for most cases of pancreatitis (inflammation of the pancreas), a condition that can be life threatening. The pancreatic duct, which carries digestive enzymes, joins the common bile duct right before it enters the intestine. It is therefore not unusual for stones that pass through or lodge in the lower portion of the common bile duct to obstruct the pancreatic duct.

Gallstones are present in about 80% of people with gallbladder cancer. Symptoms of gallbladder cancer usually do not appear until the disease has reached an advanced stage and may include weight loss, anemia, recurrent vomiting, and a lump in the abdomen. When the cancer is caught at an early stage and has not spread beyond the mucosa (the inner lining), removal of the gallbladder results in a 5-year survival rate of 68%. If cancer has spread to deeper layers, more extensive surgery or other treatments may be required.

This cancer is very rare, however, even among people with gallstones. Certain conditions in the gallbladder, however, pose a higher than average risk for cancer.

Gallbladder Polyps and Primary Sclerosing Cholangitis. Polyps (growths) are sometimes detected during diagnostic tests for gallbladder disease. Small gallbladder polyps (up to 10 mm) pose little or no risk, but large ones (greater than 15 mm) pose some risk for cancer, so the gallbladder should be removed. Patients with polyps 10 - 15 mm have a lower risk, but they should still discuss removal of their gallbladder with their doctor.

Primary Sclerosing Cholangitis. Primary sclerosing cholangitis is a rare disease that causes inflammation and scarring in the bile duct. It is associated with a lifetime risk of 7 - 12% for gallbladder cancer. The cause is unknown although it tends to strike younger men with ulcerative colitis. Polyps are often detected in this condition and have a very high likelihood of malignancy.

Anomalous Junction of the Pancreatic and Biliary Ducts. With this rare congenital condition, the junction of the common bile duct and main pancreatic duct is located outside the wall of the small intestine and forms a long channel between them. This problem poses a very high risk of cancer in the biliary tract.

Porcelain Gallbladders. Gallbladders are referred to as porcelain when their walls have become so calcified that they look like porcelain on an x-ray. Porcelain gallbladders have been associated with a very high risk of cancer, although recent evidence suggests that the risk is lower than previously thought. The incidence appears to depend on the presence of specific factors, such as partial calcification involving the mucosal lining. This condition may develop from a chronic inflammatory reaction that may actually be responsible for the cancer risk. Studies are reporting no higher risk with "true" porcelain gallbladders, in which the gallbladder walls are entirely calcified.

Risk Factors

About 20 million Americans harbor gallstones. Only 1 - 3% of the population, however, complains of symptoms during the course of a year, and less than half of these people will experience recurrent symptoms.

Women are much more likely than men to develop gallstones. Gallstones occur in nearly 25% of women in the U.S. by age 60 and as many as 50% by age 75. In most cases, they are asymptomatic. In general, women are probably at increased risk because estrogen stimulates the liver to remove more cholesterol from blood and divert it into the bile.

Pregnancy. Pregnancy increases the risk for gallstones, and pregnant women with stones are more likely to have symptoms than nonpregnant women. Surgery should be delayed until after delivery if possible. In fact, gallstones may disappear after delivery. If surgery is necessary, laparoscopy is the safer approach.

Hormone Replacement Therapy. Several large studies have shown that use of hormone replacement therapy (HRT) doubles or triples the risk for gallstones or gallbladder surgery. A 2005 Journal of the American Medical Association study found that while all types of HRT raise the risks, estrogen alone has higher risks than combined estrogen and progesterone therapy. Estrogen has an effect on the liver and raises triglycerides, a fatty acid that increases the risk for cholesterol stones. Recent studies on HRT reporting negative effects on the heart and increased risks for breast cancer are also making this treatment a less attractive option for most postmenopausal women.

About 20% of men have gallstones by the time they reach age 75. Because most cases are asymptomatic, however, the rates may be underestimated in elderly men. One study of nursing home residents reported that 66% of the women and 51% of the men had gallstones. Men who have their gallbladders removed, moreover, are more likely to have severe disease and operative complications than women.

Gallstone disease is relatively rare in children. When gallstones occur in this age group they are more likely to be pigment stones. Girls do not seem to be more at risk than boys are. The following conditions may put children at higher risk:

Spinal injury
History of abdominal surgery
Sickle-cell anemia
Impaired immune system
Intravenous nutrition

Because gallstones are related to diet, particularly fat intake, the incidence of gallstones varies widely among nations and regions. For example, Hispanics and Northern Europeans have a higher risk for gallstones than people of Asian and African descent do. People of Asian descent who develop gallstones are most likely to have the brown pigment type.

Native North and South Americans, such as Pima Indians in the U.S. and native populations in Chile and Peru, are especially prone to developing gallstones. Pima women have an 80% chance of developing gallstones during their lives, and virtually all native Indian females in Chile and Peru develop gallstones. Such cases are most likely due to a combination of genetic and dietary factors.

Having a family member or close relative with gallstones may increase the risk of gallstones. Up to one-third of cases of painful gallstones may be related to genetic factors.

Defects in transport proteins involved in biliary lipid secretion appear to predispose certain people to gallstone disease, but this alone many not be sufficient to create gallstones. Studies indicate that the disease is complex and may result from the interaction between genetics and environment. Some studies suggest immune and inflammatory mediators may play key roles.

People with diabetes are at higher risk for gallstones and have a higher-than-average risk for acalculous gallbladder disease (without stones). Gallbladder disease may progress more rapidly in patients with diabetes, who tend to suffer worse infections.

In theory, drugs designed to improve insulin resistance should reduce the incidence of gallstones. However, this may not always occur. Researchers were surprised when animal studies showed that the type 2 diabetes drug pioglitazone (Actos) caused gallbladder volume to increase, indicating that its function may be compromised. This may raise the risk of gallstone formation.

Obesity. Being overweight is a significant risk factor for gallstones. In such cases, the liver over-produces cholesterol, which is delivered into the bile and causes it to become supersaturated. Some evidence suggests that specific dietary factors (saturated fats and refined sugars) are the primary culprit in these cases, although studies are conflicting. Animal studies, however, suggest that obesity itself, not any particular foods, triggers the process leading to cholesterol supersaturation and the formation of stones.

Weight Cycling. Rapid weight loss or cycling (dieting and then putting weight back on) further increases cholesterol production in the liver, with resulting supersaturation and risk for gallstones. A 2000 study suggested the following rates for gallstones related to extreme and rapid weight loss:

The risk for gallstones is as high as 12% after 8 -16 weeks of restricted-calorie diets.
The risk is more than 30% within 12 -18 months after gastric bypass surgery.

About one-third of gallstone cases in these situations are symptomatic. The risk for gallstones is highest in the following dieters:

Those who lose more than 24% of their body weight.
Those who lose more than 1.5 kg (3.3. lb.) a week.
Those on very low-fat, low-calorie diets.

Weight cycling also puts people at risk for gallstones. For example, a 16-year study found that the risk for gallstone surgery was 68% higher for women who lost and then regained more than 20 pounds at least once, as compared with women whose weight remained stable.

Men are also at increased risk for developing gallstones when their weight fluctuates. The risk increases proportionately with dramatic weight changes as well as with frequent weight cycling.

Bariatric Surgery. Patients who have either Roux-en-Y or laparoscopic banding bariatric surgery are at increased risk for gallstones. For this reason, many centers request the patient undergo cholecystectomy before their bariatric procedure. Doctors are now questioning this practice. A study of nearly 1,000 patients who did not have gallbladder surgery before their Roux-en-Y found that only 8% developed symptomatic gallstones requiring cholecystectomy, and that all cases occurred within 29 months of the bariatric procedure. In another study of 261 patients who underwent lap banding, only 3 developed symptomatic gallstones after the procedure.

Metabolic syndrome is a cluster of conditions that includes obesity (especially belly fat), low HDL (good) cholesterol, high triglycerides, high blood pressure, and high blood sugar. Research suggests that metabolic syndrome is a risk factor for gallstones.

Although gallstones are formed from supersaturation of cholesterol in the bile, high total cholesterol levels themselves are not necessarily associated with gallstones. Gallstone formation, however, is associated with low levels of "good" HDL cholesterol and high triglyceride levels. Some evidence suggests that high triglycerides may impair the emptying actions of the gallbladder.

Unfortunately, some fibrates (drugs used to correct these conditions) actually increase the risk for gallstones by increasing the amount of cholesterol secreted into the bile. They include gemfibrozil (Lopid), fenofibrate (Tricor), and bezafibrate (Bezalip). Other cholesterol-lowering agents do not have this effect. [See In-Depth Report #23: Cholesterol.]

Prolonged Intravenous Feeding. Prolonged intravenous feeding reduces the flow of bile and increases the risk for gallstones. Up to 40% of patients on home parenteral nutrition develop gallstones, and the risk may be higher in patients on total parenteral nutrition. It is suspected that the cause is lack of stimulation in the gut, since patients who also take some food by mouth have less risk of developing gallstones. However, treatment for gallstones in this population is associated with a low risk of complications.

Crohn's Disease. Crohn's disease, an inflammatory bowel disorder, leads to poor reabsorption of bile salts from the digestive tract and substantially increases the risk of gallbladder disease. Patients over age 60 and those who have had numerous bowel operations (particularly in the region where the small and large bowel meet) are at especially high risk.

Cirrhosis. Cirrhosis poses a major risk for gallstones, particularly pigment gallstones.

Organ Transplantation. Bone marrow or solid organ transplantation increases the risk. The complications can be so severe that some organ transplant centers require the patient's gallbladder be removed before the transplant is performed.

Medications. Octreotide (Sandostatin) poses a risk for gallstones. In addition, the cholesterol-lowering drugs known as fibrates and thiazide diuretics may slightly increase the risk for gallstones.

Blood Disorders. Chronic hemolytic anemia, including sickle cell anemia, increases the risk for pigment gallstones.

Heme Iron. High consumption of heme iron, the type of iron found in meat and seafood, has been shown to lead to gallstone formation in men. Gallstones are not associated with diets high in non-heme iron foods such as beans, lentils, and enriched grains.

Prevention

Diet plays a role in gallstones. The following discussions are some observations on specific dietary factors.

Fats. Although fats (particularly saturated fats found in meats, butter, and other animal products) have been associated with gallstone attacks, some studies have found a lower risk for gallstones in people who consume foods containing monounsaturated fats (found in olive and canola oils) or omega-3 fatty acids (found in canola, flaxseed, and fish oil). Fish oil may be of particular benefit in patients with high triglyceride levels by improving the emptying actions of the gallbladder.

Fiber. High intake of fiber has been associated with a lower risk for gallstones.

Nuts. Studies suggest that people may be able to reduce their risk of gallstones by eating more nuts (peanuts and tree nuts such as walnuts and almonds).

Fruits and Vegetables. Researchers who followed more than 77,000 healthy women for 16 years in the Nurses' Health Study found that those who ate the most fruits and vegetables had the lowest risk of developing symptomatic gallstones requiring removal of the gallbladder. The effect was consistent regardless of which fruits or vegetables they ate.

Vegetable Protein. A 2004 epidemiologic study found evidence that consumption of vegetable protein (such as soybean products) can help to prevent symptomatic gallstones.

Lecithin. Lecithin is a key component of bile. It contains choline and inositol, two compounds that are important for the breakdown of fat and cholesterol. Low levels of lecithin may precipitate the formation of cholesterol gallstones. Animal studies have suggested that lecithin-rich soy and buckwheat protein may protect against gallstones. (Buckwheat may be more protective than soy.) Dietary lecithin is available in health food stores and is found in eggs, soybeans, liver, wheat germ, and peanuts. There is no evidence, however, that lecithin supplements or foods containing it can prevent gallstones in humans.

Sugar. High-intake of sugar has been associated with an increased risk for gallstones. Diets that are high in carbohydrates such as pasta and bread can also increase risk, since carbohydrates are converted to sugar in the body.

Alcohol. A few studies have reported a lower risk for gallstones with alcohol consumption. Even small amounts (1 ounce per day) have been found to reduce the risk of gallstones in women by 20%. Moderate intake (defined as 1 - 2 drinks a day) also appears to have heart protection benefits. It should be noted, however, that even moderate intake increases the risk for breast cancer in women. Pregnant women, people who can't drink moderately, and people with liver disease should not drink at all.

Vitamin C. Ascorbic acid (vitamin C) appears to help break cholesterol down in bile. Vitamin C deficiencies have been associated with a higher risk for gallstones.

Coffee. In one study, men who drank 2 or more cups of regular coffee daily (either instant, filtered, or espresso) had a 40% lower risk of developing gallbladder disease over 10 years than men who did not drink coffee regularly. Those who drank more than 4 cups had the lowest risk. A more recent study in 2000 did not find any general protective effect, although women with gallstones who drank coffee reported fewer symptoms than those who didn't.

Maintaining a normal weight and avoiding rapid weight loss are the keys to reducing the risk of gallstones. Taking the medication ursodiol (also called ursodeoxycholic acid, or Actigall) during weight loss may reduce the risk for people who are very overweight and need to lose weight quickly. This medication is ordinarily used to dissolve existing gallstones. A promising 2001 study suggested that orlistat (Xenical), a drug for treating obesity, may protect against gallstone formation during weight loss. The drug appeared to reduce bile acids and other components involved in gallstone production.

Exercising regularly and vigorously may reduce the risk of gallstones and gallbladder disease, even in people who are overweight. Studies are reporting a lower risk for gallstones in both men and women who exercise. Active sports exercise appears to be most protective for both men and women. A 1999 study of women reported that exercise reduced gallstone risk regardless of whether the women lost weight or not. Some evidence suggests that, in addition to controlling weight, exercise helps reduce cholesterol levels in the biliary tract, which could help prevent gallstones.

Some data have indicated that taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen protects against the development of gallstones. Recent studies have been mixed, although a 2001 study reported significant protection against gallstone recurrence in people who took NSAIDs after being treated with lithotripsy.

NOTE: Long-term use of NSAIDS can cause stomach problems, such as ulcers and bleeding, and possible heart problems. In April 2005, the FDA asked drug manufacturers of NSAIDs to include a warning label on their product that alerts users of an increased risk for cardiovascular events and gastrointestinal bleeding. Talk to your doctor before taking these drugs.

Although it would be reasonable to believe that agents used to lower cholesterol would protect against gallstones, they either have little effect or, in the case of fibrates, actually increase the risk. One study reported a weak association between statins and a lower risk for gallstones. These are the most effective drugs for treating high cholesterol and include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). Most evidence, however, has found no protection even from these agents. Reducing cholesterol itself, then, does not have any effect on cholesterol gallstones.

Diagnosis

The diagnostic challenge posed by gallstones is to verify that abdominal pain is caused by stones and not by some other condition. Ultrasound or other imaging techniques can usually detect gallstones. Nevertheless, because gallstones are common and most cause no symptoms, simply finding stones does not necessarily explain a patient's pain, which may be caused by any number of ailments.

In patients with abdominal pain, causes other than gallstones are usually responsible if the pain lasts less than 15 minutes, frequently comes and goes, or is not severe enough to limit activities.

Irritable Bowel Syndrome. Irritable bowel syndrome (IBS) has some of the same symptoms as gallbladder disease, including difficulty digesting fatty foods. However, the pain of IBS usually occurs in the lower abdomen.

Pancreatitis. It is sometimes difficult to differentiate between pancreatitis and acute cholecystitis, but a correct diagnosis is critical, since treatment is very different. About 40% of pancreatitis cases are associated with gallstones. The risk for gallstone-associated pancreatitis is highest in older Caucasian and Hispanic women. About 25% of pancreatitis cases are severe, and the rate is much higher in people who are obese.

Blood tests showing high levels of pancreatic enzymes (amylase and lipase) usually indicate a diagnosis of pancreatitis. Elevated levels of the liver enzyme alanine aminotransferase (ALT) are very specific in identifying gallstone pancreatitis.

Imaging techniques are useful in confirming a diagnosis. Ultrasound is often used. A computed tomography (CT) scan, along with a number of laboratory tests, can determine the severity of the condition.

Pancreatic Cancer. Symptoms of pancreatic cancer may be very similar to those of gallbladder disease. It should be suspected if such symptoms are accompanied by weight loss or suspicious results from imaging tests of the pancreas.

Other Conditions with Similar Symptoms. Acute appendicitis, inflammatory bowel disease (Crohn's disease or ulcerative colitis), pneumonia, stomach ulcers, gastroesophageal reflux and hiatal hernia, viral hepatitis, kidney stones, urinary tract infections, diverticulosis or diverticulitis, pregnancy complications, and even a heart attack may mimic a gallbladder attack.

In patients with known gallstones, the doctor can often diagnose acute cholecystitis (gallbladder inflammation) based on classic symptoms (constant and severe pain in the upper right quadrant of the abdomen). Imaging techniques are necessary to confirm the diagnosis. There is usually no tenderness in chronic cholecystitis.

Blood tests are usually normal in people with simple biliary colic or chronic cholecystitis. The following abnormalities may indicate gallstones or complications:

The enzyme alkaline phosphatase and bilirubin are usually elevated in acute cholecystitis, and especially choledocholithiasis (common bile duct stones). Bilirubin is the orange-yellow pigment found in bile. High levels cause jaundice, which gives the skin a yellowish tone.
Liver enzymes known as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are elevated when common bile duct stones are present. A threefold or more increase in ALT strongly suggests pancreatitis.

A high white blood cell count is a common finding in many (but not all) patients with cholecystitis.

General Guidelines. Common duct stones (choledocholithiasis) may be detected at one of several points:

When the patient complains of gallbladder symptoms.
At the same time that gallstones are diagnosed. (Common duct stones often accompany gallstones.)
During or after performing surgery to remove the gallbladder for gallstones (cholecystectomy).

If the doctor only suspects common duct stones, however, identifying them is problematic. It requires blood tests, imaging tests, invasive procedures, or some combination that serve both for detection and possibly removal.

Laboratory Tests. Evidence that may suggest common bile duct stones includes dark urine, jaundice, or pancreatitis. In such cases, the doctor may perform certain blood tests. Elevated levels of the following suggest the presence of common duct stones:

Alkaline phosphatase (ALP). Elevated levels of this enzyme are typically the first signs of common bile duct stones.
Bilirubin (the orange-yellow pigment found in bile). Bilirubin levels increase after alkaline phosphatase rises.
Liver enzymes known as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). These enzymes may temporarily spike if the stone passes into the small intestine.

A number of techniques, particularly endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound (EUS) and magnetic resonance cholangiography (MRC), are proving to be equally effective for detecting common bile duct stones. Only ERCP, however, allows removal of the stones, but it is invasive. A National Institutes of Health expert panel has endorsed the use of ERCP as a diagnostic technique for patients who are clearly ill with symptoms of gallstones. For patients who are not as sick, the panel recommended noninvasive imaging techniques.

Ultrasound. Ultrasound is a simple, rapid, and noninvasive imaging technique. It is the diagnostic method most frequently used to detect gallstones and is the method of choice for detecting acute cholecystitis. The patient must not eat for 6 or more hours before the test, which takes only about 15 minutes. During the procedure, the doctor can check the liver, bile ducts, and pancreas, and quickly scan the gallbladder wall for thickening (characteristic of cholecystitis).

Ultrasound detects gallstones as small as 2 mm in diameter with an accuracy of 90 - 95%. Some experts recommend that if an ultrasound does not detect stones, but gallstones are still strongly suspected, the test should be repeated.

Air in the gallbladder wall may indicate gangrene.

Ultrasound does not appear to be very useful for identifying cholecystitis in symptomatic patients who do not have gallstones. In one study, ultrasound detected some gallbladder abnormalities, no matter what the cause of the abdominal pain. In only a few cases, however, were the symptoms actually caused by cholecystitis.

Ultrasound is also not as useful for common bile duct stones and cannot image the cystic duct. Nevertheless, normal ultrasound results along with normal bilirubin and liver enzyme tests are very accurate indications that there are no stones in the common bile duct.

An ultrasound variation called endoscopic ultrasound (EUS) is accurate and useful for patients with an intermediate risk for common bile ducts stones. Its accuracy is comparable to endoscopic retrograde cholangiopancreatography (ERCP), the standard for diagnosing stones in the common bile duct. However, if common duct stones are detected, they cannot be removed. It is useful, then, when common bile duct stones are suspected, but the patient is not clearly ill.

X-Rays. Standard x-rays of the abdomen may detect calcified gallstones and gas. Variations include oral cholecystography or cholangiography.

In oral cholecystography the patient takes a tablet containing a dye the night before the test. The dye fills the gallbladder, and x-ray images are taken the next day. The test has largely been replaced by ultrasound. It is more sensitive than standard x-rays, however, and may be useful in some cases for determining the structural and functional status of the gallbladder, often before nonsurgical procedures.

Cholangiography uses a dye injected into the bile duct and x-ray to view the common bile duct. It is typically used during operations to provide a clear image of the biliary tract.

Cholescintigraphy (Also Called Gallbladder Radionuclide Scan). Cholescintigraphy, a nuclear imaging technique, is more sensitive than ultrasound for diagnosing acute cholecystitis. It is noninvasive but can take 1 - 2 hours or longer. The procedure involves the following steps:

A tiny amount of a radioactive dye is injected intravenously. This material is excreted into bile.
The patient lies on a table under a scanning camera, which detects gamma rays emitted by the dye as it passes from the liver into the gallbladder.
The test can take up to 2 hours, since each image takes about a minute, and they are taken every 5 -15 minutes.

If the dye does not enter the gallbladder, the cystic duct is obstructed, indicating acute cholecystitis. The scan cannot identify individual gallstones or chronic cholecystitis. Occasionally, the scan gives false positive results (detecting acute cholecystitis in people who do not have the condition). Such results are most common in alcoholic patients with liver disease or patients who are fasting or receiving all nutrition intravenously.

Endoscopic Retrograde Cholangiopancreatography (ERCP). Endoscopic retrograde cholangiopancreatography (ERCP) has been the gold standard for detecting common bile duct stones, particularly because they can be removed during the procedure. However, it is invasive and carries a risk for complications. With the advent of noninvasive imaging techniques, ERCP is now generally limited to patients who have a high likelihood of common bile ducts stones, which would need to be removed.

Computed Tomography. Computed tomographic (CT) scans may be a valuable additional imaging technique if the doctor suspects complicating features, such as perforation, common duct stones, or other problems such as cancer in the pancreas or gallbladder. Helical (spiral) CT scanning is advanced technique that shortens the time and obtains clearer images. With this process, the patient lies on a table while a donut-like, low-radiation x-ray tube rotates around the patient.

Magnetic Resonance Imaging (MRI). MRIs may be very useful for detecting common bile duct stones, particularly a specific MRI technique called magnetic resonance cholangiography (MRC). It employs MRI and cholangiography, in which a dye is injected into the bile duct and x-rays are used to view the duct. MRC is extremely sensitive in detecting biliary tract cancer. This imaging procedure is very expensive, however, and may not detect very small stones or chronic infections in the pancreas or bile duct. As with EUS, it is most likely to be useful in a small subset of patients and would not eliminate the need for ERCP in most patients.

Click the icon to see an image of a cholangiogram.

Virtual Endoscopy. Virtual endoscopy is an investigative technique that uses data from CT and MRI scans to generate a 3-dimensional view of various body structures. The images resemble those used in endoscopy, but the procedure is noninvasive. It one study it was able to detect smaller stones in the common bile duct than MRI. At this time it is still experimental.

Treatment

Acute pain from gallstones and gallbladder disease is usually treated in the hospital, where diagnostic procedures are performed to rule out other conditions and complications. There are 3 approaches to gallstone treatment:

Expectant management ("wait and see")
Nonsurgical removal of the stones
Surgical removal of the gallbladder

Guidelines from the American College of Physicians state that when a person has no symptoms, the risks of both surgical and nonsurgical treatment for gallstones outweigh the benefits. Experts suggest a wait-and-see approach for such patients, which they have termed expectant management. Exceptions to this policy are those at risk for complications from gallstones, including the following:

People at risk for gallbladder cancer
Pima Native Americans
Patients with stones larger than 3 cm

One study reported that very small gallstones increase the risk for acute pancreatitis, a serious condition. Some experts therefore believe that gallstones smaller than 5 mm warrant immediate surgery.

There are some minor risks with expectant management for asymptomatic or low-risk individuals. Gallstones almost never spontaneously disappear, except sometimes when they are formed under special circumstances, such as pregnancy or sudden weight loss. At some point, then, the stones may cause pain, complications, or both, and require treatment. Some studies suggest the patient's age at diagnosis may be a factor in the possibility of future surgery. The probabilities are as follows:

15% likelihood of future surgery at age 70
20% at age 50
30% at age 30

The slight risk of developing gallbladder cancer might encourage young adults who are asymptomatic to have their gallbladders removed.

Gallstones are the most common cause for hospital admissions of patients with severe abdominal pain. Diagnostic tests are performed and, depending on results, the approach may be as follows:

Normal Test Results and No Severe Pain or Complications. If the patient has no fever or underlying serious medical problems and shows no signs of severe pain or complications, and if laboratory tests are normal, then the patients may be discharged with oral antibiotics and pain relievers.

Gallstones and Presence of Pain (Biliary Colic) but No Infection. Patients with pain and tests that indicate gallstones but who do not show signs of inflammation or infection have the following options:

Intravenous painkillers are administered for severe pain. Such drugs include meperidine (Demerol) or the potent NSAID ketorolac (Acular, Toradol). Ketorolac should not be used for patients who are likely to need surgery. These drugs can cause nausea, vomiting, and drowsiness. Opioids such as morphine may have fewer adverse effects, but some doctors avoid them for gallbladder disease.
They may electively choose to have the gallbladder removed (called cholecystectomy) at their convenience.
A minority of such patients may be candidates for a stone-breaking technique called lithotripsy. The treatment works best on solitary stones that are less than 2 cm in diameter.
Drug therapy for gallstones is available for some patients who are unwilling to undergo surgery or who have serious medical problems that increase the risks of surgery. Recurrence rates are high with nonsurgical options. The introduction of laparoscopic cholecystectomy has greatly reduced the use of nonsurgical therapies. Note: Drug treatments are generally inappropriate for patients who have acute gallbladder inflammation or common bile duct stones, since delaying or avoiding surgery could be hazardous.

Acute Cholecystitis (Gallbladder Inflammation). The first step if there are signs of acute cholecystitis is to "rest" the gallbladder in order to reduce inflammation. This involves the following treatments:

Fasting
Intravenous fluids and oxygen therapy
Intravenous painkillers, usually meperidine (Demerol). Potent NSAIDs, usually indomethacin, may be particularly useful. Indomethacin, for example, can reduce pain and inflammation and improve emptying actions of the gallbladder. Some doctors believe morphine should be avoided for gallbladder disease.
Intravenous antibiotics. These are administered if the patient shows signs of infection, including fever or an elevated white blood cell count, or in patients without such signs who do not improve after 12 - 24 hours.

Surgery to remove the gallbladder (called cholecystectomy) is nearly always indicated in people with acute cholecystitis. The most common procedure is now laparoscopy, a less invasive technique than open cholecystectomy (which involves a wide abdominal incision). Timing can be within hours to weeks after the acute episode, depending on the severity of the condition.

Click the icon to see an illustrated series detailing a gallbladder removal.

Gallstone-Associated Pancreatitis. Patients who have developed gallstone-associated pancreatitis almost always require surgery with either laparoscopic or open cholecystectomy.

Common Duct Stones. If noninvasive diagnostic tests suggest obstruction from common duct stones, the doctor will perform a procedure called endoscopic retrograde cholangiopancreatography (ERCP) to confirm the diagnosis and remove stones. This technique is used urgently along with antibiotics if infection is present in the common duct (cholangitis). In most cases, common duct stones are discovered during or after gallbladder removal.

Surgery

The gallbladder is not an essential organ, and even today, only surgical removal of the gallbladder (cholecystectomy ) guarantees that the patient will not suffer a recurrence of gallstones. This is one of the most common surgical procedures performed on women, and it can even be performed on pregnant women with low risk to the baby and the mother. The primary advantages of surgical removal of the gallbladder over nonsurgical treatment are elimination of gallstones and prevention of gallbladder cancer.

Open Procedures versus Laparoscopy. Until the early 1990s, open cholecystectomy (the removal of the gallbladder through a wide abdominal incision) was the standard treatment. Now, laparoscopic cholecystectomy (commonly called lap choly), which uses small incisions, is the most commonly used surgical approach. First performed in 1987, lap choly is now used in most cholecystectomies in the United States. In fact, about 700,000 people now have their gallbladders removed each year -- 200,000 more than before the introduction of laparoscopy. Of concern, then, is a significant increase in its use in patients who have inflammation in the gallbladder but no infection or gallstones and in those who have gallstones but no symptoms.

Laparoscopy has largely replaced open cholecystectomy because of some significant advantages:

The patient can leave the hospital and resume normal activities earlier than with open surgery.
The incisions are small, and there is less postoperative pain and disability than with the open procedure.
Laparoscopy has fewer complications.
It is less expensive than open cholecystectomy in the long term. The immediate treatment cost of laparoscopy may be higher than the open procedure, but the more rapid recovery with lap choly and fewer complications translate into shorter hospital stays and fewer sick days, and so a greater reduction in overall costs.

Some experts believe, however, that the open procedure still has a number of advantages compared to laparoscopy:

It is faster to perform.
It poses less of a risk for bile duct injury, which occurs in only 0.1 - 0.5% of open procedures, compared to about 0.3 - 2% with laparoscopy. Open surgry has more overall complications than laparoscopy, however, and bile-duct injury rates with laparoscopy are declining.

The type of surgery performed on specific patients may vary depending on different factors.

Appropriate Surgical Candidates. Candidates for gallbladder removal often have, or have had, one of the following conditions:

A very severe gallstone attack
Several less severe gallstone attacks
Endoscopic sphincterotomy for common bile duct stones i(n patients with residual gallbladder stones)
Cholecystitis (gallbladder inflammation).
Pncreatitis (inflammation of the pancreas)
High risk for gallbladder cancer (e.g., patients with anomalous junction of the pancreatic and biliary ducts or patients with certain forms of porcelain gallbladder)
Acalculous biliary pain (gallbladder disease symptoms without the presence of gallstones). The best candidates are those with evidence of impaired gallbladder emptying.

Timing of Surgery. Cholecystectomy may be performed within days to weeks after hospitalization for an acute gallbladder attack, depending on the severity of the condition.

Emergency gallbladder removal within 24 - 48 hours is warranted in about 20% of patients with acute cholecystitis. Indications for surgery include deterioration of the patient's condition, or signs of perforation or widespread infection.
The timing and type of surgery in patients with acute cholecystitis whose condition improves and have no signs of severe complications are under debate. Previously, the standard was open cholecystectomy between 6 - 12 weeks after the acute episode. Some evidence now suggests that early surgery performed between 72 - 96 hours after symptoms have lower complications than surgery performed after that.

General Outlook. Although cholecystectomy is very safe, as with any operation, there are risks of complications depending on whether the procedure is done on an elective or emergency basis.

When cholecystectomy is performed as elective surgery, the mortality rates are very low. (Even in the elderly, mortality rates are only 0.7 - 2%.)
Emergency cholecystectomy carries a much higher mortality rate (as high 19% in ill elderly patients).

Long-Term Effects of Gallbladder Removal. Although removal of the gallbladder has not been known to cause any long-term adverse effects aside from occasional diarrhea, some researchers have been concerned about its long-term impact on the body's cholesterol levels.

One study found that within 3 days of the operation, levels of total cholesterol and LDL returned to their preoperative levels. After 3 years, however, some types of cholesterol not ordinarily associated with coronary artery disease had risen significantly. These results did not necessarily indicate any increased risk for coronary artery disease, but they did show that the metabolism of cholesterol by the liver had been altered. People who have had their gallbladders removed should have their cholesterol levels checked periodically, as should every adult. Short-term treatment with the cholesterol-lowering known as statins, such as pravastatin (Pravachol), appears to lower cholesterol levels in surgical patients.


Laparoscopy	Open Cholecystectomy
Treatment of choice for most adult gallstone patients with or without symptoms, who have electively chosen to have their gallbladders removed.	Patients who have had extensive previous abdominal surgery.
Most patients with acute cholecystitis not accompanied by infection or perforation. (Up to 30% will need to convert to open surgery, depending on the severity of the condition.)	Patients with complications of acute cholecystitis (empyema, gangrene, perforation of the gallbladder).
Patients with acalculous gallbladder disease (without stones) who choose to have surgery. (if the patients have inflammation, however, the procedure of choice is percutaneous cholecystostomy to drain the gallbladder.	Very elderly patients. (Those over 80 are likely to have lower complication rates from open cholecystectomy than laparoscopy, although laparoscopy may even be appropriate in these patients.)
Patients with residual gallbladder stones after endoscopic sphincterotomy for common bile duct stones.
Candidates when experienced surgeons are available: Patients with acute gallstone pancreatitis that has subsided. Severely obese patients Patients with prior surgery in the upper abdomen. Patients with severely infected gallbladders. Pregnant women with symptomatic gallstones.	Seriously ill patients with acute cholecystitis who do not respond to fluid aspiration (percutaneous cholecystostomy).

The Procedure. With laparoscopy, removal of the gallbladder is typically performed as follows:

Laparoscopic cholecystectomy requires general anesthesia, although it is now mostly done as outpatient surgery.

The surgeon inserts a needle through the navel and pumps carbon dioxide gas through it to create space in the abdomen. This step may raise blood pressure. The antihypertensive drug clonidine may be helpful during surgery to protect patients with high blood pressure or heart or kidney disease. Of note, a 2000 study recommended that elderly patients not receive gas. Such patients are more likely to require a longer operating time, and the on-going pressure from the carbon dioxide increases the risk for problems that require conversion to an open procedure.
One or two 10 - 12 mm (about one-half inch) and three 5 mm (.20 inches), are made in the abdomen.
The surgeon inserts a laparoscope (a thin telescope) which contains a small surgical instrument and a tiny camera that relays an image to a video monitor.
The surgeon separates the gallbladder from the liver and other areas and removes it through one of the incisions.
Evidence suggests that the use of cholangiography during the operation helps prevent injury in the bile ducts, a serious complication of cholecystectomy. With this procedure, dye is injected into the bile duct, and moving x-rays are used to view the duct.
In general, the patient can go home the same day. In a 2001 study, however, some patients were found to be at higher risk for readmission later on, including those operation took longer than 1 hour or who had thicker gallbladder walls

Risk Factors for Conversion from Laparoscopy to an Open Procedure. In about 5 - 10% of laparoscopies, conversion to open cholecystectomy is required during the procedure. The rate of conversion to open surgery is higher in men than in women. This may be due to the higher rate of inflammation and fibrosis in men with symptomatic gallstones. Other reasons for conversion from laparoscopic to open surgery include:

Possible or known injury to major blood vessels
Internal structures not clearly visible
Unexpected problems that cannot be corrected with laparoscopy
Common bile duct stones that cannot be removed with laparoscopy or subsequent ERCP.
Previous endoscopic sphincterotomy
A thickened gallbladder wall

Complications and Side Effects of Surgery

Pain and fatigue are common side effects of any abdominal surgery. Patients should abstain from light recreational activities for about 2 days and from work and more strenuous activities for about a week.
There is a relatively high incidence of nausea and vomiting after laparoscopic cholecystectomy, which can be treated with injections of metoclopramide. Preoperative anti-nausea agents such as granisteron may prevent these effects. One study reported that patients who received a local anesthesia at the incision sites (in addition to general anesthesia) before surgery had less pain and nausea afterwards.
Injury to the bile duct. Bile duct injury is the most serious complication of laparoscopy. It can include leakage, tears, and the development of narrowing (strictures) that can lead to liver damage. In order to minimize such injuries, some experts recommend that surgeons perform laparoscopy with a procedure called cholangiography, in which a dye is injected into the bile duct and x-rays are used to view the duct. Bile duct injury has been a more common problem than with the open procedure but increasing surgical experience and the use of cholangiography is reducing this complication and studies are now reporting more comparable rates between the two procedures.
In about 6% of procedures, the surgeon misses some gallstones, or they are spilled and remain in the abdominal cavity. In a small percentage of these cases, the stones cause obstruction, abscesses, or fistulas (small channels) that require open surgery.
As with all surgeries, there is a risk for infection, but it is very low.

Patients should not be shy about inquiring into the number of laparoscopies the surgeon has performed (the minimum should be 40). Obese patients were originally thought to be poor candidates for laparoscopic cholecystectomy, but recent research indicates that this surgery is safe for them.

Before the development of laparoscopy, the standard surgical treatment for gallstones was open cholecystectomy (surgical removal of the gallbladder through an abdominal incision), which requires a wide incision and leaves a large surgical scar. In this procedure, the patient usually stays in the hospital for 5 - 7 days and may not return to work for a month. Complications include bleeding, infections, and injury to the common bile duct. The risks of this procedure increase with other factors, such as the age of the patient or if the surgeon needs to explore the common bile duct for stones at the same time.

Whether or not to insert a drain in the wound after surgery is under debate. Many surgeons implant drains primarily to prevent abscess or peritonitis. That practice may change. A recent analysis of all randomized clinical trains comparing drains versus no drains or type of drain used found that patients who received drains had a dramatically increased risk of wound and chest infection. The type of drain used made no difference.

Percutaneous Cholecystostomy. Percutaneous cholecystostomy is a procedure that may be used in seriously ill patients with severe gallbladder infection who cannot tolerate immediate surgery. It is also the standard treatment for patients with acalculous cholecystitis (gallbladder inflammation without stones). This procedure uses a needle to withdraw fluid (aspirate) from the gallbladder. A drainage catheter is inserted through the skin and into the gallbladder while the fluid drains out. In some cases, it may be left in place for up to 8 weeks. After that time, if possible, laparoscopy or an open cholecystectomy may be performed. Without a laparoscopy, recurrence rates with this procedure are high.

Gallbladder Aspiration. With this procedure, fluid is aspirated in one procedure while the gallbladder is viewed using ultrasound. It does not require an indwelling catheter afterward and may have fewer complications than percutaneous cholecystostomy.

Mini-Laparotomy Cholecystectomy. Mini-laparotomy cholecystectomy uses small abdominal incisions but, unlike laparoscopy, it is an "open" procedure, and the surgeon does not operate through a scope. The surgical instruments used are very small (2 - 3 mm in diameter, or about a tenth of an inch). Eventually, this technique may reduce operative time and enable surgeons to obtain better results than with laparoscopy.

Needlescopic Cholecystectomy. Procedures that use even fewer and smaller incisions than laparoscopy are being developed. There are many variations, including those referred to as twin-port, mini-site, or mini- or micro-laparoscopic surgeries. These procedures make even fewer incisions (2 - 3) and smaller ones (1.2 - 3 mm, or less than one-tenth of an inch). It should be noted, however, that these procedures still require one larger incision (10 - 12 mm, or about one-half inch). They are still investigative and have some disadvantages:

Fiberoptics, used to view the surgical areas, do not provide light that is as bright as the light used in conventional laparoscopy.
The instruments are very fragile.
The field of vision is very limited.

Although experience is very limited, studies are showing promise for reducing postoperative pain and improving recovery time beyond that of standard laparoscopy.

Telerobotic Surgery. In one high-tech experiment, surgeons in New York removed the gallbladder of a woman in France in a laparoscopic procedure using tools controlled by a remote robotic device. The procedure took 54 minutes and was free of complications.

Lithotripsy and Dissolution Therapies

Oral agents used to dissolve gallstones, and lithotripsy alone or in combination with other drugs had gained some popularity in the 1990s. But these oral agents have lost favor with the increase in laparoscopy. They still may have some value in specific circumstances.

Oral Dissolution Therapy. Oral dissolution therapy uses bile acids in pill form to dissolve gallstones and may be used in conjunction with lithotripsy, although both techniques are rarely used at present. Ursodiol (ursodeoxycholic acid, Actigall) and chenodiol (Chenix) are the standard oral bile acid dissolution drugs. Most doctors prefer ursodeoxycholic acid, which is considered to be among the safest of common drugs and without significant side effects. Long-term treatment appears to notably reduce the risk of biliary pain and acute cholecystitis. The treatment is only moderately effective, however, since gallstones recur in the majority of patients.

Patients most likely to benefit from oral dissolution therapy are those with small stones (less than 1.5 cm in diameter) that have a high cholesterol content.

Patients who probably will not benefit from this treatment include obese patients and those with gallstones that are calcified or composed of bile pigments

Only about 30% of patients are candidates for oral dissolution therapy; the number actually may be much lower, since compliance is often a problem. The treatment can take up to 2 years and can cost thousands of dollars per year.

Contact Dissolution Therapy. Contact dissolution therapy requires the injection of the organic solvent methyl tert-butyl ether (MTBE) into the gallbladder to dissolve gallstones. This is a somewhat technically difficult and hazardous procedure and performed only by experienced doctors in hospitals where research on this treatment is being done. Preliminary studies indicate that MTBE rapidly dissolves stones. The ether remains liquid at body temperature and dissolves gallstones within 5 - 12 hours. Serious side effects include severe burning pain.

Investigative Agents. Fatty acid bile acid conjugates (FABACs) are experimental agents that are being investigated for dissolving gallstones and for preventing gallstone formation.

Gallstone fragmentation by extracorporeal shock wave lithotripsy (ESWL) may be an appropriate therapy for some patients who cannot undergo surgery, but it is no longer widely used. The treatment works best on solitary stones that are less than two centimeters in diameter. Less than 15% of patients are good candidates for lithotripsy. The typical procedure is as follows:

The patient typically sits in a tub of water.
High-energy, ultrasound shock waves are directed through the abdominal wall toward the stones.
The shock waves travel through the soft tissues of the body and break up the stones.
The stone fragments are then usually small enough to be passed through the bile duct and into the intestines.
Lithotripsy is generally combined with oral dissolution (bile acid) treatment to help dissolve the fragmented pieces of the original gallstone.

Complications. Complications include pain in the gallbladder area and pancreatitis, usually occurring within a month of treatment. In addition, not all of the fragments may clear the bile duct. Adding erythromycin to the treatment regimen may help remove these fragments. About 35% of patients who are left with fragments are at risk for further problems, which can be severe. The chance of recurrence is high with this procedure, and in one study, 45% of patients eventually required surgery. Elderly people may have a lower risk for recurrence than younger adults, which may make this a good choice for some.

Managing Common Bile Duct Stones

Common duct stones (choledocholithiasis) pose a high risk for complications and nearly always warrant treatment. There are various options available. It is not clear yet which one is optimal.

In the past, when common bile duct stones were suspected, the approach was open surgery (open cholecystectomy) and surgical exploration of the common bile duct. This required a wide abdominal incision.
Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES) is now the most frequently used procedure for detecting and managing common duct stones. The procedure involves the use of an endoscope (a flexible telescope containing a miniature camera and other instruments), which is passed down the throat to the bile duct entrance.

Laparoscopic cholecystectomy also is increasingly being used for detection and removal of common duct stones. This is an approach through the abdomen but uses small incisions. In such cases, it is used in combination with ultrasound or a cholangiogram (an imaging technique in which a dye is injected into the bile duct and moving x-rays are used to view any stones).

Experts are currently debating the choice between laparoscopy (an abdominal approach) and ERCP (approaching through a tube down the throat). Many surgeons believe that laparoscopy is becoming safe and effective and should be the first choice. Still, laparoscopy for common duct stones should be performed only by surgeons experienced in this technique.


Endoscopic Retrograde Cholangiopancreatography (ERCP)	Laparoscopic Common Bile Duct Exploration	Open Common Bile Duct Exploration (Choledocholithotomy)
Before gallbladder surgeries when there is strong suspicion that common bile duct stones are present. After gallbladder surgeries in which the surgeon detects stones in the common bile duct (only if there are experts in ERCP and equipment is available). For patients with gallstone cholangitis (serious infection in the common bile duct). In such cases urgent ERCP plus antibiotics is required. When acute pancreatitis is caused by gallstones. In such cases urgent ERCP plus antibiotics is required. (The use of ERCP compared to conservative treatment has been controversial. One study reported that only patients who had infection and persistent obstruction in the ducts benefited from urgent ERCP intervention. In a 2000 analysis of four studies, however, ERCP significantly improved survival rates and reduced complications.)	As an alternative to ERCP before gallbladder surgeries when there is high suspicion of common bile duct stones. (Should be performed only in centers with expertise in this procedure, where it may actually be preferable to ERCP.) During gallbladder surgeries when common duct stones are detected or highly suspected. (Only for centers with expertise in this procedure.)	During or after some gallbladder operations when stones are detected. If procedure is laparoscopy, surgeon may convert to open procedure. Less often used now. When ERCP or laparoscopic procedures are not available.

The ERCP and ES Procedure. A typical ERCP and endoscopy sphincterotomy (ES) procedure includes the following steps:

The patient is given a sedative and asked to lie on his or her left side.
An endoscope (a tube containing fiber optics connected to a camera) is passed through the mouth and stomach and into the duodenum (top part of the small intestine) until it reaches the point where the common bile duct enters. This does not interfere with breathing, but the patient may have a sensation of bloating.
A thin catheter (tubing) is then passed through the endoscope.
Contrast material (a dye) is injected through the catheter into the opening of the duct. The dye allows x-ray visualization of the biliary tree (the system of ducts through which bile flows, including the common bile duct) and any stones contained in the area.
Instruments may also be passed through the endoscope to remove any stones that are detected.
The next phase of the procedure is known as endoscopic sphincterotomy (ES). (It is also sometimes referred to as papillotomy, although this is a slightly different variation.) It serves to widen the junction between the common bile duct and intestine (called the ampulla of Vater) so that the stones can be extracted more easily. With ES a tiny incision is usually made in the orifice of the common bile duct and through the muscles that enclose the lower common bile duct (called the sphincter of Oddi).
One recent alternative to ES is the use of a small inflatable balloon (called endoscopic balloon dilation) that opens up the ampulla of Vater to allow stones to pass and so avoid cutting the muscles. According to 2003 studies, it is equal in effectiveness to ES but offers no advantage at this time.
Once the junction has been opened, the stones may pass out on their own or they may be extracted with the use of tiny baskets or balloons.

Complications. Complications of ERCP and ES occur in 5 - 8% of cases, and some can be serious, with mortality rates of 0.2 - 0.5%. They include the following:

Pancreatitis (inflammation of the pancreas) occurs in 3 - 9% of cases and can be very serious. Younger adults are at higher risk than the elderly. The risk is also higher with more complex procedures. The drugs somatostatin or gabexate are sometimes used to reduce the risk, although evidence suggests somatostatin may not reduce this risk. Gabexate appears to be more effective, although studies are mixed on whether its benefits are significant, particularly with short-term administration.
Postoperative infection. Antibiotics may be given before the procedure to prevent infection, although one study reported that they had little benefit.
Bleeding occurs in 2% of cases. There is an increased risk in patients taking anti-clotting drugs and those who have cholangitis. This complication is treated by flushing the area with epinephrine.
Perforations (rare).
Long-term complications include stone recurrence and abscesses.

ERCP and ES are difficult procedures, and patients must be certain their doctor and the medical center have experience with them. The surgeon should have performed at least 180 ERCPs. Under such circumstances, ERCP can usually be performed successfully even in critically ill patients on mechanical ventilators.

ERCP and Gallbladder Removal (Cholecystectomy). ERCP is often performed after gallstones in the common duct are discovered during cholecystectomy (removal of the gallbladder).

In some cases, stones in the gallbladder are detected during ERCP. In such cases laparoscopic cholecystectomy is usually warranted. There is some debate about whether the gallbladder should be removed in such cases at the same time as ERCP or if patients should wait. A 2002 study suggested that immediate gallbladder removal is preferred, since the risk for recurring symptoms is very high.

Surgeons are now increasingly using laparoscopy plus an imaging technique called cholangiography instead of ERCP when common duct stones are suspected. The laparoscopic procedure for common duct stones should be performed only in centers where there is expertise. It generally proceeds as follows:

The initial approach is the same as with laparoscopic cholecystectomy. Small incisions, one or two 10 - 12 mm (around half an inch) and three 5 mm (.20 inches), are made in the abdomen.
A tiny opening is made in the cystic duct that connects the gallbladder to the bile duct, and a thin tube is introduced to perform a cholangiogram. (In this procedure, a dye is administered to reveal the stone's location on x-rays.)
The procedure is typically used in combination with cholangiography, an imaging technique in which a dye is injected into the bile duct and x-rays are used to view any stones. Cholangiography reduces the risk for injury in the common duct.
If stones are identified, the surgeon inserts a tube with an inflatable balloon that is used to widen the duct.
Stones are usually retrieved or withdrawn from the duct either with the use of a balloon or with a tiny basket.
If laparoscopy is unsuccessful, then ERCP or open surgery is performed.

Experts are debating whether the use of this procedure is better than ERCP. Many surgeons believe that laparoscopy is becoming safe and effective and should be the first choice. Still, laparoscopy for common duct stones should be performed only by surgeons experienced in this new and demanding technique.

Choledocholithotomy, or common bile duct exploration, is used to remove large stones or in cases when the duct anatomy is complex. In this procedure, the doctor carries out open abdominal surgery and extracts gallstones through an incision in the common bile duct. Routinely, a so-called "T-tube" is temporarily left in the common bile duct after surgery and the doctor x-rays the bile duct through the tube 7 - 10 days postoperatively to determine if any stones remain in the duct.

Shock wave lithotripsy is an option in certain cases for bile duct stones that cannot be extracted.

Mechanical Endoscopic Lithotripsy. Endoscopy with mechanical lithotripsy employs a tiny steel crushing basket, which is inserted through the endoscope and into the common bile duct. The basket opens to trap and then crush the stone. It is capable of crushing and removing very large stones. The overall success rate is 80 - 90%, although 20 - 30% of patients require more than one treatment.
Extracorporeal Shock Wave Lithotripsy. Extracorporeal shock wave lithotripsy is an option in certain cases of bile duct stones as it is for stones in the gallbladder.

Resources

http://digestive.niddk.nih.gov -- National Digestive Diseases Information Clearinghouse
www.gastro.org -- American Gastroenterological Association
www.acg.gi.org -- American College of Gastroenterology
www.liverfoundation.org -- American Liver Foundation

References

Al-Azzawi HH, Mathur A, Lu D, Swartz-Basile DA, Nakeeb A, Pitt HA. Pioglitazone increases gallbladder volume in insulin-resistant obese mice. J Surg Res. 2003;136(2):192-197.

Dray X, Joy F, Reijasse D, et al. Incidence, risk factors, and complications of cholelithiasis in patients with home parenteral nutrition. J Am Coll Surg. 2007;204(1):13-21.

Grunhage F, Lammert F. Gallstone disease. Pathogenesis of gallstones: A genetic perspective. Best Pract Res Clin Gastroenterol. 2006;20(6):997-1011.

Gurusamy K, Samraj K. Routine abdominal drainage for uncomplicated open cholecystectomy. Cochrane Database Syst Rev. 2007;18;(2):CD006003.

Lyons MA, Wittenburg H. Susceptibility to cholesterol gallstone formation: evidence that LITH genes also encode immune-related factors. Biochim Biophys Acta. 2006;1761(10):1133-1147.

Masannat Y, Masannat Y, Shatnawei A. Gallstone ileus: a review. Mt Sinai J Med. 2006;73(:1132-1134.

Morimoto LM, Newcomb PA, Hampton JM, Trentham-Dietz A. Cholecsytectomy and endometrial cancer: a marker of long-term elevated estrogen exposure? Int J Gynecol Cancer. 2006;16(3):1348-1353.

Myers JA, Fischer GA, Sarker S, Shayani V. Gallbladder disease in patients undergoing laparoscopic adjustable gastric banding. Surg Obes Relat Dis. 2005;1(6)561-563.

Portenier DD, Grant JP, Blackwood HS, Pryor A, McMahon RL, Demaria E. Expectant management of the asymptomatic gallbladder at Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2007. Epub Apr 17 ahead of print.

Sarkio S, Salmela K, Kyllonen L. Rosliakova M, Honkanen E, Halme L. Complications of gallstone disease in kidney transplantation patients. Nephrol Dial Transplant. 2007;22(3):886-890.

Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Fruit and vegetable consumption and risk of cholecystectomy in women. Am J Med. 2006;119(9):760-767.

Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Heme and non-heme iron consumption and risk of gallstone disease in men. Am J Clin Nutr. 2007;85(2):518-522.

Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Weight cycling and risk of gallstone disease in men. Arch Intern Med. 2006;166(21):2369-2374.

Wittenburg H, Lammert F. Genetic predisposition to gallbladder stones. Semin Liver Dis. 2007;237(1):109-121.

Yol S, Kartal A, Vatansev C, Aksoy F, Toy H. Sex as a factor in conversion from laparoscopic cholecystectomy to open surgery. JSLS. 2006;10(3):359-363.

Review Date:
5/15/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Psoriasis

FitSugar — Wed, 08 Oct 2008 17:35:27 -0700

In This Report

Highlights
Introduction
Types of Psoriasis
Causes
Risk Factors
Diagnosis
Treatment
Topical Medications
Systemic Medications
Phototherapy
Managing Psoriasis
Outlook
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Treatment

Psoriasis that develops on the hands or feet is often very difficult to treat. However, an advanced clinical trial showed that a medication called efalizumab (Raptiva) effectively cleared or nearly cleared moderate-to-severe symptoms in adults after 12 weeks.

Several studies have shown that most people with severe psoriasis who are treated with infliximab (Remicade) have significant improvement in symptoms by week 10. The findings were presented at the 2007 annual meeting of the American Academy of Dermatology.

Continuing etanercept (Enbrel) after 12 weeks improves disease severity without an increase in infections or side effects, according to a study published in the Archives of Dermatology.

Disease classification

The National Psoriasis Foundation has proposed a new way to classify psoriasis. Instead of being grouped as mild, moderate, or severe, the group suggests a new two-tiered system that classifies patients as needing either local or body-wide (systemic) treatment.

Coexisting conditions

Studies from Newfoundland and Germany have revealed increased cases of diabetes, obesity, arthritis, and cancer in patients with psoriasis. Previous research has found an increased risk of heart disease in psoriasis patients. Research is underway to determine if there are genetic links between psoriasis and these conditions.

Severe psoriasis has been linked to a significant increase in a patient's risk of death. A study of more than 713,000 patients showed that severe psoriasis increased mortality by 50%. Such patients should receive comprehensive health examinations to reduce the risk, the authors recommended. Study participants were considered to have severe psoriasis if they required systemic treatment.

Smoking and psoriasis

Introduction

Psoriasis is a chronic skin disorder marked by periodic flare-ups of sharply defined red patches, covered by a silvery, flaky surface. The main disease activity leading to psoriasis occurs in the epidermis, the top five layers of the skin.

The process starts in the basal (bottom) layer of the epidermis, where keratinocytes are made. Keratinocytes are immature skin cells that produce keratin, a tough protein that helps form hair, nails, and skin. In normal cell growth, keratinocytes grow and move from the bottom layer to the skin's surface and shed unnoticed. This process takes about a month.

In persons with psoriasis, the keratinocytes multiply very rapidly and travel from the basal layer to the surface in about 4 days. The skin cannot shed these cells quickly enough, so they build up, leading to thick, dry patches, or plaques. Silvery, flaky areas of dead skin build up on the surface of the plaques before being shed. The underlying skin layer (dermis), which contains the nerves and blood and lymphatic vessels, becomes red and swollen.

Types of Psoriasis

Various forms of psoriasis exist. Some can occur alone or at the same time as other types, or one may follow another. The most common type is called plaque psoriasis, also known as psoriasis vulgaris.

Plaque psoriasis leads to skin patches that start off in small areas, about one-eighth of an inch wide. They usually appear in the same areas on opposite sides of the body.

The patches slowly grow larger and develop thick, dry plaque. If the plaque is scratched or scraped, bleeding spots the sizes of pinheads appear underneath. This is known as the Auspitz sign.

Some patches may become ring shaped (annular), with a clear center and scaly raised borders that may appear wavy and snake-like.

As the disease progresses, eventually separate patches may join together to form larger areas. In some cases, the patches can become very large and cover wide areas of the back or chest. This is known as geographic plaques because the skin lesions resemble maps.

Plaque psoriasis may persist for long periods. More often it flares up periodically, triggered by certain factors such as cold weather, infection, or stress.

Patches most often occur on the:

Elbows
Knees
Lower back

The may also be seen on the:

Upper pelvic bone area
Bottom of the feet
Calves and thighs
Genital areas
Palms of hands

Psoriasis of the scalp affects about 50% of patients. In some cases, the psoriasis may cover the scalp with thick plaques that extend down from the hairline to the forehead.

Psoriasis patches rarely affects the face in adulthood. In children, psoriasis is most likely to start in the scalp and spread to other parts of the body. Unlike in adults, it also may occur on the face and ears.

Psoriatic arthritis (PsA) is an inflammatory condition characterized by stiff, tender, and inflamed joints. Estimates on its prevalence among those with psoriasis range from 2 - 42%. AIDS patients and those with severe psoriasis are at higher risk for developing PsA.

About 80% of PsA patients have psoriasis in the nails. Arthritic and skin flare-ups tend to occur at the same time. It is not clear whether psoriatic arthritis is a unique disease or a genuine variation of psoriasis, although evidence suggests they are both caused by the same immune system problem.

Although patients with psoriatic arthritis tend to have mild skin symptoms, the disease affects the entire body. PsA, therefore, is more serious than the more common plaque psoriasis. Infrequently, the course of PsA has been associated with a syndrome known by the acronym SAPHO, which stands for:

Synovitis (inflammation in the joints)
Acne
Pustule eruptions
Hyperostosis (abnormal bony growths)
Osteolysis (bone destruction)

Some experts group PsA into five forms. The forms differ according to the location and severity of the affected joint:

Symmetric PsA: Symptoms occur in the same location on both sides of the body. It usually affects multiple joints. In about half of the cases, the condition will get worse. The condition is very similar to, but less disabling than, rheumatoid arthritis. The psoriasis itself is often severe.
Asymmetric PsA: This form involves periodic joint pain and redness, usually in only one to three joints, which can be the knee, hip, ankle, wrist, or one or more fingers. The pain does not occur in the same location on both sides of the body.
Distal interphalangeal predominant (DIP): DIP involves the joints of the fingers and toes closest to the nail. It occurs in about 5% of PsA cases.
PsA in the spine: Inflammation in the spinal column (spondylitis) is the primary symptom in about 5% of PsA cases. Such patients may have stiffness and burning sensations in the neck, lower back, sacroiliac, or spinal vertebrae. The spine can be involved in many patients with PsA, even though stiffness and burning sensations in these areas are not the primary symptoms. When it affects the spine, psoriatic arthritis most frequently targets the sacrum (the lowest part of the spine). Movement is difficult.
Arthritis mutilans: This is a severe, deforming, and progressive form of arthritis. It affects less than 5% of PsA cases. It mainly affects the small joints of the hands and feet, but it can also be found in the neck and lower back. Arthritic and skin flares and remissions tend to coincide.

People who start to smoke after developing psoriasis may delay the onset of psoriatic arthritis, according to research presented at the 2007 annual meeting of the Society for Investigational Dermatology. Researchers found that in nonsmokers, the time between psoriasis diagnosis and psoriatic arthritis development was 13 years, compared to 23 among those who started smoking after the onset of psoriasis. Study participants who smoked before developing psoriasis had psoriatic arthritis occur in about 8 years. However, smoking causes serious health problems and should not be considered as a way to delay this type of psoriasis.


Psoriasis Form	Description of Skin Patches	Comments
Guttate Psoriasis	The patches are teardrop-shaped and appear suddenly, usually over the trunk and often on the arms, legs, or scalp. They often disappear without treatment.	Guttate psoriasis can occur as the initial outbreak of psoriasis, often in children and young adults 1 - 3 weeks after a viral or bacterial (usually streptococcal) respiratory or throat infection. A family history of psoriasis and stressful life events are also highly linked with the start of guttate psoriasis. Guttate psoriasis can also develop in patients who have already had other forms of psoriasis, most often in people treated with widely-applied topical (rub-on) products containing corticosteroids.
Inverse Psoriasis	Patches usually appear as smooth inflamed patches without a scaly surface. They occur in the folds of the skin, such as under the armpits or breast, or in the groin.	Inverse psoriasis may be especially difficult to treat.
Seborrheic Psoriasis	Patches appear as red scaly areas on the scalp, behind the ears, above the shoulder blades, in the armpits or groin, or in the center of the face.	Seborrheic psoriasis may be especially difficult to treat.
Nail Psoriasis	Tiny white pits are scattered in groups across the nail. Toenails and sometimes fingernails may have yellowish spots. Long ridges may also develop across and down the nail. The nail bed often separates from the skin of the finger and collections of dead skin can build up underneath the nail.	Over half of patients with psoriasis have abnormal changes in their nails, which may appear before other skin symptoms. In some cases, nail psoriasis is the only symptom.
Generalized Erythrodermic Psoriasis (also called psoriatic exfoliative erythroderma)	This is a rare and severe form of psoriasis, in which the skin surface becomes scaly and red. The disease covers all or nearly all of the body.	About 20% of such cases evolve from psoriasis itself. The condition may also be triggered by certain psoriasis treatments, and other medications such as corticosteroids or synthetic antimalarial drugs.
Pustular Psoriasis	Patches become pus-filled and blister-like. The blisters eventually turn brown and form a scaly crust or peel off. Pustules usually appear on the hands and feet. When they form on the palms and soles, the condition is called palmar-plantar pustulosis.	Pustular psoriasis may erupt as the first occurrence of psoriasis, or it may evolve from plaque psoriasis. A number of conditions may trigger pustular psoriasis, including infection, pregnancy, certain drugs, and metal allergies. It can also accompany other forms of psoriasis and be very severe.

Causes

The precise causes of psoriasis are unknown. It is generally believed to be due to damage in factors in the immune system, enzymes, and other materials that control skin cell division. This prompts an abnormal immune response, which causes rapid production of immature skin cells and inflammation.

The Normal Immune System Response. The inflammatory process is the result of the body's immune response, which fights infection and heals wounds and injuries:

When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign invaders, such as bacteria or viruses.
The masses of blood cells that gather at the injured or infected site produce factors to repair wounds, clot the blood, and fight infections.
In the process, the surrounding area becomes inflamed (red and swollen), and some healthy tissue is injured.

The Infection Fighters. The primary infection-fighting units are two types of white blood cells: lymphocytes and leukocytes.

Lymphocytes include two subtypes known as T cells and B cells. Both types of cells are designed to recognize foreign substances (antigens) and launch an offensive or defensive action against them:

B cells produce antibodies, which are designed to attack the antigens. Antibodies can either ride along with a B cell or travel on their own.
T cells have special receptors attached to their surface that recognize the specific antigen.

T cells are further categorized as killer T cells or helper T cells (TH cells).

Killer T cells directly attack antigens found on bacteria or other cells.
Helper T stimulate B cells and other white cells to attack the antigen.

The actions of the helper T cells are of special interest. Researchers have found high numbers of helper T cells in psoriatic plaques. Helper T cells normally stimulate B cells to produce antibodies. In psoriasis, however, they appear to direct the B cells to produce autoantibodies ("self" antibodies), which attack skin cells. In psoriatic arthritis, cells in the joints also come under attack.

Helper T cells also release or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are very important for healing. If overproduced, however, they can cause serious damage, including inflammation and injury during the psoriasis disease process. In psoriasis, researchers are particularly interested in cytokines known as GRO-alpha, tumor necrosis factor, and certain interleukins.

Cytokines attract large numbers of other large white blood cells known as neutrophils. Neutrophils stimulate the production of arachidonic acid, producing two key players in the inflammatory process:

Leukotrienes: These chemicals attract even more white blood cells to the inflamed area.
Prostaglandins: These chemicals widen blood vessels and increase blood flow.

A combination of genes is involved with increasing a person's susceptibility to the conditions leading to psoriasis.

HLA Molecules. The processes leading to all autoimmune diseases involve the human leukocyte antigen (HLA) system. HLA molecules pick off parts of antigens and present them on the surface of a cell so that the various infection-fighting factors in the immune system can recognize and destroy them. Most immune disorders, including psoriatic arthritis, are due to problems with this system. For example, psoriasis patients with an HLA genetic factor called HLA-CW6 tend to develop psoriasis at an earlier than average age. However, only 10% of people who have this gene develop psoriasis. Other genetic and environmental factors are required to actually trigger the disease.

PSORs. Researchers have now identified four key genes (named PSOR 1 - 4) that are involved with psoriasis. Of particular interest are the genes located in regions on specific chromosomes that are linked to HLA and tumor necrosis factor, another immune factor strongly associated with psoriasis.

Weather, stress, injury, infection, and medications, while not direct causes, are often important in triggering the disease process leading to the start and worsening of psoriasis.

Weather. Cold, dry weather is a common trigger of psoriasis flare-ups. Hot, damp, sunny weather helps relieve the problem in most patients. However, some people have photosensitive psoriasis, which actually improves in winter and worsens in summer when skin is exposed to sunlight.

Stress and Strong Emotions. Stress, unexpressed anger, and emotional disorders, including depression and anxiety, are strongly associated with psoriasis flare-ups. In one study, nearly 40% of patients remembered a specific stressful event that occurred within a month of a psoriasis flare. Other research has suggested that stress can trigger specific immune factors associated with psoriasis flares.

Infection. Infections caused by viruses or bacteria can trigger some cases of psoriasis. For example:

Streptococcal infections in the upper respiratory tract, such as tonsillitis, sinusitis, and strep throat, are known to trigger guttate psoriasis in children and young adults. The infections may make ordinary plaque psoriasis worse.
Human immunodeficiency virus (HIV) is also associated with psoriasis.
An uncommon form of human papillomaviruses (HPV) called EV-HPV has been associated with psoriasis. Although EV-HPV is probably not a direct cause, it may play a role in the continuation of psoriasis. This HPV form is not the virus associated with cervical cancer and genital warts.

Skin Injuries and the Köbner Response. The Köbner response is a delayed response to skin injuries, in which psoriasis develops later on at the site of the injury. In some cases, even mild abrasions can cause an eruption, which may be a factor in the frequency of psoriasis on the elbows or knees. It should be noted that psoriasis can develop in areas with no history of skin injury.

Medications. Drugs that can trigger the onset of the disease, worsen symptoms, or cause a flare-up include:

Angiotensin-converting enzyme (ACE) inhibitors, drugs used to treat high blood pressure and heart problems
Beta-blockers, drugs used to treat high blood pressure and heart problems
Chloroquine, a medicine used to treat malaria
Lithium for bipolar disorder treatment
Indomethacin, a nonsteroidal anti-inflammatory drug (NSAIDs) -- Note: Other NSAIDs, such as meclofenamate, may actually improve the condition.
Progesterone, used in female hormone therapies

Flare-ups of severe psoriasis may occur in persons who stop taking steroids taken by mouth, or who discontinue use of very strong steroid ointments that cover wide skin areas. The flare-ups may be of various psoriatic forms, including guttate, pustular, and erythrodermic psoriasis. Because these drugs are also used to treat psoriasis, this rebound effect is of particular concern.

Medications that cause rashes, a side effect of many drugs, can trigger psoriasis as part of the Köbner response.

Risk Factors

Between 5.8 and 7.5 million Americans have psoriasis. Risk factors for psoriasis include:

Age under 20. About 40% develop the condition before age 20. Psoriasis (most often plaque psoriasis) can even occur in infants.
Climate. Some studies have found that the disorder develops earlier and more frequently in colder climates. For example, psoriasis occurs more frequently in African-Americans and in Caucasians who live in colder climates than in people of any ethnicity who live in Africa.
Ethnicity. Psoriasis is uncommon in Native Americans of either North or South American descent.
Family history of the disease. About 35% of those with psoriasis have one or more family members with the disorder.
Male gender. Some studies have indicated that more men than women have psoriasis.

Diagnosis

A microscopic examination of tissue taken from the affected skin patch is needed to make a definitive diagnosis of psoriasis and to distinguish it from other skin disorders. Usually in psoriasis, the examination will show a large number of dry skin cells, but without many signs of inflammation or infection. Specific changes in the nails are often strong signs of psoriasis.

Several conditions produce symptoms that resemble those of psoriasis. For example:

Seborrheic psoriasis is hard to distinguish from seborrheic dermatitis (dandruff is one form of this condition). Seborrheic dermatitis patches are usually greasy, yellowish, and crusty. Nail involvement may also help differentiate psoriasis.
Generalized erythrodermic psoriasis may be confused with drug allergic reactions, atopic eczema, and symptoms of lymphomas.
Fungal infections, other skin conditions, or circulation problems may also cause nail changes typical of psoriasis.

Symptoms of psoriatic arthritis may also resemble the following:

Rheumatoid arthritis (RA). As in rheumatoid arthritis, psoriatic arthritis can cause pain or tenderness in one or more joints, and morning stiffness is common. People with psoriatic arthritis, however, lack a particular antibody, called rheumatoid factor, which is found in the blood of many people with rheumatoid arthritis.
Systemic lupus erythematosus (SLE). Symptoms of SLE may include both a psoriasis-like rash and arthritis, which could make the diagnosis difficult.
Reiter's disease. Reiter's disease is a syndrome that includes arthritis and inflammation in the eyes and urinary tract. It also causes skin lesions that are very similar to psoriasis, which are usually raised patches on the lips, penis, palms, and soles.
Gout. Gout causes pain, often in the fingers and toes.

Some evidence now indicates that inflammation in psoriatic arthritis may be distinguished from other arthritic conditions by its occurrence in sites where muscle tissue inserts into the bone (called enthesitis) rather than in the joint, which is a common site in other inflammatory arthritic conditions.

Severity of psoriasis itself ranges from one or two flaky inflamed patches to widespread pustular psoriasis that, in rare cases, can be life threatening. To help determine the best treatment for a patient, doctors usually classify the disease as mild to severe. The classification depends on how much of the skin is affected:

Mild psoriasis affects less than 3% of the body surface. Most cases of psoriasis are limited to less than 2% of the skin.
Moderate psoriasis covers 3 - 10% of the skin.
If more than 10% of the body is affected, the disease is considered severe.

The palm of the hand equals 1% of the body. The severity of the disease is also measured by its effect on a person’s quality of life.

However, the National Psoriasis Foundation has proposed a new classification method. The group suggests a new two-tiered system that classifies patients as needing either local or body-wide (systemic) treatment.

While disease severity impacts treatment success, some forms of psoriasis can be very resistant to treatment even though they are not categorized as severe. They include:

Any psoriasis on the palms and soles (hand and foot psoriasis)
Inverse psoriasis (which occurs in the folds of the skin)
Scalp psoriasis
Psoriatic arthritis

Treatment

Many creams, ointments, lotions, and pills are available for the treatment of psoriasis. Many patients require only over-the-counter treatment, or even none at all during relapses.

About a third of patients with psoriasis, however, do not respond to over-the-counter remedies and lifestyle changes, and require aggressive treatments. In some cases, such treatments need to be lifelong.

In general, there are three treatment options for patients with psoriasis.

Topical medications such as lotions, ointments, creams, and shampoos
Body-wide (systemic) medications, which involve pills or injections that affect the whole body, not just the skin
Phototherapy, which uses light to treat psoriasis lesions

Individual requirements vary widely, and treatment selection must be carefully discussed with the doctor.

Giving treatment in a particular order is a strategy for providing both quick relief of symptoms and long-term maintenance. It involves three main steps:

The quick fix, to clear the psoriatic lesions during an acute outbreak (for example, a high-strength topical steroid in mild-to-moderate psoriasis, or an oral immunosuppressant in more severe cases)
The transitional phase, intended to gradually introduce the maintenance drug
Ongoing maintenance therapy

Choices for transitional or maintenance treatments depend on the severity of the condition. Some examples are described in the following sections.

In severe chronic cases, a doctor may recommend rotational therapy. This approach alternates treatments. The goal is to prevent severe side effects or build-up of resistance from long-term use of a single medicine. An example of a rotational schedule may be the following:

The patient gets phototherapy for about 2 years.
The patient then takes one or two powerful body-wide drugs for 1 - 2 years and stops.
Phototherapy starts again, and the cycle repeats.

Some doctors use the Koo-Menter Psoriasis Instrument (KMPI) to decide which patients should receive a pill or an injection. The KMPI’s questions include:

Does psoriasis cover at least 5% of the patient’s body?
Is the patient disabled by psoriasis?
Does psoriasis affect the patient’s quality of life?

If the answer to these questions is "yes," three additional questions are considered:

Is light therapy inappropriate for the patient?
Is the patient’s psoriasis resistant to light therapy?
Does the patient have psoriatic arthritis?

If the answer to these questions is “yes,” a doctor may decide to prescribe a pill or injected drugs.

Doctors increasingly use combinations of pills, creams, ointments, and phototherapy instead of single medications. Combinations of oral treatments are particularly useful, since the doses of each drug can be reduced. This lowers the risk of severe side effects. Thousands of combinations are possible, and the patient and doctor should discuss the best treatment for individual needs.

Topical Medications

Topical medications are those applied only to the surface of the body. They come in the following forms:

Creams
Foams
Gels
Lotions
Occlusive tapes
Ointments
Shampoos
Solutions
Sprays

In general, topical treatments are the first line for mild-to-moderate psoriasis, but they may also be used, alone or in combination, with more powerful treatments for moderate-to-severe cases. Topical medicines rarely produce complete clearance, however.

Corticosteroid topical treatments are the mainstay of psoriasis treatments in the United States. They work for most patients. Such treatments:

Decrease inflammation
Block cell production
Relieve itching

Corticosteroids are available in a wide range of strengths, and are generally given as follows:

Less potent drugs are used for mild-to-moderate psoriasis.
Stronger drugs are reserved for more severe disease.

In the past, topical steroids have been used twice a day. Studies are reporting, however, that certain drugs may work just as well if taken once a day. Most studies have evaluated high-potency steroids, but one study suggested that those of medium strength, such as triamcinolone (Aureocort, Tri-Adcortyl), may be equally beneficial as a once-daily treatment. However, corticosteroids used alone clear psoriasis in only 4 - 36% of patients.

Combination therapy. Combinations with other drugs are often needed. For example, an effective, topical regimen uses the following combination for maintenance therapy:

A high-potency steroid (such as halobetasol) on the weekend
A vitamin D3 topical medication called calcipotriene, twice daily on weekdays

In one study, more than 75% of patients with mild-to-moderate psoriasis remained in remission for at least 6 months with this regimen.

Side Effects. The more powerful the corticosteroid, the more effective it is. But it also has a higher risk for severe side effects. Side effects may include:

Burning
Irritation
Dryness
Acne
Thinning of the skin; skin may become shiny, fragile, and easily cut
Dilated (widened) blood vessels
Loss of skin color

Loss of Effectiveness. In most cases, the patients become tolerant to the effects of the drugs, and the drugs no longer work as they should. Some experts recommend using intermittent therapy (also called weekend or pulse therapy). This type of treatment involves applying a high-potency topical medication for 3 full days each week.

Note: This list is not all inclusive.
Low potency (some are available over the counter)	Desonide (Tridesilon, DesOwen) Flumethasone pivalate (Locorten) Fluocinolone acetonide (Synalar, Derma-Smoothe) Hydrocortisone (Hytone, Penecort, Synacort, Cort-Dome, Nutracort, Westcort) Triamcinolone acetonide (Aristocort)
Low to medium potency	Alclometasone dipropionate (Aclovate) Hydrocortisone (Locoid, Pandel) Hydrocortisone valerate (Westcort) Prednicarbate (Dermatop)
Medium to upper-mid potency	Clocortolone pivalate (Cloderm) Fluticasone propionate (Cutivate) Mometasone furoate (Elocon) Triamcinolone acetonide (Aureocort, Tri-Adcortyl, Kenalog)
High potency	Betamethasone (Diprosone) Amcinonide (Cyclocort) Desoximetasone (Topicort) Diflorasone diacetate (Florone, Maxiflor) Fluocinonide (Lidex) Halcinonide (Halog)
Very high potency	Halobetasol propionate (Ultravate) Betamethasone (Diprolene, Luxiq) Clobetasol propionate (Temovate, Olux) Diflorasone diacetate (Florone, Maxiflor, Psorcon)

Coal tar preparations have been used to treat psoriasis for about 100 years, although their use has declined with the introduction of topical vitamin D3-related medicines. Crude coal tar stops the action of enzymes that contribute to psoriasis, and helps prevent new cell production. Tar is often used in combination with other drugs and with ultraviolet B (UVB) phototherapy.

Side Effects. Preparations have the following drawbacks:

Stains on clothing
Skin irritation
Sun sensitivity and increased risk of sunburn for up to 24 hours after use

Anthralin (Dritho-Scalp, Drithocreme, Micanol) is related to a medication called chrysarobin, in use since the early 1900s. Anthralin slows skin cell reproduction and can produce remissions that last for months. It is recommended only for chronic or inactive psoriasis, not for acute or inflamed eruptions. Persons with kidney problems should use anthralin with caution.

As with tar, its use has also declined with introduction of the topical vitamin D-related medicines, but newer formulations, such as Micanol, have made its use more tolerable. Micanol (Psoriatec) is an anthralin formulated in microcapsules, which dissolve and allow the drug to be delivered directly to the target skin areas. It is particularly useful for scalp psoriasis, and it is less likely to stain.

Side Effects. Anthralin may cause the following side effects:

Skin irritation and burning
Staining of clothes, hair, fabrics, plastics, and other household products

Patients should not use anthralin on their faces. Fair skinned people should generally avoid it. Triethanolamine (CuraStain) is a chemical that can neutralize anthralin and help reduce irritation from short-contact anthralin treatment. It should be applied 1 or 2 minutes before washing off the anthralin. It is then reapplied after drying the skin.

Washing stained items with hypochlorite (Clorox) detergents can help remove stains. Many people use disposable gloves while applying the treatment to avoid staining hands.

Application. Apply anthralin only to the psoriasis plaques. Rub the cream in well, and wipe off any excess. Wash off only with lukewarm water, not soap. Using hot water will trigger the staining action. A technique called short-contact anthralin therapy (SCAT), also called minute therapy, is useful for local areas of psoriasis. In such cases, anthralin is applied for only 10 minutes to an hour.

A topical form of vitamin D3, calcipotriene (Dovonex) is proving to be both safe and effective. It is now available in a foam preparation, which makes compliance even easier. Several other topical vitamin D3 related drugs showing promise include maxacalcitol (Oxarol), tacalcitol, and calcitriol (Silkis).

Calcipotriene appears to:

Block skin cell reproduction
Enhance the maturity of keratinocytes (the impaired skin cells in psoriasis)
Acts as an anti-inflammatory

It works just as well as moderate topical corticosteroids, short-term anthralin, and coal tar in improving mild-to-moderate plaque psoriasis. Unlike steroids, patients do not develop thinning of the skin or tolerance to the drug.

Using the drug in combination with other topical and systemic treatments may improve effectiveness. Calcipotriene doesn't work as well as the highest potency corticosteroids, but products or regimens that combine both medications are proving to be more effective than either one alone. Taclonex, an ointment containing both calcipotriol and betamethasone, was approved by the U.S. Food and Drug Administration (FDA) in January 2006 for the treatment of adults with psoriasis. Studies show the combination works better than either drug alone.

Combining vitamin D ointments with systemic medicines, notably methotrexate, acitretin, or cyclosporine, increases effectiveness and allows lower doses or either medication, thereby reducing side effects.

Studies also report success in some patients who use vitamin D ointments in combination with phototherapy treatment.

Side Effects. Calcipotriene may cause the following side effects:

A possible lowering of vitamin D levels, which may affect bone growth in some children
A possible increase in blood calcium levels (seen in some people who apply calcipotriene to large areas)
Skin irritation in about 20% of patients, particularly on the face and in skin folds

Calcipotriene appears to cause greater skin irritation than potent corticosteroids. Diluting the drug with petrolatum or applying topical corticosteroids to sensitive areas may prevent this problem.

Retinoids are related to vitamin A. They are used for various skin disorders. Tazarotene (Tazorac) is the first topical retinoid found to be effective for mild-to-moderate psoriasis. It is available in cream or gel form.

Unlike steroids, patients do not develop thinning of the skin or tolerance to the drug. Only a very small amount is needed on each lesion. It can be used on the scalp and nails, but it is not recommended for the genital areas or around the eyes. The gel should be used on only 20% of the body at anytime; the cream on up to 35%. (Note: The palm of the hand is about 1% of the body surface.)

Combining topical retinoids with other psoriasis treatments, such as with topical steroids, works better than using the drug by itself.

Side Effects. Tazarotene may cause dryness and irritation of healthy skin. Applying zinc oxide and moisturizer around the treated area can protect the healthy skin.

At levels high enough to be effective for psoriasis, tazarotene can cause severe skin irritation on treated areas. This medicine, then, is usually used in combination with other treatments, therefore allowing a lower dose. Mixing the drug in equal amounts with petroleum jelly (Vaseline) initially and then gradually increasing the amount of tazarotene may help the skin areas become less sensitive. It should be noted that the skin can become very red while it is actually improving.

Vitamin A derivatives (drugs related to vitamin A) have been associated with birth defects and should not be used by women who are pregnant, who wish to conceive, or who are nursing.

Salicylic acid applied to the skin helps remove scaly plaque and enhance the actions of other medications. It should not be used to cover wide areas of the body, since it can cause nausea and ringing in the ears. Combinations with high potency steroids, such as mometasone furoate (Combisor), clobetasol propionate, and betamethasone, are proving to be very helpful. Only Combisor is available in the United States.

Watertight (occlusive) tapes or wrappings may help heal psoriasis. Occlusive tapes are particularly useful for psoriatic cuts on the palms and soles. In such cases, the tape should be applied across the cuts until they heal.

Occlusive tapes retain sweat, which helps restore moisture to the outer skin layer and prevent scaling. They also protect against abrasion and irritation.

High-Potency Corticosteroid Tapes. Applying a corticosteroid beneath an occlusive tape, or using a tape that already has a potent corticosteroid (Cordran Tape) such as flurandrenolide may be especially beneficial. Studies are showing that high-potency corticosteroid-containing tapes are more effective than using high-potency corticosteroid ointments alone.

However, the tapes are expensive and are associated with a high rate of skin irritation, increased secondary infections, and a greater chance of symptoms relapse after treatment is stopped. Infection risk may be reduced by changing tapes every 12 hours.

The use of corticosteroids under occlusive tapes on large areas of psoriasis also increases the risk for adrenal insufficiency, a sometimes dangerous condition that occurs because the body loses its ability to produce natural steroids. Children are especially vulnerable to this effect.

Other Medications with Occlusive Tapes or Wrappings. The tapes may be used in combination with other medications, such as fluorouracil. Occlusive wrappings are not usually used with tazarotene (Tazorac) and should never be used without a doctor's recommendation.

Numerous topical medications are under investigation. One such medication, tacrolimus (Protopic), is an immunosuppressant that is proving to be useful in allergic skin disorders and is being studied for psoriasis. Studies have been mixed on its benefits, although new delivery methods may make it more effective. It may prove to be safe for sensitive areas, such as the face. Pimecrolimus (Elidel), a similar medication, is also being studied.

Systemic Medications

Systemic treatment uses various medications that affect the whole body, not just the skin. Many systemic drugs used for psoriasis are also used for other severe diseases, including autoimmune diseases (especially rheumatoid arthritis) and cancer.

Systemic treatments for psoriasis may be taken by mouth or injection. The medicines can have significant side effects and are generally reserved for severe psoriasis.

At this time, the only systemic medications specifically approved for psoriasis are:

Cyclosporine
Methotrexate
Retinoids

As with all medications for psoriasis, the patient should use the lowest strength medication first. The primary treatment is called a first-line treatment, the next is known as a second-line treatment, and so on. Combinations of medications are often used.

Methotrexate (Rheumatrex) is a biologic drug that interferes with cell reproduction and has anti-inflammatory properties. It is a first line, or primary, systemic drug used to treat adults with severe psoriasis. The medicine is one of the few systemic drugs proven to help patients with psoriatic arthritis.

The drug is taken weekly, not daily. (Deadly reactions have been reported in people who mistakenly took it once a day.)

Side Effects. Common side effects of methotrexate include:

Anemia
Headache
Mild hair loss
Mouth sores
Nausea
Possible muscle aches
Rash
Vomiting

Many of these side effects are due to folic acid deficiency. Patients should ask their doctor if folic acid supplements (generally recommended at 1 - 5 mg daily) are necessary.

More serious side effects include:

Increased risk for infections, particularly shingles and pneumonia. Methotrexate suppresses the immune system. Patients with active infections should avoid this drug.
Infertility, miscarriage, and birth defects. If used during pregnancy, the drug can cause miscarriages or birth defects in the baby. It may harm fertility in men.
Kidney complications.
Liver damage. In one study, 25% of patients taking methotrexate for 5 years developed scarring of the liver. Those with existing liver problems should not take this medicine, if possible. Regular monitoring for liver toxicity, including blood tests and liver biopsies, is important in patients who take the drug.
Lung disease. This side effect can be sudden and severe, and occurs in up to 5% of people who take methotrexate. Risk factors include diabetes, existing lung inflammation, protein in urine, and use of rheumatoid arthritis drugs called DMARDs.
Lymphomas. A few cases have been reported, which are most likely related to the drug's immune-suppressing (lowering) effects. In most instances, the disease has gone into remission when the drug was stopped. Most studies have found no significant risk for cancers in patients taking methotrexate.
Osteoporosis. Low doses of methotrexate do not appear to have any significant effect on bone loss, but long-term studies are needed to confirm this.
Radiation recall: An uncommon side effect in patients who have previously been burned by radiation cancer treatments or sunburns. In such cases, a flare-up of symptoms occurs in the previously affected skin areas.
Severe anemia. Folic acid supplements can offset this effect.
Toxic effects on bone marrow. This can cause reduced blood cell production.

Despite its side effects, some experts view methotrexate as the best therapy for widespread plaque psoriasis. It may also be effective for some patients with other severe forms of the disease, including psoriatic arthritis, generalized erythrodermic, and pustular psoriasis.

Methotrexate appears to be effective in children, but more safety research is needed.

Drug Interactions. Many drugs interact with methotrexate, occasionally with harmful results. For example, the antibiotic trimethoprim-sulfamethoxazole increases the toxicity of methotrexate.

A serious, harmful reaction can occur if methotrexate is taken with common, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, or naproxen. Other NSAIDs, namely ketoprofen, flurbiprofen, and piroxicam, appear to be safe when given with methotrexate and may be used in patients with psoriatic arthritis. Rheumatoid arthritis (RA) patients who take methotrexate often take NSAIDs as well, but methotrexate doses in psoriasis patients are usually much higher than those in RA.

People Who Should Avoid Methotrexate. Pregnant and nursing mothers should never take methotrexate because it increases the risk for severe, even fatal, birth defects and miscarriage. The drug should be discontinued several months before planning a pregnancy. It may also cause temporary impairment of fertility in men.

Persons with the following conditions should also avoid taking methotrexate:

Alcoholism
Anemia or other blood abnormalities
Immunosuppression
Kidney problems
Liver problems (including hepatitis)
Rheumatoid arthritis
Peptic ulcers

Patients at risk for liver complications include those with diabetes and obesity. Anyone with a history of hepatitis should have a liver biopsy before taking methotrexate.

Oral retinoids are vitamin A-related medications taken by mouth. This group of medicines is also a first-line treatment for adults with severe psoriasis. Oral retinoids used for psoriasis include acitretin (Soriatane) and isotretinoin (Accutane).

Acitretin is the retinoid of choice and may be dramatically effective for severe psoriasis, particularly pustular or erythrodermic variants. When used alone, it is much less effective against more common forms, such as plaque or guttate psoriasis. However, combinations with PUVA phototherapy can markedly improve the response even in these patients.

Accutane, more commonly used to treat acne, is far less potent than acitretin, but may still be effective against pustular psoriasis and also be effective with phototherapy.

Oral retinoids help control cell reproduction and have anti-inflammatory properties. They may even improve arthritis that accompanies psoriasis.

Combination therapy. Acitretin may work the best when combined with other treatments, usually topical drugs and especially phototherapy. Combination therapy allows lower doses of oral retinoids to be used, which diminishes many skin and mucous membrane side effects. Acitretin combined with phototherapy has some of the highest clearance rates of any treatment.

Side Effects. All retinoids have the same potentially serious toxicities as do high doses of vitamin A. Side effects include:

Bone and joint pain
Bruising
Depression and possible suicide risk (with isotretinoin)
Eye problems, including blurred vision, cataracts, conjunctivitis, and a sudden deterioration in night vision
Fatigue
Headache
Increased bone growth, particularly in the ankles, pelvic area, and knees
Increased triglyceride levels
Liver damage
Nail problems
Skin and mucous membrane problems, including dry nose, nosebleeds, dry eyes, chapped lips, thinning hair, dry or "sticky" feeling skin, and peeling of the palms and soles

In rare cases, retinoids, particularly isotretinoin, may cause a condition called benign intracranial hypertension (pseudotumor cerebri), which occurs in the brain. Symptoms include headache, nausea, vomiting, and blurred vision. Patients experiencing these symptoms should call a doctor immediately and stop taking the drug.

Oral retinoids should not be taken during pregnancy.

Despite these side effects, oral retinoids remain among the safest systemic therapies for psoriasis. A low-fat diet, aerobic exercise, and fish oil supplements may help reduce the side effects. Certain cholesterol-lowering drugs, including gemfibrozil (Lopid) or certain statins, such as atorvastatin (Lipitor), may help control triglyceride levels.

Maintenance doses should be as low as possible and should be taken every second or third day.

Taking retinoids during pregnancy significantly increases the risk for severe birth defects in the unborn child. Pregnant or nursing women or those planning to become pregnant should not use these drugs. Women of childbearing age who take retinoids should have regular pregnancy tests.

Doctors recommend that acitretin should not be given to any woman who may become pregnant within 3 years of taking it. Drinking alcohol changes acitretin to a retinoid that is stored in fat cells for 3 years. It may have the potential for causing birth defects during that time. It's important to note that cooking products and over-the-counter preparations, such as cough syrup, may contain alcohol and be inadvertently consumed.
Women who are pregnant or plan to become pregnant should not use isotretinoin. As of December 31, 2005, everyone who takes, prescribes, or dispenses the drug must enroll in a national registry called iPLEDGE.

Cyclosporine (Neoral, Sandimmune, SangCya) blocks certain immune factors and may be effective for all forms of psoriasis. It is also a first line, or primary, systemic drug used to treat adults with severe psoriasis. Neoral is the preparation used most often for psoriasis and clears psoriasis in many patients within 8 - 12 weeks.

Side Effects. Cyclosporine has significant side effects if used for a long time, notably kidney problems and non-melanoma skin cancers. It should be reserved for patients who do not respond to phototherapy or less potent systemic medications (for example, methotrexate or acitretin).

Common and temporary side effects include:

Fatigue
Gingivitis
Gout
Hair growth
Headaches
Joint pain
Tremor

More serious complications may include:

Kidney damage
High blood pressure (Some doctors advise treating high blood pressure with calcium channel blockers, since other standard blood pressure drugs may worsen psoriasis. Calcium channel blockers also help prevent kidney problems.)
High cholesterol and lipid levels
High levels of calcium and low levels of magnesium
Increased risk for infections
Liver problems
Lymphomas
Skin cancers (Patients who have taken cyclosporine after PUVA therapy have a higher incidence of squamous cell skin cancer. According to a 2003 study, the risk is six times that of the general population. The risks are highest with long use and previous use of PUVA, methotrexate, or other immunosuppressants.)

To reduce complications of cyclosporine, the dosage is decreased after improvement occurs. Maintenance therapy is usually limited to a year, although some experts believe that a microemulsion form of Neoral (Neoral-Neo) may be safe for up to 2 years. Patients should be monitored regularly for high blood pressure and signs of kidney or liver problems and skin cancers.

Patients Who Should not Use Cyclosporine. Because the drug suppresses the immune system, people with active infections or cancer should avoid it. Patients with uncontrolled high blood pressure and impaired kidney function should also not use this medication. Cyclosporine therapy for children with psoriasis has not been well studied.

Drug and Food Interactions. Cyclosporine interacts with numerous drugs -- both prescription and over-the-counter preparations -- and also grapefruit and grapefruit juice.

Biological response modifiers, sometimes called "biologics," belong to a new class of drugs that are considered the most exciting development in psoriasis treatment. Biologics are genetically engineered drugs that interfere with specific components of the autoimmune response. Because of their precise targets, these drugs do not damage the entire immune system the way that general immunosuppressants do.

Biologics are considered second- or third-line treatments, and may be used alone or sometimes in combination with first-line systemic drugs.

There are different types of biologics used to treat psoriasis:

T cell blockers block immune cells linked to inflammation.
Tumor necrosis factor (TNF) blockers target the chemical messenger TNF-alpha, which is released during the inflammatory response.

Types of T-cell blockers:

Alefacept (Amevive). This drug is approved for the treatment of moderate-to-severe plaque psoriasis. Studies suggest that the drug produces 50 - 75% improvement in symptoms. Alefacept is given in a doctor's office or clinic. Patients receive weekly injections for 12 weeks. Patients need weekly blood tests to make sure T cell levels do not drop too low. Side effects are generally mild and include sore throat, dizziness, and cough. There have been a few reports of serious infection and cancer.
Efalizumab (Raptiva). This drug is approved for the treatment of moderate-to-severe plaque psoriasis. Many patients experience 50 - 75% improvement in symptoms within 4 - 6 weeks of starting the drug. Patients give themselves shots of this drug for 12 weeks. Some clinical trials suggest that a longer course of treatment (24 weeks) may also be safe and effective for patients with chronic plaque psoriasis. Some patients have flare-ups of psoriatic lesions after stopping efalizumab. Very serious, but rare, side effects include hemolytic anemia and antibiotic-resistant infections.

Types of TNF blockers:

Etanercept (Enbrel) is approved for the treatment of psoriatic arthritis and moderate-to-severe plaque psoriasis. The drug is given either alone or in combination with methotrexate. Side effects include infections and lymphoma, a type of cancer. Patients inject themselves under the skin, once or twice a week for 12 weeks. However, a 2007 study published in the Archives of Dermatology found that continuing etanercept after 12 weeks lowers the severity of disease without increasing infections or side effects. Study participants randomly received 50 milligrams of the drug or a placebo biweekly up to 84 weeks. Strongest improvements were noted at 48 weeks among those who received the drug.
Infliximab (Remicade) is approved for the treatment of psoriatic arthritis. Patients receive three intravenous infusions during the first 6 weeks of treatment. After the initial treatment period, patients receive an infusion every 8 weeks. Therapy takes 2 hours and is given in a doctor’s office or clinic. Patients with a history of infection or heart failure should not take this drug. Several studies have shown that symptoms improve significiantly by week 10 in the majority of patients with severe psoriasis who are treated with infliximab.
Adalimumab (Humira) is being tested in clinical trials for treatment of psoriasis and psoriatic arthritis. Results from a Phase III (late-stage) study show that the drug works better than methotrexate in the treatment of moderate-to-severe psoriasis.
Efalizumab (Raptiva) appears to effectively clear or nearly clear moderate-to-severe hand and foot psoriasis after 12 weeks. This type of psoriasis is often very difficult to control and treat.

Interleukins (IL) being investigated as sources or targets of therapy include IL-4, IL-2, IL-8, IL-11, and IL-12. For example, in a 2003 study, 75% of patients with severe psoriasis who were treated with interleukin-4 (rhuIL-4) experienced improvement rates of more than 68%.

A study of 180 patients with moderate-to-severe plaque psoriasis has shown that an investigational medicine called ABT-874 greatly reduced symptoms in most patients. ABT-874 targets proteins that are responsible for psoriasis-related inflammation.

Leflunomide. Leflunomide (Arava) is a disease-modifying antirheumatic drug (DMARD), which blocks autoimmune antibodies and is a powerful anti-inflammatory medication. It is proving to be active against psoriatic arthritis. Reports of adverse effects are comparable to those with methotrexate. Common problems include nausea, diarrhea, hair loss, and rash. Potentially serious side effects include infections and liver injury.

Sulfasalazine. Sulfasalazine (Azulfidine) is sometimes used for psoriasis. In one major analysis, sulfasalazine and methotrexate were the only medications proven to help patients with psoriatic arthritis. Many people, however, stop taking the drug because of common side effects that include headaches, gastrointestinal complaints, and rash. Benefits, if any, should be apparent in 4 - 6 weeks.

Immunosuppressants. Some immunosuppressants being studied for psoriasis include tacrolimus (Prograf), pimecrolium, and sirolimus. In one study, for example, tacrolimus showed an 83% reduction in symptoms in patients with psoriasis who used the drug. Studies have been limited, however. Side effects of these medications are similar to those of cyclosporine. Pimecrolimus may specifically target the skin and so have fewer side effects. (Some are also being studied as topical treatments.)

Phototherapy

Phototherapy means to treat with light.

When sunlight penetrates the top layers of the skin, this ultraviolet radiation bombards the DNA inside skin cells and injures it. This can cause wrinkles, aging skin, and skin cancers. However, these same damaging effects can destroy the skin cells that form psoriasis patches.

Phototherapy for psoriasis can be given as ultraviolet A (UVA) light in combination with medications, or as variations of ultraviolet B (UVB) light with or without medications. Not everyone is a candidate. For example, it may not be appropriate for patients who should avoid sunlight or those with very severe psoriasis.

Ultraviolet A (UVA) is a main part of sunlight. UVA phototherapy uses a photosensitizing medication (usually psoralen) in combination with UVA radiation to be effective. A photosensitizing medication makes a person more sensitive to light. Treatment with psoralen and UVA is referred to as PUVA. This approach is very powerful and effective in more than 85% of patients who use it. However, it poses a higher risk for skin cancers than UVB.

PUVA treatments cause inflammation and redness in the skin to develop within 2 - 3 days after treatment. Such damage inhibits skin cell proliferation and reduces psoriasis plaque formation.

Forms of psoralen include methoxsalen, 8-methoxypsoralen (8-MOP), or bergapten (5-MOP). The effectiveness of the treatment is based on a chemical reaction in the skin between the psoralen and light, which creates redness and inflammation that prevents the psoriasis disease process.

People should avoid this treatment if they are taking drugs or have conditions that cause them to be light sensitive. They should also take protective measures before, during, and after each treatment.

Initial PUVA Treatment Phase. The initial phase typically follows these steps:

Psoralen is typically taken by mouth in the form of 8-methoxypsoralen (for example, Oxsoralen) 75 minutes to 2 hours before the treatment starts. Psoralen reaches the skin through the bloodstream, where it increases the skin's sensitivity to UVA radiation.
Topical preparations of psoralen are alternatives to pills. They can be "painted on" or applied to the affected areas by soaking or bathing in a psoralen solution. PUVA-bath therapy may be especially useful for persistent psoriasis on the palms and soles or for patients with liver disease or who get severe nausea from taking the pill form. UVA should be given within 15 minutes of using topical psoralen.
The patient enters and stands in a light box, a unit lined with ultraviolet lamps. The initial UVA exposure time is very short (seconds to several minutes), and then increases to 20 minutes or longer. The amount of time a person is exposed to UVA rays depends on the skin type, with the shortest times recommended for fair-skinned patients.
Treatments may be repeated two or three times a week. They should never be performed more frequently than once every other day, since the full effects of the treatments are not evident for 48 hours.

It takes an average of about 25 PUVA treatments for full effect, but during that period, treatment intensity may vary.

If there is no response after 10 treatments, the doctor may increase the UVA energy.
If there is still no response after 15 treatments, the psoralen dosage may be increased.
If a patient's skin does not improve at all or worsens after these changes, the treatment is temporarily stopped. PUVA may be causing a toxic response in such cases, and, often, the condition gradually improves over the following 2 weeks.
If the skin does not improve over the following 2 weeks, PUVA treatment has failed. If skin improves during this resting period, treatment resumes.

Maintenance Phase. Once the psoriasis has improved by about 95%, the patient may be put on a maintenance schedule. Often only one or two treatments a month are needed, but some people may need more frequent treatments. As maintenance continues and the interval between treatments lengthens, the patients may become more susceptible to tanning and sunburn. They should reduce exposure to natural sunlight during this time.

Success Rates. Nearly 90% of patients achieve marked improvement or clearing within 20 - 30 treatment sessions.

Combinations. Combining acitretin, calcipotriene, methotrexate, or tazarotene gel with PUVA may enhance effectiveness or increase response. In addition, combinations may allow for lower doses of radiation or medications to be used, minimizing side effects. Retinoids may also help protect against skin cancers, while methotrexate may increase the risk. In some cases, patients resistant to PUVA or UVB may respond when the phototherapies are combined.

Side Effects and Complications of PUVA.

The psoralen methoxsalen causes a general ill-feeling and nausea in 20% of patients. Dividing up the dose and taking it in 15-minute intervals with food, or taking ginger 20 minutes before taking the drug, may be helpful.
Skin reactions, including itching, sunburn, and blistering, are common. These can generally be avoided with careful administration of PUVA therapy and protective measures. Antihistamines, baths with special oatmeal preparations (Aveeno), and capsaicin ointment (Zostrix) may be helpful.
After treatment, white spots commonly develop where psoriasis plaques had been, particularly in people with naturally darker skin. If they are troublesome, tanning products may help darken them. Small, dark raised spots called PUVA lentigines may also develop in affected areas with long-term treatment
Prolonged standing may trigger fainting in people with certain heart or blood pressure problems.
People with liver disease should discuss using topical psoralens, since oral forms may have adverse effects on the liver.
UVA penetrates the skin more deeply than UVB, so there is a greater danger of deep skin damage, accelerated skin aging, and skin cancers. Anyone who needs to avoid sunlight should not get this treatment.
The procedure increases the risk for cataracts if eyes are not protected for up to 24 hours after treatment.

Special Warning on PUVA and Skin Cancers. It has been known for some time that PUVA can change DNA and cause genetic mutations. PUVA is known to increase the risk for squamous cell skin cancer and slightly increase the risk for basal cell skin cancer, both of which are nearly always curable. One study reported an increased risk of melanoma. The risk for skin cancers is higher in persons who have:

A family or personal history of skin cancer
Light skin and fair or red hair
Received radiation or x-ray treatments or taken immunosuppressant drugs
Received over 200 PUVA treatments

Discussions are under way about discontinuing PUVA for psoriasis. The arguments generally are as follows:

Opponents of PUVA argue that studies suggest a long-term risk for melanoma, starting about 15 years after treatment, particularly in people who receive more than 250 treatments. In one long-term study, only 9 out of 1,380 patients developed melanoma. However, 7 of these cases occurred in the last 5 years of the study, indicating that the danger persists and more patients in this study are likely to develop this serious skin cancer as time goes on.
Supporters of PUVA argue that it is not yet known if the people who developed melanoma experienced sunburn during the procedures or if they already had risk factors for skin cancers. If so, then properly given treatments could still be considered safe for patients without risk factors. They also argue that PUVA is still the most effective treatment for severe psoriasis, and the alternatives are usually very powerful and relatively new drugs that may have even more serious side effects. Furthermore, the addition of retinoids may protect against skin cancers while proving to be a very effective combination.

Side effects of UVA radiation can be severe. Protective measures are needed during, before, and after treatment. Patients should avoid prolonged exposure to the sun for 24 hours before the oral treatment starts.

Protective Measures During Treatment:

Patients should wear specially designed goggles to protect the eyes from UVA radiation.
Sensitive areas, such as genitals, abdominal skin, and breasts, should be covered until tanning occurs in the exposed areas, after about a third of the treatment period. Note that PUVA is associated with a high risk for genital skin cancers, so male genitals must be covered throughout the process.

The following safety features should be available in the PUVA chamber:

Lamps with protective shields
A viewing window for a health professional to check the patient periodically
A door that can be opened by the patient easily and with little pressure
A timer that terminates the session automatically
An accessible alarm device

Protective Measures After Treatment. The drugs used in PUVA increase susceptibility for a natural sunburn for hours after treatment. The patient should take the following precautions:

Patients should wear UVA absorbing wrap-around sunglasses that are designed to completely block out stray radiation. They should begin wearing them as soon as they take the drug, and for at least 12 hours after the treatment. This is important to prevent a PUVA reaction around the eyes that can cause cataracts. There is no need to wear these glasses after sundown.
For about 8 hours after taking the drug, patients must also avoid exposure to daylight, even if the day is cloudy or exposure occurs through windows.
Patients who must go out should wear heavy opaque clothing (clothes that do not let light through), including hats and gloves.
Patients should apply sunblock over all exposed areas, including the lips. The sunblock should have an SPF (sun protection factor) of more than 15 and include ingredients that block both UVB and UVA radiation.
No patient should spend a long time in sunlight for at least 2 days after the combined treatment.

Ultraviolet B is another main part of sunlight, and is the main cause of sunburn. It generally affects the outer skin layers. UVB radiation reduces the abnormally rapid skin cell growth that occurs with psoriasis.

Types of UVB therapy:

Broadband UVB
Narrowband UVB (NB-UVB)
Laser treatments

Broad spectrum or broad band UVB is radiation in the wavelength of 290 - 350 nanometers, and is the standard UVB phototherapy treatment in the United States. It is not as potent as the treatments that use narrow-band UVB or PUVA, and is not useful for chronic psoriasis.

Broadband UVB may be given with or without medications. When used without medication (known as selective ultraviolet phototherapy), UVB treatment generally is given as follows:

Treatment starts in the doctor's office or another medical setting. Once the disease has stabilized, the patient can obtain a prescription for equipment that can be used at home. Even at home, treatment must always be supervised.
In preparation, the patient fully undresses, although unaffected areas may be covered to avoid overexposure.
The initial session may last as little as a few seconds, depending on whether the patient has a lighter or darker skin, with the lightest skin exposed to the briefest session. The duration increases with each treatment until the skin clears or the patient experiences itching or irritation. It should be noted that the condition may worsen initially.
UVB therapy usually requires about 20 - 40 treatments (about three per week). Full results take about 3 weeks.

Use of Medication. UVB was commonly used with coal tar (the Goeckerman regimen) in past decades, and then with anthralin (the Ingram regimen). Other medications are being studied with some success, and may prove to be tolerated better.

The Goeckerman regimen requires daily treatments for up to 4 weeks. The coal tar or anthralin are applied once or twice each day and then washed off before the procedure. Studies indicate that a low-dose (1%) coal tar preparation is as effective as high dose (6%). Such regimens are unpleasant, but still useful for some patients with severe psoriasis, since they can achieve long-term remission (up to 6 - 12 months).

Some evidence suggests that using a simple emollient (such as Vaseline or mineral oil) that enhances UVB light penetration can be effective. This addition to the treatment increases the risk for sunburns, however, and patients must be careful to avoid sun exposure. Researchers are tring combinations of other topical and oral medications. For example, combining UVB with methotrexate, or retinoids such as a tazarotene gel or oral acitretin, is producing positive results. Combinations with any of these drugs, however, must be supervised carefully to avoid serious reactions.

Side Effects of UVB. The treatment can cause itching and redness. UVB radiation from sunlight is known to increase the risk for skin cancers. There is no strong evidence, however, that UVB treatments pose any risk for skin cancers except on male genitalia. This risk, however, can be significant (4.5%) at high doses.

Narrow band radiation may be safer than other approaches, and some experts now believe it should be the first option for patients with chronic plaque psoriasis.

NB-UVB is used without medications and is very strong. Whether it has any affect, however, on the disease process itself is unclear. The light wavelength is between 310 - 312 nanometers, which, theoretically, is the most beneficial part of sunlight.

Exposure times are shorter but of higher intensity than with broadband UVB. This therapy is probably less likely than PUVA to cause skin cancers.

Clearance of 75% typically occurs after 10 - 12 treatments. NB-UVB treatments performed three times a week achieve results that are equal to twice-weekly PUVA treatments. Weekly NB-UVB treatments are not effective. Studies so far are mixed on whether NB-UVB remission rates are equal to those of PUVA.

Patients prefer NB-UVB over other PUVA treatments because they do not have to wear protective eyewear, take medications, or experience unpleasant side effects, notably nausea. It is also safe for pregnant women and children.

Combinations with topical medications, such as tazarotene or psoralens, may help NB-UVB therapy work better.

Laser UVB Treatment. A recent variation of a device called an excimer laser (Xtrac) delivers a precise UVB wavelength of 308 nanometers. The laser is more effective than narrow-band UVB for localized psoriasis, since it allows very specific areas of skin to be targeted. (Note: The therapy is not suitable for the scalp.) Generally, 8 - 10 treatments given twice a week will clear psoriasis. Remission rates are similar to NB-UVB, but the excimer laser can clear the psoriasis faster and at lower doses. It also spares the healthy skin around it. Blistering is a common side effect. More comparison studies are needed to determine risk and benefits compared to NB-UVB, particularly any long-term risk for skin cancer.

Pulsed-Dye Lasers. Pulsed-dye lasers give off high-intensity yellow light, which destroys the tiny blood vessels that make up psoriatic plaques. This treatment has been used for years to remove birthmarks, such as port wine stains and unsightly blood vessels on the skin. Some studies have reported significant (but not complete) improvement, and remissions that have lasted up to 13 months. Treatment sessions last up to 30 minutes and can feel uncomfortable (similar to being repeatedly snapped with a rubber band). It typically takes up to six sessions to clear the target areas. Bruising is common, and there is a small risk for scarring.

Home tanning devices and tanning salons are not usually recommended, but they may be helpful for patients without access to a medical unit. In a 2003 study, many patients achieved a significant reduction in symptoms when taking acitretin and exposed to a UVB commercial tanning unit (specifically, a Wolff tanning bed).

However, UV outputs can vary widely among tanning beds and salons. Some units emit UVA radiation, which poses a higher risk for skin cancers. Adverse effects of tanning salons that use UVA or UVB radiation are the same as with any UV phototherapies, including a risk for skin cancer.

Managing Psoriasis

Although sunburn carries a risk for skin cancer and can make psoriasis worse, regular exposure to the sun helps clear psoriasis in people with mild-to-moderate conditions. People should cover non-affected areas with clothing or sunscreen and sun bath only until the skin starts to tan.

Vacations in sunny areas, such as Hawaii or the Caribbean, can offer relief. For those who can afford it, a prolonged stay of several weeks at the Dead Sea in Israel has proven to significantly improve or clear 88% of those with psoriasis who go there. The region offers a unique combination of intense but naturally filtered UVA radiation combined with minerals and salts from the sea.

Because of the association between negative emotions and psoriatic flare-ups, relaxation and anti-stress techniques may be helpful. A small 1999 study found that hypnosis aimed at reducing stress may relieve symptoms.

Another study found that some patients with psoriasis had a traumatic or stressful event coincide with the appearance of psoriasis. Talking to a psychiatrist about the issue resulted in significant symptom improvement in 62% of study patients who recalled such an event.

If skin becomes dry and itchy, the patient may try the following:

Soak in a warm bath for about 15 minutes.
Afterward, apply salicylic acid first, which removes scaly skin and may promote the penetration of both moisturizers and topical prescription medications.
Then, apply a thick moisturizer or emollient, such as Vaseline, Cetaphil cream, or Eucerin cream. Lotions are not good enough moisturizers.
Special gloves made of Gore-Tex (DermaPore) may be worn at night over a thick moisturizer cream. These gloves are protective but also allow moisture to escape.

Some experts suggest that many common moisturizers may actually increase water loss in psoriasis, but studies still have to confirm this. In the meantime, if moisturizers help relieve the condition, patients should use them.

Capsaicin (Zostrix) is an ointment prepared from the active ingredient in hot chili peppers. It is used to relieve arthritic pain and may help relieve psoriatic itching. Capsaicin should be handled using a glove and applied to affected areas three or four times daily. The patient will usually have a burning sensation when the drug is first applied, but this sensation lessens with use.

Folic Acid. Patients should be sure they get enough of the B vitamin folate (folic acid). Folate-rich foods include liver, asparagus, fruits, green leafy vegetables, dried beans and peas, orange juice, and yeast. Many types of bread and other commercial grain products now have added folic acid.

Omega-3 Fatty Acids. Omega-3 fatty acids, particularly those found in some fish oil, have anti-inflammatory properties that may benefit some patients with psoriasis and other autoimmune conditions.

Patients with persistent psoriasis may be tempted to try alternative or untested treatments, including herbs and other nontraditional therapies. Researchers at the Medical College of Georgia say green tea slowed the growth of skin cells in animal studies and may one day prove to be useful in treating psoriasis. More research is needed.

Several traditional remedies for psoriasis include various other herbal supplements, but to date no clinical studies have been reported on these substances. No one should use any unproven therapy without consulting a doctor to be sure such treatment is not harmful, and does not interfere with any standard medications they take.

Herbal remedies and dietary supplements are not regulated by the FDA. This means that manufacturers and distributors do not need FDA approval to sell their products. In addition, any substance that affects the body's chemistry can, like any drug, produce side effects that may be harmful. There have been many reported cases of serious and even deadly side effects from herbal products.

The following are special concerns for people taking natural remedies for psoriasis:

Zinc pyrithione is sometimes used, but its effectiveness is doubtful. A number of so-called natural psoriasis products (Skin-Cap, Blue Cap, Miralex) that contain this compound also contain prescription-strength corticosteroids. Such steroids have the same side effects as those in standard psoriasis agents. These products have been banned in the U.S. and Canada, but similar untested medications are available over the Internet.
Gotu Kola (Centella asiatica) is sometimes applied in a cream for psoriasis. The oral form of the herb has serious side effects, however, including increasing the risk for miscarriage in pregnant women.

Outlook

Psoriasis is lifelong and not curable. Although it is also marked by rapid cell growth, psoriasis is neither cancerous nor contagious.

In general, studies report the following features of its course:

The condition almost always relapses. In a few cases, large areas of plaque can persist for years.
Psoriasis nearly always goes into remission, however, often clearing on its own. In one study, 30% of patients reported untreated psoriasis going into remissions that lasted 1 - 54 years.
Psoriasis can improve during pregnancy, especially during the second and third months. Increased levels of estrogen may be responsible for this improvement. Relapse may occur after giving birth.

The emotional and social consequences of psoriasis should not be underestimated.

Many patients suffer severe humiliation and depression if plaques are visible. Some even withdraw from society and become isolated.
Some patients are forced to leave their jobs and go on disability if the condition becomes incapacitating.

Researchers have reported the following:

Surveys of patients with psoriasis report a negative mental and physical impact that is nearly equivalent to that of other major chronic conditions, including cancer, high blood pressure, diabetes, heart disease, and depression.
In one study, 75% of patients reported that psoriasis hurt their confidence.
Another study reported that 8% of people with psoriasis felt their life was not worth living.

Some patients, particularly men, use alcohol and smoking as self-medication to reduce the emotional consequences of psoriasis. In fact, studies have found that people with psoriasis have higher mortality rates, mostly from heavy drinking. Smoking has also been cited as a major risk, particularly for pustular psoriasis. Some experts believe that drinking and smoking may actually cause biological damage that contributes to psoriasis itself.

However, smoking may delay the onset of psoriatic arthritis in some patients, depending on when they started the habit. Psoriatic arthritis tends to occur about a decade after psoriasis develops. The review of 281 psoriasis patients showed that the condition appeared after about 13 years in nonsmokers, compared to 23 years in those who began smoking after the first onset of psoriasis. Psoriatic arthritis appeared after 8 years in people who smoked before developing psoriasis.

Folate Deficiency in Severe Psoriasis. Severe psoriasis can also cause folate deficiency. Folate is a B vitamin that is important for nerve function, preventing birth defects. It also prevents elevations of homocysteine, a factor that may play a critical role in heart disease.

Skin Cancers. In one study, patients with severe psoriasis (who receive medications that affect the whole body) were at higher than normal risk for developing cancers, primarily skin cancers and lymphomas. The risk was not any higher for patients with milder psoriasis. There is some indication, however, that patients with psoriasis have a higher risk for non-melanoma skin cancers regardless of treatments.

Heart Attacks. A study released in October 2006 shows an increased risk of heart attacks in people with psoriasis. The risk was highest in young patients with severe psoriasis.

Other Coexisting Conditions: Studies done in Newfoundland and Germany have also revealed increased cases of diabetes, obesity, arthritis, and cancer in patients with psoriasis. Research is underway to determine if there are genetic links between psoriasis and these conditions.

Increased Risk of Death. Severe psoriasis has been linked to a significant increase in a patient's risk of death. A study of more than 713,000 patients showed that severe psoriasis increased mortality by 50%. Study authors encourage patients to receive comprehensive health examinations to reduce the risk. Study participants were considered to have severe psoriasis if they required systemic treatment.

Impaired Temperature Regulation. Erythrodermic psoriasis, in which psoriasis covers the entire skin, can cause abnormalities in the body's ability to regulate temperature.

Zumbusch Psoriasis. A combination of erythrodermic and pustular psoriasis causes a serious condition called Zumbusch psoriasis:

The condition can develop abruptly.
Symptoms may include fever, chills, weight loss, and muscle weakness.
Patients may develop excessive fluid build-up, protein loss, and electrolyte imbalances. In such cases, hospitalization is required. Fluid and chemical balances must be restored and temperature stabilized as soon as possible.

Zumbusch psoriasis can be life threatening, particularly in the elderly. The condition is very rare in children and, if it occurs, tends to improve more quickly than in adults, possibly even without medication.

Most cases of psoriatic arthritis (PsA) are mild, but complications can occur:

Severe joint deformity and destruction (called arthritis mutilans) may develop, generally in the small joints of the hands and feet. Studies report this happens in about 5 - 16% of patients. Psoriasis patients with other arthritic conditions (osteoarthritis or rheumatoid arthritis) in the joints of the fingers tend to have a higher risk.
People with PsA may have a higher risk for respiratory illnesses.

Some earlier studies indicated that patients with psoriatic arthritis had a shorter lifespan than the general population, but more recent studies found no significant difference.

Resources

www.psoriasis.org -- National Psoriasis Foundation
www.aad.org -- American Academy of Dermatology
www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.clinicaltrials.gov -- Find clinical trials

References

Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006 Oct 11;296(14):1735-41.

U.S. Food and Drug Administration. CDER Drug and Biologic Approvals for Calendar Year 2006 -- Updated through August 31, 2006. Last accessed on 15 October, 2006.

FDA Announces Strengthened Risk Management Program to Enhance Safe Use of Isotretinoin (Accutane) for Treating Severe Acne. US Food and Drug Administration. Rockville, MD: National Press Office; August 12, 2005.

Anstey AV and Kragballe K. Retrospective assessment of PASI 50 and PASI 75 attainment with a calcipotriol/betamethasone dipropionate ointment. Int J Dermatol. 2006 Aug;45(:970-5.

National Psoriasis Foundation. About Psoriasis: Statistics. Last Accessed 9 October, 2006.

Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 2005;52(4):1227-1236.

Bowcock AM, Cookson WO. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Human Mol Genet. 2004;13 Spec No 1:R43-55.

Feldman SR, Koo JY, Menter A, Bagel J. Decision points for the initiation of systemic treatment for psoriasis. J Am Acad Dermatol. 2005;53(1):101-107.

Murase JE, Chan KK, Garite TJ, Cooper DM, Weinstein GD. Hormonal effect on psoriasis in pregnancy and post partum. Arch Dermatol. 2005;141(5):601-6.

Review Date:
9/19/2007
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Systemic lupus erythematosus

FitSugar — Wed, 08 Oct 2008 17:35:17 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Symptoms
Complications
Diagnosis
Treatment
Treatment for Cutaneous and...
Treatment for Severe SLE...
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Systematic Lupus Erythematosus (SLE)

SLE is an autoimmune disease that causes a chronic inflammatory condition. The inflammation triggered by SLE affects many organs in the body, including skin, joints, kidneys, lung, and nervous system. Women, especially African-American and Asian women, are at highest risk for developing SLE.

Symptoms and Diagnosis

Not all patients with SLE experience the same symptoms. The most common symptoms are joint pain, skin rash, and fever. Symptoms can develop slowly or appear suddenly. Many patients with SLE have “flares,” in which symptoms suddenly worsen and then disappear for long periods of time. Diagnosing SLE is complicated because symptoms vary widely and can resemble other conditions. A doctor will base an SLE diagnosis on certain specific criteria including symptom history and the results of blood tests for antinuclear antibodies.

Treatment

No drug can cure SLE, but many different drugs can help control symptoms and relieve discomfort. The choice of drugs depends on the severity of the condition as well as other factors. Patients with mild SLE may be helped by nonsteroidal anti-inflammatory drugs (NSAIDs) while patients with more severe SLE may require corticosteroids or immunosuppressants. Researchers are working to develop new drugs and treatments for SLE.

Living with SLE

Patients can make lifestyle changes to help cope with SLE. These include:

Avoid excessive sunlight exposure, and wear sunscreen (ultraviolet light is the one of the main triggers of flares).
Get plenty of rest (fatigue is another common SLE symptom).
Engage in regular light-to-moderate exercise to help fight fatigue and heart disease, and to keep joints flexible.

Introduction

Systemic lupus erythematosus (SLE) is a chronic, often life-long, autoimmune disease. It can be mild to severe, and affects mostly women. SLE may affect various parts of the body, but it most often manifests in the skin, joints, blood, and kidneys. SLE was first described in 1828. Its very name helps define the disease:

Systemic is used because the disease can affect organs and tissue throughout the body.
Lupus is Latin for wolf. It refers to the rash that extends across the bridge of the nose and upper cheekbones and was thought to resemble a wolf bite.
Erythematosus is from the Greek word for red and refers to the color of the rash.

Lupus has many different symptoms. Common ones include:

Fatigue
Joint pain or swelling
Skin rashes

Causes

Systemic lupus erythematosus is a complex disorder that occurs as a consequence of a number of independent processes and factors.

Environmental factors, such as viruses, exposure to chemicals, or sunlight trigger inflammatory or immune activity. This immune activation may begin as an appropriate response to an unwanted "invader." But, because of a combination of genetic factors, an individual with lupus develops an ongoing immune response that does not shut itself off appropriately. This leads to waxing and waning flares of inflammation that can involve various organs of the body, depending on specific features of this self-perpetuating immune response in individual patients.

The exact combination of genes that predispose individuals to SLE may differ somewhat from patient to patient, but probably share certain common features which tend to impair the ability of the body to get rid of immune-triggering particles and which tend to prolong or increase the degree of immune responsiveness to these triggers.

A major characteristic of lupus is that it is an autoimmune response in which immune factors, called autoantibodies, attack the person's own cells. Some autoantibodies are normal in a well-balanced immune system, and serve various roles to help the body dispose of wastes, protect from infectious invaders, and to keep blood vessels clear. In healthy people, autoantibodies tend to be well-regulated and well "masked," or covered up, until needed. Therefore, it is probably the high activity and high detectability of autoantibodies that makes lupus unique, not the fact that they exist.

The Normal Immune System Response. The inflammatory process is a byproduct of the activity of the body's immune system, which fights infection and heals wounds and injuries:

When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as a virus.
The masses of blood cells that gather at the injured or infected site produce factors to fight any infections.
In the process, the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called upon to repair wounds by clotting any bleeding blood vessels and initiating fiber-like patches to the tissue.
Under normal conditions, the immune system has special factors that control and limit this inflammatory process.

The Infection Fighters. B cells and T cells are two important components of the immune system that play a role in the inflammation associated with lupus. Both B cells and T cells belong to a family of immune cells called lymphocytes. Lymphocytes help fight infection.

B cells and T cells are involved in the immune system's response to infection. Antigens are foreign bodies (such as bacteria and viruses) that stimulate the immune system to produce autoantibodies. When a T cell recognizes an antigen it will produce chemicals (cytokines) that cause B cells to multiply and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign particles and triggering inflammation in order to rid the body of the invasion.

An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

For reasons that are still not completely understood, both the T cells and B cells become overactive in lupus patients. In lupus, a complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal range of what the antibodies recognize. Eventually, antibodies are made that recognize more of the body's own tissues in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.

Autoantibodies. In the majority of patients with SLE, antinuclear antibodies (ANA) are detectable. Such autoantibodies may be present in individuals up to 7 years prior to their developing symptoms of lupus. Some subtypes of ANA are found in lupus patients and only rarely in people without lupus. These include:

Anti-ds DNA. An autoantibody called anti-double stranded DNA (anti-ds DNA) may play an important role in some lupus patients.
Anti-Sm antibodies. This antibody is found most often in lupus patients of African descent and is almost never detected in people without lupus.
Anti-Ro (SSA) and Anti-La (SSB)
Antiphospholipid antibodies

Cytokines. Most immune cells secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for maintaining the balance of the body during immune responses, including:

Infections
Injuries
Tissue repair
Blood clotting
Clearing of debris from inflamed blood vessels
Other aspects of healing.

If overproduced, however, they can cause serious damage, including dangerous levels of inflammation and cellular injury. Specific cytokines called interferons and interleukins play a critical role in SLE by regulating the secretion of autoantibodies by B cells.

Complement. Another immune factor of high interest in SLE is the complement system. This is comprised of more than 30 proteins and is important for defending and regulating the immune response. Inherited deficiencies in certain complement components (C1q, C1r, C1s, C4, and C2) have long been associated with SLE.

Researchers estimated that 20 - 100 different genetic factors may be involved in the alterations of the immune system set point that could make a person susceptible to SLE.

Research published in 2003 identified a particular set of genes, now commonly called the "interferon signature," that is activated by interferon in patients with severe lupus. This discovery may help doctors identify patients at particular risk for severe disease before they develop symptoms.
A genetic risk factor for lupus in African-American women has been identified.
Other research has identified defects in genes that regulate apoptosis, the natural process by which cells self-destruct.
An abnormal gene identified in some patients with SLE promotes the build-up of immune complexes that can cause kidney damage. HLA (human leukocyte antigen) is a protein that presents antigens to T cells by holding them up from the surface of macrophages or other antigen-presenting cells. Among the types of HLA associated with lupus are HLA-DR2, -DR3, -A1, -B8, and DMA-0104.

In genetically susceptible people, there are various external factors that can provoke an immune response. Possible SLE triggers include colds, fatigue, stress, chemicals, sunlight, and certain drugs.

Viruses. Blood tests reveal that patients with SLE are more likely to have been exposed to certain viruses than the general population. These viruses include the Epstein-Barr virus (the cause of mononucleosis), cytomegalovirus, and parvovirus-B1.

Results from a 2005 study, conducted by researchers at the National Institute of Environmental Health Sciences, suggested a strong association between Epstein-Barr virus (EBV) and increased risk of lupus, particularly for African-Americans. The association was not as strong for whites, but increased with age (patients over 50 years of age had four times higher risk).

The researchers also observed that a genetic variation in CTLA-4, a protein that helps regulate T cell immune system response, appeared to modify the risk of lupus associated with EBV-IgA antibodies. Therefore, an individual’s CTLA-4 genotype could determine the immune system’s responsiveness in fighting repeat episodes of EBV infection.

Click the icon to see an image of mononucleosis.

Some research suggests that different viruses may imprint specific types of SLE. For instance cytomegalovirus may affect blood vessels and cause problems such as Raynaud's phenomenon or blood abnormalities, but may not affect the kidney as much. These are speculations, however, and not a proven association.

Sunlight. Ultraviolet (UV) rays found in sunlight are important SLE triggers. When they bombard the skin, they can alter the structure of DNA in cells below the surface. The immune system may perceive these altered skin cells as foreign and trigger an autoimmune response against them. UV light is categorized as UVB or UVA depending on the length of the wave.

UVB are short waves (280 - 320 nm). The shorter the wavelengths, the more damage they do.
UVA are longer waves (320 - 400 nm). Some research suggests that UVA wavelengths in the longest range, known as UVA1 (340 - 400 nm), may actually repair DNA and normalize immune responses.

Chemicals. Clusters of SLE cases have occurred in populations with high exposure to certain chemicals. Chlorinated pesticides and crystalline silica are two suspects. A number of other chemicals are under investigation. However, it is very difficult to determine a causal role for any specific chemicals. (Silicone breast implants have been under intense scrutiny as a possible trigger of autoimmune diseases, including SLE. The weight of evidence to date, however, finds no support for this concern.) Some drugs have been associated with a temporary lupus syndrome (drug-induced lupus), which resolves when these drugs are stopped.

Hormones. Cytokines, major immune factors that are active in SLE, are directly affected by sex hormones. In general, estrogen enhances antibody production, and testosterone reduces antibody production, although their exact role in SLE may be more complicated than that since there are various ways in which each hormone might influence various immune cells. Women with SLE may have lower levels of several active male hormones (androgens), and some men who are affected by SLE may also have abnormal androgen levels.

Premature menopause, and its accompanying symptoms (such as hot flashes), is common in women with SLE. Hormone replacement therapy (HRT), which is used to relieve these symptoms, increases the risk for blood clots and heart problems. It is not clear whether HRT triggers SLE flares. Women should discuss with their doctors whether HRT is an appropriate and safe choice. Guidelines recommend that women who take HRT use the lowest possible dose for the shortest possible time. Women with SLE who have active disease, antiphospholipid antibodies, or a history of blood clots or heart disease should not use HRT.

Oral Contraceptives. Female patients with lupus used to be cautioned against taking oral contraceptives (OCs) due to the possibility that estrogen could trigger lupus flare-ups. However, recent evidence indicates that OCs are safe, at least for women with inactive or stable lupus. Women who have been newly diagnosed with lupus should avoid OCs. Lupus can cause complications in its early stages. For this reason, women should wait until the disease reaches a stable state before taking OCs. In addition, women who have a history of, or who are at high risk for, blood clots (particularly women with antiphospholipid syndrome) should not use OCs. The estrogen in OCs increases the risk for blood clots.

Risk Factors

The number of people diagnosed with lupus has more than tripled over the past four decades. Some experts believe this may simply indicate a greater degree of doctor training in recognizing the syndrome.

About 90% of lupus patients are women, most diagnosed when they are in their childbearing ages. Hormones may be an explanation. After menopause, women are only 2.5 times as likely as men to contract SLE. Flares also become somewhat less common after menopause in women who have chronic SLE.

African-Americans are three to four times more likely to develop the disease than Caucasians and to have severe complications. Hispanics and Asians are also more susceptible to the disease.

A family history plays a strong role in SLE. A brother or sister of a patient with the disorder has 20 times the risk as someone without an immediate family member with SLE.

The disease is rare in childhood. When it does occur, it is often associated with thrombotic thrombocytopenia purpura, a condition resulting from abnormally low levels of blood platelets. SLE in children may also be caused by certain medications, including minocycline and zafirlukast.

Rheumatoid Arthritis. Studies have investigated the relationship among hormones, SLE, and rheumatoid arthritis, another autoimmune disease. Higher levels of estrogen are associated with SLE, while lower levels are associated with rheumatoid arthritis. Some research suggests that some patients, in fact, progress from one disease to the other, and that such transitions occur during major hormonal shifts, such as the onset of menopause or pregnancy.

Rheumatoid arthritis is a systemic autoimmune disease that initially attacks the lining, or synovium, of the joints.

Many prescription drugs can cause lupus-like skin symptoms. In one study, the most common drugs causing these symptoms were high blood pressure (hypertension) medications, including hydrochlorothiazide, angiotensin-converting-enzyme inhibitors, and calcium-channel blockers. About 40 different drugs have been linked to lupus onset. Anyone diagnosed with cutaneous lupus erythematosus should be sure to tell their doctors all the medications (including herbs and supplements) that they are taking.

Smoking. Smoking may be a risk factor for triggering SLE and can increase the risk for skin and kidney problems in women who have the disease.

Symptoms

SLE symptoms may develop slowly over months or years, or they may appear suddenly. Symptoms tend to be worse during winter months, perhaps because prolonged exposure to sunlight in the summer causes a gradual build-up of factors that trigger symptoms months later.

The most common symptom is joint pain, which occurs in about 90% of patients with SLE. Characteristics of this symptom vary widely:

It is often accompanied by swelling and redness.
It can last from hours to months.
It may be mild or severe.
It can occur in one joint, move from one to another, or flare erratically.
Pain often occurs in the morning and improves during the day, only to return later when the patient tires.
The joints most affected are fingers, wrists, elbows, knees, and ankles. (Joints in the spine and neck are not affected.)

Children may experience these symptoms as growing pains, and, in all patients, they may be the only symptoms for many years.

Fever occurs in 90% of patients with SLE and is usually caused by the inflammatory process of the disease, not by infection. It is low-grade except during an acute lupus crisis.

Three-quarters of patients with SLE have skin inflammation and skin lesions (ulcers, rashes, or other injured areas). About half of these lesions are photosensitive; that is, they are aggravated by ultraviolet (UV) radiation from sunlight, even from light coming through a window. (UV radiation may even trigger systemic flares in patients with SLE.)

A number of different skin conditions have been described in patients with SLE.

Discoid Lupus Erythematosus. About 20% of patients have discoid lesions. In such cases, the condition is often known as discoid lupus erythematosus (DLE). Patients with this condition may have the following skin abnormalities:

Discoid means coin-shaped, so these lesions are round and raised. They are also scaly. Untreated, the margins gradually extend outward as the center dries out and shrivels, causing severe scarring. If discoid lesions appear on the scalp, they can plug hair follicles and cause irreversible hair loss. Discoid lesions can also appear on the upper body.

Lupus, discoid -- view of lesions on the chest: This close-up picture of the neck clearly shows the typical rounded appearance of discoid lupus. The whitish appearance is caused by scaling. The two dark spots are biopsy sites and are not part of the disease.

A butterfly-shaped rash across the face may accompany this condition. This rash causes little scarring, although spidery, branching lines of swollen capillaries (the tiniest blood vessels) may appear.

Click the icon to see an image of systemic lupus erythematosus.

Most patients with this condition have only a limited skin disorder. In only about 10% of cases does discoid lupus develop into full-blown SLE.

Subacute Cutaneous Lupus Erythematosus. Subacute cutaneous lupus erythematosus (SCLE) can cause skin lesions on parts of the body that are exposed to sunlight. These lesions do not cause scarring.

Vasculitis. Patients with SLE sometimes develop inflammation in the blood vessels (vasculitis) that may have the following effects on the skin:

Red welts may form across large areas of the body.
Sometimes deep red bumps may appear, particularly on the leg, where they may ulcerate.
In some people, reddish-purple lesions appear on the pads of fingers and toes or near the nails of fingers and toes.
Lesions caused by vasculitis may ulcerate or blister if they erupt on mucous membranes in the mouth, nose, or vagina and can be painful if they occur on the throat.
Vasulitis can attack blood vessels in almost any other organ, including the brain, the heart, and the gastrointestinal tract.

Click the icon to see an image of vasculitis.

Other symptoms include:

Fatigue
Loss of appetite, nausea, and weight loss
Chest pain
Bruising
Menstrual irregularities
Thought and concentration disturbances
Personality changes
Sleep disorders, such as restless legs syndrome and sleep apnea
Dryness of the eyes and mouth
Brittle hair or hair loss

Hair loss or breakage may also occur in about half of patients with SLE during severe flares or after pregnancy or severe illness. In such cases, hair grows back.

Raynaud's phenomenon is a condition in which cold or stress can cause spasms in impaired blood vessels, resulting in pain in fingers and toes. It occurs as part of the inflammatory response in blood vessels, which can narrow them and reduce circulation. In extreme cases, gangrene can result.

Click the icon to see an image of Raynaud's phenomenon.

A number of conditions may resemble SLE:

Scleroderma: Hardening of the skin caused by overproduction of collagen
Multiple sclerosis: Fatigue, heaviness or clumsiness in the arms and legs
Rheumatoid arthritis: Inflammation of the lining of the joints
Sjögren syndrome: Characterized by dry eyes and dry mouth
Mixed connective tissue disorder: Similar to SLE, but milder
Myositis: Inflammation and degeneration of muscle tissues
Rosacea: Flushed face with pus-filled blisters
Seborrheic dermatitis: Sores on lips and nose
Lichen planus: Swollen rash that itches, typically on scalp, arms, legs, or in the mouth
Dermatomyositis: Bluish-red skin eruptions on face and upper body
Lyme disease: Bulls-eye rash, joint inflammation, and flu-like symptoms

Complications

Systemic lupus erythematosus (SLE) is one of the most serious rheumatic diseases. According to a 2002 government study, the annual number of deaths has risen from 879 - 1,406 since 1979. About a third of these deaths occur in people aged 15 - 44 years, mostly women. Such numbers may be underestimates, since SLE can affect so many organs that a cause of death in some people with SLE may not be directly attributed to the condition. A primary cause of death among patients with lupus is atherosclerosis, a disease of the coronary blood vessels resulting from accelerated buildup of plaque.

SLE is unpredictable and varies greatly form one individual to the next. Severity also appears to differ among ethnic groups and countries. In European and North American patients with SLE for example, overall 5-year survival rates are 93 - 95%, while in Asia or Africa they are considerable lower (60 - 70%). Other research indicates that African-American and Hispanic American patients suffer greater organ damage than Caucasian patients. Genetic factors appear to have some influence on specific effects of SLE on organ damage among ethnic groups. However, the poorer outlook among minority groups and in underdeveloped nations is probably due to less access to good health care.

Mild SLE. About 20 - 30% of cases are mild. For many of these patients, the only symptoms may be the skin rashes of discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) with or without joint aches. The number and intensity of symptoms in mild cases often decrease over time, as does the likelihood of major organ involvement. These skin conditions, however, are not absolute insurance against more severe disease, and patients with mild SLE should be tested for organ involvement.

Widespread SLE. Most commonly, SLE is a chronic, life-long disease, alternating between periods of symptom relapse, (called flares), and remission. The disease may begin in any of the various systems of the body and progress unpredictably to others. The following are typical patterns:

Symptom relapses, or flares, occur on the average of two or three times a year.
Between flares, most patients with SLE function at about 90% of normal capacity.

The degree of severity depends on different factors:

Severity of the inflammatory response
Frequency of episodes
The degree of organ or system involvement

Vital organs or systems, such as lungs, kidneys, nervous system, joints skin, and others are affected in 50 - 75% of patients with SLE. Infections followed by kidney failure are the chief causes of death in patients with SLE.

Because of more effective and aggressive treatment, the prognosis for SLE has improved markedly over the past two decades. Long-term progress of the disease is affected greatly by treatment in the initial acute phase of the disease, so a speedy and accurate diagnosis is all-important. The 10-year survival rate with treatment is now 85 - 95%, and many people have a normal life span. SLE that develops later in life is generally less serious than SLE that strikes in childhood.

Almost 85% of patients with SLE experience problems associated with abnormalities in the blood.

Anemia. About half of patients with SLE are anemic. Causes include:

Iron deficiencies resulting from excessive menstruation
Iron deficiencies from gastro-intestinal bleeding caused by some of the treatments
A specific anemia called hemolytic anemia, which destroys red blood cells
Anemia of chronic disease

Hemolytic anemia can occur with very high levels of the anticardiolipin antibody. It can be chronic or develop suddenly and be severely (acute).

Antiphospholipid Syndrome. Between 34 - 42% of patients with SLE have antiphospholipid syndrome (APS). This is a specific set of conditions related to the presence of autoantibodies called lupus anticoagulant and anticardiolipin. These autoantibodies react against fat molecules called phospholipids, and so are called antiphospholipids. Their actions have complex effects that include causing narrowing and abnormalities of blood vessels.

Patients who have APS have a very incidence of blood clots, which most often occur in the deep veins in the legs (32%). Blood clotting, in turn, puts patients at higher risk for stroke (13%) and pulmonary embolism (clots in the lungs) (9%).

This picture shows a red and swollen thigh and leg caused by a blood clot (thrombus) in the deep veins in the groin (iliofemoral veins). Such a clot prevents normal return of blood from the leg to the heart.

About 22% of patients have thrombocytopenia -- a reduction in blood platelets that can cause bleeding.
The effects on blood vessels have also been associated with confusion, headaches, and seizures. Leg ulcers can also develop.
Patients with APS who become pregnant have a high incidence of pregnancy loss, especially in the late term.

Not all patients with APS carry both of the autoantibodies, and they can also wax and wane and so have varying effects. APS also occurs without lupus in about half of patients with the syndrome.

Thrombocytopenia. In thrombocytopenia, antibodies attack blood platelets. In such cases, blood clotting is impaired, which causes bruising and bleeding from the skin, nose, gums, or intestines. (This condition can also occur in APS, but it is not considered to be one of the standard features of the syndrome.)

Neutropenia. Neutropenia is a drop in the number of white blood cells. Patients with SLE often neutropenia, but the condition is usually harmless unless the reductions are so severe that they leave the patient vulnerable to infections.

Acute Lupus Hemophagocyte Syndrome. A rare blood complication of SLE that occurs primarily in Asians is called acute lupus hemophagocytic syndrome. It is generally of short duration and characterized by fever and a sudden drop in blood cells and platelets.

Lymphomas. Patients with SLE and other autoimmune disorders have a greater risk for developing lymph system cancers such as Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL). A 2005 study reported that patients with SLE were over seven times more likely to develop NHL than healthy patients.

Heart disease is a primary cause of death in lupus patients. The immune response in SLE can cause inflammation and other damaging effects that can cause significant injury to the arteries and tissues associated with the circulation and the heart. In addition, SLE treatments (particularly corticosteroids) affect cholesterol, weight, and other factors that can also affect the heart. For decades, experts questioned the extent to which the drugs used to treat SLE contributed to the high rate of atherosclerosis in such patients. Numerous studies now suggest that something about the disease process itself, possibly the chronic inflammation of the blood vessels, probably lies at the root of this dangerous problem. In any event, patients with SLE, have a higher chance for the following conditions, which put them at risk for heart attack or stroke:

Atherosclerosis, or plaque buildup in the arteries
Increased stiffness in the arteries
Unhealthy cholesterol and lipid (fatty molecules) levels
High blood pressure, most likely because of kidney injury and corticosteroid treatments
Congestive heart failure
Pericarditis, an inflammation of the tissue surrounding the heart (occurs in about 30% of patients)
Myocarditis, an inflammation of the heart muscle itself (rare)

Click the icon to see an image of pericarditis.

Abnormalities in the valves of the heart (rare)
Blood clots

The risk for cardiovascular disease, heart attack, and stroke is much higher than average in younger women with SLE. The risks decline as such women age.

SLE affects the lungs in about 60% of patients:

Recurrent inflammation of the membrane lining the lung (pleurisy) is the most common problem.
In some cases, fluid accumulates, a condition called pleural effusion, and can cause stabbing localized pain that worsens when coughing, sneezing, laughing, or taking a deep breath.
Inflammation of the lung itself in SLE is called lupus pneumonitis. It can be caused by infections or by the SLE inflammatory process. Symptoms are the same in both cases: fever, chest pain, labored breathing, and coughing. Rarely, lupus pneumonitis becomes chronic and causes scarring in the lungs, which reduces their ability to deliver oxygen to the blood.
A very serious and also rare condition called pulmonary hypertension occurs when high pressure develops in the vessels supplying blood to the lungs.

Click the icon to see an image of primary pulmonary hypertension.

The kidneys are a crucial battleground in SLE because it is here that the debris left over from the immune attacks is most likely to be deposited. About 50% of patients with SLE exhibit inflammation of the kidneys (called lupus nephritis).This condition occurs in different forms and can vary widely in severity.

Click the icon to see an image of the kidney.

Proliferative nephritis is a serious variant of lupus nephritis. It occurs when the inflammatory process causes widespread damage and scarring in the blood vessels of the kidneys, which filters waste products, water, and salts out of the blood. The condition is associated with high blood pressure and kidney deterioration.
Membranous lupus nephritis is another variant that is often associated with a good outlook. In some cases, however, if the kidney is persistently exposed to high protein levels, the disorder can progress to fatal end-stage kidney (renal) disease.

Serious complications occur eventually in about 30% of patients. If kidney injury develops, it almost always occurs within 10 years of the onset of SLE, rarely after that.

Nearly all patients with SLE report some symptoms relating to problems that occur in the central nervous system (CNS), which includes the spinal cord and the brain. Most of these symptoms are minor and some, such as headache, may be related to depression rather than the disease itself. CNS involvement is more likely to occur in the first year, usually during flare-ups in other organs. Symptoms vary widely and may be indistinguishable from psychiatric or neurologic disorders or from the side effects of some medications used for SLE. Central nervous system symptoms are usually mild, but there is little effective treatment available for them. CNS symptoms get worse as the disease progresses.

The most serious CNS disorder is inflammation of the blood vessels in the brain, which occurs in 10% of patients with SLE. Fever, seizures, psychosis, and even coma can occur. Other CNS side effects include:

Irritability
Emotional disorders (anxiety, depression)
Mild impairment of concentration and memory
Migraine and tension headaches
Problems with the reflex systems, sensation, vision, hearing, and motor control

Infections are a common complication and a major cause of death in all stages of SLE. The immune system is indeed overactive in SLE, but it is also abnormal and reduces the ability to fight infections. Patients are not only prone to the ordinary streptococcal and staphylococcal infections, but they are also susceptible to fungal and parasitic infections (called opportunistic infections), which are common in people with weakened immune systems. They also face an increased risk for herpes, salmonella, and yeast infections. Corticosteroid and immunosuppressants, treatments used for SLE, also increase the risk for infections, thereby compounding the problem.

About 45% of patients with SLE suffer gastrointestinal problems, including nausea, weight loss, mild abdominal pain, and diarrhea. Severe inflammation of the intestinal tract occurs in less than 5% of patients and causes acute cramping, vomiting, diarrhea, and, rarely, intestinal perforation, which can be life-threatening. Fluid retention and swelling can cause intestinal obstruction, which is much less serious but causes the same type of severe pain. Inflammation of the pancreas can be caused by the disease and by corticosteroid therapy.

Arthritis caused by SLE almost never leads to destruction or deformity of joints. The inflammatory process can, however, damage muscles and cause weakness. Patients with SLE also commonly experience reductions in bone mass density (osteoporosis) and have a higher risk for fractures, whether or not they are taking corticosteroids (which can increase the risk for osteoporosis). Women who have SLE should have regular bone mineral density scans to monitor bone health.

Click the icon to see an image of osteoporosis.

Inflamed blood vessels in the eye can reduce blood supply to the retina, resulting in degeneration of nerve cells and a risk of hemorrhage in the retina. The most common symptoms are cotton-wool-like spots on the retina. In about 5% of patients sudden temporary blindness may occur.

In one study, 40% of patients with SLE quit work within 4 years of diagnosis, and many had to modify their work conditions. Significant factors that predicted job loss included high physical demands from the work itself, a more severe condition at the time of diagnosis, and lower educational levels. People with lower income jobs were at particular risk for leaving them.

Women with lupus who conceive face high-risk pregnancies. It is important for women to understand the potential complications and plan accordingly. The most important advice is to avoid becoming pregnant when lupus is active.

Research suggests that the following factors predict a successful pregnancy:

Disease state at time of conception. Experts strongly recommend that women wait to conceive until their disease state has been inactive for at least 6 months.
Kidney (renal) function. Women should make sure that their kidney function is evaluated prior to conception. Poor kidney function can worsen high blood pressure and cause excess protein in the urine. These complications increase the risk for preeclampsia and miscarriage.
Lupus-related antibodies. Antiphospholipid and anticardiolipin antibodies can increase the risks for preeclampsia, miscarriage, and stillbirths. Anti-SSA and anti-SSB antibodies can increase the risk for neonatal lupus erythematosus, a condition that can cause skin rash and liver and heart damage to the newborn baby. Levels of these antibodies should be tested at the start of pregnancy. Certain medications (aspirin, heparin) and tests (fetal heart monitoring) may be needed to ensure a safe pregnancy.
Medication use during pregnancy. Women with active disease may need to take low-dose corticosteroids, but women with inactive disease should avoid these drugs. Steroids appear to pose a low risk for birth defects, but can increase a pregnant woman’s risks for gestational diabetes, high blood pressure, infection, and osteoporosis. For patients who need immunosuppressive therapy, azathioprine (Imuran) is an option. Methotrexate (Rheumatrex) and cyclophosphamide (Cytoxan) should not be taken during pregnancy.

Pregnancy Risks

Women with lupus are 20 times more likely to die during pregnancy than women without the disease. The risk for maternal death is due to the following serious conditions that can develop during pregnancy:

Miscarriages. About 25% of lupus pregnancies result in miscarriage. The risk is highest for patients with antiphospholipid antibodies, active kidney disease, or high blood pressure.
Blood clots. Women with lupus have a 6 times greater risk for developing deep vein thrombosis (blood clots) than women without the disease.
Clotting complications. Low blood platelet count and anemia are also risks. Women with lupus are 3 times more likely to need a transfusion during pregnancy than women without lupus.
Infections. Blood infections (sepsis), pneumonia, and urinary tract infections are more common in pregnant women with lupus.
Preeclampsia. Women with lupus are three times more likely than healthy women to develop preeclampsia (pregnancy-related high blood pressure), which can be potentially life threatening.

Birth Complications

Pre-term birth. Women with lupus are 2.5 times more likely to have pre-term labor than women without lupus. Pre-term labor increases the risk for giving birth to low-weight babies.
Stillbirths. A 2005 study reported that the risk of still births was 10 times greater for women who had not yet been diagnosed with lupus, and 4 times greater for women with diagnosed lupus, compared with healthy women. This suggests that lupus may have a pre-disease state.
Caesarean section. Thirty-seven percent of women with lupus require a C-section compared with 22% of women without the disease.

Despite these obstacles, many women with lupus have healthy pregnancies and deliver healthy babies. To increase the odds of a successful pregnancy, it is important for women to plan carefully before becoming pregnant. Be sure to find knowledgeable doctors with whom you can communicate and trust. Experts recommend that pregnant women with lupus assemble an interdisciplinary health care team that includes a rheumatologist, high-risk obstetrician, and (for patients with kidney disease) a nephrologist.

Diagnosis

No single test can confirm or rule out SLE. A number of tests are required before SLE can be diagnosed definitively. The first symptoms of SLE can resemble one of many syndromes or disorders, including rheumatoid arthritis, Still's disease, rheumatic fever, Lyme disease, multiple sclerosis, thrombotic thrombocytopenia purpura, cryoglobulinemia, Weber-Christian disease, viral infections, vasculitis, psychosis, and other conditions. Other autoimmune disorders, such as Sjögren syndrome or scleroderma, may even be present at the same time as SLE.

1. Characteristic rash across the cheek

2. Discoid lesion rash

3. Photosensitivity

4. Oral ulcers

5. Arthritis

6. Inflammation of membranes in the lungs, the heart, or the abdomen

7. Evidence of kidney disease

8. Evidence of severe neurologic disease

9. Blood disorders, including low red and white blood cell and platelet counts

10. Immunologic abnormalities

11. Positive antinuclear antibody (ANA)

Note: A patient must experienced four of the criteria before a doctor can classify the condition as SLE. These criteria, proposed by the American College of Rheumatology, are not to be relied upon solely for diagnosis, however.

Methods for measuring the antibodies involved with SLE vary, and the range of results can be bewildering. Repeat tests may be needed.

Antinuclear Antibodies (ANAs). A primary test for SLE checks for antinuclear antibodies (ANA), which attack the cell nucleus.

High levels of ANA are found in more than 98% of patients with SLE. A number of other conditions, however, also cause high levels of ANA, so a positive test is not a definite diagnosis for SLE:

Antinuclear antibodies may be strongly present in other autoimmune diseases (such as scleroderma, Sjögren syndrome, or rheumatoid arthritis).
They also may be weakly present in about 20 - 40% of healthy women.
Some drugs can also produce positive antibody tests, including hydralazine, procainamide, isoniazid, and chlorpromazine.

A negative ANA test makes a diagnosis of SLE unlikely but not impossible. High or low concentrations of ANA also do not necessarily indicate the severity of the disease, since antibodies tend to come and go in patients with SLE.

In general, the ANA test is considered a screening test:

If SLE symptoms are present and the ANA test is positive, other tests for SLE will be administered.
If SLE symptoms are not present and the test is positive, the doctor will look for other causes, or the results will be ignored if the patient is feeling healthy.

ANA Subtypes. In some cases, doctors may test for specific ANA subtypes.

Anti-double stranded DNA (Anti-ds DNA) is usually found only in patients with SLE. It may play an important role in injury to blood vessels found in SLE, and high levels often indicate kidney involvement. Anti-ds DNA levels tend to fluctuate over time and may even disappear.
Anti-Sm antibodies are also usually found only with SLE. They are more constant and are more likely to be detected in African-American patients. Although the antibody is not usually seen in lupus patients, its confirmed presence almost always indicates SLE.
When the ANA is negative but the diagnosis is still strongly suspected, a test for anti-Ro (also called anti-SSA) and anti-La (also called anti-SSB) antibodies may identify patients with a rare condition called ANA negative, Ro lupus. These autoantibodies may be involved in the sun-sensitive rashes experienced by patients with SLE and are also found in association with neonatal lupus syndrome, in which a pregnant mother's antibodies cross the placenta and cause inflammation in the developing child's skin or heart.

Antibodies to SR Proteins. An advance in diagnosing SLE has been the detection of antibodies to molecules called SR proteins, which are carried by most patients. The test accurately detects lupus in 50 - 70% of patients who test positive for these antibodies.

Antiphospholipid Antibodies. In patients with SLE in whom blood abnormalities are suspected, tests may be able to detect the presence of the two major antiphospholipid antibodies:

A quarter to a half of patients with SLE may have these antibodies. They attack blood-clotting regulator proteins that stick to phospholipids, fatty compounds found in cell membranes throughout the body. Antiphospholipid antibodies increase the risks for blood clots and may be responsible for narrowing of (and irregularities in) blood vessels. Antiphospholipid antibodies are linked with miscarriages and other pregnancy complications, strokes, heart attacks and blood clots in almost any part of the body, including kidneys, legs, lungs, and eyes.
The test for the lupus anticoagulant antibody measures the time it takes blood to clot. A longer than normal blood clotting time indicates a higher chance for clotting in the body and, therefore, the presence of lupus anticoagulant.
An ELISA test (enzyme-linked immunosorbent assay) is performed to detect the anticardiolipin antibody.

As with the ANA, these antibodies also have a tendency to appear and disappear in a single patient. Patients who have these autoantibodies as well as blood clotting problems or frequent miscarriage are diagnosed with antiphospholipid syndrome (APS), which often occurs in SLE but can also develop independently.

Complement. Blood tests of patients with SLE often show low levels of serum complement, a protein in the blood that aids the body's infection fighters. Individual proteins are termed by the letter "C" followed by a number. Common complement tests measure C3, C4, C1q, and CH50. There is some evidence that complete deficiencies of C1q may be a key factor in the inability of the immune system to contain the autoimmunity process. Complement levels are especially low if there is kidney involvement or other disease activity.

LE Cell Tests. The first blood test ever used for SLE called LE (lupus erythematosus) cell test is positive in only about half of patients with SLE and is no longer used that often.

Blood Count. White and red blood cell and platelet counts are usually lower than normal and, depending on severity, are used to determine complications, such as anemia or infection.

Click the icon to see an image of the formed elements of blood.

If a skin rash is present, the doctor may take a biopsy (a tissue sample) from the margin of a skin lesion. A test known as a lupus band detects antibodies known as immunoglobulin G (IgG), which are located just below the outer layer of the tissue sample. They are present in about 80% of patients with active SLE and in 30 - 40% of those with inactive disease. The biopsy will not differentiate between systemic and discoid lupus, but it can rule out other diseases. Tests for other antibodies will rule out or confirm discoid lupus and subacute cutaneous lupus.

Kidney Damage and Lupus Nephritis. Kidney damage in patients already diagnosed with SLE may be detected from the following tests:

Blood tests that measure creatinine, a protein metabolized in muscles and excreted in the urine. High levels suggest kidney damage, although it can also be present with normal creative levels.
Tests for detecting anti-ds DNA antibodies and complement. High levels of anti-ds DNA and low levels of complement C3 suggest kidney damage. (It should be noted, however, that some patients with severe kidney damage show low levels of anti-ds DNA.) Testing for anti-C1q antibodies now appears to be an even more reliable indicator of lupus nephritis.
Urine analysis. Urine analyses should be performed at 4- to 6-month intervals to check for signs of kidney involvement.
A kidney biopsy. This may be performed to determine if lupus nephritis is present when less invasive tests indicate kidney involvement. It is not absolutely accurate but it helps determine treatment. Electron microscopy (very high-powered electronic microscopes) may be especially important in obtaining critical information on the degree of kidney damage.

Lung and Heart Involvement. A chest x-ray may be performed to check lung and heart function. An electrocardiogram and an echocardiogram are administered if heart disease is suspected.

Click the icon to see an image of an electrocardiogram.

Central Nervous System Complications. SLE occurring in the central nervous system (CNS) can be difficult to diagnose because its symptoms are easily confused with other psychiatric and neurologic conditions.

Tests of the cerebrospinal fluid (CSF) for elevated levels of autoantibodies are the most reliable ways to detect CNS complications caused by a faulty immune system.
Additional tests, including electroencephalograms (EEGs), magnetic resonance imaging (MRI), computed tomography (CT), or x-rays may be useful when blood vessel blockage in the brain is suspected.
If the doctor suspects that CNS symptoms are caused by infection, especially for patients who are receiving immunosuppressant therapy, a lumbar puncture should be performed.

Osteoporosis. To detect early osteoporosis in patients with SLE whose disease has lasted more than 3.5 years, experts recommend an imaging test called dual energy x-ray absorptiometry (DEXA) to measure bone mineral density.

Treatment

No treatment cures systemic lupus erythematosus, but many therapies can suppress symptoms and relieve discomfort. Treatment of SLE varies depending on the extent and severity of the disease.

Only three drugs are FDA-approved for the treatment of lupus:

Prednisone
Aspirin
Hydroxychloroquine

However, none of these drugs are the current standard of care. In everyday practice, numerous other drugs are commonly used. Researchers are conducting numerous clinical studies and drug investigations. Genetic research in lupus is progressing very rapidly, and hopefully new drugs will be approved in the future. There are also different drugs available to treat some of the conditions associated with lupus.

Less intensive treatments may be effective for symptoms of mild lupus. They include:

Creams and sunblocks for rashes
Nonsteroidal anti-inflammatory drugs for fever, arthritis, and headache
Antimalarial drugs for pleurisy, mild kidney involvement, and inflammation of the tissue surrounding the heart

More aggressive treatment is needed if there is serious disease progression, as evidenced by:

Hemolytic anemia
Low platelet count with an accompanying rash (thrombocytopenia purpura)
Major involvement in the lungs or heart
Significant kidney damage
Acute inflammation of the small blood vessels in the extremities or gastrointestinal tract
Severe central nervous system symptoms

The primary approach to treating severe SLE is to suppress the immune factors, most often first with corticosteroids and other immunosuppressant drugs. Investigational drugs and procedures are also showing promise.

The major complications of the disease must be treated as separate problems, keeping in mind the specific aspects of SLE. They are discussed elsewhere in this report.

Treatment for Cutaneous and Mild SLE

Creams. Steroid creams are often used for skin lesions. However, many patients with discoid lupus do not respond to steroids, particularly if they have eruptions that are caused by sun sensitivity. A cream derived from vitamin A (Tegison) may help some lesions that do not clear up with steroid creams.

Sun Protection. Sun protection is essential. Patients should always use sunblock creams (not just sunscreens) and always wear hats and clothing made of tightly woven fabrics.

Common NSAIDs. NSAIDs block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. There are dozens of NSAIDs.

Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin, Advil), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil).

For people with lupus, NSAIDs may help relieve:

Joint pain and swelling
Muscle pain

Side Effects. Regular, long-term use of NSAIDs can cause ulcers and gastrointestinal bleeding, which can lead to anemia. To avoid these problems, it’s best to take NSAIDs with food or immediately after a meal. Long-term use of NSAIDs (with the exception of aspirin) can also increase the risk for heart attack and stroke.

Other NSAID side effects may include:

Upset stomach
Dyspepsia (burning, bloated feeling in pit of stomach)
Drowsiness
Skin bruising
High blood pressure
Fluid retention
Headache
Rash
Reduced kidney function

Patients who have kidney problems associated with lupus (lupus nephritis) should be especially cautious about using NSAIDs. Experts recommend that patients with lupus who take NSAIDs on a regular basis should have their liver and kidney function tested every 3 - 4 months.

An ulcer is a crater-like lesion on the skin or mucous membrane caused by an inflammatory, infectious, or malignant condition. Patients can take certain medicines to suppress the acid in the stomach causing the erosion of the stomach lining. Endoscopic therapy can be used to stop bleeding from the ulcer.

Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of ulcers. Ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) are more likely to bleed than those caused by the bacteria Helicobacter pylori.

Those at high risk for bleeding include people over age 60, anyone with a history of ulcers or gastrointestinal bleeding, patients with serious heart conditions, people who abuse alcohol, and those who take medications such as anticoagulants (blood thinners) and corticosteroids.

Proton-pump inhibitor (PPI) drugs may help prevent and heal ulcers caused by NSAIDs. PPIs include omeprazole (Prilosec), esomeprazole (Nexium), and lansoprazole (Prevacid).

A doctor may prescribe antimalarial drugs for discoid lupus (skin sores) or mild lupus when skin problems and joint pains are the predominant symptoms:

Hydroxychloroquine (Plaquenil) is the most common antimalarial drug used for lupus. This drug is effective as maintenance therapy to reduce flares in patients with mild or inactive disease. Hydroxychloroquine may help protect against blood clots in people with antiphospholipid syndrome, high cholesterol levels, and bone loss.
Other antimalarial drugs include chloroquine (Aralen) or quinacrine (Atabrine).

Treatment may start initially with high doses in order to accumulate high levels of the drug in the bloodstream. It is not known exactly why antimalarials work. Some researchers believe they inhibit the immune response, and others think they interfere specifically with inflammation.

A 2006 study suggested that anti-malarial drugs work best in patients who have genetic predispositions to certain types of immune-fighting proteins. The study found that patients who had genetic variations causing abnormally high levels of tumor necrosis alpha (TNF-alpha) and abnormally low levels of interleukin-10 (IL-10) responded best to these drugs.

Side Effects. Side effects of antimalarials may include:

Skin rash
Change in skin color (yellow in the case of quinacrine)
Gastrointestinal problems
Headache
Hair loss
Muscle aches
Eye damage

The most serious is damage to the retina, although this is very uncommon at low doses. Eye damage after taking hydroxychloroquine is reversible when caught in time and treated, but it is not reversible if the damage develops after taking chloroquine. An eye exam is advisable about every 6 months.

Antimalarials may also be used in combination with other anti-SLE drugs, including immunosuppressants and corticosteroids. It should be noted that smoking significantly reduces the effectiveness of antimalarial drugs.

Treatment for Severe SLE

Severe SLE is treated with corticosteroids, also called steroids, which suppress the inflammatory process. Steroids can help relieve many of the complications and symptoms, including anemia and kidney involvement.

Oral prednisone (Deltasone, Orasone) is usually prescribed. Other drugs include methylprednisolone (Medrol, Solumedrol), hydrocortisone, and dexamethasone (Decadron).

Some people need to take oral prednisone for only a short time; others may require it for a long duration. An intravenous administration of methylprednisolone using "pulse" therapy for 3 days is proving useful for flare-ups in the joints. Combinations with other drugs, particularly immunosuppressants, may be beneficial.

Regimens vary widely, depending on the severity and location of the disease. Most patients with SLE can eventually function without prednisone, although some may have to choose between the long-term toxicity of corticosteroids and the complications of active disease.

Side Effects of Long-Term Oral Corticosteroids. Unfortunately, serious and even life-threatening complications have been associated with long-term steroid use. The bone-thinning condition osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, alendronate etidronate, risedronate, or hormone replacement therapy in post-menopausal women. Vitamin C and E may help reduce the risk of cataracts.

Other side effects associated with prolonged use of oral steroids include:

Cataracts
Glaucoma
Diabetes
Fluid retention
Susceptibility to infections
Weight gain
High blood pressure
Acne
Excess hair growth
Wasting of the muscles
Menstrual irregularities
Irritability
Insomnia
Psychosis

Withdrawal from Long-Term Use of Oral Corticosteroids. Long-term use of oral steroid medications suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this so-called adrenal suppression persists and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again. A few cases of severe adrenal insufficiency have occurred when patients switched from oral to inhaled steroids, which, in rare cases, has resulted in death.

No one should stop taking any steroids without consulting a doctor first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their doctors measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times, when the risk increases.

Drugs known as immunosuppressants are often used, either alone or with corticosteroids for very active SLE, particularly when kidney or neurologic involvement or acute blood vessel inflammation is present. These drugs suppress the immune system by damaging cells that grow rapidly, including those that produce antibodies. About a third of patients take immunosuppressants at some point in the course of the disease.

Specific Immunosuppressants. The most common immunosuppressants are:

Cyclophosphamide (Cytoxan) used to be considered the gold standard of treatment for lupus kidney disease (lupus nephritis). Cyclophosphamide is given intravenously and is sometimes used in combination with corticosteroids or other drugs. It has been used for lupus since the 1970s. Side effects are very severe and include nausea, vomiting, hair loss, infertility, and infections.
Mycophenolate mofetil (CellCept) is now becoming the new standard. Many recent studies have shown that CellCept works better than cyclophosphamide and causes far fewer severe side effects (diarrhea is the main side effect). Unlike cyclophosphamide, it is taken by mouth. Most doctors now recommend CellCept as a first-line treatment for newly diagnosed patients with mild or moderate lupus kidney disease. It may not be appropriate for patients with kidney failure or rapidly progressing kidney disease.
Azathioprine (Imuran) has the lowest toxicity, but is less effective than other immunosuppressants.
Cyclosporine (Sandimmune) has been used for years, mostly for SLE associated with kidney involvement. High blood pressure is common, however, with this drug.

The most frequent side effects of immunosuppressants include:

Stomach and intestinal problems
Skin rash
Mouth sores
Hair loss

Serious side effects of immunosuppressants include:

Low blood cell counts
Anemia
Menstrual irregularity
Early menopause
Ovarian failure
Infertility
Herpes zoster (shingles)
Liver and bladder toxicity
Increased risk of cancer

In general, immunosuppressants should not be used alone unless corticosteroids are ineffective or inappropriate. Grapefruit juice has an enzyme that may enhance the effects of some immunosuppressants.

Monoclonal Antibodies (MAbs). A MAb is a laboratory-made protein that targets specific immune cells, such as B cells. B cell over-activation has been identified as a key component of the lupus disease process. Promising MAbs in development for SLE treatment include:

Epratuzumab is being investigated for treatment of moderate-to-severe lupus. It is currently in Phase III trials.
Belimumab (Lymphostat-B) is also in Phase III trials.
Rituximab (Rituxan), a lymphoma cancer and rheumatoid arthritis drug, has shown good results in early trials in improving lupus symptoms. Researchers think it may affect how T cells and B cells interact. However, in December 2006 the FDA warned of several cases of progressive multifocal leukoencephalopathy (PML) in patients with lupus who took this drug. PML is a life-threatening brain infection. Some patients developed PML as late as 12 months after their last dose of rituximab. Two patients with lupus died from PML.

Intravenous Immunoglobulins. Intravenous immunoglobulins (IVIG) are sometimes used for patients who have not responded to other SLE treatments. Immunoglobulins are antibodies produced by immune system B-lymphocyte cells. IVIG is a blood product that contains these antibodies.

Dehydroepiandrosterone (DHEA). Dehydroepiandrosterone (DHEA) is a natural steroid hormone that is produced by the adrenal glands and converted into estrogen and androgen. The synthetic equivalent of DHEA, prasterone (Prestara), is being investigated as a potential treatment for SLE. Several clinical trials have indicated promising, although mixed, results for prasterone’s effect on preventing bone mineral density loss in women who take prednisone. Prasterone is still in the drug development stage and it is not clear when, or if, it will be commercially available.

Autologous Stem Cell Transplantation. Some patients with severe lupus have achieved at least short-term remission after undergoing autologous transplantation of stem cells and high-dose drug therapy to suppress the damaging immune factors. Stem cells are the early forms for all blood cells in the body. An autologous transplant is one in which marrow or blood cells used are the patient's own. (The advantage to an autologous transplant is that the patient's own cells are not at risk for rejection by the immune system.)

The procedure first removes the cells from the patient, who then receives high-dose immunotherapy. The stem cells are then reintroduced. Early results of small studies are encouraging, especially for treatment of antiphospholipid syndrome. Evidence suggests that these re-introduced stem cells do not repeat the original autoimmune errors. A 2006 study in the Journal of the American Medical Association indicated that autologous stem cell transplantation can help boost the immune system and lead to remission. Patients in the study had severe lupus that was resistant to standard treatments. Results were long-lasting. Researchers calculated that patients had a 50% chance of remaining disease-free after 5 years.

UVA-1 Phototherapy. A promising treatment uses ultraviolet A-1 (UVA-1) radiation, long UVA wave lengths that do not promote sunburn and may actually block inflammatory immune factors. Small studies have suggested that UVA-1 phototherapy may have some benefits for lowering disease activity in SLE.

Plasmapheresis. Plasmapheresis is a process in which the fluid part of the blood, called plasma, is removed from blood cells. The procedure involves first taking blood from the patient. The plasma, which contains the inflammatory antibodies and other immunologically active substances, is discarded and replaced with other fluids. The blood is then returned. Plasmapheresis is not useful for routine management of patients but may have some benefits for patients who do not respond to standard treatments or in specific cases, such as lupus patients with hemolytic anemia.


Infections, Inflammation, or Hypertension in the Lungs	Preventive Measures. Immunizations with inactive viruses and preventive antibiotics should be considered for patients with SLE who are at high risk for infection. Treating Infections. Lung infections need to be treated aggressively with antibiotics. However, antibiotic drugs such as penicillin or the sulfa drugs may cause sensitivity rashes that can be confused with SLE rash. Treating Lung Inflammation. While inflammation of the lung (pneumonitis) resembles pneumonia, it is not an infection but is a result of the autoimmune process. This condition needs to be treated with corticosteroids or immunosuppressants, but only if the doctor is sure infection is not present. Treating Pulmonary Hypertension. Pulmonary hypertension is very serious. Drugs known as prostacylins -- which include epoprostenol, iloprost, and treprostinil -- are standard drugs. Bosentan (Tracleer) is the first oral drug approved for pulmonary hypertension. An inhaled iloprost formulation (Ventavis) was approved in 2004. Sildenafil (Viagra, Revatio) may also be used for this condition. Lung transplantation may be required.
Bleeding and Clotting Disorders	Antiphospholipid Syndrome and Clotting Disorders. Hydroxychloroquine or aspirin may help prevent blood clots in women with antiphospholipid syndrome (APS). (Aspirin does not appear to be protective in men who carry the autoantibodies responsible for APS.) In patients who have experienced blood clots, treatment with the anticoagulant warfarin (Coumadin) is advisable. This blood-thinning drug may be needed lifelong. Scientists are investigating other treatment options, including autologous stem cell transplantation. The procedure has shown promise in studies for treating lupus-associated APS, but it is still experimental. Excess Bleeding from Thrombocytopenia (Drop in Blood Platelets). Treatments that may be effective for thrombocytopenia include combinations of a corticosteroid and either danazol (a male hormone) or the antimalarial hydroxychloroquine. Immunosuppressants or intravenous immunoglobulin IgG may be helpful in some patients. Surgical removal of the spleen may be advisable if bleeding disorders are a serious problem, but this option should be considered carefully, because the spleen provides one line of defense against infection. (Abnormal spleen function, in any case, appears to be fairly common in SLE.)
Kidney Disease	Drugs. Mycophenolate mofetil (CellCept), a newer drug, can help treat kidney disease associated with SLE and has fewer side effects than other immunosuppressants. It is taken by mouth. Recent studies suggest that it works better than cyclophosphamide. CellCept may be best for patients with mild-to-moderate lupus kidney disease and may not be appropriate for patients with advanced kidney disease. Intravenous cyclophosphamide is the most effective drug at this time for proliferative lupus nephritis, and, in combination with a steroid, has been shown to control advanced kidney disease in 60 - 90% of patients. It has severe side effects, including nausea, vomiting, hair loss, and infertility. Steroids are also useful for treating active kidney disease and for managing milder forms of nephritis. Procedures. Kidney transplant or dialysis should be considered for patients with SLE with severe kidney damage. For unknown reasons, SLE does not generally recur in the transplanted kidneys. Studies are conflicting, however, over whether SLE transplant patients have higher organ-rejection rates than other kidney-transplant recipients. Both transplantation and dialysis have potentially serious complications. Plasmapheresis. It is not clear if plasmapheresis is beneficial for SLE kidney disease.
Osteoporosis	Treatments for osteoporosis include calcium, vitamin D, bisphosphonates, parathyroid hormone, and selective estrogen-receptor modulators (SERMs). [For more information, see In-Depth Report #18: Osteoporosis.]
Heart Disease	The need for aggressive treatment of high blood pressure often accompanies kidney disease. SLE is also accompanied by high cholesterol levels, which requires diet changes and drug therapies. [For more information, see In-Depth Reports #3: Coronary artery disease; #14: High blood pressure; #23: Cholesterol; and #43: Heart healthy diet.]

The spleen is an organ that helps produce and maintain red blood cells. It also aids the body's immune system by producing white blood cells that destroy harmful substances in the body. Removal of the spleen makes a person more susceptible to infection.

Click the icon to see an illustrated series detailing kidney transplant.

Lifestyle Changes

People with SLE should try to maintain a healthy and active lifestyle. Light-to-moderate exercise, interspersed with rest periods, is good for the heart, helps fight depression and fatigue, and can help keep joints flexible.

Patients should minimize their exposure to crowds or people with contagious illnesses. Careful hygiene, including dental hygiene, is also important.

It is very important that patients with SLE avoid excessive exposure to sunlight. Simple preventive measures include avoiding overexposure to ultraviolet rays and wearing protective clothing and sunblocks. There is some concern that allergy shots may cause flare ups in certain cases. Patients who may benefit from them should discuss risks and benefits with an SLE specialist. In general, patients with SLE should use only hypoallergenic cosmetics or hair products.

Chronic stress has profound physical effects and influences the progression of SLE. Getting adequate rest of at least 8 hours and possibly napping during the day may be helpful. Maintaining social relationships and healthy activities may also help prevent the depression and anxiety associated with the disease.

Resources

www.lupus.org -- Lupus Foundation of America
www.lupusny.org -- SLE Foundation of America
www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.rheumatology.org -- American College of Rheumatology
www.lupusresearchinstitute.org -- Lupus Research Institute

References

Bernatsky S, Ramsey-Goldman R, Isenberg D, Rahman A, Dooley MA, Sibley J, et al. Hodgkin's lymphoma in systemic lupus erythematosus. Rheumatology (Oxford). 2007 May;46(5):830-2. Epub 2007 Jan 25.

Crosbie D, Black C, McIntyre L, Royle PL, Thomas S. Dehydroepiandrosterone for systemic lupus erythematosus. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005114.

D'Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. 2007 Feb 17;369(9561):587-96.

Dörner T, Kaufmann J, Wegener WA, Teoh N, Goldenberg DM, Burmester GR. Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther. 2006;8(3):R74. Epub 2006 Apr 21.

Gompel A, Piette JC. Systemic lupus erythematosus and hormone replacement therapy. Menopause Int. 2007 Jun;13(2):65-70.

Harel-Meir M, Sherer Y, Shoenfeld Y. Tobacco smoking and autoimmune rheumatic diseases. Nat Clin Pract Rheumatol. 2007 Dec;3(12):707-15.

Khamashta MA. Systemic lupus erythematosus and pregnancy. Best Pract Res Clin Rheumatol. 2006 Aug;20(4):685-94.

Klareskog L, Padyukov L, Alfredsson L. Smoking as a trigger for inflammatory rheumatic diseases. Curr Opin Rheumatol. 2007 Jan;19(1):49-54.

Kocis P. Prasterone. Am J Health Syst Pharm. 2006 Nov 15;63(22):2201-10. Lane NE. Therapy Insight: osteoporosis and osteonecrosis in systemic lupus erythematosus. Nat Clin Pract Rheumatol. 2006 Oct;2(10):562-9.

Mackillop LH, Germain SJ, Nelson-Piercy C. Systemic lupus erythematosus. BMJ. 2007 Nov 3;335(7626):933-6.

Mease PJ, Ginzler EM, Gluck OS, Schiff M, Goldman A, Greenwald M, et al. Effects of prasterone on bone mineral density in women with systemic lupus erythematosus receiving chronic glucocorticoid therapy. J Rheumatol. 2005 Apr;32(4):616-21.

Sabahi R, Anolik JH. B-cell-targeted therapy for systemic lupus erythematosus. Drugs. 2006;66(15):1933-48.

Sánchez-Guerrero J, González-Pérez M, Durand-Carbajal M, Lara-Reyes P, Jiménez-Santana L, Romero-Díaz J, et al. Menopause hormonal therapy in women with systemic lupus erythematosus. Arthritis Rheum. 2007 Sep;56(9):3070-9.

Vigna-Perez M, Hernández-Castro B, Paredes-Saharopulos O, Portales-Pérez D, Baranda L, Abud-Mendoza C, et al. Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther. 2006;8(3):R83. Epub 2006 May 5.

Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2007 Sep;2(5):968-75. Epub 2007 Aug 8.

Walsh M, Jayne D. Rituximab in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis and systemic lupus erythematosus: past, present and future. Kidney Int. 2007 Sep;72(6):676-82. Epub 2007 Jul 4.

Review Date:
1/21/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Infertility in women

FitSugar — Wed, 08 Oct 2008 17:35:02 -0700

In This Report

Highlights
Introduction
The Reproductive System
Risk Factors
Causes
Diagnosis
Treatment
Lifestyle Changes
Medications
Assisted Reproductive Techn...
Complications of Assisted R...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

New At-Home Fertility Test for Couples

Fertell is a new at-home fertility test kit for couples. It screens for sperm motility concentrations and follicle-stimulating hormone (FSH) levels. Fertell may be helpful as an initial test for infertility, but for a definitive diagnosis it is important to consult a doctor. Infertility can be due to many different factors.

Intracytoplasmic Sperm Injection Overused for Female Infertility

The assisted reproductive technology intracytoplasmic sperm injection (ICSI) is being increasingly used in combination with in vitro fertilization (IVF), even for couples who do not have problems with male infertility, suggests a 2007 study in the New England Journal of Medicine. Researchers found that use of ICSI has increased 5-fold in the past decade. Some doctors are now recommending ICSI for women who have failed prior IVF cycles or who have few or poor-quality eggs. Doctors caution that ICSI should be used only to improve pregnancy chances for couples with male-factor infertility.

Clomiphene Best for PCOS-Associated Infertility

The infertility drug clomiphene (Clomid) works better than the diabetes drug metformin (Glucophage) for treating infertility resulting from polycystic ovarian syndrome (PCOS), indicates a 2007 study in the New England Journal of Medicine.

Fertility Drugs and Breast Cancer

Fertility drugs such as clomiphene and gonadotropins do not increase the risk for breast cancer, indicate several studies. In fact, according to a 2006 study in the Archives of Internal Medicine, clomiphene may decrease breast cancer risk.

Iron Deficiency and Female Infertility

Iron deficiency may increase the risk for ovulatory infertility, suggests a 2006 study in Obstetrics and Gynecology. Researchers found that women who took daily iron supplements were 40% less likely to be infertile than women who did not take supplements. Some experts recommend screening for iron deficiency as part of the clinical evaluation for infertility.

Introduction

Infertility is the failure of a couple to become pregnant after one year of regular, unprotected intercourse. In both men and women the fertility process is complex.

About 10% of couples who wish to have a baby are still unable to after a year of unprotected sex. About half of these couples can achieve pregnancy within 2 years after appropriate treatment of the woman, the man, or both. Even under ideal circumstances, the probability that a woman will get pregnant during a single menstrual cycle is only about 30%. And, when conception does occur, only 50 - 60% of pregnancies advance beyond the 20th week. (The inability of a woman to produce a live birth because of abnormalities that cause miscarriages is called infecundity and is not discussed in detail in this report.)

Males and females each account for 40% of infertility. In the remaining 20%, either both partners are responsible or the cause is unclear. Although this report specifically addresses infertility in women, it is equally important for the male partner to be tested at the same time. [See In-Depth Report #67: Infertility in men.]

The Reproductive System

The Primary Organs and Structures in the Reproductive System. The primary structures in the reproductive system are:

The uterus is a pear-shaped organ located between the bladder and lower intestine. It consists of two parts, the body and the cervix.
When a woman is not pregnant the body of the uterus is about the size of a fist, with its walls collapsed and flattened against each other. During pregnancy the walls of the uterus are pushed apart as the fetus grows.
The cervix is the lower portion of the uterus. It has a canal opening into the vagina with an opening called the os, which allows menstrual blood to flow out of the uterus into the vagina.
Leading off each side of the body of the uterus are two tubes known as the fallopian tubes. Near the end of each tube is an ovary.
Ovaries are egg-producing organs that hold 200,000 - 400,000 follicles (from folliculus, meaning "sack" in Latin). These cellular sacks contain the materials needed to produce ripened eggs, or ova.
The inner lining of the uterus is called the endometrium. During pregnancy, it thickens and becomes enriched with blood vessels to house and support the growing fetus. If pregnancy does not occur, the endometrium is shed as part of the menstrual flow. Menstrual flow also consists of blood and mucus from the cervix and vagina.

The uterus is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Reproductive Hormones. The hypothalamus (an area in the brain) and the pituitary gland regulate the reproductive hormones.

Click the icon to see an image of the hypothalamus and pituitary gland.

The pituitary gland is often referred to as the master gland because of its important role in many vital functions, many of which require hormones. In women, six key hormones serve as chemical messengers that regulate the reproductive system:

The hypothalamus first releases the gonadotropin-releasing hormone (GnRH).
This chemical, in turn, stimulates the pituitary gland to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

Click the icon to see an image of the pituitary gland.

Estrogen, progesterone, and the male hormone testosterone are secreted by the ovaries at the command of FSH and LH and complete the hormonal group necessary for reproductive health.

Ovulation. The process leading to fertility is very intricate. It depends on the healthy interaction of two sets of organs and hormone systems in both the male and female. In addition, reproduction is limited by the phases of female fertility. Nevertheless, this astonishing process results in conception within a year for about 80% of couples. Only 15% conceive within a month of their first attempts, however, and about 60% succeed after 6 months.

A woman's ability to produce children occurs after she enters puberty and begins to menstruate. The process of conception is complex:

With the start of each menstrual cycle, follicle-stimulating hormone (FSH) stimulates several follicles to mature over a 2-week period until their eggs nearly triple in size. Only one follicle becomes dominant, however, during a cycle.
FSH signals this dominant follicle to produce estrogen, which enters the bloodstream and reaches the uterus. There, estrogen stimulates the cells in the uterine lining to reproduce, therefore thickening the walls.
Estrogen levels reach their peak around the 14th day of the cycle (counting days beginning with the first day of a period). At that time, they trigger a surge of luteinizing hormone (LH).

LH serves two important roles:

First, the LH surge around the 14th cycle day stimulates ovulation. It does this by causing the dominant follicle to burst and release its egg into one of the two fallopian tubes. Once in the fallopian tube, the egg is in place for fertilization.
Next, LH causes the ruptured follicle to develop into the corpus luteum. The corpus luteum provides a source of estrogen and progesterone during pregnancy.

Click the icon to see an image of the corpus luteum.

Fertilization. The so-called "fertile window" is 6 days long and starts 5 days before ovulation and ends the day of ovulation. Fertilization occurs as follows:

The sperm can survive for up to 3 days once it enters the fallopian tube. The egg survives 12 - 24 hours unless it is fertilized by a sperm.
If the egg is fertilized, about 2 - 4 days later it moves from the fallopian tube into the uterus where it is implanted in the uterine lining and begins its 9-month incubation.
The placenta forms at the site of the implantation. The placenta is a thick blanket of blood vessels that nourishes the fertilized egg as it develops.

Click the icon to see an image of the placenta.

The corpus luteum (the yellow tissue formed from the ruptured follicle) continues to produce estrogen and progesterone during pregnancy.

If the egg is not fertilized, the corpus luteum degenerates into a form called the corpus albicans, and estrogen and progesterone levels drop. Finally, the endometrial lining sloughs off and is shed during menstruation.


Menstrual Phases	Typical No. of Days	Hormonal Actions
Follicular (Proliferative) Phase	Cycle Days 1 - 6: Beginning of menstruation to end of blood flow.	Estrogen and progesterone start out at their lowest levels. FSH levels rise to stimulate maturity of follicles. Ovaries start producing estrogen and levels rise, while progesterone remains low.
	Cycle Days 7 - 13: The endometrium (the inner lining of the uterus) thickens to prepare for the egg implantation.
Ovulation	Cycle Day 14:	Surge in LH. Largest follicle bursts and releases egg into fallopian tube.
Luteal (Secretory) Phase, also known as the Premenstrual Phase	Cycle Days 15 - 28:	Ruptured follicle develops into corpus luteum, which produces progesterone. Progesterone and estrogen stimulate blanket of blood vessels to prepare for egg implantation.
	If fertilization occurs:	Fertilized egg attaches to blanket of blood vessels that supplies nutrients for the developing placenta. Corpus luteum continues to produce estrogen and progesterone.
	If fertilization does not occur:	Corpus luteum deteriorates. Estrogen and progesterone levels drop. The blood vessel lining sloughs off and menstruation begins.

Onset of Menstruation (Menarche). Previous evidence had set the onset of menstruation, called the menarche, at an average age of 12 or 13. Recent studies, however, set the time of onset earlier by about 1 year in Caucasian girls and 2 years in African-American girls. Currently, the youngest possible age for normal puberty is 7 years old for Caucasians and 6 years old for African-Americans, down from a previous low of 8 years for both.

Evidence is pointing to the increasing incidence of childhood obesity as a major cause of the trend in earlier menarche onset. (Obesity is also highly associated with hormonal disorders in girls entering puberty at young ages.) Environmental estrogens found in chemicals and pesticides are also suspects.

Length of Monthly Cycle. The menstrual cycle can be very irregular for the first 1 - 2 years, usually being longer than the average of 28 days. The length then generally stabilizes to an average of 28 days, although the cycle length may range from 20 - 45 days and still be considered normal. A variation of 10 days or more -- either more or fewer days -- may have an impact on fertility, however. When a woman reaches her 40s the cycle lengthens, reaching an average of 31 days by age 49. Several factors can affect cycle length at any age.


Risk Factors for Shorter Cycles	Risk Factors for Longer Cycles
Regular alcohol use	Being under 21 and over 44
Stressful jobs	Being very thin (also at risk for short bleeding periods)
	Competitive athletics (also at risk for short bleeding periods)

Length of Periods. Periods average 6.6 days in young girls. By the age of 21, menstrual bleeding averages 6 days until women approach menopause. However, about 5% of healthy women menstruate less than 4 days, and 5% menstruate more than 8 days.

Normal Absence of Menstruation. Normal absence of periods can occur in any woman under the following circumstances:

Menstruation stops during the duration of pregnancy. Some women continue to have irregular bleeding during the first trimester. This bleeding may indicate a threatened miscarriage and requires immediate attention by the doctor.
When women breastfeed they are unlikely to ovulate. After that time, menstruation usually resumes, and they are fertile again.
Perimenopause starts when the intervals between periods begin to lengthen, and it ends with menopause itself (the complete cessation of menstruation). Menopause usually occurs at about age 51, although smokers often go through menopause earlier.

Risk Factors

In the U.S., an estimated 10.2% of women ages 15 - 44, or about 6.1 million women, have impaired fertility, and the incidence is increasing. About 25% of women experience some period of infertility during their reproductive years.

As a woman ages, her chances for fertility decline. Infertility in older women appears to be mostly due to a higher risk for chromosomal abnormalities that occur in her eggs as they age. Older women are also more likely to have health problems that may interfere with fertility. If fertilization occurs, older, healthy women can usually successfully bear a fetus to term, although they have a higher risk for miscarriage. Using population studies, experts have come up with estimated odds for pregnancy at different ages, given no fertility intervention. One analysis of pregnancy rates based on conception on the day of ovulation suggested that women ages 19 - 26 have twice the pregnancy rates as those ages 35 - 39.


Age	Fertility %
Up until age 34	90%
By age 40	Declining to 67%
By age 45	Declining to 15%

Although most of a woman's estrogen is manufactured in her ovaries, 30% is produced in fat cells by a process that transforms circulating adrenal male hormones into estrogen. Because a normal hormonal balance is essential for the process of conception, it is not surprising that extreme weight levels, either high or low, can contribute to infertility.

Being Overweight. Being overweight or obese (fat levels that are 10 - 15% above normal) can contribute to infertility in various ways. Obesity is highly associated with polycystic ovarian syndrome (PCOS), which is the cause of infertility in some cases. In one study, overweight women without PCOS were classified in one of five grades, depending on the severity of the obesity. The risk for irregular or absent periods increased two-fold by each increase in grade. In this group, amenorrhea (absent periods) was also highly associated with type 2 diabetes and blood sugar abnormalities.

Being Underweight. Body fat levels 10 - 15% below normal can completely shut down the reproductive process. Women at risk include:

Women with eating disorders, such as anorexia or bulimia.
Women on very low-calorie or restrictive diets are at risk, especially if their periods are irregular.
Strict vegetarians might have difficulties if they lack important nutrients, such as vitamin B12, zinc, iron, and folic acid.
Marathon runners, dancers, and others who exercise very intensely. (Lower body fat contributes to menstrual irregularities in competitive athletes, but other mechanisms are also involved.)

Exposure to environmental hazards (herbicides, pesticides, industrial solvents) may affect fertility. Estrogen-like hormone-disrupting chemicals are of particular concern for infertility in men and for effects on offspring of women.

Phthalates, chemicals used to soften plastics, are under particular scrutiny for their ability to disrupt hormones. Specific phthalates of special concern include dibutyl phthalate (DBP) and others found in many products, including cosmetics and clay products sold to children (Fimo, Sculpey). Animals exposed to phthalates have significantly impaired sperm count and abnormalities in reproductive structures, such as the testes. In addition, there is some concern that exposure in pregnant women may affect the offspring.

Neurotransmitters (chemical messengers) act in the hypothalamus gland, which controls both reproductive and stress hormones. Severely elevated levels of stress hormone can, in fact, shut down menstruation. Whether stress has any significant effect on fertility or fertility treatments is unclear. One 2005 study found that psychological stress does not affect the success or failure of in vitro fertilization.

Click the icon to see an image of the hypothalamus.

Causes

Causes of infertility can be found in about 90% of infertility cases but, despite extensive tests, about 10% of couples will never know why they cannot conceive. Between 10 - 30% of cases of infertility have more than one cause. Male or female infertility each account for about 30 - 40% of cases. In men, sperm defects (their quality and quantity) are usually responsible. Female infertility is more complex.

Pelvic inflammatory disease (PID) is the major cause of female infertility worldwide. PID comprises a variety of infections caused by different bacteria that affect the reproductive organs, appendix, and parts of the intestine that lie in the pelvic area. The sites of infection most often implicated in infertility are in the fallopian tubes, a specific condition referred to as salpingitis.

Causes of PID. PID may result from many different conditions that cause infections. Among them are:

Sexually transmitted diseases (cause of most PIDs). Chlamydia trachomatis is an infectious organism that causes 75% of infertility in the fallopian tubes. Gonorrhea is responsible for most of the remaining cases.
Pelvic tuberculosis (a growing global problem as tuberculosis cases increase)
Nonsterile abortions
Ruptured appendix
Herpes virus (suggested for some cases, but not confirmed as a cause).

Symptoms of PID. The infection may be subclinical (occurring without any symptoms), or there may be fever, chills, or pelvic pain indicating inflammation of the entire pelvic area.

Effects of PID. Severe or frequent attacks of PID can eventually cause scarring, abscess formation, and tubal damage that result in infertility. About 20% of women who develop symptomatic PID become infertile. PID also significantly increases the risk of ectopic pregnancy (fertilization in the fallopian tubes). The severity of the infection, not the number of the infections, appears to pose the greater risk for infertility.

Endometriosis may account for as many as 30% of infertility cases. Some evidence suggests that between 30 - 50% of women with endometriosis are infertile. Often, however, it is difficult to determine if endometriosis is the primary cause of infertility, particularly in women who have mild endometriosis. Endometriosis rarely causes an absolute inability to conceive, but, nevertheless, it can contribute to it both directly and indirectly.

Endometriosis is the condition in which the tissue that normally lines the uterus (endometrium) grows on other areas of the body causing pain and irregular bleeding.

Direct Effect of Endometrial Cysts. Endometrial cysts may directly cause infertility in several ways:

If implants occur in the fallopian tubes, they may block the egg's passage.
Implants that occur in the ovaries prevent the release of the egg.
Severe endometriosis can eventually form rigid webs of scar tissue (adhesions) between the uterus, ovaries, and fallopian tubes, thereby preventing the transfer of the egg to the tube.

Immune Factors and the Inflammatory Response. Researchers are focusing on defects in the immune system that not only may be responsible for endometriosis in the first place but may also cause the infertility associated with endometriosis. Even in early stage endometriosis, investigators have observed increased immune system activity.

Other Conditions Linking Endometriosis and Infertility. Researchers have sometimes noted unusually low levels of specific substances that enable a fertilized egg to adhere to the uterine lining. (Such abnormalities are more often a factor in infertility in women with mild-to-moderate endometriosis than in those with severe cases.)

One study found that the eggs in women with endometriosis appeared to have more genetic abnormalities than those in women without the disorder.

Polycystic ovarian syndrome (PCOS) is a condition in which the ovaries produce high amounts of androgens (male hormones), particularly testosterone. PCOS occurs in about 6% of women, and amenorrhea or oligomenorrhea (infrequent menses) is quite common. According to one study, nearly 30% of obese women with PCOS had amenorrhea. (The rate was lower -- 4.7% -- in women with normal weight.)

Click the icon to see an image of polycystic ovarian syndrome.

In PCOS, increased androgen production produces high luteinizing hormone (LH) levels and low follicle-stimulating hormone (FSH) levels, so that follicles are prevented from producing a mature egg. Without egg production, the follicles swell with fluid and form into cysts. Every time an egg is trapped within the follicle, another cyst forms, so the ovary swells, sometimes reaching the size of a grapefruit. Without ovulation, progesterone is no longer produced, whereas estrogen levels remain normal.

The elevated levels of androgens (hyperandrogenism) can cause obesity, facial hair, and acne, although not all women with PCOS have such symptoms. Other male characteristics, such as deepening voice and clitoral enlargement, are rare.

PCOS also poses a high risk for insulin resistance, particularly in women who are also obese. Insulin resistance is associated with diabetes type 2, in which insulin levels are normal or high but the body cannot use this hormone efficiently. About half of PCOS patients, in fact, also have diabetes.

Premature ovarian failure is the early depletion of follicles before age 40, which, in most cases, leads to premature menopause. It affects about 1% of women and is typically preceded by irregular periods, which might continue for years. In this condition, follicle-stimulating hormone (FSH) levels are elevated, as they are during perimenopause. Premature ovarian failure is a significant cause of infertility, and women who have this condition have only a 5 - 10% chance to conceive without fertility treatments.

Causes of Premature Ovarian Failure. There are numerous causes of premature ovarian failure. Often the cause of this disorder or other causes of premature ovarian failure is unknown. In some cases, premature ovarian failure may represent an acceleration of the aging process.

The following conditions may produce premature ovarian failure:

Adrenal, pituitary, or thyroid gland deficiencies.
Genetic factors related to the X chromosome. A woman needs two functioning X chromosomes for normal reproduction. When one is abnormal, ovarian function fails. The most severe example is Turner syndrome, a genetic condition, in which one of the two X-chromosomes is missing or malfunctioning. Milder cases of ovarian failure can occur in fragile X syndrome and other rare inherited conditions that cause partial X-chromosome abnormalities.
Cancer treatments (radiation, chemotherapy, or both). Women who are undergoing cancer treatments and who want to become pregnant should see a reproductive specialist to discuss their options. According to the American Society of Clinical Oncology's 2006 guidelines, the fertility preservation method with the best chance of success is embryo cryopreservation. This procedure involves harvesting a woman's eggs (oocytes), followed by in vitro fertilization and freezing of embryos for later use. Other treatments under investigation include egg preservation, collecting and freezing unfertilized eggs, removing and freezing a part of the ovary for later reimplantation, and using hormone therapy to protect the ovaries during chemotherapy. Women may be able to access these investigational approaches through enrolling in clinical trials.
Autoimmunity. Autoimmune diseases -- including type 1 diabetes, systemic lupus erythematosus, autoimmune hypothyroidism, and autoimmune Addison's disease -- are associated with a higher risk for early menopause. Autoimmunity, however, may also play a role in some cases of premature ovarian failure without the presence of specific autoimmune diseases. In such cases, antibodies specifically attack the cells that secrete reproductive hormones thus causing ovarian failure.
Other causes of premature ovarian failure include sarcoidosis, mumps, some sexually transmitted diseases, and tuberculosis. Women with epilepsy are at higher risk for premature ovarian failure.

Idiopathic hypogonadotropic hypogonadism is a rare condition in which follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are underproduced, preventing the development of functional ovaries. There are no other abnormalities in the hypothalamus-pituitary axis (such as tumors or abnormal stress hormones or prolactin). In most cases, the causes of hypergonadotropic hypogonadism are unknown. Genetic factors, including Kallman syndrome, have been identified in about 20% of these cases.

Functional hypothalamic amenorrhea (FHA) is the absence of menstruation due to disturbances in the thyroid gland and hypothalamus-pituitary-adrenal (HPA) system, which regulates reproduction and other important functions. The eating disorders anorexia and bulimia are most often associated with FHA. FHA may be due to other different factors, most unknown.

Luteal phase defect is a general term referring to problems in the corpus luteum that result in inadequate production of progesterone. Because progesterone is necessary for thickening and preparing the uterine lining, the ovum fails to successfully implant in the endometrium. Between 25 - 60% of women who have recurrent miscarriages may have a luteal phase defect. A luteal phase defect, however, can also occur in fertile women, so other factors may be responsible for implantation failure.

Benign fibroid tumors in the uterus are extremely common in women in their 30s. The effect of fibroids on fertility is controversial. One analysis suggested that they may account for infertility in only 1 - 2.4% of women who are having trouble conceiving.

Large fibroids may cause infertility impairing the uterine lining, by blocking the fallopian tube, or by distorting the shape of the uterine cavity or altering the position of the cervix.

Some evidence suggests that even small fibroids may reduce the chances of pregnancy in women who are undergoing assisted reproductive techniques. Treatments to reduce fibroids may be helpful in such women, although there has been little research on this subject.

Click the icon to see an image of uterine fibroids.

Prolactin is a hormone produced in the pituitary gland that stimulates breast development and milk production in association with pregnancy. High levels of prolactin (hyperprolactinemia) reduce gonadotropin hormones and inhibit ovulation. Hyperprolactinemia in women who are not pregnant or nursing can be caused by hypothyroidism or pituitary adenomas. (These are benign tumors that secrete prolactin. They can cause headache and visual problems as well as breast secretions.) Some drugs, including oral contraceptives and some antipsychotic drugs, can also elevate levels of prolactin.

Secretions from the breast not related to pregnancy or nursing (called galactorrhea) are a telltale symptom of high prolactin levels and should be investigated.

Inborn Abnormalities. Inborn genital tract abnormalities may cause infertility. Mullerian agenesis is a specific malformation in which no vagina or uterus develops. Even in these cases, some women can become mothers by undergoing in vitro fertilization and having the fertilized egg implanted in another woman who is willing and able to carry the pregnancy (a surrogate mother).

Uterine or Abdominal Scarring. Bands of scar tissue that bind together after abdominal or pelvic surgery or infection (called adhesions) can restrict the movement of ovaries and fallopian tubes and may cause infertility. Asherman syndrome, for example, is scarring in the uterus that can cause obstructions and secondary amenorrhea. It may be caused by surgery, repeated injury, or unknown factors. Laparoscopic surgery is less likely to cause adhesions than standard open surgery.

In some of these cases, surgery may be helpful. One technique, called pressure lavage under ultrasound guidance (PLUG), may prove to be useful for treating some cases of mild scarring in the uterus (intrauterine adhesions). This technique is based on transvaginal sonohysterography, which uses ultrasound along with saline infused into the uterus to enhance visualization. Continuous accumulation of saline in the procedure is used to break up the scars.

Ectopic Pregnancies. Ectopic pregnancies increase the risk for infertility, although subsequent pregnancy rates are quite variable. Ectopic pregnancies that terminate without treatment appear to pose a lower risk for future infertility. Even a ruptured tube does not appear to reduce the chance for a future pregnancy in most women. Such an event however can be dangerous and even life threatening for the woman. Laparoscopic surgery to remove a fallopian tube affected by an ectopic pregnancy may preserve fertility better than traditional abdominal surgery.

Click the icon to see an image of an ectopic pregnancy.

Medications. Among the medications that can cause temporary infertility are those used to treat chronic disorders, as well as antidepressants, hormones, painkillers, and antipsychotic drugs.

Inflammatory Bowel Disease. Inflammatory bowel disease (particularly Crohn's disease or surgery for ulcerative colitis) can affect fertility.

Click the icon to see an image of Crohn's disease.

Celiac Sprue. Celiac sprue is a disease in which the patient cannot tolerate gluten, a common food chemical. The disorder is also highly associated with infertility in men and women, possibly through multiple effects on nutrition, immune factors, and hormones. The mechanisms are not altogether clear, but infertility is usually reversible with strict dietary control.

Click the icon to see an image of celiac sprue.

Iron Intake. Nutritional iron deficiency may contribute to female infertility. According to a 2006 study, women who take iron supplements are 40% less likely to experience ovulatory infertility than women who do not take iron supplements. Some researchers suggest that screening for iron deficiency should be part of the standard work-up of infertility tests.

Epilepsy. In one study of women with epilepsy, fertility rates were 33% lower than among women in the general population, perhaps due to certain antiepileptic drugs that increase the risk for birth defects. The social effects of epilepsy may also lead to marriage at an older age, which can be associated with delayed attempts to get pregnant and thereby affect fertility.

Thyroid Problems. Thyroid problems, either too much thyroid hormone (hyperthyroidism) or too little (hypothyroidism), can interrupt cycles.

Click the icon to see an image of hyperthyroidism.

Click the icon to see an image of hypothyroidism.

Metabolic Syndrome (also Called Syndrome X). Doctors diagnose this condition when at least three of the following abnormalities are present:

Abdominal obesity
Low HDL (good) cholesterol levels
High triglyceride levels
High blood pressure
Insulin resistance

Metabolic syndrome is a pre-diabetic condition that is significantly associated with heart disease. One study reported that, as with polycystic ovarian syndrome, women with metabolic syndrome have higher levels of male hormones and are therefore at risk for infertility. Another study estimated that 24% of the population now has this condition.

Other Medical Conditions. Medical conditions associated with delayed puberty and amenorrhea (absence of periods) include Cushing's disease, sickle cell disease, HIV, kidney disease, and diabetes. Genetic mutations that affect luteinizing hormone may also be responsible for some cases of light or absent menstruation. Other rare genetic disorders, such as Kallman syndrome, cause abnormalities in the hypothalamus of the brain.

Diagnosis

In any fertility work-up, both male and female partners are tested if pregnancy fails to occur after a year of regular unprotected sexual intercourse. Fertility testing should be done earlier if a woman is over 35 years old or if either partner has known risk factors for infertility. An analysis of the man's semen should be performed before the female partner undergoes any invasive testing.

The first step in any infertility work up is a complete medical history and physical examination. Sexual technique and timing, menstrual history, lifestyle issues (such as smoking and drug, alcohol, and caffeine consumption), any medications being taken, and a profile of the patient's general medical and emotional health can help the doctor decide on appropriate tests.

Before embarking on an expensive fertility work-up, the following steps are free or low-cost and can be helpful:

Monitor basal body temperature. This is accurate in determining if ovulation is actually taking place.
Test the consistency of your cervical mucus. Collect some mucus between your two fingers and stretch it apart. If you are near the time of ovulation, the mucus will stretch more than 1 inch before it breaks. As an alternative, at-home kits can test saliva as substitute for checking cervical mucus.
Take an over-the-counter urine test for detecting luteinizing hormone (LH) surges. This helps determine the day of ovulation.
Fertell is the first at-home test kit for couples that is approved by the Food and Drug Administration. Women can test their urine for levels of follicle-stimulating hormone (FSH), while men can test their semen for sperm motility (ability of sperm to move). Fertell became available online and in some pharmacies in June 2007.

Several laboratory tests may be used to detect the cause of infertility and monitor treatments:

Hormonal Levels. Blood and urine tests are taken to evaluate hormone levels. Hormonal tests for ovarian reserve (the number of follicles and quality of the eggs) are especially important for older women.

Examples of possible results include:

High follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and low estrogen levels suggest premature ovarian failure or hypogonadotropic hypogonadism.
High LH and low FSH may suggest polycystic ovary syndrome or luteal phase defect.
High FSH and high estrogen levels on the third day of the cycle predicts poor success rates in older women trying fertility treatments.
LH surges indicate ovulation.
Blood tests for prolactin levels and thyroid function are also measured. These are hormones that may indirectly affect fertility.

Clomiphene Challenge Test. Clomiphene citrate (Clomid, Serophene), a standard fertility drug, may be used to test for ovarian reserve. With this test, the doctor measures FSH on day 3 of the cycle. The woman takes clomiphene orally on days 5 and 9 of the cycle. The doctor measures FSH on the tenth day. High levels of FSH either on day 3 or day 10 indicate a poor chance for a successful outcome.

Tissue Samples. To rule out luteal phase defect, premature ovarian failure, and absence of ovulation, the doctor may take tissue samples of the uterus 1 - 2 days before a period to determine if the corpus luteum is adequately producing progesterone. Tissue samples taken from the cervix may be cultured to rule out infection.

Tests for Autoimmune Disease. Tests for autoimmune disease, such as hypothyroidism and diabetes, should be considered in women with recent ovarian failure that is not caused by genetic abnormalities.

If an initial fertility work-up does not reveal abnormalities, as happens in about 40% of cases, more extensive tests will reveal abnormal tubal or uterine findings. The three major approaches for examining the uterus are ultrasound (particularly a variation called saline-infusion sonohysterography), hysterosalpingography, and hysteroscopy. Although combinations of these diagnostic approaches are often used to confirm diagnoses, one study indicated that with the introduction of saline-infusion sonohysterography, all are equally accurate and combinations do not increase accuracy. Furthermore, the ultrasound procedure is significantly less painful than the other two, suggesting that this should be the procedure of choice, if available.

Ultrasound and Sonohysterography. Ultrasound is the standard imaging technique for evaluating the uterus and ovaries, detecting fibroids, ovarian cysts and tumors, and also obstructions in the urinary tract. It uses sound waves to produce an image of the organs and entails no risk and very little discomfort.

Transvaginal sonohysterography uses ultrasound along with saline infused into the uterus, which enhances the visualization of the uterus. This technique is proving to be more accurate than standard ultrasound in identifying potential problems. It is currently the gold standard for diagnosing polycystic ovaries.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) gives a better image of any fibroids that might be causing bleeding, but it is expensive and not usually necessary.

Hysteroscopy. Hysteroscopy is a procedure that may be used to detect the presence of endometriosis, fibroids, polyps, pelvic scar tissue, and blockage at the ends of the fallopian tubes. Some of these conditions can be corrected during the procedure by cutting away any scar tissue that may be binding organs together or by destroying endometrial implants. (It may miss cases of uterine cancer, however, and is not a substitute for more invasive procedures, such as dilation and curettage ( D&C) or endometrial biopsy, if cancer is suspected.)

It is done in the office setting and requires no incisions. The procedure uses a long flexible or rigid tube called a hysteroscope, which is inserted into the vagina and through the cervix to reach the uterus. A fiber optic light source and a tiny camera in the tube allow the doctor to view the cavity. The uterus is filled with saline or carbon dioxide to inflate the cavity and provide better viewing. This frequently causes cramping.

There are small risks of bleeding, infection, and reactions to anesthesia. Many patients experience temporary discomfort in the shoulders after the operation due to residual carbon dioxide that puts pressure on the diaphragm. The wound itself is minimally painful.

Hysterosalpingography. Hysterosalpingography is performed to discover possible blockage in the fallopian tubes and abnormalities in the uterus:

The doctor inserts a tube into the cervix through which a special dye is injected. (The patient may experience some cramping and discomfort.)
The dye passes into the uterus and up through the fallopian tubes.
An x-ray is taken of the dye-filled uterus and tubes.
If the dye is seen emerging from the end of the tube, no blockage is present. (In some cases, hysterosalpingography may even restore fertility by clearing away tiny tubal blockages.)
If results show blockage or abnormalities, the test may need to be repeated. In case of blockage, hysterosalpingography may reveal a number of conditions, including endometrial polyps, fibroid tumors, or structural abnormalities of the uterus and tubes.

The test has significant rates of false diagnoses, both positive and negative. There is a small risk of pelvic infection, and antibiotics may be prescribed prior to the procedure. One study suggested that flushing the tubes with an oil-based fluid (lipiodol) during this procedure may improve fertility rates in women with infertility of unknown causes.

As women age, the number of follicles (and therefore their egg supply) declines. Researchers are developing tests that may help determine how many are left. Such tests include the following:

Calculating the volume of the ovaries. In general, the smaller the ovaries, the fewer the remaining eggs.
Counting antral follicles. Antral follicles are those that develop but do not become dominant follicles. Instead, they form a fluid-filled space called an antrum. Women who have fewer than three to five antral follicles appear to have a poor chance of fertility.
Measuring inhibin B. Inhibin B is a growth factor produced in the ovaries. Low levels suggest fewer eggs.

Eventually these markers may be useful for determining which women need more aggressive treatments.

Genetic testing may be warranted in cases of male infertility or when genetic factors may be causing pregnancy failure in the woman. If genetic abnormalities are suspected in either partner, counseling is recommended.

A technique called preimplantation genetic diagnosis (PGD) is now available in some centers that can examine all the chromosomes in a human embryo. It helps identify abnormalities that increase the risk for infertility, treatment failures, or genetic defects in the offspring.

Treatment

Some doctors recommend that if a couple fails to conceive after 1 - 2 years of frequent unprotected sex, they should consult a fertility expert. Women who are 35 or older, however, may want to begin exploring their options if they do not become pregnant within 6 months to a year.

Several approaches can treat infertility, depending on the cause:

Lifestyle measures (healthy lifestyle, planning sexual activity with ovulation cycle, managing stress and emotions)
Treatments for endometriosis, fibroids, or menstrual disorders
Use of anti-estrogen drugs, such as clomiphene, to induce ovulation in women with ovarian dysfunction
Surgery (standard or laparoscopic) to unblock fallopian tubes
Use of hormone treatments (clomiphene or progestins) for luteal phase defect
Assisted reproductive technologies (ART) such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)

Choosing a good fertility clinic is important. Those offering assisted reproductive techniques are not always regulated by the government, and abuses have been reported, including lack of informed consent, unauthorized use of embryos, and failure to routinely screen donors for disease.

The clinic should always provide the following information:

The live-birth rate (not just pregnancy success rate) for other couples with similar infertility problems. (Multiple births, such as twins or triplets, are counted as one live birth.)
Such statistics should include high-risk women, such as those who are older or fail to produce eggs. (Some disreputable clinics give success percentages that exclude high-risk women from their total, thereby making the percentage of success much higher.)

Advanced fertility procedures and medications are extremely expensive and often not covered by insurance. Couples should be cautious about offers of rebates in the event of failure; the clinics offering them are often significantly more expensive than those that don't offer such gimmicks.


Causes of Infertility	Treatments
Endometriosis	Conservative surgery (typically laparoscopy) is the appropriate approach for restoring fertility. GnRH agonists or progestins, used to treat endometriosis itself, have no effect on fertility. Possible exceptions are GnRH agonists used after surgery. In one study, this treatment helped improve conception rates in women who subsequently underwent assisted reproductive techniques. Assisted reproductive technologies (ART). (Fertility drugs alone have no effect.) It is not clear, in any case, whether either laparoscopy for removing endometrial implants or ART has additional advantages in many of these women compared to simply trying to become pregnant through non-aggressive means.
Hyperprolactinemia	Dopamine agonists, including bromocriptine (Parlodel) or cabergoline (Dostinex). Surgery in some cases.
Luteal phase defect	Clomiphene or superovulation drugs (FSH drugs or hMG).
Hyperprolactinemia (elevated prolactin)	Bromocriptine, cabergoline to shrink tumors that result in over secretion of prolactin. Cabergoline is more effective, but bromocriptine has been used longer. Once ovulation starts, women who want to become pregnant should stop cabergoline one month before attempting conception. Surgery may be needed for women who do not respond to medications or who have large tumors.
Hypogonadotropic Hypogonadism	Fertility drugs (hMG preferable to FSH alone) with or without assisted reproductive technologies.
Pelvic Inflammatory Disease	Screening high-risk women for the presence of Chlamydia trachomatis and treating the organism before it causes symptoms could reduce the risk of PID by almost 60%. If any sexually transmitted infection is detected, both partners should receive antibiotics, even if there are no symptoms. If PID symptoms develop, particularly lower abdominal pain, fertility can be preserved if women receive antibiotics within 2 days. A delay significantly increases the risk for scarring.
Polycystic Ovarian Syndrome	Lifestyle changes (weight loss and exercise in women who are overweight.) Clomiphene is the standard first-line treatment for polycystic ovarian syndrome (PCOS)-related infertility. Although some research has indicated that the diabetes drug metformin (Glucophage) might help treat infertility in women with PCOS, a 2007 study in the New England Journal of Medicine indicated that clomiphene is much more effective.
Premature Ovarian Failure	Assisted reproductive technologies with donor eggs.
Preserving fertility after cancer treatments	Removal and freezing (called cryopreservation) of ovarian tissue containing embryos or freezing immature and unfertilized eggs to use for later reimplantation. (Freezing before cancer treatment appears to offer the best chance.) Under investigation: Ovarian transplantation procedures and gonadotropin-releasing hormone analogues, which put women in a temporary pre-pubescent state during chemotherapy and may preserve fertility.
Fallopian tubal blockage	Surgical procedures (laparoscopy or salpingostomy) to clear the tubes. (Average pregnancy rate after salpingostomy is about 30%, but they can vary widely.) Flushing the tubes with an oil-based fluid (lipiodol) during hysterosalpingography (investigative). In a 2002 study, this procedure improved pregnancy rates in women with infertility of unknown causes. Assisted reproductive technologies.
Unexplained infertility	Lifestyle measures. Fertility drugs. Assisted reproductive technologies.

Lifestyle Changes

Although there are no dietary or nutritional cures for infertility, a healthy lifestyle is important. Ovulatory problems are reversible by changing behavioral patterns. Such conditions include:

Maintain a healthy weight. Women who are either over- or underweight are at risk for fertility failure, including a lower chance for achieving success with fertility procedures. Everyone should have a diet rich in fresh fruits and vegetables and whole grains and low in saturated fats.
Stop smoking. Smoking increases the risk for infertility in both men and women, and poses a future health risk for the mother and infant. Everyone should quit.
Avoid caffeine and alcohol.
Avoid excessive exercise if it causes menstrual irregularity. However, moderate and regular exercise is essential for good health. Few women exercise to the extent that their periods are affected. For those who do, one study found that simply adding calories can restore menstruation in many cases.
Don't use electric blankets. In one study, a 74% higher incidence of spontaneous abortion was associated with using an electric blanket during the month of conception. There was no association with heated waterbeds or electromagnetic waves.
Avoid any unnecessary medications.

There is no evidence of harm to a developing fetus from low exposure to microwaves or electromagnetic waves. Women who remain anxious may derive comfort by avoiding some of these devices (such as cellular phones or electric blankets) and remaining a foot or so away from others (such as computers or microwave ovens).

Both male and female hormone levels fluctuate according to the time of day, and they vary from day to day and month to month. Some timing tips might be helpful.

Male Hormone Levels and Sexual Activity. Male hormone levels are highest in the morning. (Sexual interest also tends to be higher in the morning.) In one study of men, their sexual activity was highest in October, when conception rates were also high.

Fertility and Seasonal Changes. Different studies have reported higher sperm counts in the winter than in the summer. For women, fertility rates as measured by treatment success are highest in months when days are longest.

Monitoring Basal Body Temperature. To determine the most likely time of ovulation and therefore the time of fertility, a woman is instructed to take her body temperature, called her basal body temperature. This is the body's temperature as it rises and falls in accord with hormonal fluctuations.

Each morning before rising, the woman takes her temperature with a specialized basal body thermometer and marks the result on a graph-paper chart.
The woman also notes the days of menstruation and sexual activity.
The so-called "fertile window" is 6 days long, starts 5 days before ovulation, and ends the day of ovulation.
The chances for fertility are considered to be highest between days 10 and 17 in the menstrual cycle (with day 1 being the first day of the period, and ovulation occurring about 2 weeks later). However, cycles vary from woman to woman. Researchers suggest that women track the length of their cycles, which can run anywhere from between 19 and 60 days. A long cycle, for example, suggests a delayed ovulation date.
Immediately after ovulation the body temperature increases sharply in about 80% of cases. (Some women can be ovulating normally yet not show this temperature pattern.)

By studying the temperature patterns after a few months, couples can begin to anticipate ovulation and plan their sexual activity accordingly. Couples must try to avoid becoming fixated on the chart, however, in scheduling their sexual activity. Spontaneity can be lost, and the stress on the relationship can be quite severe.

Hormone Monitoring Systems. A device called a saliva fertility monitor (Fertility Tracker) uses a microscope to view slides containing saliva and monitors estrogen levels. Home test kits that monitor reproductive hormone levels in the urine (ClearBlue) are also available. They are less costly than the saliva test but are messier. Monitoring hormones levels helps to determine when a woman is ovulating.

Frequency of Intercourse. The question of how often a couple should have intercourse is in debate. Some doctors say that having sex more than 2 days a week adds no benefits. Moreover, frequent sexual activity lowers sperm count per ejaculation. Other studies have indicated, however, that having intercourse every day, or even several times a day, before and during ovulation, improves pregnancy rates. Although sperm count per ejaculation is low, a constantly replenished semen supply is more likely to result in a fertilized egg.

The fertility process is a roller coaster of emotions that are present throughout and in both failure and success. There are almost no sure ways to predict which couples will eventually conceive. Some couples with multiple problems will overcome great odds, while other, seemingly fertile, couples fail to conceive. Many of the new treatments are remarkable, but a live birth is never guaranteed. The emotional burden on the couple is considerable, and some planning is helpful.

Planning for Emotional Turmoil.

Decide in advance how many and what kind of procedures will be emotionally and financially acceptable and attempt to determine a final limit. Fertility treatments are expensive. A successful pregnancy often depends on repeated attempts.
Determine alternatives (adoption, donor sperm or egg, or having no children) as early as possible in the fertility process. This can reduce anxiety during treatments and feelings of hopelessness in case conception does not occur.

Managing Emotional Stress During the Process. Managing negative emotions can be viewed as important as medical treatment. The following are some ways women reduce stress while trying to conceive:

Talking to one's spouse, family, and friends is very beneficial. The best support comes from the spouse. Studies suggest that a positive attitude on the husband's part is essential for enabling his wife to deal effectively with either the success or failure of fertility treatments. Men and women may cope differently with the stress, and each should understand the other's special needs. Women tend to want greater personal space and also to want to share the burden with their husbands. Men tend to cope by seeking to improve themselves (for example being strong, or being the "best").
Almost half of women seeking fertility treatments practice good-luck rituals, including praying and wearing charms or special jewelry. No evidence exists that these practices increase fertility, but they may help reduce anxiety and enhance a sense of control.
Cognitive-behavioral therapy, which uses methods that include relaxation training and stress-management, have been associated with higher pregnancy rates. (In one study, 42% became pregnant without medical intervention.)
Attending support groups or counseling services before and after treatment helps many women endure the process and ease the grief should treatment fail. One study indicated that pregnancy rates were twice as high in women who coped with their depression by reaching out to others rather than repressing guilt or rage. (These results held only in cases in which women, not their mates, were infertile.)
Acupuncture may help some women. Some evidence suggests that this alternative treatment has beneficial effects on chemicals in the brain involved with stress and reproduction. Acupuncture is safe, but studies have been mixed on whether it can help improve pregnancy rates. One study indicated that women who received acupuncture achieved significantly higher success rates during fertility treatments (42.5%) than those who did not receive it (26.3%). Several 2006 studies suggested that acupuncture may improve pregnancy success for women who undergo in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) procedures. One of these studies found that acupuncture had a positive effect if it was given during the luteal phase (post-ovulatory period of menstrual cycle.) Another study suggested that acupuncture should be given on the day of embryo transfer.

Managing the Emotional Effects of the Outcome. After enduring the process, the couple must face the outcome, and even a positive outcome has emotional repercussions.

Effects of Failure. The emotional stress of failure can be devastating even on the most loving and affectionate relationships and even in those who have prepared for the possibility of failure. Neither the male nor female partner should hesitate to seek professional help if the emotional burdens are too heavy.
Effects of Genetic Testing. As advanced technologies allow testing and greater genetic information at the earliest stage, potential parents will have to learn to deal with the uncertainties of possible chromosomal abnormalities, which may or may not be significant.
Effects of Successful Treatments. Some studies have indicated that even if successful, some women experience higher stress and fear of failure during pregnancy. According to one study, however, women who achieved pregnancy using fertility treatments felt increasingly better and had higher self esteem and less anxiety as the pregnancy progressed than women whose pregnancies were not due to medical intervention.
Effects of Multiple Births. A successful pregnancy that results in a multiple birth introduces new complexities and emotional problems. One study reported a very high rate of depression in women with triplets, particularly if they had little help from others, and especially if their husbands weren't involved.
Effects on Parenting. Once the fertility treatment-assisted child arrives, parents (both men and women) are more likely to be anxious and to have less confidence than those who conceive naturally.

Medications

Fertility drugs are often used alone as initial treatment to induce ovulation. If they fail as sole therapy, they may be used with assisted reproductive procedures or artificial insemination to produce multiple eggs, a process called superovulation.

Clomiphene citrate (Clomid, Serophene) is usually the first fertility drug of choice for women with infrequent periods and long cycles. Unlike more potent drugs used in superovulation, clomiphene is gentler and works by blocking estrogen, which tricks the pituitary into producing

follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This boosts follicle growth and the release of the egg. Clomiphene can be taken orally, is relatively inexpensive, and the risk for multiple births (about 5%, mostly twins) is lower than with other drugs.

Women with the best chances for success with this drug are those who have the following conditions:

Polycystic ovarian syndrome (PCOS)
Ability to menstruate but irregular menstrual cycle

Women with poorer chances of success with this drug have the following conditions:

Infertility but with normal ovulation
Low estrogen levels
Premature ovarian failure (early menopause)

One or two tablets are taken each day for 5 days, usually starting 2 - 5 days after the period starts. If successful, ovulation occurs about a week after the last pill has been taken. If ovulation does not occur, then a higher dose may be given for the next cycle. If this resgimen is not successful, treatment may be prolonged or additional drugs may be added. Doctors usually do not recommend more than 6 cycles.

Clomiphene often reduces the amount and quality of cervical mucus and may cause thinning of the uterine lining. In such cases, other hormonal drugs may be given to restore thickness. Other side effects of clomiphene include ovarian cysts, hot flashes, nausea, headaches, weight gain, and fatigue. There is a 5% chance of having twins with this drug, and a slightly increased risk for miscarriage.

If clomiphene does not work or is not an appropriate choice, gonadotropin drugs are a second option. Gonadotropins include several different types of drugs that contain either a combination of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), or only FSH. Clomiphene works indirectly by stimulating the pituitary gland to secrete FSH, which prompts follicle production. In contrast, the gonadtropin hormones directly stimulate the ovaries to produce multiple follicles.

Gonadotropins are given in a shot. (Your doctor may show you how to self-administer the injection.) Gonadotropins include:

Human Menopausal Gonadtropins (hMG), also called menotropins
Human Chorionic Gonadotropins (hCG)
Urofollitropin and Follitropin, natural and synthetic forms of FSH
Gonadotropin-releasing hormone (GnRH) analogs, which include GnRH agonists and GnRH antagonists

Gonadotropin drugs are either natural compounds extracted from urine or synthetic compounds that are genetically engineered in a laboratory using recombinant DNA.

Human Menopausal Gonadotropin (hMG). HMG drugs, also called menotropins, contain a mixture of both FSH and LH. These drugs (Pergonal, Repronex, Metrodin, Humegon) are all derived from the urine of postmenopausal women. HMG is administered as a series of injections 2 - 3 days after the period starts. Injections are usually given for 7 - 12 days, but the time may be extended if ovulation does not occur. In such cases, a shot of human chorionic gonadotropin (hCG) may trigger ovulation.

Human Chorionic Gonadotropin (hCG). Human chorionic gonadotropin (hCG) is similar to LH. It mimics the LH surge, which stimulates the follicle to release the egg. Natural hCG drugs, derived from the urine of pregnant women, include Pregnyl, Profasi, Novarel, APL, Chorex, and Follutein. Ovidrel is the only available genetically modified hCG drug. Ovidrel has fewer side effects at the injection site, and its quality can be better controlled than the natural drugs. It is generally used after hMG or FSH to stimulate the final maturation stages of the follicles. Ovulation, if it occurs, does so about 36 - 72 hours after administration.

Urofollitropin and Follitropin. Urofollitropin (Bravelle, Fertinex) is a purified form of FSH, derived from the urine of postmenopausal women. Follitropin drugs (Gonal-F, Follistim) are synthetic versions of FSH. These FSH drugs are sometimes given in combination with an hCG drug.

GnRH Analogs (Agonists or Antagonists). Gonadotropin-releasing hormone (GnRH) is a hormone produced in the hypothalamus part of the brain. GnRH stimulates the pituitary gland to produce LH and FSH. GnRH analogs are synthetic drugs that are classified as either agonists or antagonists. They are similar to natural GnRH but have very different actions. While natural GnRH stimulates LH and FSH, these drugs actually prevent the LH and FSH surge that occurs right before ovulation. This action helps prevent the premature release of the eggs before they can be harvested for assisted reproductive technologies.

GnRH agonists include leuprolide (Lupron), nafarelin (Synarel), and goserelin (Zoladex).
GnRH antagonists include ganirelix (Antagon) and cetrorelix (Cetrotide). GnRH antagonists suppress FSH and LH more than GnRH agonists, and they may require fewer injections.

Women with endometriosis often have an especially hard time getting pregnant. A 2006 review suggested that GnRH agonists may help women with endometriosis quadruple their chances of becoming pregnant when the drug is used 3 - 6 months prior to in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). [See In-Depth Report #74: Endometriosis.]

Multiple Births. Overproduction of follicles can lead to ovarian enlargement. This event increases the risk for multiple births. There is a 25% chance of multiple births (about 17% for twins and 8% for triplets and or more).

Ovarian Hyperstimulation Syndrome. The most serious complication with superovulation is ovarian hyperstimulation syndrome (OHS), which is associated with the enlarged ovary (although the precise cause is unknown). This can result in dangerous fluid and electrolyte imbalances and endanger the liver and kidney. OHS is also associated with a higher risk for blood clots. In rare cases, it can be fatal. Symptoms include abdominal bloating, nausea, vomiting, and shortness of breath.

Bleeding and Rupture of Ovarian Cysts. Overproduction of follicles, if unchecked, may result in bleeding and rupture of ovarian cysts.

Cancer Concerns. There has been concern that clomiphene and gonadotropins may increase the risks for ovarian and breast cancer. Most evidence to date does not indicate that ovulation-stimulating drugs increase the risks for these types of cancers. However, more research needs to be done. Some studies suggest that clomiphene, which is chemically related to the breast cancer drug tamoxifen, may actually decrease the risk for breast cancer.

Progesterone. Progesterone is a hormone that is produced by the body during the menstrual cycle. Progesterone drugs are sometimes given to women who have experienced frequent miscarriages (a possible sign of progesterone deficiency). A progesterone drug may also be given after egg retrieval during an in vitro fertilization (IVF) cycle to help thicken the uterine lining (endometrium) so it can better hold the egg following implantation.

Aromatase Inhibitors. Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues. These drugs include anastrozole (Arimidex) and letrozole (Femara). These drugs are used for treating breast cancer and are being investigated for stimulating ovulation in infertile women. Although letrozole is not approved for treatment of infertility, it has become widely used for this purpose in recent years. Some doctors were concerned that letrozole could increase the risk of birth defects. However, a major 2006 study indicated that letrozole does not increase risk to the fetus. The study compared the rate of birth defects among babies whose mothers conceived with letrozole and those who used clomiphene (the standard first-line fertility drug). Researchers found no differences in birth outcomes between the two groups.

Tamoxifen. Tamoxifen (Nolvadex) is a drug known as a selective estrogen-receptor modulator (SERM). It is used to prevent breast cancer in high-risk women. Studies suggest that it may equal clomiphene in its ability to induce ovulation. It may be especially useful when used along with IVF for preserving fertility in breast cancer patients. This drug is less expensive than clomiphene, but it poses some health hazards, including a risk for blood clots and uterine cancer.

Glucocorticoids. Glucocorticoids are steroid hormones that are sometimes used in combination with IVF and intracytoplasmic sperm injection (ICSI). It is thought that anti-inflammatory effect of these drugs can help make the lining of the uterus more responsive to egg implantation. However, a 2007 review indicated that glucocorticoids do not help improve pregnancy success rates and should not be used routinely with assisted reproductive technologies.

Regimens to induce ovulation vary widely according to individual need. A typical procedure, involving superovulation and in vitro fertilization (IVF) may be as follows:

Doctors make sure that the patient is not pregnant or in the luteal phase of her menstrual cycle (the premenstrual period).
Injections of either human menopausal gonadtropins, which contains luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or pure FSH are administered daily 2 - 4 days after day 1 of the next cycle. Either drug may be used.
After 4 - 8 days of treatment, estrogen levels are monitored. Increasing levels on the fourth day of treatment may be strong indicators of success. If estrogen levels indicate that ovaries are responding, ultrasound is then performed to detect possible overproduction of follicles. Such evaluation should then be conducted every 1 - 2 days and dosages adjusted accordingly.
Gonadotropin-releasing hormone analogs are used to prevent a premature release of LH hormone (and therefore ovulation). GnRH agonists are typically administered either early on or a few days after ovulation in the cycle previous to the one planned for IVF. This approach is referred to as the long protocol, and it serves to suppress the pituitary gland and allows time for the eggs to mature before harvesting. Other protocols using GnRH antagonists are under investigation, but to date the long protocol has the best pregnancy rates.
When at least three follicles have reached a diameter of 18 mm, human chorionic gonadotropins (hCG) is typically administered to release the egg. It is not given if there are signs of overproduction of follicles, which suggests a risk for ovarian hyperstimulation syndrome (OHS), a dangerous complication. (One study reported that giving high doses of progesterone to high-risk women the day of hCG administration may prevent OHS.)
Egg retrieval may be performed about 36 hours following hCG administration, with the transfer of the embryo (the fertilized egg) back into the woman 2 - 3 days after retrieval.
Embryos are transferred to the uterus through a small tube. This process does not require an anesthetic, although the procedure can cause cramping.

Natural (Unstimulated) In Vitro Fertilization Cycles. An alternative to superovulation for some couples is natural in vitro fertilization (IVF) cycles. It allows multiple, consecutive cycles of treatment. Natural IVF is far less expensive than standard hyperstimulation methods and avoids their risks, including multiple births and ovarian hyperstimulation syndrome (OHS).

The process involves ultrasound and hormonal monitoring starting 5 days before the estimated ovulation day.
No superovulation drugs are used, such as follicle-stimulating hormone (FSH) and human menopausal gonadtropins (hMG). The doctor, however, may administer an injection of human chorionic gonadotropins (hCG) to stimulate the luteinizing hormone (LH) surge.
The egg retrieval timing is based on detecting LH surge.
A single egg is retrieved. The procedure that follows is similar to other IVF cycles.

The basic disadvantage to this approach is that the eggs may be released before there is a chance for them to be harvested. Women report far lower stress levels with this approach, however, even though it requires more treatment cycles. In one study, the live-birth rate was 32%. Not all women are appropriate candidates, however. Women should have regular menstrual cycles and infertility of unknown cause or associated with problems in the fallopian tubes. Pregnancy rates are still very low in older women.

Clomiphene. Another gentler alternative to superovulation is the use of clomiphene before IVF, which works slightly better than unstimulated IVF.

Assisted Reproductive Technologies

Assisted reproductive technologies (ART) are medical techniques that help couples conceive. These procedures involve either:

A couple’s own eggs or sperm
Donor eggs, sperm, or embryos

Fertilization may occur either in the laboratory or in the uterus. In the U.S., the number of live birth deliveries from ART increased by 128% between 1996 and 2002. More than 45,000 babies are now born in the U.S. each year using assisted reproductive technologies.

ART includes fertility drug treatments, artificial insemination (AI), in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and other procedures.

Artificial insemination (AI) is the least complex of the assisted reproductive technologies and is often tried first in uncomplicated cases of infertility. AI either involves placing the sperm directly in the cervix (called intracervical insemination) or into the uterus (called intrauterine insemination, or IUI). IUI is the standard AI procedure.

It is useful under the following circumstances:

When the woman's cervical mucus is unreceptive
When donor sperm are required
If the man's sperm count is very low
When unexplained infertility exists in both partners

Those in whom AI fails, couples with specific fertility defects, or older women may be candidates for more advanced reproductive technologies.

Pregnancy Rates. A review of 45 studies reported that in unexplained infertility cases, the per-cycle pregnancy rates were 4% for intrauterine insemination (IUI) alone and 8 - 17% per cycle for IUI combined with superovulation, a procedure that uses fertility drugs to bolster egg recovery.

Researchers in one study suggested IUI as a reasonable first option for many women under age 43. It is less expensive and poses less risk for multiple births than the more advanced assisted reproductive technologies (ART), such as in vitro fertilization. Although IVF procedures are more effective per cycle, couples tend to be able to afford more IUI cycles, so the pregnancy rates over time are very similar.

The Artificial Insemination Procedure. The AI procedure is as follows:

A woman usually (but not always) takes fertility drugs in advance.
The man must produce sperm at the time the woman is ovulating.
The sperm are subjected to certain so-called "washing" procedures. They are then inserted into the uterine cavity through a long, thin catheter.

The administration of fertility drugs and sperm retrieval is timed so that the process can coincide with ovulation.

About 71% of assisted reproductive technologies (ART) procedures now use in vitro fertilization (IVF) with the woman's own eggs. An in vitro procedure is one that is performed in the laboratory. Advances in these procedures have dramatically increased the rate of live births.

The best candidates for IVF are women with damaged fallopian tubes, and some experts believe it is a better option than attempting surgical repair. IVF is also used when infertility is unexplained or when the male partner has the infertility problem. A typical IVF procedure is as follows:

The doctor first induces superovulation using fertility drugs so that several eggs can be harvested from the ovary before they have been released from the follicles. Higher doses of fertility drugs for subsequent cycles do not appear to add any advantage in women who have a poor response the first time.
To harvest eggs, the doctor generally inserts a probe into the vagina and is guided by ultrasound. A needle is then used to drain the liquid from the follicles, and several eggs are retrieved.
The eggs and sperm are combined in a Petri dish. Between 48 - 72 hours later the eggs are usually fertilized.
The resulting embryos (the first stage toward the development of the fetus) are reimplanted into the woman's uterus.
It takes about 2 weeks to determine if the process is successful.

IVF success rates for the first three cycles of treatment are about equal. They then decline modestly for the fourth cycle and drop significantly after the fifth cycle.

Gamete/Zygote Intrafallopian Transfer. Gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT) are adaptations of IVF. GIFT and ZIFT are used in unexplained female infertility and in mild male infertility. The success rates are similar to those of IVF, but a woman must have at least one functioning fallopian tube.

GIFT: The procedure is as follows:

The eggs are harvested as in IVF.
They are mixed with the sperm but not actively fertilized.
They are immediately injected back into the woman. Laparoscopy, a technique that employs a miniature viewing device, is used with this procedure to guide the placement of the embryos or egg through a long, thin catheter into the fallopian tubes.
The sperm and egg are placed exactly where they would be in natural fertilization.

ZIFT: The procedure is as follows.

The eggs are harvested as in IVF.
They are then mixed with the sperm and, in this case, are fertilized in the laboratory.
They are then implanted in the fallopian tubes as in GIFT. (The advantage of this procedure over GIFT is that the doctor and couple are assured that fertilization has taken place, and the eggs can be examined for defects before implantation.)

In 2002, more than 45,000 American babies were born using in vitro fertilization (IVF). Success rates have increased in all age groups (although they are still considerably lower in older than in younger women). Chances for assisted reproductive technologies (ART) success are also greater among women who do not have uterine abnormalities and have had previous successful pregnancies.

Success rates are also higher or lower depending on whether the woman uses her own eggs or whether they are donated and also whether the eggs are fresh or frozen. The highest live birth rates are with donated fresh eggs (an average of 50% per transfer). The lowest rates are when a woman uses her own frozen eggs (an average of 29% per transfer). However, using frozen eggs is less expensive than fresh eggs, so a couple may be able to afford more cycles with frozen eggs.

Use of Donor Eggs. Older women are more likely to use donor eggs. In a 2002 study, success rates were the same for women who used donors with an age range of 20 - 40. There were also no differences in delivery rates for recipients up to age 45. Women over 45, however, increasingly had problems with implantation, pregnancy, and delivery.

Use of Frozen Eggs. Frozen eggs tend to have lower success rates because of toxins released by cells damaged in the freezing and thawing tissues.

Intracytoplasmic sperm injection (ICSI) is an assisted reproductive technology used for couples when male infertility is the main problem. It involves injecting a single sperm into an egg obtained from in vitro fertilization (IVF). The procedure is very simple:

A tiny glass tube (called a holding pipet) stabilizes the egg.
A second glass tube (called the injection pipet) is used to penetrate the egg's membrane and deposit a single sperm into the egg.
The egg is released into a drop of cultured medium.
If fertilized, the egg is allowed to develop for 1 - 2 days, then it is either frozen or implanted.

The greatest concern with this procedure has been whether it increases the risk for birth defects. However, several studies have reported no higher risks of birth defects in children born using ICSI procedures. While some studies have shown a higher number of birth defects in children conceived with ICSI, experts think that this may have more to do with the genetic background of the parents than ICSI itself. Recent research suggests that ICSI children develop normally. A 2006 study of 8-year-old children conceived with ICSI found no important differences between these children and children who were conceived naturally.

A 2007 study in the New England Journal of Medicine indicated that ICSI use has increased 5-fold over the past decade, even though the proportion of men receiving treatment for male infertility has remained the same. In 1995, 11% of IVF cycles used ICSI. By 2004, 57.5% of IVF cycles used ICSI. Doctors caution that while ICSI is an important assisted reproductive technology for male infertility, it may be overused. Some doctors recommend ICSI for women who have failed prior IVF attempts or who have few or poor-quality eggs, even if their male partners have normal semen measurements. There is little evidence that ICSI helps improve pregnancy success for couples who do not have a problem with male factor infertility, according to the Society for Assisted Reproductive Technology.

In Vitro Maturation. A technique called in vitro maturation allows fertilization without the use of fertility drugs. In this process, follicles are harvested a few days before ovulation. In such cases, up to 50 have already begun to mature. At this time, about 15 of these maturing follicles can be removed, out of which 2 or 3 can produce healthy embryos.

Blastocyst Transfer. Blastocyst transfer is very promising. Instead of implanting the standard 2- or 3-day-old embryos in the uterus, the procedure implants blastocysts, which are more complex, 5-day-old embryos. Fewer blastocysts than embryos need to be implanted, reducing the risk for multiple births. (There is, however, a higher risk for identical twins compared to other procedures.) Offspring may be more likely to be males than females. Pregnancy rates are about 36% with a first attempt but then drop significantly. The procedure is more likely to be successful in younger than older women.

Ooplasmic Transfer. Ooplasmic transfer is a controversial experimental procedure that uses the woman's own egg and a female donor's egg and the male sperm for fertilization. Genetic material from the donor's egg plus the sperm are added to the woman's own egg. This has been successful in a few cases, but studies are very early and long-term effects are unknown. Research on this and similar procedures is currently conducted outside the U.S.

Complications of Assisted Reproductive Technologies

Since assisted reproductive technology (ART) procedures have become more widespread since 1980, multiple births have significantly increased. About 35% of all ART births are multiple ones, with 4.3% being triplets or more. Multiple births increase the risk of complications, for both the mother and the child.

Assisted reproductive technology (ART), and multiple births, increase the risks for pregnancy complications. According to a 2005 study, the type of complications may depend on the infertility treatment:

Fertility drugs. Increase risks of the placenta becoming detached from the uterus (“placental abruption”), third trimester miscarriage, and gestational diabetes.
In vitro fertilization. Increase risks of placental abruption, the placenta developing in the lower section of the uterus (“placenta previa”), dangerously high blood pressure during pregnancy (“pre-eclampsia”), and Caesarean sections.

Multiple births can also increase the risk of pregnancy death. A 2006 study indicated that women who carry multiple fetuses have a 3.6 times greater risk of dying from pregnancy complications than women with singleton pregnancies. The leading causes of death were blood clot (embolism), high blood pressure complications, excessive bleeding (hemorrhage), and infections.

The main risks for children conceived with assisted reproductive technology (ART) are complications associated with pregnancy problems and multiple births. Children conceived with ART are more likely to be born premature and to have extremely low birth weight. These conditions increase the risk for heart and lung problems, as well as learning and developmental disabilities. Premature delivery is also associated with cerebral palsy, a brain injury condition that affects muscle coordination. A 2006 study indicated that children born after in vitro fertilization have an increased risk for cerebral palsy.

However, studies suggest that ART does not increase the risk for chromosomal damage or other major birth defects. Couples undergoing ART may have other factors, such as older age or genetic predispositions, which make complications more likely. Infertility itself, even without ART, can pose a risk factor for birth defects. Children conceived naturally by couples with infertility problems tended to have more disorders of the nervous system, digestive system, and musculoskeletal system than children born to fertile couples, according to a 2006 study in the British Medical Journal. Children born to couples treated for infertility with ART may also have a slightly increased risk for these problems, as well as genital organ malformations, but the overall risk for birth defects appears to be very small.

ART remains a good option for many infertile couples. The likelihood of having a healthy single child of normal birth weight using ART is about 94%. The likelihood of having a child free of major birth defects is about 91%. Frozen eggs do not appear to pose any higher risk for developmental problems.

Preimplantation genetic diagnosis (PGD) is now available in some fertility centers. It can help identify genetic defects in the offspring and may help parents determine future problems. Such testing, however, also raises significant emotional issues that should be addressed beforehand.

Given the hazards of multiple births, parents must make some hard decisions if the treatment produces multiple embryos. The choices are limited:

Carry all of them to term, which increases health risks for both the mother and the developing fetuses
Complete abortion
Embryo reduction, in which the doctor removes one or more embryos (possibly endangering the remaining embryos)

At this time, the best approach is to limit the number of implanted embryos in the first place. Researchers are attempting to develop methods to reduce the risk for multiple births:

Most centers now implant two to three embryos at a time, and the remainder can be frozen for future use. (Frozen eggs do not appear to pose a risk for developmental problems in children conceived using them.) This limits the chance for success, but implanting more than three embryos only increases success rates very slightly, whereas the risk for multiple births increases significantly.
Reducing the dosage of fertility drugs also reduces the risk for multiple births, but not significantly, and it also reduces the chance for successful outcome.
Blastocyst transfer may help reduce the chances for multiple births.

Resources

www.resolve.org -- National Infertility Association
www.asrm.org -- American Society for Reproductive Medicine
www.theafa.org -- American Fertility Association
www.endometriosisassn.org -- The Endometriosis Association
www.acog.org -- American College of Obstetricians and Gynecologists
www.endo-society.org -- The Endocrine Society
www.aace.com -- American Association of Clinical Endocrinologists
www.cdc.gov/reproductivehealth/index.htm -- Centers for Disease Control: Assisted Reproductive Technology Reports

References

Boomsma CM, Keay SD, Macklon NS. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005996.

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Iron intake and risk of ovulatory infertility. Obstet Gynecol. 2006 Nov;108(5):1145-52.

Dieterle S, Ying G, Hatzmann W, Neuer A. Effect of acupuncture on the outcome of in vitro fertilization and intracytoplasmic sperm injection: a randomized, prospective, controlled clinical study. Fertil Steril. 2006 May;85(5):1347-51.

Hvidtjorn D, Grove J, Schendel DE, Vaeth M, Ernst E, Nielsen LF, et al. Cerebral palsy among children born after in vitro fertilization: the role of preterm delivery--a population-based, cohort study. Pediatrics. 2006 Aug;118(2):475-82.

Jain T, Gupta RS. Trends in the use of intracytoplasmic sperm injection in the United States. N Engl J Med. 2007 Jul 19;357(3):251-7.

Jensen A, Sharif H, Svare EI, Frederiksen K, Kjaer SK. Risk of breast cancer after exposure to fertility drugs: results from a large Danish cohort study. Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1400-7. Epub 2007 Jun 21.

Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006 Jun 20;24(18):2917-31.

Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66.

Mackay AP, Berg CJ, King JC, Duran C, Chang J. Pregnancy-Related Mortality Among Women With Multifetal Pregnancies. Obstet Gynecol. 2006 Mar;107(3):563-568.

Ombelet W, Martens G, De Sutter P, Gerris J, Bosmans E, Ruyssinck G, et al. Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study. Hum Reprod. 2006 Apr;21(4):1025-32.

Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004635.

Shevell T, Malone FD, Vidaver J, Porter TF, Luthy DA, Comstock CH, et al. Assisted reproductive technology and pregnancy outcome. Obstet Gynecol. 2005 Nov;106(5 Pt 1):1039-45.

Smith C, Coyle M, Norman RJ. Influence of acupuncture stimulation on pregnancy rates for women undergoing embryo transfer. Fertil Steril. 2006 May;85(5):1352-8.

Terry KL, Willett WC, Rich-Edwards JW, Michels KB. A prospective study of infertility due to ovulatory disorders, ovulation induction, and incidence of breast cancer. Arch Intern Med. 2006 Dec 11-25;166(22):2484-9.

Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril. 2006 Jun;85(6):1761-5.

Westergaard LG, Mao Q, Krogslund M, Sandrini S, Lenz S, Grinsted J. Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective, randomized trial. Fertil Steril. 2006 May;85(5):1341-6.

Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ. 2006 Sep 30;333(7570):679. Epub 2006 Aug 7.

Review Date:
10/29/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Kit Kittredge: An American Girl: Interview with Chris O'Donnell

LilSugar — Tue, 17 Jun 2008 08:00:25 -0700

He caught our eye as Charlie Simms, the kind hearted collegian, playing opposite Al Pacino in Scent of a Woman and young ladies swooned when he broke up a Circle of Friends as Jack Foley. Chris O'Donnell is the quintessential American male with conventional good looks, smarts and the friendly disposition of the boy, now man, next door. He's the kind of guy that men and mothers like. And, he's the only actor that made us believe that Meredith might pass up McDreamy.

The real life father of five - Lily, 8, Chip, 7, Charlie, 4, Finley, 2 and Maeve, 6 months - who is married to wife, Caroline, is spending the summer on the silver screen as Mr. Kittredge in Kit Kittredge: An American Girl starring Abigail Breslin. The scenes between the dapper dad and his precocious daughter who face hardship during the Great Depression leave a lump in your throat. We recently had a chance to chat with the actor about his latest film.

There are two moments in the film, when Kit spots her dad in the soup kitchen and the ensuing conversation they have by the tree-house, that have an incredible impact on the audience. It's that notion of a parent not being able to provide for his children. How did you prepare for the scene?

I've got kids of my own; We all love our parents and we love our spouses, but until you have your own kid you don't really know what that kind of love is. It's where you would put yourself in front of a moving train for your kid and I think that you understand what that must have felt like. Mr. Kittredge's trying to protect his daughter as most parents do and not have her worry about the hardships of what was going on in their time. And when she sees him in the soup kitchen, he's forced to tell her a little bit more about what the realities are and what they are going to have to do. He tries to put the best spin on it or prepare her for it by telling her that story about his car - don't let it beat ya, and as parents that's about all you can do. It's a situation where he has to go off to find work.

To see the actor's fears as a father, read more.

In that same vein, as the father of five who found early success much like Mr. Kittredge, is being able to provide for your children a legitimate fear of yours, or do you have others?

What's tough for me is when I'm away on location because in my business it's feast or famine when it comes to spending time with my kids. I either have more time than I know what to do with or I don't have any time with them, so I try to maximize my time when I'm with them. But when I'm away on location, thank God for Apple iChat because I can see them on the computer. It's scary - part of being a parent is trying to teach the kids the lessons they need to learn. And sometimes, the kid comes home and asks you a question and you're kind of stalling thinking what's the answer that I am supposed to give here. I'll be calling my older brothers or sisters and asking what do we tell them about this again? Because you realize they are coming to you for all this information and most of it is instinctual, but every once in a while they'll come up with something and you'll think that's a tricky one. You know, let me get back to you on that one.

It's been said that you did Batman for your sons and this movie for your daughters? Is Lily a fan of the American Girl series?

She is a fan and I knew about it because I'm from Chicago and I had visited the store before with my nieces and now with my daughter and we've got a lot of the dolls and that sort of thing. I was highly aware of the whole American Girl phenomenon and I think that for people that do know about the dolls they are going to be so excited about the movie. And, for everyone else that wants to take their kids to a movie on the weekend, they are going to be really pleased because there's so many times that kids want to go to a movie and I can't tell you how many bad family movies I've sat through. This one really works; It's a great ride. It teaches kids a great lesson and they don't even realize they are being taught a lesson. When I left the theater with my daughter, she started asking me all about the people who lost their houses and it was great to have brought that subject up especially now - it's going to be so timely.

Do you think there's a difference between the way kids are said to grow up fast today versus the way they did during The Great Depression?

We've had an incredibly successful run in the economy for the last however many years. I mean obviously it's stalled and heading in a recession now. Then, the economy starts to get tough and that trickles down and you kind of get back to basics. Certainly anyone who lives through a depression and my father did, they don't forget the lessons they learned the same way that the men and women that fought in WWII don't. People don't always have an appreciation of what happened unless they were there and I think that's what's so great about films and books. If you saw Band of Brothers you have such an appreciation for what these guys went though in that generation. And not to compare this to Band of Brothers, but I think it's a great way for kids to get some understanding of what the depression was about, what people went through in a way that they will be excited to see and learn about it.

You've gone from being the naive character in Scent of a Woman to the father in American Girl. Is that transition hard to take or a natural transition?

It felt like the role was easy for me to relate to because I've got an 8-year-old daughter and the emotions that Mr. Kittredge is feeling for his daughter - I just understood and connected with that. But it was the first time I played a parent and I've been doing this for a long time and you start to play different roles. I'm not the kid anymore and I'm a dad so it's just kind of a natural evolution.

The Kittredges lived by the motto, "Don't let it beat you." Do the O'Donnells have a motto?

I don't know that we have a motto. That's a pretty good one right there.

So you'll adapt that one?

We might have to.

We're celebrating Kit Kittredge: An American Girl with a special giveaway next week. Stay tuned for more details.

Source and Cylla von Tiedemann

Lyme disease and related tick-borne infections

FitSugar — Wed, 08 Oct 2008 17:35:15 -0700

In This Report

Highlights
Introduction
Symptoms
Risk Factors
Complications
Diseases with Similar Sympt...
Diagnosis
Treatment
Prevention
Human Granulocytic Anaplasm...
Babesiosis
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Lyme Disease Rates Double in Past 15 Years

The annual number of people newly infected with Lyme disease has doubled from around 10,000 cases per year in the early 1990s to about 20,000 cases per year now. Improved diagnosis and reporting probably contribute to this increase. In the United States, Massachusetts, New Jersey, and Pennsylvania have reported the highest number of Lyme disease cases in recent years. People ages of 5 - 14 years and 45- 54 years are at highest risk for contracting Lyme disease.

New Guidelines for Treatment of Neurological Lyme Disease

Most cases of Lyme disease can be prevented or cured with prompt antibiotic treatment following a deer tick bite. However, neurological complications can later develop in some patients. In 2007, the American Academy of Neurology released new guidelines for the treatment of nervous system Lyme disease. The guidelines recommend that patients with severe disease receive a 2 - 4 week course of intravenous antibiotics (penicillin, ceftriaxone, or cefotaxime). Patients with milder neurological cases may do well with a 2 - 4 week course of oral doxycycline. No guidelines currently recommend long-term antibiotic treatment for any stage or complication of Lyme disease.

Introduction

Lyme disease is the most commonly reported vector-borne disease in the United States. Vector-borne infections are transmitted by insects.

The Lyme disease infection in the U.S. is caused by a spirochete called Borrelia (B.) burgdorferi. A spirochete is a bacteria-like organism with a cylinder-like shape surrounded by an outer membrane.

Lyme researchers have the completion of DNA encoding of B. burgdorferi. Researchers learned that certain proteins coat its outer surface. These proteins, collectively called Osp, are responsible for attaching the spirochete to cells in humans and other mammals.

The vector that carries B. burgdorferi in the U.S. Northeast and North Central states is the Ixodes scapularis tick. The Ixodes scapularis tick goes through three stages over the course of about two years:

It is born from eggs as a larva.
It develops into the nymph stage.
It develops into the adult stage.

Cycle of Infection in the Northeast and North Central U.S. For Lyme disease to exist in these regions, three factors must come into close contact:

The Borrelia (B.) burgdorferi spirochete
The spirochete's host, the Ixodes scapularis tick
The mammal for the tick to bite

The following describes the most common cycle in the Northeast and North Central U.S. by which the Lyme disease infection eventually reaches a person:

The cycle of infection is related to the tick's life cycle, which requires 2 years to complete. The tick typically first picks up the spirochete during its larva stage, when it needs a blood meal to mature further.
The tick's initial meal is typically blood from the white-footed mouse, which is commonly infected with Borrelia burgdorferi. After it dines on the infected blood, the tick then becomes a carrier of this spirochete.
Borrelia burgdorferi lodges in the tick throughout one of both of its following life stages, nymph and adult. It is during these stages that the infection is passed on to other animals, including humans. Nymph ticks emerge around mid-June and can be about the size of poppy seeds. They are very difficult to spot and are estimated to be responsible for 90% of all Lyme disease cases. Adult ticks can be as large as a raisin after feeding, and easy to spot, but they usually prefer their dinner on the white-tailed deer.
The infected nymph or adult tick crawls (it does not fly or jump) onto another animal, which can be mice or larger animals, such as deer, birds, or humans. If the tick bites these animals, it may then infect them with the B. Burgdorferi spirochete. (It should be noted that infected humans cannot pass the spirochete on to other humans by any means, including infected blood or urine or sexual contact.)
A tick can feed for several days while being imbedded in the skin, after which it falls off. The tick's bite is painless, however, so only about half of people with Lyme disease recall being bitten.

Cycle of Infection in the Northwest. In the Northwest, the infecting insect is the Western blacklegged tick, Ixodes Pacificus. Here, the frequency of Lyme disease is much lower than in the other two regions because the animal carrier of the infection is the dusky-footed wood rat. This animal is bitten and infected by the Ixodes neotomae tick, which does not bite humans. The actual tick that spreads B. burgdorferi to people is Ixodes pacificus, which must feed first on an already infected wood rat.

The two other important infections carried by the Ixodes scapularis tick are human granulocytic anaplasmosis (HGA) and babesiosis. Although they are both borne by the same tick as Lyme disease, all three of these infections are entirely different diseases.

Risk for Coinfection. Because Lyme disease, HGA, and babesiosis can all be carried by the same tick, there is some risk for co-infection with two or more of these organisms. The risk, however, is not wholly known. Studies have reported that 2 - 25% of ticks in several high-tick locations carry both HGA and Lyme. In one study of patients located in high-risk areas in New England, 39% had more than one of these infections transmitted by the Ixodes tick. There is no evidence that co-infection with one or more of these infections causes a more severe condition than either infection separately.

Symptoms

Symptoms of Lyme disease are diverse and often occur in early and late phases. They vary widely from person to person. Any one symptom may fail to appear, and symptoms may overlap in various combinations. Death from Lyme disease is very rare and occurs only in a few cases in which the heart is severely affected.

Stage 1. In the majority of cases, the first sign of early Lyme disease is the appearance of a bull's-eye skin rash. It usually develops about 1 - 2 weeks after the bite, although it may appear as soon as 3 days, and as late as 1 month. In some cases, it is never detected. Flu-like symptoms (joint aches, fever, and general fatigue) commonly develop.
Stage 2. Untreated, the infection spreads through the bloodstream and lymph nodes within days to weeks, involving the joints, nervous system, and possibly the heart. Multiple rashes may erupt in other places. If the infection affects the nervous system in stage 2, it most often causes weakness or paralysis in the nerves of the face (Bell's palsy) or in nerves of the spine.
Stage 3. If the disease remains untreated, a persistent infection can occur after a few weeks or months, leading to prolonged bouts of arthritis and neurologic problems, such as concentration problems or personality changes. Fatigue is a prominent feature of both early and late stages.

Evidence suggests that up to 90% of patients with Lyme disease exhibit a rash a few days to a month after a tick bite. The rash, known as erythema migrans, usually first appears on the thigh, buttock, or trunk in older children and adults, and on the head or neck in young children.

The bull's eye rash, which is commonly believed to be the classic sign of Lyme disease, may take the following course:

It can first appear as a pimple-like spot, which expands over the next few days into a purplish circle. The circle may reach up to 6 inches in diameter with a deeper red rim. In some cases the ring is incomplete, forming an arc rather than a full circle.
The center of the rash often clears or may turn bluish. Or secondary concentric rings may develop within the original ring, creating the bull's-eye pattern. Over the next several weeks, the circular rash may grow to as large as 20 inches across.
Patients often describe the sensation of the rash as burning rather than itching.

It is important to note that in one study, only 9% of patients diagnosed with Lyme disease exhibited this classic pattern. Nearly 60% had a rash that was more general in appearance and 32% had a circular dense red rash.

In most patients, any rash fades completely after 3 - 4 weeks, although secondary rashes may appear during the later stages of disease.

A flu-like condition is the most common sign of Lyme infection, and it can occur with or without a rash. Symptoms can last from 5 - 21 days and may include:

Fatigue
Chills and fever (100 - 103° F)
Headache (usually most prominent at the back of the head)
Joint aches (usually in the large joints)
Stiff neck
Backache
Swollen glands (in the area around the tick bite or elsewhere)
Less often, nausea, vomiting, and sore throat occur

Some experts recommend that children in high-risk areas be tested for Lyme in the summer months if they have the most common Lyme symptoms (fever, headache, joint aches) -- even if they have no tell-tale rash. Severe and sustained flu symptoms without the rash in such patients may indicate the presence of human granulocytic anaplasmosis (HGA) or babesiosis -- the other infections carried by the Ixodes tick.

Joint pain can arise at any time after the appearance of a skin rash. In the absence of a rash, arthritic symptoms may be the first indication of Lyme disease. Or, as suggested by some studies, it can develop months after the disease has been diagnosed. Arthritic symptoms may occur as follows:

Aches, stiffness, and swelling, sometimes massive, of large joints, such as the knee, elbow, or shoulder. One or both knees are affected most often. The ankle, wrist, jaw, and finger joints are involved less often.
Typically, no more than three joints are affected during the course of the disease. If several joints are involved, they tend to be asymmetrically distributed.
Joint pain flare-ups are often accompanied by muscle pain.
Arthritis symptoms usually last for a few days or weeks and are interspersed with longer periods during which the joints feel fine.
The severity and frequency of attacks peak within 1 - 2 years then decrease and usually resolve, even without treatment.

About 15% of untreated patients develop neurologic symptoms. They can occur in all stages of the disease and can affect any part of the nervous system.

Common Early Neurologic Symptoms. Most often, neurologic symptoms first appear while the initial skin rash is still present or within 6 weeks after its disappearance. Sometimes they are the first symptoms that the patient experiences. The most common neurologic symptoms may be headaches, sleep problems, and mood disturbance. Memory problems can also occur. Neurologic symptoms typically improve or resolve within a few weeks or months, even in untreated patients.

Bell's Palsy. In 5 - 10% of untreated Lyme patients, the facial nerve is affected, which results in Bell's palsy. This is a sudden weakness and drooping of the facial muscles and eyelid on one side of the face. Nerves around the facial area may also cause numbness, dizziness, double vision, and hearing changes. Another common neurologic problem is pain in the lower spine. It resembles low back pain from arthritis (although in the case of Lyme disease the skin near the spine may have abnormal sensations). Of note, Lyme disease has been observed in more than half the children who develop Bell's palsy.

Symptoms of Meningitis. In about 10 - 15% of patients, the infection takes place in the membranes that surround the brain and spinal cord (called meningitis). This can cause:

Episodes of headache not relieved by over-the-counter medication
Mild stiff neck
Sensitivity to light

Symptoms of Lyme Encephalopathy. In some cases of untreated disease, the infection causes a condition called Lyme encephalopathy or neuroborreliosis. This causes the following symptoms:

Unexplained mood changes
Depression
Trouble concentration and remembering
Irritability
Feelings of "pins and needles" or numbness in the arms or legs

Other Neurologic Symptoms.

If the infection affects the white brain matter, symptoms resemble multiple sclerosis.
If the infection occurs in the nerves affecting the skin, some patients experience pricking, tingling, or creeping feelings.
Children have a higher risk than adults for neurologic effects on the eye. (This is still rare, however.)

The infection may affect electrical conduction to the heart and cause symptoms suggesting heart rhythm disturbances:

Palpitations
Shortness of breath
Chest pain
Dizziness
Fainting can occur if the infection affects the heart

These symptoms almost never produce serious problems in people without other types of heart disease.

Symptoms in the eyes have been reported at every stage. Conjunctivitis ("pink eye") may be a symptom in the early stages. In late, untreated Lyme disease, neurologic problems can affect the eye, causing pain and sensitivity to light.

Risk Factors

Since 1991, when Lyme disease became a reportable disease, annual cases have doubled. (This increase is probably both due to increased infection rates as well as better diagnosis.) In general, about 21,000 cases of Lyme disease are now reported in the U.S. each year.

Anyone exposed to ticks is at risk for Lyme disease and other tick-borne diseases. Pets are also at risk. Naturally, anyone who is regularly outside in areas where tick rates are high has a greater than average risk for becoming infected.

Age. The highest reported incidence of Lyme disease occurs among children 5 - 14 years old and adults 45 - 54 years old.

Sex. Men and women are equally at risk.

In general, the risk for developing Lyme disease after a tick bite is only between 1 - 3%. The risk varies depending on different factors:

The longer the tick has fed, the greater the risk. In fact, in one study, no individuals developed Lyme disease after being bitten by a nymph tick for fewer than 72 hours. The risk was 25% in people on whom the tick had been feeding for longer than 72 hours.
Nymph ticks carry a greater risk than adult ticks, probably because they are often too small to be detected (about the size of a pinhead). In addition, only nymph ticks that are at least partially swollen when removed pose any significant risk. (This suggests that they have feeding for a prolonged period.)

Locations in the U.S. Lyme disease has been reported in nearly all U.S. states. However, most Lyme disease cases are concentrated in the northeastern, mid-Atlantic, and north central states. Although Lyme disease was named for a town in Connecticut where the first American cases of the disease were described, in recent years Massachusetts, New Jersey, and Pennsylvania have reported the greatest number of cases.

Worldwide Locations. Pockets of Lyme disease exist around the world. The disease is common in Europe, particularly in forested areas of middle Europe and Scandinavia. The Borrelia family is also responsible for tick infections in Europe, but different subspecies (B. garinii and B. afzelii) may be more common there and cause slightly different symptoms. The infection has also been reported in Russia, China, and Japan.

Deer ticks thrive in grassy areas that have low sunlight and high humidity. Woodlands and fields are prime habitats, but these ticks can also be found in the long grasses adjacent to beaches. The ticks are not confined to rural settings. In suburban areas, they can live in overgrown lawns, groundcover plants, and leaf litter.

The exact time of year for risk depends on a geographic region’s seasons and how they affect the tick’s breeding cycle. In general, the highest risk for Lyme disease onset is from June through August, and the lowest risk is from December through March.

Complications

Prompt treatment with antibiotics is very effective in curing Lyme disease in nearly all infected people, including children. One study showed that the long-term outcome of patients with Lyme disease who are treated with antibiotic therapy is excellent. However, even if Lyme disease has been successfully treated, it may be possible to become reinfected with Lyme disease again at a later date. The risk appears to occur only in patients who had been treated for the rash. In those who also developed arthritic symptoms, the antibody response appears to persist and prevent reinfection.

People at highest risk for persistent symptoms are those who go the longest before treatment. Fortunately, public vigilance has significantly reduced the rates of late-stage Lyme disease. Antibiotics given at late stages will relieve symptoms in most people, although about 5% may continue to have problems. Also at risk for persistent symptoms are those who show evidence of having severe infections. Retreatment at later stages has been shown to be effective in about three quarters of these patients.

Left untreated, Lyme disease can spread (disseminate). The infection may affect almost any part of the body and cause the following complications:

Severe arthritis
Persistent fatigue
Mood disturbances and loss of concentration
Neuropathy (numbness, tingling, or other odds sensations in the hands, arms, feet or legs)
Life-threatening disorders affecting the heart, lungs, or nervous system can occur, but are very rare.

Arthritis. Without treatment, 60% of patients develop intermittent joint inflammation, especially in the knees. Lyme arthritis usually responds to a 28-day course of oral antibiotics (doxycycline, amoxicillin, or cefuroxime). A small number of patients may require intravenous antibiotics.

If the arthritis persists or joint swelling recurs after several months, patients may be treated by another 4-week course of oral antibiotics or 2 - 4 weeks of intravenous antibiotics (ceftriaxone). If symptoms still persist, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid injections, or disease-modifying antirheumatic drugs may be recommended by a rheumatologist. In severe cases, patients may require surgery (synovectomy) to reduce joint inflammation.

Persistent Neurological Disorders. In general neurological problems persist in 5% of patients, although some studies have reported much higher rates of up to 50%. Persistent symptoms usually include headache, attention and memory problems, and depression. Patients may also experience neurologic pain, numbness, or abnormalities in the face. Neurologic symptoms generally resolve and improve within a year.

Heart Problems. About 5% of untreated patients experience acute heart events from electrical conduction problems caused by the infection. Heart symptoms can appear within a few days to several months after the onset of disease. They include:

Arrhythmias (irregular heartbeats)
Pericarditis (inflammation of the lining of the heart), which occurs in about 5% of patients

Lyme-related heart problems almost always resolve without serious consequences within a week. About 30% of patients may need a temporary pacemaker, however. In very rare cases, these heart rhythm abnormalities have been fatal. There is some debate about whether there are any long-term consequences to the heart, such as the development of heart failure in some patients. One study of patients who had Lyme-related heart effects reported no greater long-term risk for heart problems than in people without a history of Lyme disease.

Miscellaneous Complications. Other complications reported include:

Problems in the eye, including swelling that can cause pain and sensitivity to light
Hepatitis (inflammation in the liver)
Respiratory difficulties

Infections in the Pregnant Patient. The occurrence of any infection during pregnancy is of special concern. While the current research indicates that complications during pregnancy due to Lyme disease are very rare, pregnant women should still adhere scrupulously to preventive measures.

Some studies indicate that Borrelia burgdorferi may be transmitted to the fetus during pregnancy, with the risk highest during the first trimester. If this occurs, however, it is likely to be very rare and not an issue of great concern. There is no evidence of any severe effects in the offspring of infected pregnant women.
There are no reports of human infant Lyme disease infection from breast-feeding. Studies on animals, however, have reported transmission of the organism to infant mice through breast milk, but these findings do not appear to be applicable to people.

Lyme disease is a curable condition. Nearly all patients (95%) improve after a short course of antibiotics. In very rare cases, patients continue to complain of persistent non-specific symptoms, such as fatigue, muscle aches, cognitive problems, and headache lasting years after completing antibiotic treatment for the initial infection.

This syndrome, which resembles chronic fatigue syndrome (CFS) or fibromyalgia, is referred to as post-Lyme disease syndrome. In the past, it has been called “chronic Lyme disease.” However, based on many reviews of scientific literature, experts strongly believe that Lyme disease does not have a chronic state. According to the 2006 guidelines from the Infectious Diseases Association of America, post-Lyme disease syndrome is the preferred name for this condition.

Patients are considered to have this syndrome if they still have symptoms 6 months after treatment. Most importantly, there must be definitive evidence that the patient was originally infected by the B. burgdorferi spirochete. If there is no documented evidence of infection, it could be that the patient never had Lyme disease, or may be experiencing a new or different type of illness. If the patient did have Lyme disease, symptoms should eventually resolve without additional antibiotic treatments.

Experts strongly advise against prolonged antibiotic treatment. There is no evidence that long-term antibiotics help treat post-Lyme disease syndrome symptoms. In addition, long-term antibiotic treatment carries its own serious risks, such as the development of antibiotic-resistant superbugs.

Diseases with Similar Symptoms

Many other illnesses can mimick various features of Lyme disease. Depending on the symptoms, a doctor may be able to perform the evaluations necessary to rule out other conditions.

Other infections can produce fever, headache, muscle aches, fatigue, and some of the neurologic or cardiac features of early Lyme disease. Some are transmitted by the same tick as Lyme disease.

Co-Infections Transmitted by the Ixodes Tick. Babesiosis and human granulocytic anaplasmosis (HGA) are transmitted by the same tick that carries Lyme disease. People may be co-infected with one or more of these infections, all of which can cause flu-like symptoms. If these symptoms persist and there is no rash, it is less likely that Lyme disease is present. Still, diagnosing a co-infection is difficult.

Other Spirochete Infections. Leptospirosis is a spirochete infection spread through animals or contaminated water that most often affects young people during the summer or fall.

Other Tick-Borne Infections. A number of other tick-borne diseases may resemble Lyme disease, although they are more common in parts of the U.S. where Lyme disease is less prevalent.

Tick-borne relapsing fever (TBRF), a flu-like illness that occurs in mountainous areas of the West during the summer, may be misdiagnosed as Lyme disease. The antibiotic doxycycline may be prescribed to patients who have been bitten by ticks suspected of carrying TBRF, to help prevent development of the disease.
Rocky Mountain spotted fever, which is also transmitted by ticks, is most prevalent in the south central and southeastern parts of the United States, but occurs throughout North and South America. The most characteristic symptom is a spotty rash that appears 5 - 10 days after infection. The disease is caused by ticks that carry the bacterial organism Rickettsia rickettsii, and is considered the most severe tick-borne illness in the United States. Unlike Lyme disease, which is rarely fatal, Rocky Mountain spotted fever causes death in 10% of all cases. Recent outbreaks of Rocky Mountain spotted fever have been linked to increases in wild dog populations.
A tick-borne infection called by human monocyte ehrlichiosis (HME), carried by the Lone Star tick, strongly resembles Lyme disease, including a similar rash. It is not caused by the Lyme spirochete, however, and has been identified in patients who live in the southern United States.

Researchers speculate that ticks may be responsible for other diseases not previously thought to be carried by these vectors. For example, the Bartonella family of bacteria causes cat-scratch fever (which is transmitted from cat to cat by fleas) and trench fever (historically transmitted by lice).

Allergic Reaction to the Tick. If a rash, even ring-shaped, appears hours rather than days after a tick bite, it is most likely an allergic reaction to the tick, not a symptom of Lyme disease.

Other Insect Bites. Not every rash seen in regions where Lyme disease is common is caused by a tick. The bites of many insects and spiders can cause a skin reaction.

A number of autoimmune diseases have chronic and low-level symptoms that may be confused with Lyme disease.

Systemic lupus erythematosus (SLE) produces a rash (usually on the face), flu-like symptoms, and arthritis, but they usually develop very slowly over time.
Rheumatoid arthritis or Reiter syndrome causes pain, swelling, or stiffness of the joints that may be confused with post-Lyme disease syndrome.
Scleroderma has a limited form of the disease called morphea, which produces hard patches of skin. Some studies have even reported an association between B. burgdorferi and some cases of morphea. However, the evidence is weak and if it exists it is possibly limited to a specific variant in Europe and Asia. There is no association between severe scleroderma and Lyme disease.
In children, juvenile rheumatoid arthritis or rheumatic fever, which follows strep throat, should be considered.

A number of conditions cause chronic fatigue and joint and muscle aches that resemble descriptions of post-Lyme disease syndrome:

Mononucleosis -- this viral infection is common in adolescents
Chronic fatigue syndrome (CFS)
Fibromyalgia
Depression (may include persistent fatigue and vague aches and pains)

The early neurologic symptoms of Lyme disease (headache, stiff neck, and fatigue) can easily be mistaken for viral meningitis. Children with viral meningitis are more likely to have a higher fever. Patients with Lyme disease often have other symptoms, such as the bull's-eye rash.

Diagnosis

Proper diagnosis of Lyme disease is important. A diagnosis of Lyme disease is straightforward if the patient meets the following criteria:

Lives in an area of tick-infestation
Has the tell-tale bulls-eye rash
Has other symptoms (headache, joint aches, malaise, flu-like symptoms)

If the patient meets all the criteria, except the rash, the doctor may undertake the enzyme-linked immunosorbent assay (ELISA) or the Western Blot test.

In some cases, if the patient seeks a diagnosis within the first 2 - 3 weeks, the doctor may take a sample of the skin or of the blood. If Lyme spirochete is present, it may be identified in the laboratory in a culture medium (a substance in which the organism can thrive and reproduce). This is necessary only if a doctor suspects Lyme but the diagnosis is not clear.

If the infection is not obvious from the patient's history and physical symptoms, but Lyme disease is suspected, the doctor may run tests for evidence of specific factors that suggest infection with B. burgdorferi. Such factors include:

Proteins referred to as Osps. These proteins (referred to as Osp A through F) coat the outer surface of the B. burgdorferi spirochete and then attach to human cells after infection.
Antibodies that attack these Osps. Antibodies are the weapons of the immune system that are launched when foreign invaders (called antigens) are detected. In the case of Lyme disease, these antigens are the Osps.

Specific Tests.

The U.S. Centers for Disease Control (CDC) recommends a two-step process for Lyme disease blood tests:

ELISA and Other Initial Tests. The first tests used are either enzyme-linked immunosorbent assay (ELISA) or an indirect fluorescent antibody (IFA) test. ELISA is the immune test used most often for Lyme disease. (The IFA test is less accurate but may be used when ELISA isn't available.) ELISA measures antibodies that are directed against the B. burgdorferi spirochete. A newer variant is a rapid test (PreVue) that can provide results within an hour. Positive results from any of these tests still require confirmation with a Western blot test. Negative results do not require further testing.
Western Blot. If any of these tests is positive or uncertain, they are followed by the Western immunoblot (WB). This test is more accurate and is very helpful in confirming the diagnosis. The Western blot creates a visual graph showing bands of different colors or shading that experts use to interpret the immune response.

The CDC recommends only these tests. In 2005, the CDC warned against tests -- such as urine antigen, immunofluroescent staining, and lymphocyte transformation -- that do not have enough scientific evidence to support their use.

Accuracy of the Tests. These tests are very expensive, and none are completely accurate in either identifying Lyme or ruling it out. They should never be used to make a primary diagnosis of Lyme disease in patients who do not have obvious symptoms of the disease.

Both false positive and false negative results are common with these tests.

False positive results occur when the test suggests the presence of the disease, but the person does not actually have an active infection. This may occur in different ways:

The antibodies to the infectious organism triggering the antibodies are not the Lyme spirochetes. Other organisms that can trigger such antibodies include syphilis and relapsing fever. Dental infections may trigger a false positive response.
The patient may have been infected with Lyme disease previously and harbor antibodies to the disease.

False negative results miss the actual presence of the disease. These results are also common. (If the results are negative but Lyme disease is highly suspected, the doctor will probably prescribe antibiotics anyway.) False negative results occur for a number of reasons:

The test is taken too early in the course of Lyme disease. In such cases, the antibodies that fight the spirochete might not have reached a level that is high enough to be detected. (Only about 20 - 30% of patients can be identified using immune system tests in the first 2 - 4 weeks. By the fourth week, up to 80% of patients will have detectable antibodies.)
The patient has taken certain medications, such as steroids or certain anti-cancer drugs, which reduce the immune system's ability to produce antibodies, including those in response to Lyme disease.
There are too many infection-fighting antibodies attached to the bacteria. In this case, there are not enough loose antibodies in the blood sample to trigger a response.
The laboratory itself has set its sensitivity point too high. Some laboratories establish a standard of very high antibody levels before the test results will trigger a finding of Lyme disease. (They do this to avoid too many false-positive responses.) In so doing, however, their tests may miss the disease in patients with lower antibody levels. A related diagnostic problem concerns the possibility of missing persistent Lyme disease after antibiotic treatments, when antibody levels would be low.

All of this means that a negative blood test does not rule out a diagnosis of Lyme disease, particularly if symptoms strongly suggest its presence. Conversely, a weakly positive blood test does not prove that Lyme disease is causing the symptoms. A second blood test, taken several weeks later, may help.

The polymerase chain reaction (PCR) test detects the DNA of the bacteria that causes Lyme disease. However, it requires technical expertise and expensive equipment, and can be performed only in a few laboratories in the country. The test also has a high risk of false-positive results. Research indicates that blood or urine samples do not provide accurate results, but skin biopsies may be useful in some cases. At this point, the PCR test is reserved for certain patients with specific diagnostic problems. For most patients, standard antibody tests are preferred.

Analysis of Spinal Fluid. In patients who have neurologic symptoms, a lumbar puncture (a spinal tap) may be used to test for the bacteria in spinal fluid and may be useful for an early diagnosis of Lyme disease.

Treatment

Antibiotics are the drugs of choice for all phases of Lyme disease. In nearly all cases they can cure Lyme, even in later stages.

According to the 2006 guidelines from the Infectious Diseases Society of America (IDSA), people bitten by deer ticks should not routinely receive antibiotics to prevent the disease.

A single dose of the antibiotic doxycycline may be given in situations that meet all of the following conditions:

The tick is still attached to the patient and is positively identified as an adult or nymphal I. scapularis (the tick that carries the Lyme disease B. burgdorferi spirochete).
Doxycycline treatment can be started within 72 hours of the tick bite.
There is proof that at least 20% of ticks in that geographic area are infected with B. burgdorferi.
It is safe for the patient to receive doxycycline (this drug should not be given to pregnant women or children younger than 8 years of age).

In general, the risk of developing Lyme disease after being bitten by a tick is only 1 - 3%. However, patients who have removed attached ticks from themselves should inform their doctors. Patients who have been bitten by a tick should be monitored for up to 30 days to make sure they do not develop symptoms of Lyme disease, especially the tell-tale bull’s-eye rash. If you do develop a skin lesion or flu-like illness during this time, be sure to tell your doctor.

The early stages of Lyme disease usually involve classic bull’s-eye rash (erythema migrans) and flu-like symptoms of chills and fever, fatigue, muscle pain, and headache. In rare cases, patients develop an abnormal heartbeat (Lyme carditis).

All of these conditions are treated with 10 - 28 days of antibiotics. The exact number of days depends on the drug used, and the patient’s response to it. Antibiotics for treating Lyme disease generally include:

Doxycycline. This antibiotic is effective against both Lyme disease and human granulocytic anaplasmosis (HGA) and so is the standard antibiotic for any patient over 8 years old (except pregnant women). Doxycycline cannot be used routinely in children under 8 years old. It is a form of tetracycline and as such discolors teeth and inhibits bone growth. It can also cause birth defects, so it should not be used during pregnancy.
Either amoxicillin (one of the penicillins) or cefuroxime (Ceftin) -- a drug known as a cephalosporin -- are the alternative treatments for young children and some adults. Amoxicillin is the first choice and also probably the best antibiotic for pregnant women. Unfortunately, many people are allergic to penicillin. In addition, strains of bacteria are emerging that are resistant to penicillins.
Intravenous ceftriaxone -- another cephalosporin -- may be warranted if there are signs of infection in the central nervous system (the brain or spinal region) or heart problems.
Other types of antibiotics, such as macrolides, are not recommended for first-line therapy.

Side Effects of Antibiotics. The most common side effects of nearly all antibiotics are gastrointestinal problems, including cramps, nausea, vomiting, and diarrhea. Allergic reactions can also occur with all antibiotics, but are most common with medications derived from penicillin or sulfa. These reactions can range from mild skin rashes to rare but severe, even life-threatening, anaphylactic shock. Some drugs, including certain over-the-counter medications, interact with antibiotics. Patients should report to their doctors all medications they are taking.

Most cases of Lyme disease involve a rash and flu-like symptoms that resolve within 1 month of antibiotic treatment. However, some patients go on to develop late-stage Lyme disease, which includes Lyme arthritis and neurologic Lyme disease.

Slightly more than half of patients infected with B. burgdorferi develop Lyme arthritis. About 10 - 20 % of patients develop neurologic Lyme disease. A very small percentage of patients may develop acrodermatitis chronica atrophicans, a serious type of skin inflammation. These conditions are treated for up to 28 days with antibiotic therapy. If arthritis symptoms persist for several months, a second 2 - 4 week course of antibiotics may be recommended. Oral antibiotics (doxycycline, amoxicillin, or cefuroxime) are used for Lyme arthritis and acrodermatitis chronica atrophicans. (In rare cases, patients with arthritis may need intravenous antibiotics.)

A 2 - 4 week course of intravenous penicillin, ceftriaxone, or cefotaxime is used for treating severe cases of neurological Lyme disease. For milder cases, 2 - 4 weeks of oral doxycycline is an effective option.

In about 5% of cases, symptoms persist after treatment, a condition referred to as post-Lyme disease syndrome. The treatment of post-Lyme disease syndrome is a controversial issue. Most experts do not recommend continuing antibiotic therapy beyond 30 days. Scientific studies do not show any evidence that the benefits of long-term antibiotic treatment outweigh its risks. Long-term antibiotic treatment can lead to a serious and difficult-to-treat infection called Clostridiumdifficile, and can also cause the patient to become resistant to all types of antibiotics.

Experimental and alternative remedies are also not recommended. However, some patients may benefit from learning pain control and cognitive behavioral techniques to help them cope with and manage their symptoms.

Some people use vitamin B complex, omega-3 and omega-6 fatty acids (found in primrose oil and fish oils), and magnesium supplements (magnesium L-lactate dihydrate) to help relieve symptoms. No evidence suggests that they are beneficial. Any such therapies should be discussed with a doctor. Newsletters and Internet sites have cropped up in recent years advertising untested treatments to patients with symptoms of Lyme disease who are frustrated with traditional medical channels. Some remedies are dangerous, and most are ineffective.

In 2006, the Food and Drug Administration (FDA) warned people not to use an alternative medicine product called bismacine (also known as chromacine). This injectable product contains high amounts of bismuth, a heavy metal that can be poisonous. People who have taken bismacine have experienced heart and kidney failure, and one death has been reported. Although some people claim that bismacine can help treat Lyme disease, it is not approved for the treatment of any illness or condition.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

Prevention

Everyone should avoid specific tick-infested areas, including tall grass, woods, and bushes where ticks tend to congregate. If this is not possible, people should take additional preventive measures. The U.S. Centers for Disease Control (CDC) also recommends:

Use of tick repellant.
Routine tick checks -- removal of infected ticks within 48 hours of attachment substantially reduces the likelihood of transmission.
Prompt antibiotic prevention for tick bites -- although this method is controversial, the CDC concludes that it is probably beneficial.
Removing brush and leaves -- such landscaping measures can reduce transmission rates by 50 - 90%.
Applying pesticides to yards once or twice per year, which can decrease the number of ticks by 68 - 100%

Mowing the grass regularly, clearing away leaves, and placing wood chips as a barrier around a lawn can help greatly reduce the tick population.

Permethrin for the Lawn. Insecticides can reduce tick infestation by 90%. Insecticides should be applied in late spring or early fall in a strip a few feet wide along the perimeter of the lawn where small animals are likely to enter or live.

The most commonly used insecticides are pyrethrins, which are compounds derived from the Chrysanthemum family. They are available as natural products or in synthetic forms (permethrin). They are poisons that affect the nerve system of insects. They are safe, particularly the natural products, for humans and pets. All pyrethrins are highly toxic for certain fish and slightly toxic for birds, such as mallard ducks. Some people do experience an allergic reaction to them. As with all insecticides, there is some concern about the possible consequences of long-term exposure, but to date there is no evidence of any harm.

Damminix, available in hardware stores, consists of cardboard tubes stuffed with permethrin-treated cotton. The tubes are placed where mice can find them (dense, dark brush) and collect the cotton for lining their nests. The pesticide on the cotton kills any immature ticks that are feeding on the mice. Best results are obtained with regular applications early in the spring and again in late summer. As many neighbors as possible should use it to be effective.

Other Pesticides. Other tick-killing spray pesticides that have been used include those containing diazinon, chlorpyrifos, and carbaryl. Animal studies have reported severe toxic effects associated with these chemicals. Some of these chemicals are being phased out for home use. Parents should balance the effects of a very negligible risk for a highly treatable infection versus excessive use of possibly harmful chemicals.

Fencing. Deer fencing, a wire fence about 3 - 4 yards high, or electrified fencing can be helpful, but it is costly to put up and maintain.

Ivermectin. Corn that is laced with the anti-parasite medication ivermectin (Ivomec and others) and then eaten by deer helps prevent ticks from feeding on them. Ivermectin is present in a number of products used by veterinarians to control parasites, such as heartworm. It has potential toxic effects in collie or collie mixed breeds, however.

Hiking and camping in the Northeastern woods carries a significant risk for tick bites and Lyme disease (3% in one study). Anyone out in the woods during tick season should wear protective clothing, including:

Light-colored clothing -- makes it easier to spot ticks
Long-sleeved shirts and long pants with cuffs tucked into shoes or socks
High boots, preferably rubber boots
Tick-collars for small dogs -- can be worn around a person's ankles over socks or pants

Simply washing clothes will not kill ticks. After venturing outdoors, people should run their clothes through a dryer at high temperature for a half hour. Spraying clothes with solutions containing permethrin (Permanone, Duranon, Permakill) affords additional protection. Keep in mind that these sprays should not be applied to the skin. Clothes should not be retreated with permethrin for 48 hours unless they are washed.

DEET. Most insect repellents contain the chemical DEET (N,N-diethyl-meta-toluamide), which remains the gold standard of currently available mosquito and tick repellents. DEET has been used for more than 40 years and is safe for most children when used as directed. Comparison studies suggest that DEET preparations are the most effective insect repellents now available.

Concentrations range from 4% to almost 100%. The concentration determines the duration of protection. Experts recommend that most adults and children over 12 years old use preparations containing a DEET concentration of 20 - 35% (such as Ultrathon), which provides complete protection for an average of 5 hours. (Higher DEET concentrations may be necessary for adults who are in high-risk regions for prolonged periods.)

DEET products should never be used on infants younger than 2 months. According to the Environmental Protection Agency, DEET products can safely be used on all children age 2 months and older. The EPA recommends that parents check insect repellant product labels for age restrictions.

If there is no age restriction listed, the product is safe for any age. The American Academy of Pediatrics recommends that children use concentrations of 10% or less; 30% DEET is the maximum concentration that should be used for children. In deciding what concentration is most appropriate, parents should consider the amount of time that children will be spending outside, and the risk of mosquito bites and mosquito-borne disease.

When applying DEET, take the following precautions:

Do not use on the face, and apply only enough to cover exposed skin on other areas.
Do not over apply and do not use under clothing.
Do not apply over any cuts, wounds, or irritated skin.
Parents or an adult should apply repellent to a child and not let the child apply it. They should first put DEET on their own hands and then apply it to the child. They should avoid putting DEET not only near the child's eyes and mouth but also on the hands (since children frequently touch their faces).
Wash any treated skin after going back inside.
If using a spray, apply DEET outdoors -- never indoors. Spray repellents should not be applied inside or directly on anyone's face.

Other Insect Repellent Products. In 2005, the CDC added two new mosquito repellents to its list of recommended products:

Picaridin. Picaridin, also known as KBR 3023 or Bayrepel, is an ingredient that has been used for many years in repellents sold in Europe, Latin America, and Asia. A product containing 7% picaridin is now available in the United States. Picaridin can safely be applied to young children and is also safe for women who are pregnant or breastfeeding. According to the CDC, insect repellents containing DEET or picaridin work better than other products.
Oil of lemon eucalyptus. In scientific tests, oil of lemon eucalyptus, also known as PMD, worked as well as low concentrations of DEET. However, oil of lemon eucalyptus is not recommended for children under the age of 3 years.

Self-Inspection. The tick is unlikely to transmit the infection within 3 days of the bite, but prompt removal is still important. The following tips are important for self-inspection:

Ticks responsible for Lyme disease are very small and may resemble freckles or scabs.
People spending time in tick-infested locations should inspect themselves several times a day, including at bedtime.
Check nonexposed areas, such as the back of the knee, as well as exposed areas. Someone else should check the scalp, back of the neck, and other difficult to reach areas.
Check clothing as well as skin. A tick on can be hidden in folds or creases.

Tick Removal. If an attached tick is discovered, there is no reason to panic. Do not put a hot match to the tick or try to smother it with petroleum jelly, nail polish, or other noxious substances. This only prolongs exposure time and may cause the tick to eject the Lyme organism into the body.

The safest and most effective way to remove an attached tick is:

Grasp the tick's mouth area with clean tweezers as close to the skin as possible. (Take care not to handle it with bare fingers as this can also spread infection.)
Next, pull upward with a steady even pressure. Do not twist, crush, or squeeze the body area of the tick, because this region contains the infectious organism. In fact, do not be alarmed if some of the mouth parts remain in the skin. They are not infectious.
Put the tick in a jar or container of alcohol, which will kill it. Some people lay a piece of adhesive tape to the top of the tick and fold it over, without touching the insect. Then they simply throw it away. Tape is also effective for trapping a tick that has not yet attached to the skin.
Once the tick is removed, wash the bite area with soap and water or with an antiseptic to destroy any contaminating microorganisms. Wash hands as well.

The LYMErix Vaccine. The LYMErix vaccine, previously approved, was taken off the market because of poor sales and because of problems encountered with its use. A primary limitation was that the vaccine was effective only in about 75% of cases, and the effects were not long lasting. There were also reports of arthritic and neurologic symptoms in a few vaccinated people. There is no definitive evidence, however, that the vaccine was responsible for these symptoms.

Other Vaccines. Deer ticks lay their eggs on mice and other small rodents. These eggs develop into larvae that feed on these small animals. When the larvae develop into nymphs, they seek a larger host like a deer or human. Scientists are exploring the idea of vaccinating mice and other rodents against B. burgdorferi. Inserting an oral vaccine into these animals’ food supply helps reduce the number of nymph ticks and may be a more effective preventive strategy than vaccinating humans. Recent studies suggest that vaccination of mice produces 89 - 100% protection from B. burgdorferi infection.

Since dogs, cats and even horses can get Lyme disease, inspect pets for ticks regularly. Symptoms in animals include lameness and lethargy. Dogs are much more likely to get Lyme disease than cats, but both are susceptible. In dogs, symptoms occur 2 - 5 months after a tick bite and include fever, lameness, and lack of appetite. In rare cases, Lyme disease can cause kidney damage in dogs if it is left untreated.

Preventive Products. Products containing permethrin (Bio Spot, EXspot), amitraz (Preventic), or fipronyl (Frontline) can be used safely on dogs. Not all of these products are safe in cats. Only permethrin is also effective against fleas. Some veterinarians suggest that the combination of BioSpot and Preventic is very effective. [Another product-- selamectin (Revolution) --is sold for flea and tick control, but it appears to have very limited effect against ticks.]

Pet Vaccines. Lyme disease vaccines are available for dogs, but they do not offer total protection. Veterinarians vary in their use of the vaccines.

Treatment. As with people, antibiotics almost always cure the infection in animals.

Human Granulocytic Anaplasmosis (HGA)

In addition to Lyme disease, I. scapularis deer ticks can carry other types of infections that cause disease in humans. Human granulocytic anaplasmosis (HGA) is another illness spread by the deer tick. (HGA was formerly called human granulocytic ehrlichiosis. Another type of ehrlichiosis, human monocytic ehrlichiosis, is carried by a different type of tick.)

Typical HGA symptoms appear very suddenly within 4 - 14 days of being bitten by an infected tick. Symptoms include headache, fever, chills, headache, and muscle pains. Vomiting, diarrhea, and loss of appetite are also common. Blood tests may indicate a low blood platelet count, low white blood cell count, and increased liver enzyme levels.

HGA is caused by a species of bacteria called Anaplasma phagocytophilum. A blood test can identify the presence of this bacterium.

All patients who show signs of symptoms should be treated with doxycycline to reduce the risk of complications. Another type of antibiotic, rifampin, is an alternative option for pregnant women, children younger than 8 years of age, or patients who are allergic to doxycycline. Treatment is not recommended for people who do not exhibit symptoms, even if they test positive for antibodies to A. phagocytophilum.

Babesiosis

The tick that carries Lyme disease and human granulocytic anaplasmosis (HGA) can also carry babesiosis. Babesiosis is caused by a parasite called protozoa. It has been detected in about 10% of Lyme disease patients, and has been reported in Massachusetts, New York, Connecticut, Rhode Island, New Jersey, Minnesota, Wisconsin, Georgia, California, and Washington.

When babesiosis is acquired from ticks, the infection occurs only in the summer. However, unlike in Lyme disease, blood transfusions have also been known to transmit babesiosis, so it can also occur other times of the year. The disease is still very rare, but people in tick-infested areas should be aware of it.

Symptoms of babesiosis occur 1 - 4 weeks after a tick bite and are similar to those of malaria. Most cases are very mild and nearly unrecognizable. More severe symptom may resemble those in malaria and include:

Headache
Fever and chills, with night sweats
Nausea and vomiting
Muscle aches
Anemia

In healthy people, babesiosis generally causes only mild and temporary problems, but research indicates that the infection might persist in some people and may be spreading faster than previously reported. In rare cases, it can be severe and even life-threatening, particularly in elderly people or those with chronic health problems or compromised immune systems. In such cases, the infection can cause altered mental states, anemia and other blood abnormalities, very low blood pressure, respiratory distress, and kidney insufficiency. Coinfection with Lyme disease may also increase its severity. Unfortunately, it is very difficult to diagnose.

Babesiosis is caused by a protozoon parasite, not a bacteria, so antibiotics alone won’t cure the disease. Treatment involves a two-drug combination of an anti-malaria medication and an antibiotic. The standard drug combinations are atovaquone (Mepron) plus azithromycin (Zithromax, Zmax) or clindamycin plus quinine. About 25% of patients cannot tolerate quinine. Adverse effects associated with quinine include hearing loss, tinnitus, stomach upset, diarrhea, and dizziness.

Resources

www3.niaid.nih.gov -- National Institute of Allergy and Infectious Disease
www.cdc.gov/ncidod/dvbid/lyme -- Centers for Disease Control
www.idsociety.org -- Infectious Diseases Society of America
www.aldf.com -- American Lyme Disease Foundation
www.rheumatology.org -- American College of Rheumatology
www.arthritis.org -- The Arthritis Foundation

References

Centers for Disease Control and Prevention. Lyme disease -- United States, 2003-2005. MMWR Morb Mortal Wkly Rep. 2007 Jun 15;56(23):573-6.

Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP; Ad Hoc International Lyme Disease Group. A critical appraisal of "chronic Lyme disease." N Engl J Med. 2007 Oct 4;357(14):1422-30.

Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2007 Jul 3;69(1):91-102. Epub 2007 May 23.

Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006 Nov 1;43(9):1089-134.

Review Date:
1/26/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

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Exercise

FitSugar — Wed, 08 Oct 2008 17:35:02 -0700

In This Report

Highlights
Introduction
Recommended Exercise Method...
Exercise's Effects on the H...
Exercise's Effects on Diabe...
Exercise's Effects on Bones...
Exercise's Effects on the L...
Exercise's Effects on Weigh...
Exercise's Effects on Other...
Complications
Motivation
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Chronic Conditions and Exercise:

A new study found that aerobic and resistance training significantly reduced fatigue in men undergoing radiation treatments for prostate cancer. Fatigue is a common side effect of such treatments.
Doctors at the Mayo Clinic found that exercise improves the physical and emotional well-being of patients with Alzheimer's disease. The patients exercised for as little as 60 minutes each week. Doctors noted improvements in areas ranging from depression to wandering.

Exercise and Smoking:

A 2007 review of existing studies found that moderate exercise, for as little as 5 minutes, can help combat the nicotine withdrawal symptoms people experience when they try to stop smoking.

Exercise and Aging:

A 2006 report found that older and elderly adults who exercised twice a week for 4 months significantly increased their body strength, flexibility, balance, and agility. The average age of the study participants was 83.5.

Before and After Exercising:

You should do warm-up exercises for 5 - 10 minutes at the beginning of an exercise session. Low-level aerobic exercise is the best warm-up.
To cool down, you should walk slowly until your heart rate is 10 - 15 beats above your resting heart rate. Stopping too suddenly may sharply reduce blood pressure or cause muscle cramping.
You must be careful when stretching during your warm-up to avoid injuring cold muscles.

Definitions:

Aerobic exercise: Aerobic exercise forces the heart and lungs to work harder for longer periods. It builds endurance, improves blood flow throughout the body, and increases the levels of "good" cholesterol.
Resistance Training: Resistance training works muscles against a force (usually weights). It burns fat and builds muscle.

Introduction

Everyone's goal of living a long and healthy life should include a healthy diet, regular exercise, and maintaining normal weight. The combination of inactivity and eating the wrong foods is the second most common preventable cause of death in the United States (smoking is the first).

Most research on the benefits of exercise focuses on heart protection. Studies clearly show that exercise helps the heart. In addition, new studies are reporting that even people at higher risk for heart disease may lower their risk of dying from it if they exercise.

Evidence suggests that our genes evolved to favor exercise. In other words, during prehistoric times, if a person couldn't move quickly and wasn't strong, he or she died. Those who were fit survived to reproduce and pass on these "fitter" genes. Some researchers believe that with our current inactive lifestyle, these genes produce a number of bad effects, which can lead to many chronic illnesses.

The benefits of exercise include:

Improved oxygen delivery throughout the body
Improved metabolic processes - the way the body breaks down and builds necessary substances
Improved strength and endurance
Decreased body fat
Improved movement of joints and muscles
Improved sense of well-being

In addition, exercise can help change other dangerous lifestyle habits. A 2007 review of existing studies found that moderate exercise, for as little as 5 minutes at a time, can help combat the nicotine withdrawal symptoms people experience when they try to stop smoking.

No one is too young or too old to exercise. The United States Surgeon General recommends at least 30 minutes of moderate exercise, such as brisk walking, nearly every day. However, vigorous exercise carries risks that people should discuss with a doctor. You should always check with your doctor before starting a new exercise program, especially if you have any of the following risk factors:

History of smoking
Obesity
Family history of a long-term disease
A symptom you haven’t told your doctor about
Chest pain
Shortness of breath
Heart palpitations
Blood clots
Infections
Fever
Unexplained weight loss
Foot or ankle sores that won’t heal
Joint swelling
Pain or trouble walking after a fall
Eye injury or eye surgery
Hernia
Hip surgery

Fifty percent of all people who begin a vigorous training program drop out within a year. The key to reaching and maintaining physical fitness is to find activities that are exciting, challenging, and satisfying.

Recommended Exercise Methods

A few simple rules are helpful as you develop your own routine.

Don't eat for 2 hours before vigorous exercise.
Drink plenty of fluids before, during, and after a workout.
Adjust your activity level according to the weather, and reduce it when you are fatigued or ill.
When exercising, listen to the body's warning symptoms, and consult a doctor if exercise causes chest pain, irregular heartbeat, undue fatigue, nausea, unexpected breathlessness, or light-headedness.

Heart rate is the standard guide for determining aerobic exercise intensity. It can be determined by counting one's own pulse or with the use of a heart rate monitor. To feel your own pulse, press the first two fingers of one hand gently down on the inside of the wrist or under the jaw on the right or left side of the front of the neck. You should feel a faint pounding as blood passes through the artery. Each pounding is a beat.

Click the icon to see how to take a radial pulse

Click the icon to see how to take a carotid pulse.

There are different types of heart rates.

Resting heart rate. The average heart rate for a person at rest is 60 - 80 beats per minute. It is usually lower for people who are physically fit, and often rises as you get older. You can determine your resting heart rate by counting how many times your heart beats in one minute. The best time to do this is in the morning after a good night’s sleep before you get out of bed.

Maximum heart rate. To determine your own maximum heart rate per minute subtract your age from 220. For example, if you are 45, you would calculate your maximum heart rate as follows: 220 - 45= 175.

Target heart rate. Your target rate is 50 - 75% of your maximum heart rate. You should measure your pulse off and on while your exercise to make sure you stay within this range. After about 6 months of regular exercise, you may be able to increase your target heart rate to 85% (but only if you can comfortably do so).

Certain heart medications may lower your maximum and target heart rates. Always check with your doctor before starting an exercise program.

Note: Swimmers should use a heart rate target of 75% of the maximum and then subtract 12 beats per minute. The reason for this is that swimming will not raise the heart rate quite as much as other sports because of the so-called "diving reflex," which causes the heart to slow down automatically when the body is immersed in water.


Age	Low	High
	(50% max.)	(75% max.)
20	100	150
30	95	142
40	90	135
50	85	127
60	80	120
Source: American Heart Association

VO2 Max. Serious exercisers may use a VO2 max calculation, which measures the amount of oxygen consumed during intensive, all-out exercise. The most accurate testing method uses computers, but anyone can estimate V02 without instrumentation (with an accuracy of about 95%):

After running at top pace for 15 minutes, round off the distance run to the nearest 25 meters.
Divide that number by 15.
Subtract 133.
Multiply the total by 0.172, then add 33.3.

Olympic and professional athletes train for VO2 max levels above 80. But for the average person interested in fitness, a VO2 max equaling between 50 and 80 is considered an excellent score for overall fitness.

Click the icon to see an image on exercise and heart rate.

Warming up and cooling down are important parts of every exercise routine. They help the body make the transition from rest to activity and back again, and can help prevent soreness or injury, especially in older people.

Warm-up exercises should be practiced for 5 - 10 minutes at the beginning of an exercise session. Older people need a longer period to warm up their muscles. Low-level aerobic exercise such as brisk walking, swinging the arms, or jogging in place, is the best approach.
To cool down, you should walk slowly until the heart rate is 10 - 15 beats above your resting heart rate. Stopping too suddenly can sharply reduce blood pressure, and is dangerous for older people. It may also cause muscle cramping.
Stretching may be appropriate for the cooling down period, but it must be done carefully for warming up because it can injure cold muscles. (There is no clear evidence, however, that stretching reduces muscle injuries.)

Warming up before exercise and cooling down after is just as important as the exercise itself. By properly warming up the muscles and joints with low-level aerobic movement for 5 - 10 minutes, one may avoid injury and build endurance over time. Cooling down after exercise by walking slowly, then stretching muscles, may also prevent strains and blood pressure fluctuation.

For most people, exercise may be divided into three general categories:

Aerobic or endurance
Strength or resistance
Flexibility

A balanced program should include all three. Speed training is also a major category, but generally only competitive athletes practice it.

Benefits of Aerobic Exercise. Regular aerobic exercise provides the following benefits:

Builds endurance
Keeps the heart pumping at a steady and high rate for a long time
Boosts HDL ("good") cholesterol levels
Helps control blood pressure
Strengthens the bones in the spine
Helps maintain normal weight
Improves one's sense of well-being

Types of Aerobic Exercise. Aerobic exercise is usually categorized as high or low impact. Examples of each include the following:

Low- to moderate-impact exercises: Walking, swimming, stair climbing, step classes, rowing, and cross-country skiing. Nearly anyone in reasonable health can engage in some low- to moderate-impact exercise. Brisk walking burns as many calories as jogging for the same distance and poses less risk for injury to muscle and bone.
High-impact exercises: Running, dance exercise, tennis, racquetball, squash. High-impact exercises should be performed no more than every other day, and less often for those who are overweight, elderly, out of condition, or have an injury or other medical problem that would rule out high-impact.

Click the icon to see an image of aerobic exercise.

Aerobic Regimens. As little as one hour a week of aerobic exercises is helpful, but 3 - 4 hours per week are best. Some research indicates that simply walking briskly for 3 or more hours a week reduces the risk for coronary heart disease by 65%. In general, the following guidelines are useful for most individuals:

For most healthy young adults, the best approach is a mix of low- and higher-impact exercise. Two weekly workouts will maintain fitness, but three to five sessions a week are better.
People who are out of shape or elderly should start aerobic training gradually. For example, they may start with 5 - 10 minutes of low-impact aerobic activity every other day and build toward a goal of 30 minutes per day, three to seven times a week. (For heart protection, frequency of exercises may be more important than duration.)
Swimming is an ideal exercise for many elderly and certain people with physical limitations, including pregnant women, individuals with muscle, joint, or bone problems, and those who suffer from exercise-induced asthma.
People who seek to lose weight should aim for six to seven low-impact workouts a week.

One way of gauging the optimal intensity of exercise is to aim for a "talking pace," which is enough to work up a sweat and still be able to converse with a friend without gasping for breath. As fitness increases, the "talking pace" will become faster and faster.

Shoes. All that's really necessary for a workout is a good pair of shoes that are made well and fit well. They should be broken in, but not worn down. They should support the ankle and provide cushioning for impact sports such as running or aerobic dancing. Airing out the shoes and feet after exercising reduces chances for skin conditions such as athlete's foot.

Clothing. Comfort and safety are the key words for workout clothing. For outdoor nighttime exercise, a reflective vest and light-colored clothing must be worn. Bikers, roller bladers, and equestrians should always wear safety devices such as helmets, wrist guards, and knee and elbow pads. Goggles are mandatory for indoor racquet sports. For vigorous athletic activities, such as football, ankle braces may be more effective than tape in preventing ankle injuries.

Aerobic-Exercise Equipment. Home aerobic exercise machines can be adapted to any fitness level and used day or night. Before investing in any exercise machine, however, it is wise to first test it at a gym. In addition, initial supervised training when using these machines can reduce the risk of injury that might occur with self-instruction.

Very inexpensive exercise machines tend to be flimsy and hard to adjust, but many sturdy machines are available at moderate prices. The higher-end models may utilize computers to record calories burned, speed, and mileage. While their readouts may provide motivation and gauge the intensity of a workout, however, they are not always accurate.

The following are a few observations on specific equipment:

A good floor mat is important to provide cushioning for all home exercises.
A simple jump rope improves aerobic endurance for people who are able to perform high-impact exercise. Jumping rope should be done on a floor mat plus a surface that has some give to avoid joint injury.
For burning calories, the treadmill has been ranked best, followed by stair climbers, the rowing machine, cross-country ski machine, and stationary bicycle. (Elliptical trainers, however, may be even better than treadmills for increasing heart rate, calorie expenditure, and oxygen consumption.)
Stationary bikes condition leg muscles and are fairly economical and easy to use safely. The pedals should turn smoothly, the seat height should adjust easily, and the bike's computer should be able to adjust intensity.
Stair machines also condition leg muscles. They offer very intense, low-impact workouts and may be as effective as running with less chance of injury.
Rowing and cross-country ski machines exercise both the upper and lower body.


Aerobic dancing	Sufficient cushioning to absorb shock and pressure that are many times greater than ordinary walking. Arches that maintain side-to-side stability. Thick upper leather support. Toe-box. Orthotics may be required for people with ankles that over-turn inward or outward. Soles should allow for twisting and turning.
Cycling	Rigid support across the arch to prevent collapse during pedaling. Heel lift. Cross-training or combination hiking/cycling shoes may be sufficient for casual bikers. Toe clips or specially designed shoe cleats for serious cyclers. In some cases, orthotics may be needed to control arch and heel and balance forefoot.
Running	Sufficient cushioning to absorb shock and pressure. Fully bendable at the ball of the foot. Sufficient traction on sole to prevent slipping. Consider insoles or orthotics with arch support for problem feet.
Tennis	Allow side-to-side sliding. Low-traction soles. Snug fitting heels with cushioning. Padded toe box with adequate depth. Soft-support arch.
Walking	Lightweight. Breathable upper material (leather or mesh). Wide enough to accommodate ball of the foot. Firm padded heel counter that does not bite into heel or touch ankle bone. Low heel close to ground for stability. Good arch support. Front provides support and flexibility.

Benefits of Strength Exercise. While aerobic exercise increases endurance and helps the heart, it does not build upper body strength or tone muscles. Strength-training exercises provide the following benefits:

Build muscle strength while burning fat
Help maintain bone density
Improve digestion

It is also associated with a lower risk for heart disease, possibly because it lowers LDL (the so-called "bad") cholesterol levels.

Click the icon to see an image of cholesterol.

Strength exercise is beneficial for everyone, even people in their 90s. It is the only form of exercise that can slow and even reverse the decline in muscle mass, bone density, and strength that occurs with aging. Please note: People at risk for cardiovascular disease should not perform strength exercises without checking with a doctor.

Types of Muscle Contractions. There are three types of muscle contractions involved in strength training:

Isometric contractions do not change the length of the muscle. An example is pushing against a wall.
Concentric contractions shorten muscles. An example is the "up" phase of a bicep curl.
Eccentric contractions lengthen muscles. An example is the "down" phase as weights are lowered.

Click the icon to see an image of isometric exercise.

Strength-Training Regimens. Strength training involves intense and short-duration activities. For beginners, adding 10 - 20 minutes of modest strength training two to three times a week may be appropriate. The following are some guidelines for starting a strength regimen:

The sequence of a strength training session should begin with training large muscles and multiple joints at higher intensity and end with small muscle and single joint exercises at lower intensities.
Both shortening and lengthening muscle actions should be performed. Emphasizing the movements that lengthen muscles is of increasing interest. This approach involves slowing and increasing the duration of these "down" movements. It appears to significantly increase blood flow, and some evidence suggests it may achieve stronger muscles more quickly. It may also improve heart function compared to standard movements. Exercises that lengthen muscles may be particularly beneficial for older people and some people with chronic health problems. This type of training increases the risk for muscle soreness and injury, however, and this approach is still controversial.
Strength training involves moving specific muscles in the same pattern against a resisting force (such as a weight) for a preset number of times. This is called a repetition. Students should first choose a weight that is about half of what would require a maximum effort in one repetition. In other words, if it would take maximum effort to do a single repetition with a 10-pound dumbbell, the person would start with a five-pound dumbbell. In the beginning, most people can start with one set of 8 - 15 repetitions per muscle group with low weights. As individuals are able to perform one or two repetitions over their routine, weights can be increased by 2 - 10%.
Breathe slowly and rhythmically. Exhale as the movement begins. Inhale when returning to the starting point.
The first half of each repetition typically lasts 2 - 3 seconds. The return to the original position lasts 4 seconds.
An alternative technique called "super slow" training stretches out one repetition to a 14-second count. This method places far more stress on the muscle group, so fewer repetitions are needed. A full week of recovery is required before repeating this workout. The goal is to initiate changes in the muscles so that the body continues to burn calories after the exercise. Some people report dramatic results from this approach, but scientific proof of these claims is not available. It is a very tedious workout, and people have a hard time sticking with it. People with high blood pressure should not use this approach.
Joints should be moved rhythmically through their full range of motion during a repetition. Do not lock up the joint while exercising it.
For maximum benefit, one should allow 48 hours between workouts for full muscle recovery.

Click the icon to see the proper way to breathe during exercise.

Strength-Training Equipment. Unlike aerobic exercise, strength training almost always requires some equipment. Strength-training equipment does not, however, have to cost anything.

Any heavy object that can be held in the hand, such as a plastic bottle filled with sand or water, can serve as a weight.
Dumbbells (1 - 10 pounds) and resistance bands are inexpensive, portable, and effective.
Wearable weights help strengthen and tone the upper body.
Ankle weights strengthen and tone muscles in the lower body. Wearable ankle weights should not be worn during high-impact aerobics or jumping.
Hand grips strengthen arms and are good for relieving tension.
A pull-up bar can be mounted in a doorway for chin-ups and pull-ups.

More elaborate and expensive home equipment for working body muscles is also available, costing from $100 to over $1,000. No one should purchase or use strength-training equipment without instruction from a professional.

Benefits of Flexibility Training. Flexibility training uses stretching exercises. Many stretching exercises are particularly beneficial for the back. In general, flexibility training provides the following benefits:

Prevents cramps, stiffness, and injuries
Improves joint and muscle movement (improved range of motion)

Certain flexibility practices, such as yoga and tai chi, also involve meditation and breathing techniques that reduce stress. Such practices appear to have many health and mental benefits. They may be very suitable and highly beneficial for older people, and for patients with certain chronic diseases.

Click the icon to see an image of flexibility exercise.

Flexibility Training Regiments. Doctors recommend performing stretching exercises for 10 to 12 minutes at least three times a week. The following are some general guidelines:

When stretching, exhale and extend the muscles to the point of tension, not pain, and hold for 20 - 60 seconds. (Beginners may need to start with a 5- to 10-second stretch.)
Breathe evenly and constantly while holding the stretch.
Inhale when returning to a relaxed position. Holding your breath defeats the purpose; it causes muscle contraction and raises blood pressure.
When doing stretches that involve the back, relax the spine to keep the lower back flush with the mat, and to work only the muscles required for changing position (often these are only the abdominal muscles).

Studies continue to show that it is never too late to start exercising. A report published in the February 2006 Journal of Aging and Health found that elderly adults who exercised twice a week for four months significantly increased their body strength, flexibility, balance, and agility. The exercise program included walking and lifting weights. The average age of the study participants was 83.5. The study adds further evidence that even small improvements in physical fitness and activity can prolong life and independent living.

Still, about half of Americans over 60 describe themselves as sedentary (inactive). According to a 2004 report by the Centers for Disease Control and Prevention, approximately 12% of people aged 65 - 75 years and 10% of people aged 75 years or older meet current recommendations for strength training.

The following tips for exercising may be helpful:

Any older person should have a complete physical and medical examination, as well as professional instruction, before starting an exercise program.
Start low and go slow. For sedentary, older people, one or more of the following programs may be helpful and safe: Low-impact aerobics, gait (step) training, balance exercises, tai chi, self-paced walking, and lower legs resistance training, using elastic tubing or ankle weights. Even in the nursing home, programs aimed at improving strength, balance, gait, and flexibility have significant benefits.
Strength training assumes even more importance as one ages, because after age 30 everyone undergoes a slow process of muscular erosion. The effect can be reduced or even reversed by adding resistance training to an exercise program. As little as one day a week of resistance training improves overall strength and agility. Strength training also improves heart and blood vessel health.
Power training, which aims for the fastest rate at which a muscle or muscle group can perform work, may be particularly helpful for older women in strengthening muscles and preventing falls.
Flexibility exercises promote healthy muscle growth and help reduce the stiffness and loss of balance that accompanies aging.
Chair exercises may be performed by people who are unable to walk.
Older women are at risk for incontinence accidents during exercise. This can be reduced or prevented by performing Kegel exercises, limiting fluids (without risking dehydration), going to the bathroom frequently, and using leakage prevention pads or insertable devices.

Exercise's Effects on the Heart

Inactivity is one of the major risk factors for heart disease. However, exercise helps improve heart health, and can even reverse some heart disease risk factors.

Like all muscles, the heart becomes stronger as a result of exercise, so it can pump more blood through the body with every beat and continue working at maximum level, if need be, with less strain. The resting heart rate of those who exercise is also slower, because less effort is needed to pump blood.

A person who exercises often and vigorously has the lowest risk for heart disease, but any amount of exercise is beneficial. Studies consistently find that light-to-moderate exercise is even beneficial in people with existing heart disease. Note, however, that anyone with heart disease should seek medical advice before beginning a workout program.

The heart is a large muscular organ that pumps blood throughout the body. Valves inside the heart open and close. This controls how much blood enters or leaves the heart.

Exercise has a number of effects that benefit the heart and circulation (blood flow throughout the body). These benefits include improving cholesterol and fat levels, reducing inflammation in the arteries, assisting weight loss programs, and helping to keep blood vessels flexible and open. Studies continue to show that physical activity and avoiding high-fat foods are the two most successful means of reaching and maintaining heart-healthy levels of fitness and weight.

The American Heart Association recommends that individuals perform moderately-intense exercise for at least 30 minutes on most days of the week. This recommendation supports similar exercise guidelines issued by the Centers for Disease Control and Prevention, and the American College of Sports Medicine.

Coronary Artery Disease. People who maintain an active lifestyle have a 45% lower risk of developing heart disease than do sedentary people. Experts have been attempting to define how much exercise is needed to produce heart benefits. In 2002, a well-conducted study on overweight adults confirmed previous research that reported beneficial changes in cholesterol and lipid levels, including lower LDL levels (bad cholesterol), even when people performed low amounts of moderate- or high-intensity exercise such as walking or jogging 12 miles a week. However, more intense exercise is required to significantly change cholesterol levels, notably increasing HDL (good cholesterol). An example of this kind of program would be jogging about 20 miles a week. Such benefits in the study occurred even with very modest weight loss, suggesting that overweight people who have trouble losing pounds can still achieve considerable heart benefits by exercising.

Some studies suggest that for the greatest heart protection, it is not the duration of a single exercise session that counts but the total daily amount of energy expended. Therefore, the best way to exercise may be in multiple short bouts of intense exercise, which can be particularly helpful for older people.

Resistance (weight) training has also been associated with heart protection. It may offer a complementary benefit to aerobics by reducing LDL levels. Exercises that train and strengthen the chest muscles may prove to be very important for patients with angina.

Effects of Exercise on Blood Pressure. Regular exercise helps keep arteries elastic (flexible), even in older people. This, in turn, ensures good blood flow and normal blood pressure. Sedentary people have a 35% greater risk of developing high blood pressure than athletes do.

Click the icon to see the risks associated with untreated hypertension.

It should be noted that high-intensity exercise may not lower blood pressure as effectively as moderate-intensity exercise. In one study, moderate exercise (jogging 2 miles a day) controlled high blood pressure so well that more than half the patients who had been taking drugs for the condition were able to discontinue their medication. However, a small study published in 2005 suggests that moderate exercise does not have a significant impact on systolic blood pressure (the top number) in older adults. While those who exercised did have notable drops in both the top and lower (diastolic) blood pressure levels, the only statistically significant change was the decrease in the lower number.

Experts recommend at least 30 minutes of exercise on most -- if not all -- days. Studies show that yoga and tai chi, an ancient Chinese exercise involving slow, relaxing movements, may lower blood pressure almost as well as moderate-intensity aerobic exercises.

Click the icon to see an image of someone practicing yoga.

Anyone with existing high blood pressure should discuss an exercise program with their doctor. Before starting to exercise, people with moderate-to-severe high blood pressure should lower their pressure, and be able to control it with medications. Everyone, and especially people with high blood pressure, should breathe as normally as possible through each exercise. Holding the breath increases blood pressure.

Effects of Exercise on Heart Failure. Traditionally, heart failure patients have been discouraged from exercising. Now, exercise performed under medical supervision is proving to be helpful for select patients with stable heart failure.

Studies continue to report benefits from exercise training. In one study, heart failure patients as old as 91 years old increased their oxygen use significantly, after 6 months of supervised treadmill and stationary bicycle exercises.
Progressive resistance training may be particularly useful for heart failure patients, since it strengthens muscles, which commonly weaken in this disorder. Even simply performing daily handgrip exercises can improve blood flow through the arteries.

Experts warn, however, that exercise is not appropriate for all heart failure patients.

All stroke survivors should have a pre-exercise evaluation done by their doctor before starting an exercise program.

The effects of exercise on stroke are less established than those on heart disease, but most studies show benefits. The following are some examples:

According to one major analysis, men cut their risk for stroke in half if their exercise program was roughly equivalent to about an hour of brisk daily walking 5 days a week. In the same study, exercise that involved recreation was more protective against stroke than exercise routines consisting simply of walking or climbing.
A 2000 study of women also found substantial protection from stroke in brisk walking or striding (rather than casual walking).

Anyone with heart disease or risk factors for developing heart disease or stroke should seek medical advice before beginning a workout program. Patients with heart disease can nearly always exercise safely as long as they work out under medical supervision. Still, it is often difficult for a doctor to predict health problems that might arise as the result of an exercise program. At-risk individuals should be very aware of any symptoms warning of harmful complications while they exercise.

Some experts believe that anyone over 40 years old, whether or not they are at risk for heart disease, should have a complete physical examination before starting or intensifying an exercise program. Some doctors use a questionnaire for people over 40 to help determine whether they require such an examination. The questions they use are as follows:

Has any doctor previously recommended medically supervised activity because of a heart condition?
Is chest pain brought on by physical activity?
Has chest pain occurred during the previous month?
Does the person faint or fall over from dizziness?
Is bone or joint pain intensified by exercise?
Has medication been prescribed for hypertension (high blood pressure) or heart problems?
Is the person aware of or has a doctor suggested any physical reason for not exercising without medical supervision?

Those who answer "yes" to any of the above questions should have a complete medical examination before developing an exercise program.

Stress Test. A stress test helps determine the risk for a heart problem resulting from exercise. Anyone with a heart condition or history of heart disease should have a stress test before starting an exercise program. Experts currently also recommend this test before a vigorous exercise program for older persons who are sedentary, even in the absence of known or suspected heart disease. The test is expensive, however, and some experts believe that it may not be necessary for many older people with no evident health problems or risk factors.

A small percentage of heart attacks occur after heavy physical work.

High-Risk Individuals. In general, the following people should avoid intense exercise or start it only with careful monitoring:

People who have certain medical conditions: These conditions include uncontrolled diabetes, uncontrolled seizures, uncontrolled high blood pressure, a heart attack within the previous 6 months, heart failure, unstable angina, significant aortic valve disease, or aortic aneurysm.
People with moderate-to-severe hypertension: Experts generally recommend that moderate or severe high blood pressure (systolic blood pressure over 160 mm Hg or diastolic (bottom number) pressure over 100 mm Hg) should be brought to lower levels before a person starts a vigorous exercise program.
Sedentary people should be cautious. One major study found that sedentary people who throw themselves into a grueling workout significantly increase their risk of heart attack.
Episodes of exercise-related sudden death in young people are rare but of great concern. Some are preceded by fainting, which is due to a sudden and severe drop in blood pressure. It should be noted that fainting is relatively common in athletes, and is dangerous only in people with existing heart conditions. Young people with genetic or congenital (present at birth) heart disorders should avoid intensive competitive sports.
Anabolic steroids or products containing ephedra have been associated with cases of stroke, heart attack, and even death.

The risk for heart attack from exercise should be kept in perspective, however. Some form of exercise, carefully personalized, has benefits for most of the individuals mentioned above. In many cases, particularly when the only risk factors are a sedentary lifestyle and older age, exercise can often be increased over time until it is intense.

Hazardous Activities for High-Risk Individuals. The following activities may pose particular dangers for high-risk individuals:

Intense workouts (snow shoveling, slow jogging, speed walking, tennis, heavy lifting, heavy gardening) may be particularly hazardous for people with risk factors for heart disease, especially older people. They tend to stress the heart, raise blood pressure for a brief period, and may cause spasms in the arteries leading to the heart. (See image: Coronary Artery Spasm)
Some studies suggest that competitive sports, which couple intense activity with aggressive emotions, are more likely to trigger a heart attack than other forms of exercise.

Listening for Warning Signs. It should be noted that according to one study, at least 40% of young men who die suddenly during a workout have previously experienced, and ignored, warning signs of heart disease. In addition to avoiding risky activities, the best preventive tactic is simply to listen to the body and seek medical help at the first sign of symptoms during or following exercise. These symptoms include the following:

Irregular heartbeat
Shortness of breath
Chest pain

Click the icon to see an image of a coronary artery spasm.

Click the icon to see an image of stable angina.

Exercise's Effects on Diabetes

Moderate aerobic exercise can lower your risk for type 2 diabetes. An important study found that adults who worked out 2 and 1/2 hours a week cut their risk by 58%.

Exercise has positive benefits for those who have diabetes. It can lower blood sugar, improve insulin sensitivity, and strengthen the heart. Strength training, which increases muscle and reduces fat, may be particularly helpful for people with diabetes, but more evidence is needed to confirm this theory. One study reported that yoga helped patients with type 2 diabetes reduce their need for oral medications.

In 2005, researchers found that people with type 2 diabetes who walked a minimum of 3 miles every day were in better health, and had lower medical expenses, after 2 years of such exercise. Those who remained sedentary for that time period experienced a decline in their overall health and higher health care-related expenses. Study participants who worked out for an average of 38 minutes per day lowered their blood pressure, cholesterol ,and A1C levels (glucose concentration over time). These participants also had lower heart disease risk, even if they didn't lose weight. The increase in the study participants' activity equaled about 2,200 extra steps a day. The findings were reported in the journal Diabetes Care.

An earlier study found that healthy lifestyle changes may work better than the prescription medication metformin (Glucophage), when it comes to preventing metabolic syndrome. Metabolic syndrome is a combination of risk factors including abdominal obesity, insulin resistance, high triglycerides, and hypertension.

The following are precautions for all people with diabetes, whether type 1 or 2:

Because people with diabetes are at higher than average risk for heart disease, they should always check with their doctors before starting a demanding exercise program. For best and fastest results, frequent high-intensity (not high-impact) exercises are best for people who are cleared by their doctor. For people who have been sedentary, or have other medical problems, lower-intensity exercises are recommended, using programs the patients designed with their doctors.
Strenuous strength training or high-impact exercise is not recommended for people with uncontrolled diabetes. Such exercises can strain weakened blood vessels in the eyes of patients with retinopathy (a common diabetic complication). High-impact exercise may also injure blood vessels in the feet.

Patients who are taking medications that lower blood glucose, particularly insulin, should take special precautions before starting a workout program.

Glucose levels swing dramatically during exercise. People with diabetes should monitor their levels carefully before, during, and after workouts.
Patients should probably avoid exercise if glucose levels are above 300 mg/dL or under 100 mg/dL.
To avoid hypoglycemia (low blood sugar), people with diabetes should inject insulin in sites away from the muscles they use the most during exercise.
People with diabetes should drink plenty of fluids. Before exercising, they should avoid alcohol, which increases the risk of hypoglycemia.
Insulin-dependent athletes may need to decrease insulin doses, or take in more carbohydrates, prior to exercise. However, they may need to take an extra dose of insulin after exercise. Stress hormones released during exercise may increase blood glucose level (in people without diabetes, insulin is released to control this increase). People with diabetes must regularly test their blood sugar, and take any medications as instructed by their doctor.

A person with diabetes must regularly check their blood sugar (glucose) level.

Exercise's Effects on Bones and Muscles

Exercise is critical for strong muscles and bones. Muscle strength declines as people age, but studies report that when people exercise they are stronger and leaner than others in their age group.

Exercise helps kids lower their risk of chronic pain in the future. Research has shown that it helps them prevent back and neck pain. The more flexible men are as teenagers, the lower their risk of neck tension in the future, according to a study published in the February 2006 British Journal of Sports Medicine. The same report found that women who had the greatest endurance strength as teenagers had a lower risk of tension neck than those with lower teenager endurance strength. However, men with the greatest endurance strength had higher rates of knee injuries later on.

Joints are complex structures. They are designed to bear weight and move the body. Above the knee is the femur (thigh bone). Below the knee is the tibia (shin bone) and fibula. The kneecap is also called the patella. It rides on top of the lower portion of the femur and the top portion of the tibia. The muscles and ligaments connect these bones and the space between them is cushioned by fluid-filled capsules (synovia) and cartilage. When you exercise, the muscles pull on the bones, strengthening them. The range of motion of a joint represents how far it can be flexed (bent) and extended (stretched).

Joints require motion to stay healthy. Long periods of inactivity cause the arthritic joint to stiffen and the adjoining tissue to weaken. A moderate exercise program that includes low-impact aerobics, power, and strength training has benefits for osteoarthritic patients, even if exercise does not slow down the disease progression. Many patients who start an exercise program report less disability and pain. They are also better able to perform daily chores, and remain independent longer than their inactive peers. Older patients and those with medical problems should always check with their doctor before starting an exercise program.

Click the icon to see an image of osteoporosis.

The following are useful exercises for osteoarthritis patients:

Strengthening exercises builds muscle strength. Some experts encourage patients to emphasize strengthening leg muscles as a first treatment step, even before using pain relievers. They fear that patients who rely on painkilling drugs may overuse knees, which do not have strong enough muscle tissue to protect the joints from further damage. Strengthening the thigh muscles is certainly protective for those who have not developed osteoarthritis.
Range-of-motion exercises increase the amount of movement in a joint and muscle. The best examples are yoga and tai chi, which focus on flexibility, balance, and proper breathing. In one 2001 study, older adults who practiced the gentle movement, breathing, and meditation exercises of tai chi for 10 weeks reported less pain than their peers who did not learn the technique.
Low-impact aerobic workouts help stabilize and support the joints. Cycling and walking are beneficial, and swimming or exercising in water is highly recommended for people with arthritis. Patients with arthritis should avoid high-impact sports, such as jogging, tennis, and racquetball.
Some researchers are now focusing on "power" training, which involves improving the muscle's ability to move more rapidly against resisting forces, such as gravity. For example, such training helps people stand up or climb stairs more quickly. Muscle power declines more rapidly than muscle strength, and may be particularly important in older people.

Exercise is very important for slowing the progression of osteoporosis, and extremely important for reducing the risk of falling, which causes fractures. Falls are one of the leading causes of death in people over the age of 65. Exercise helps build balance and flexibility, which reduces the risk of falling.

Specific exercises may be especially helpful for reducing the risk of fractures:

Weight-bearing exercise is very beneficial for bones in people of all ages, even older people. This approach applies tension to muscle and bone, and the body responds to this stress by increasing bone density, in young adults by as much as 2 - 8% a year. Careful weight training can also be very beneficial for elderly people, particularly women. In addition to improving bone density, weight-bearing exercise reduces the risk of fractures by improving muscle strength and balance, thus helping to prevent falls.
Regular brisk long walks improve bone density and mobility. In one 2002 study, for example, older women reduced their risk of hip fracture by over 40% by working out just four hours a week.
Exercises specifically targeted to strengthen the back can be beneficial in improving posture, and may even reduce kyphosis (hunchback) in people with osteoporosis.
Low-impact exercises, particularly yoga and tai chi, which improve balance and strength, have been found to decrease the risk of falling. In one study, tai chi reduced this risk by almost half.

Click the icon to see an image of the bone-building exercise.

Note on Female Athlete Triad. Some young female athletes who exercise very intensely, and are subject to intense pressure to remain thin, are at risk for the female athlete triad. This syndrome is a combination of three disorders -- an eating disorder, loss of menstrual periods, and osteoporosis.

People who do not exercise regularly face an increased risk for low back pain, especially during times when they suddenly have to perform stressful, unfamiliar activities. These activities may include shoveling, digging, or moving heavy items. Although no definitive studies have been done to prove the relationship between lack of exercise and low back pain, sedentary living is probably a primary nonmedical cause contributing to this condition.

Lack of exercise leads to the following conditions that may threaten the back:

Muscle inflexibility can restrict the back's ability to move, rotate, and bend.
Weak stomach muscles can increase the strain on the back and can cause an abnormal tilt of the pelvis (hip bones).
Weak back muscles may increase the load on the spine and the risk of disk compression.
Obesity puts more weight on the spine and increases pressure on the vertebrae and disks. Studies report only a weak association between obesity and low back pain, however.

Benefits for Chronic Back Pain. People in with sudden and severe back pain should not exercise. Exercise plays a very beneficial role in relieving chronic back pain, however. In one study, patients with back pain lasting for an average of 18 months were assigned eight 1-hour exercise sessions over 4 weeks. They showed greater improvement in nearly every area, including reduced pain, compared to patients who did not exercise.

Exercise should be considered as part of a broader program to return to normal home, work, and social activities. In this way, the positive benefits of exercise not only affect strength and flexibility but they also alter and improve the patients' attitudes toward their disability and pain.

Repetition is the key to increasing flexibility, building endurance, and strengthening the specific muscles needed to support the spine. Some exercise programs used for prevention or treatment of chronic low back pain include the following:

Low-impact Aerobic Exercises: Low-impact aerobic exercises, such as swimming, bicycling, and walking, can strengthen muscles in the abdomen and back without over-straining the back. Programs that use strengthening exercises while swimming may be a particularly beneficial approach for many patients with back pain. In one study, for example, pregnant women who engaged in a water gymnastics program had less back pain, and were able to continue working longer.
Lumbar Extension Strength Training: Exercises called lumbar extension strength training are proving to be effective. Generally, these exercises attempt to strengthen the abdomen, and improve lower back mobility, strength, and endurance. They also enhance flexibility in the hip and hamstring muscles, and in the tendons at the back of the thigh.
Yoga, Tai Chi, and Chi Kung: These exercises combine low-impact physical movements and meditation. They are based on principles of disciplining the mind to achieve a physical and mental balance, and can be very helpful in preventing recurrences of low back pain. In one study of Pilates, an exercise practice that uses yoga principles, the exercises were helpful in a woman with progressive and disabling severe low back pain resulting from early scoliosis. This approach deserves further research.
Flexibility Exercises: Whether flexibility exercises alone offer any significant benefit for chronic back pain is uncertain. One study suggested that any benefits derived from flexibility exercises are lost unless the exercise programs are sustained.
Retraining Deep Muscles: Studies are finding a link between low back pain and poor motor control of deep muscles in the back and trunk. According to these studies, contraction exercises specifically designed to retrain these muscles may be effective for patients with both acute and chronic pain.

It is important for any person who has low back pain to have an exercise program guided by professionals who understand the limitations and special needs of back pain and who can address individual health conditions. One study indicated that patients who planned their own exercise did worse than those in physical therapy or doctor-directed programs.

Hazardous Effects on the Back. Improper or excessive exercise can also cause back pain.

Exercise's Effects on the Lungs

Patients with chronic lung problems have difficulty exercising. Shortness of breath is a major limitation in most patients, but in about a third, muscle fatigue is an even greater problem. Although exercise does not improve lung function, training helps many patients with chronic lung disease by strengthening their limb muscles, thus improving endurance and reducing breathlessness.

In people who already have colds, exercise has no effect on the illness' severity or duration. People should avoid strenuous physical activity when they have fevers, muscle aches, or other symptoms of a widespread viral illnesses.

Long-term exercise may help control asthma and reduce hospitalization. One 2000 study found that aerobic exercise improves breathing capacity and function in patients with mild asthma. People with asthma who enjoy running should probably choose an indoor track, to avoid pollutants. Swimming is particularly excellent for people with asthma. Yoga practice, which uses both stretching, breathing, chest expansion, and meditation techniques may have specific benefits that include stress reduction as well as airway opening. One study reported that two thirds of patients who practiced yoga regularly were able to reduce or eliminate their asthma medications.

Exercise-Induced Asthma. About 40 - 90% of asthma cases are exercise-induced asthma (EIA), in which exercise triggers coughing, wheezing, or shortness of breath. It occurs most often in children and young adults and during intense exercise in cold dry air. EIA is triggered only by exercise. Unlike allergic asthma, there is no long-term increase in airway activity. People who only have EIA do not require long-term maintenance therapy. The warm-up and cool-down periods, which are important for any exercise regimen, may help reduce EIA events. A study of military recruits found that exercise-induced asthma attacks did not hinder their ability to perform or train, suggesting that EIA is not a reason to exclude people from physically demanding occupations.

Exercise-induced asthma is distinct from allergic asthma in that it does not produce long-term increase in airway activity. People who only experience asthma when they exercise may be able to control their symptoms with preventive measures such as warm-up and cool-down exercises.

Walking is the best exercise for people with emphysema. Patients should try to walk three to four times daily for 5 - 15 minutes each time. Devices that assist ventilation may reduce breathlessness that occurs during exercise.

Inspiratory muscle training involves exercises and devices that make inhaling (breathing in) more difficult, in order to strengthen breathing muscles. In a 2001 study, patients who took part in an inspiratory muscle training group improved their breathing, walking capacity, and quality of life. Yoga or martial arts exercises, such as tai chi, which emphasize breathing techniques and balanced movements, may be particularly beneficial for patients with emphysema.

Exercise's Effects on Weight

Exercising helps people reduce their weight, maintain weight loss, and fight obesity. Research has shown that women who regularly exercise but do not change their diet can lose significantly more weight than less active women.

Thirty minutes of moderate-intensity exercise may be adequate to maintain cardiovascular health, but it might not prevent weight gain. Recommendations published in 2003 and 2004 suggest that 45 - 60 minutes of exercise per day is necessary to promote weight loss. Children may need more activity.

Losing significant weight requires both exercise and calorie restriction. In addition, if a person exercises without dieting, any actual weight loss may be minimal because dense and heavier muscle mass replaces fat. Nonetheless, regardless of weight loss, a fit body will look more toned and be healthier.

People who exercise are more apt to stay on a diet plan. Exercise improves psychological well-being and replaces sedentary habits that usually lead to snacking. Exercise may even act as a mild appetite suppressant.

Exercising without dieting still adds health benefits. One study found that overweight but fit people have half the death rate of overweight, unfit people. Research suggests that people who have trained for a long time develop more efficient mechanisms for burning fat and are able to stay leaner.

Lifting weights builds muscle, which burns calories more efficiently than other body tissues.

The following are some suggestions and observations on exercise and weight loss:

The treadmill burns the most calories of standard aerobic machines. It may be particularly effective when used in short multiple bouts during the day. Exercise sessions as short as 10 minutes, which are done frequently (about four times a day), may be the most successful program for obese people.
The more strenuous the exercise, the longer the body continues to burn calories before returning to its resting level. This state of fast calorie burning can last for as little as a few minutes after light exercise, to as long as several hours after prolonged or heavy exercise.
Resistance (strength) training is excellent for replacing fat with muscles. It should be performed two or three times a week.
Fidgeting may be very helpful in keeping pounds off. Regular exercise is certainly the best course, but for people who must sit for hours at work, frequently shifting positions while sitting may have some benefit.
It is important to realize that as people slim down, they burn fewer calories per mile of walking or jogging. The rate of weight loss slows down, sometimes discouragingly so, after an initial dramatic head start using diet and exercise combinations. People should be aware of this trend and keep adding to their daily exercise routine.
Changes in fat and muscle distribution may differ between men and women as they exercise. Men tend to lose abdominal fat (which lowers their risk for heart disease faster than reducing general body fat). Exercise, however, does not appear to have the same effect on weight distribution in women. A study of women who practiced aerobic and strength training showed the training resulted in fat loss in the women's arms and trunk. However, they did not gain muscle tissue in those areas.

Because obesity is one of the risk factors for heart disease, anyone who is overweight must discuss their exercise program with a physician before starting.

Exercise's Effects on Other Conditions

Physical activity makes you healthier. It lowers your risk for cardiovascular disease and reduces bone loss. Physical activity also helps the body use calories more efficiently, which helps you eliminate body fat and lose weight. It also helps you maintain weight loss by increasing your metabolism and reducing your appetite.

A number of studies have indicated that regular exercise may reduce the risk of breast, colon, and possibly prostate cancers.

Studies confirm that exercise significantly reduces the risk of both colon cancer (by up to 50%) and breast cancer (by up to 30%).

A 2006 study found that, though protection from breast cancer may vary among the types of tumor, exercise offered the most marked protection from the more aggressive tumors. A second study, also done in 2006, supported this finding. Several studies also suggested that more intense exercise is more protective against breast cancer. Exercising consistently throughout life gives the best protection. Exercise not only lowers a woman's chance of getting breast cancer, it can help those who have received chemotherapy for the disease fight off fatigue.

While endurance athletes may suffer from stomach problems, low intensity exercise has a marked protective effect against colon cancer, according to studies, including the Nurses Health Study and the American Cancer Society's Cancer Prevention Study II. Furthermore, a 2006 study found that people with colon cancer who exercise reduce their risk of a recurrence.

Exercise also has a beneficial effect on people receiving treatment for prostate cancer. A new study found that aerobic and resistance training significantly reduced fatigue in men undergoing radiation treatments for prostate cancer. Fatigue is a common side effect of such treatments. In this study, 122 patients received supervised aerobic training, resistance training, or neither. At the end of 24 weeks, participants in both exercise groups noted significant improvement in their fatigue symptoms, compared to the control group. Participants in the resistance training group also lost a significant percentage of their body fat.

Endurance athletes often report stomach problems, such as bloating, diarrhea, and gas, even at rest. Experts suggest that moderate regular exercise might reduce the risk for some intestinal disorders. These disorders include ulcers, irritable bowel syndrome, indigestion, and diverticulosis. Older people who exercise moderately may have a lower risk for severe gastrointestinal bleeding.

Patients with end-stage kidney disease who exercise four to five times per week have better survival rates than those who are less active, according to researchers involved in the Dialysis Morbidity and Mortality Wave 2 study. However, the majority of study participants said that severe physical limitations prevented them from exercising so often.

Studies have shown that regular exercise, particularly walking, helps reduce one's risk for memory loss. A 2005 study found that older men who walked less than a mile daily had a 71% higher risk of dementia than those who walked more than two miles a day. A 2006 study found that people older than 65 who exercise regularly had lower risk of developing dementia, particularly Alzheimer's disease. An earlier study found that walking regularly protects women from mental decline. To date, there are no clear explanations for this apparent benefit. A preliminary study in mice suggests that physical activity changes the way brain-damaging proteins are processed in the brain, thus slowing the development of Alzheimer's disease. Aerobic exercise has been linked with improved reaction time, perception, and math skills in people of all ages.

Doctors found that exercise improves the physical and emotional well-being of patients who already have Alzheimer's disease. The patients exercised moderately for as little as 60 minutes each week. Doctors noted patients who exercised were less depressed, wandered away less, suffered fewer falls, and were placed in nursing homes later, compared to patients who did not exercise.

People with existing neurological diseases, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease, should be encouraged to exercise. Specialized exercise programs that improve mobility are particularly valuable for patients with Parkinson's disease. Patients with neurological disorders who exercise experience less stiffness, as well as reduction in, and even reversal of, muscle wasting. In addition, the psychological benefits of exercise are extremely important in managing these disorders. Exercise machines, aquatic exercises, and walking are particularly useful.

Some research has suggested that exercise may have antidepressant effects. Although there is little strong evidence that exercise can help manage depression, a number of studies have suggested benefits. Research findings include:

Just 30 minutes of brisk exercise three times a week was as effective as medication in relieving symptoms, and reducing relapse, in many patients with mild-to-moderate depression.
Over half of older women with depression that did not respond to medication improved with 10 weeks of exercise. (About a third of women who did not exercise also improved during that time.)
Studies on elderly, depressed patients report modest benefits from exercise, even in those who do not response to antidepressants. Simply participating in a group activity may help improve mood.
Teenagers who are active in sports have a greater sense of well-being than their sedentary peers. The more vigorously they exercise, the better their emotional health.
Physical inactivity is strongly linked to depression in children 8 - 12 years of age.

Specific exercises may be particularly beneficial:

Aerobics. Either brief periods of intense training or prolonged aerobic workouts can raise levels of certain chemicals in the brain. These chemicals -- which include endorphins, adrenaline, serotonin, and dopamine -- produce the so-called runner's high. Weight loss and increased muscle tone can boost self-esteem.

Yoga. Yoga practice, which involves rhythmic stretching movements and breathing, has been found to positively affect mood. It may have clinical potential as a technique for improving and stabilizing mood. A study comparing yoga to aerobic exercise found that men have significantly lower levels of tension, fatigue, and anger after yoga, compared with levels after swimming. Yoga and swimming tended to produce equal benefits in women.

Click the icon to see an image of the benefits of yoga.

Moderate exercise in healthy pregnant women does not increase the risk for miscarriage, preterm labor, or rupture of the membrane. Not exercising increases the risk for complications, including low-birth weight babies. Exercising increases the fetal heart rate, which in turn protects the baby.

Healthy women with normal pregnancies should exercise at least three times a week, being careful to warm up, cool down, and drink plenty of liquids. Many prenatal calisthenics programs are available.

The following are specific exercises that may benefit the pregnant woman:

Swimming and water aerobics may be the best option for most pregnant women. Swimming has special benefits for those with fluid buildup. Water exercises involve no impact, overheating is unlikely, and swimming face down promotes optimum blood flow to the uterus.
Performing yoga exercises under the guidance of informed instructors can be very helpful.
Walking is also beneficial.

To strengthen pelvic muscles, women should perform Kegel exercises at least six times a day. This involves contracting the muscles around the vagina and urethra for three seconds 12 - 15 times in a row.

Experts generally recommend the following precautions for pregnant women who exercise:

Fit women who have exercised regularly before pregnancy may work out intensely as long as the doctor approves and no discomfort occurs.
As a rule for previously sedentary, low-risk expectant mothers, the pulse rate should not exceed 70 - 75% of the maximum heart rate, or more than 150 beats per minute. Any sedentary expectant mother should check with her doctor before starting an exercise program.
According to one study, vigorous exercise may improve the chances for a timely delivery. All pregnant women, however, should avoid high-impact, jerky, and jarring exercises, such as aerobic dancing, which can weaken the pelvic floor muscles that support the uterus.
During exercise, women should monitor their temperature to avoid overheating, a side effect that can damage the fetus. (Pregnant women should also not use hot tubs or steam baths, which can cause fetal damage and miscarriage.)

Note: Strenuous exercise may affect the flavor of breast milk for a short time afterward. Nursing mothers who engage in such activity might want to wait about an hour after exercising before they feed their infant.

Complications

Exercise may lead to injury if not done properly. Always exercise with care.

Competitive running or high-impact aerobics pose a high risk of a number of injuries to the bones and muscle. The effect of high-impact exercise on the back is not entirely clear. Some research suggests that over time, high-impact exercise may increase the risk for degenerative disk disease. A survey of people who played tennis, however, found no increased risk for low back pain or sciatica.

High-impact exercise can also cause dizziness, ringing in the ear, motion sickness, or loss of high-frequency hearing.

Some research further suggests that in people unused to exercise, intense activity increases production of harmful particles in the body called free radicals. These unstable oxygen particles injure muscle tissue. Muscle pain in this case does not occur until 24 - 48 hours after exercise.

Some people have a higher than average risk for injury:

About half of people at any age who participate in competitive running or high-impact aerobics experience minor injuries at least once a year. Young, intensely competitive athletes may be at risk for permanent injury. Studies are mixed over whether intensive high-impact sports in younger people cause long-term degenerative joint disease.
As the number of older people who start exercising increases, there has also been an increase in injuries for this age group. Between 1990 and 1996, injuries from active sports increased by 54% in people age 65 and older.
Women are far more likely than men to suffer knee injuries.
Urinary incontinence affects many female athletes who engage in high-impact exercise.
Tennis players are at high risk for injuries from repetitive force on the shoulder joint.

Preventing High-Impact Injuries. The following may be helpful for preventing injury:

Wear shock-absorbing footwear with weight-dampening inserts.
Combine weight lifting with jumping exercises. This may prevent injury by strengthening hamstrings and improving coordination.
Vary training and alternate easy and harder workouts.
Be careful to warm up, cool down, and stretch. Flexibility is the key to preventing many muscle strains.
Take days off now and then. The risk of injury increases when athletes train more than five times a week.

Because of the association between high-impact exercises and oxidation, some experts suggest eating foods rich in antioxidants, such as vitamins A, C, and E. Such foods, which may protect against damage from free radicals, include many fresh fruits and vegetables.

Treating Minor Injuries. Most mild or moderate injuries respond well to a simple, four-step treatment: rest, ice, compression, and elevation (RICE). This combination works well for both spot injuries and chronic problems. Ice packs, which reduce inflammation and pain, can help new injuries, and can be useful for the first few hours after a chronically injured area is exercised. How much or how long to compress the injury is unclear.

Evidence suggests that early movement is helpful, although taping or bracing in people with a recurrent ankle sprain is known to be protective. It may not be helpful in those without a previous ankle injury.

Minor injuries like sprains may be treated at home if broken bones are not suspected. The acronym RICE can help you remember how to treat minor injuries: "R" stands for rest, "I" is for ice, "C" is for compression, and "E" is for elevation. Pain and swelling should decrease within 48 hours. Gentle movement may help, but pressure should not be put on a sprained joint until pain is completely gone. This can take up to a few weeks.

Heat, ultrasound, whirlpool, and massage may speed healing if applied a day or two after the initial injury or for warm-up before another workout session.

Some young female athletes who exercise very intensely, and are subject to intense pressure to remain thin, are at risk for a syndrome known as the female athlete triad. This combination of symptoms includes loss of menstruation, eating disorders, and osteoporosis. Eating disorders among young female athletes are estimated at 15 - 62%. Women at higher risk include ballet dancers, gymnasts, and divers. Continued intense exercise causes a stress response in which estrogen (the primary female hormone) is lost. Estrogen loss can lead to infertility and osteoporosis. Iron loss and anemia may also be a problem in women who exercise frequently, even at moderate intensity. A doctor should be consulted for any of these concerns.

Incorrect movements can literally cause mechanical problems in the muscles. These problems are usually the result of improper exercise instruction, and lack of attention. A single jerky golf swing, or the incorrect use of exercise equipment (especially free weights, nautilus, and rowing machines), can cause serious back injuries.

Between 30 - 70% of cyclists experience low back pain. Pain may be improved by adjusting the angle of the bicycle seat.

Everyone should drink lots of fluid during intense exercise. Thirst is often a poor indicator of dehydration in people who exercise, particularly older people. During a tough workout in a hot environment, the body can lose two liters of fluid per hour through sweat.

Anyone who exercises intensely should take the following precautions:

Drink 6 - 8 ounces of fluid about 15 minutes before a workout, and then pause regularly during exercise to drink more.
Water is the best choice for replenishing body fluids. Glucose-sodium-potassium solutions, the so-called "sports drinks," which promise instant energy, appear to be no better than water at improving endurance during prolonged intense running.
Caffeinated beverages like coffee and soft drinks give short bursts of energy, but can actually cause fluid loss. Caffeine before a workout has been shown to temporarily raise blood pressure, and reduces blood flow to inactive limbs.

Contrary to popular belief, drinking fluids will not cause cramps. Drinking enough, in fact, helps prevent the painful involuntary muscle spasms that sometimes occur during exercise.

Overheating, or hyperthermia, can be a problem with hard exercise, or when working out in hot weather. Overheating can cause mild to life-threatening conditions. Heat exhaustion, a moderate form of hyperthermia, is characterized by the following symptoms:

Lightheadedness, nausea, headache, hyperventilation, fatigue, and loss of concentration
A high temperature (above 103° F), possibly accompanied by complaints of chills and clammy skin

Individuals should rest in a cool, dry place, drink plenty of fluids, and bring down their body temperature with ice packs pressed against the skin.

Heatstroke. Heatstroke is the most dangerous complication of hyperthermia. The victim may suddenly stop sweating, after which symptoms such as altered consciousness, seizures, and even coma may quickly follow. Heat stroke is a medical emergency and requires immediate cooling of the victim in an ice-water bath or with ice packs. One study suggests that risk for serious complications from exercising in high temperatures may persist as late as the following day, even if the weather has cooled down.

Click the icon to see an image of the dangers of heatstroke.

Precautions are also necessary in cold weather. When exercising in winter dress in layers, including gloves and socks, which create insulated air pockets that trap heat. In cold weather, wear shoes with less ventilation than those worn in the summer. Fingers, toes, ears, and nose are most susceptible to frostbite. Frostbite progresses from stinging or aching to numbness. Fingers and toes may become white. Soaking the hands and feet in warm water can help, but only once there is no risk of refreezing, since a second bout of frostbite after thawing can quicken tissue damage.

Hypothermia can be life-threatening and can occur even after long exposure to temperatures that are above freezing. The condition is characterized by extreme fatigue, mental confusion, apathy, and a lack of coordination. The victim should be warmed as soon as possible with blankets, body heat, and warm fluids.

Motivation

Motivation, or a lack thereof, is one reason many people stop exercising. Here are some tips for avoiding burnout:

Think of exercise as a menu rather than a diet. Choose a number of different physical activities that are personally enjoyable such as sports, dancing, or biking. Although experts say you should get 30 minutes of aerobic exercises at least five times a week, those times can be divided into shorter periods -- such as 10 minute sessions. In addition, people can achieve health benefits from other exercise programs, including weight training, yoga, or tai chi.
Stick to a prepared schedule and record progress.
Develop an interest or hobby that requires physical activity.
Adopt simple routines such as climbing the stairs instead of taking the elevator, walking instead of driving to the local newsstand, or canoeing instead of zooming along in a powerboat.
Try cross training (regularly switching from one type of exercise to another). Studies suggest it is more beneficial than focusing only on one form of exercise.
Exercise with friends.
Join a gym or take classes. Many affordable programs are available.
For those who can afford them, personal trainers can be very helpful and are available in many gyms and exercise clubs. Personal trainers without any connection to a well-reputed gym or fitness club should be certified by a major fitness organization, such as the Aerobics and Fitness Association of America (AFAA) or the American Council on Exercise.
Exercise videos may also be helpful, but people should be sure they are suited to their individual age and health needs, and bear the seal of the AFAA.
Consider getting a dog. A study in the February 2006 American Journal of Preventive Medicine found that dog owners in Canada walk almost twice as much as those who don’t own a dog. Regular walking is a good way to improve health.

Differences in Motivation Between Men and Women. Motivation factors may differ by gender, and women appear to have a harder time. In one study, weight loss was the greatest motivator to exercise for women, and muscle tone was the primary motivator for men. Unfortunately, effects on appearances may take a long time to show, discouraging people from continuing an exercise program even though their health is improving.

Overweight among children and adolescents has now become an epidemic in the United States. Experts say that children should be vigorously active for at least 20 - 60 minutes 3 - 5 days a week. Parents and schools must be imaginative and rigorous in encouraging children to exercise.

Role of Parents. Parents must make conscious efforts to limit sedentary activities, and to encourage physical ones for their children. This includes monitoring the time children spend on the computer, in front of the TV, or playing video games. Parents should suggest different forms of entertainment. Even children who aren't interested in joining a Little League team may enjoy a round of catch with their parents, walking in the park, or swimming in a local lake.

Role of Schools. Early school physical education programs can make a significant difference and the earlier these routines are learned, the more likely they will be carried forth into a healthy adulthood. Schools should emphasize team cooperation or individual improvement and self-mastery. Studies have shown that people tend to give up more quickly and feel less competent if their perceptions of success are based only on comparison to their peers.

People mature at different rates, and there seems to be a genetic component to coordination, strength, speed, and one's response to resistance exercise. Nonetheless, everyone should strive to be as fit as they possibly can, given their strengths and limitations.

The decision to adopt a healthier behavior -- whether it's more exercise, weight loss, or quitting smoking -- is not as simple as just deciding to do it. Behavior change expert James Prochaska and his colleagues outlined a theory, which has been supported by numerous studies, showing that people cycle through a variety of stages before a new behavior is successfully adopted over the long term. It may help you to understand how this works. As you read the description of each stage -- specifically as it relates to exercise -- you may find yourself nodding and saying to yourself, "Yes, that's me!"

Stage 1: Pre-Contemplation. People at this stage have no plans or desire to exercise. They aren't even considering exercising. They are generally unaware of the specific benefits that exercise can bring -- exercise may seem more like a hassle than something worth doing. Or, they may simply have "failed" in the past and have given up.

There's no point in talking about how to start an exercise program if you are at this stage. Instead, it is important to think about how exercise might be good for you personally -- by helping you to lose weight, feel better, have more confidence, live longer, sleep better, or reduce your stress levels. The benefits must be identified before a person will consider exercise.

If you are at this stage, a good activity is to ask four friends or family members why they exercise. Their answers may show you some real-life benefits, and inspire enough interest to compel you to take the next step.

Stage 2: Contemplation. A person at this stage is thinking, "I think I should probably exercise, but I need help getting started." People at this stage know that exercise is good for them, but it seems like a daunting task or they don't think they can pull it off. Some may have tried and "failed" in the past, but they are still receptive to another go-round.

It's important for people at this stage to consider some of the truths and falsehoods of exercise. For example, it is helpful to know that there are many forms of physical activity to select from, and that you can do your exercising in small chunks. It is not true that exercise has to be painful, or that you either succeed or fail. There is no such thing as "failure" -- people become more or less active at different stages of their lives, and it is never too late to get moving again. And people at this stage should find assurance that an exercise plan can be very simple.

If you are at this stage, a good activity is to write down all the things that you believe make exercise difficult -- and to learn strategies for overcoming or side-stepping those hurdles. People at this stage might benefit from making a pledge, contract, or other commitment that they are going to get more active in the near future. The goal is to get un-stuck by identifying the roadblocks and the ways to overcome these roadblocks. The final goal at this stage is to make a commitment.

Stage 3: Preparation. These folks are primed and motivated. They are ready to give exercise a try. The goal of this stage is to create a specific action plan that takes all factors into account, so that the "launch" is successful. People at this stage need to know how much they should be exercising, their target heart rate, and the types of exercises. They should explore the different kinds of exercises and decide which ones to try.

At this stage, people will evaluate exercise machines and health plans, if that interests them, pick the proper clothing or accessories, and consult a doctor if necessary. They also need to think about how they are going to fit their exercise plans into their daily and weekly schedule.

If you are at this stage, you should also consider some backup plans -- what to do if it rains, or if you don't feel like exercising. That way you are prepared to overcome that hurdle when you encounter it. You should be aware of what to expect realistically at the beginning -- for example, be aware that weight loss takes time, but health benefits begin immediately.

Stage 4: Action! People at this stage have just started exercising. This stage is where the biggest behavior change occurs -- these people have started to exercise but it is not yet a long-term, ingrained habit. This stage requires significant commitment and energy.

If you are at this stage, keep talking to friends and family for inspiration. Review your backup plans. Reward yourself for small achievements. Give yourself notes and reminders to exercise. Having a friend to exercise with can be very helpful as you get through this stage. You want to build and maintain momentum, because exercising gets easier once it is a habit!

Stage 5: Maintenance. The people at this stage have been exercising for at least 6 months. At this point, exercising has started to become a habit. The goal here is to prevent relapse. If you are at this stage, identify ways that you can fine-tune your program. Continue to identify roadblocks and improve your backup plans. Think about what you have found most enjoyable about exercising.

What benefits have you gained? Keep reminding yourself of these perks. If giving yourself a challenge was part of your initial motivation, set new goals and find new challenges. If you risk getting bored with your routine, find ways to vary it. Or maybe you have found a comfortable routine that you enjoy -- if it's working, great! There is no need to change it. You might want to read or learn more about your method of exercising, and develop a deeper level of understanding about it. Soon you'll be a pro!

One point about this theory is that people do not proceed from one stage to another in a simple, step-by-step fashion. They actually cycle or spiral back and forth, so that they may move from stage 1 to 2 to 3, and then back to 2 again. They may stay in maintenance mode for years and then fall back to stage 2. Remember that this is normal -- if you tried exercising in the past and didn't stick with it, don't consider yourself a failure. Just know that it's time to try again!

Resources

http://fitness.gov -- The President's Council on Physical Fitness and Sports
www.ncppa.org --National Coalition for Promoting Physical Activity
www.acefitness.org --American Council on Exercise
www.arthritis.org --The Arthritis Foundation offers tips on exercising with arthritis
www.justmove.org -- Just Move (American Heart Association)

References

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Mikkelsson LO, Nupponen H, Kaprio J, Kautiainen H, Mikkelsson M, Kujala UM. Adolescent flexibility, endurance strength, and physical activity as predictors of adult tension neck, low back pain, and knee injury: A 25 year follow up study. Br J Sports Med. 2006 Feb;40(2):107-13.

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Review Date:
4/30/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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