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In This Report

•	Highlights
•	Introduction
•	Causes
•	Risk Factors
•	Symptoms
•	Complications
•	Diagnosis
•	Treatment
•	Lifestyle Changes
•	Abdominal Infections
•	Encephalopathy
•	Ascites
•	Bleeding Episodes
•	Resources
•	References

Related Reports

•	Gallstones and Gallbladder ...
•	Alcoholism

Encyclopedia

•	Cirrhosis
•	Alcoholic liver disease
•	Primary biliary cirrhosis...

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Cirrhosis

Highlights

Disease Overview

Cirrhosis damages the liver by causing scarring that blocks blood and bile flow.

The Main Causes of Cirrhosis

• Alcoholism. It is essential that people with cirrhosis stop drinking alcohol.
• Chronic hepatitis C or B.
• Autoimmune liver disease.
• Nonalcoholic fatty liver disease.
• Iron metabolism disorders.

Cirrhosis can lead to a number of serious complications including portal hypertension (increased pressure in the abdominal veins), ascites (accumulation of fluid in the abdomen), encephalopathy (brain dysfunction), and liver cancer. 

Treatment

Cirrhosis treatment first targets the conditions that have caused the disease. For example, chronic viral hepatitis is treated with interferon and other antiviral drugs. Complications are treated on an individual basis. When complications cannot be controlled or the liver ceases to function, liver transplantation may be required.

Research

• 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 chances of survival. The study emphasizes the importance, and substantial benefits, of interferon therapy.
• Encephalopathy, a complication of cirrhosis, hampers brain function. Even minimal forms of the condition can have detrimental effects on functional ability. One study suggested that minimal hepatic encephalopathy (MHE) impairs the ability to safely drive a car, and that all patients with liver cirrhosis be tested for MHE.
• The antibiotic rifaximin (Xifaxan) is being investigated for treatment of cirrhosis-associated encephalopathy.
• Kidney failure can develop in late-stage cirrhosis as a result of portal hypertension. Non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen, may increase the risk for kidney failure.

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.

A chronic liver disease which 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.

Click the icon to see an image of the liver.

Causes

There are several processes that can lead to cirrhosis.

Alcoholism

The liver is particularly endangered by alcoholism. Alcoholic cirrhosis (also sometimes referred to as portal, Laennec's, nutritional, or micronodular cirrhosis) is the primary cause of cirrhosis in the US. 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 to 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 and 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 breakdown 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

The second leading cause of cirrhosis in the US is chronic hepatitis, either hepatitis B or hepatitis C. Chronic hepatitis C is the more dangerous form and accounts for one-third of all cirrhosis cases. Overall, between 10% and 15% of patients with chronic hepatitis C develop cirrhosis. The risk varies widely, however. About 5% to 10% of hepatitis B patients eventually develop cirrhosis. Viruses or other mechanisms that cause hepatitis produce inflammation in liver cells, resulting in their 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 cause jaundice, fever and cirrhosis. Persons who are 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 Disease

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's 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 between the ages of 20 and 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 susceptible individuals.

Click the icon to see an image of mononucleosis.

Primary Biliary Cirrhosis. Up to 95% of primary biliary cirrhosis cases occur in women, usually around age 50. In the case of primary biliary cirrhosis, the cells under attack from the aberrant immune system are in the bile ducts. Liver cells are destroyed as the disease progresses. In some cases, the disease also has features that resemble autoimmune hepatitis, but these features do not appear to affect the long-term outlook.

Some research indicates that this autoimmune process may be triggered by a virus or an unknown intestinal microorganism. People with celiac sprue appear to have a higher risk. This is an intestinal disorder associated with an inability to metabolize gluten, which is found in wheat and other common grains. Genetic factors are involved, but the inheritance pattern is unclear. A 1999 English study suggested that the disease is on the rise, although it is unclear if this reflects an actual increase or simply a greater awareness of the disorder.

Click the icon to see an image of the types of food that contain gluten.

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease, also called nonalcoholic steatohepatitis (NASH), has features similar to alcohol-induced hepatitis, particularly a fatty liver, but it occurs in individuals who do not consume significant amounts of alcohol. Severe obesity and type 2 diabetes are the major risk factors for NASH, as well as for complications from NASH. NASH may occur in about half of people with diabetes and up to 75% of obese people, depending on how severe the obesity is. (It can occur in overweight children as well as adults.) Some evidence suggests that insulin resistance (the primary problem in type 2 diabetes) is a major factor in development of a fatty liver in the first place. Although NASH is generally considered to be a benign and slowly progressive disorder, the fatty liver is vulnerable to injury from oxidants (damaging particles produced by chemical processes in the body). Excessive oxidation can lead to progression to advanced liver disease. In one study of patients with NASH, about 20% had some liver damage over a period of 3.5 to 11 years, with only about 6% of all patients showing severe liver damage. Another study reported that eventually 15% to 20% of patients develop advanced liver disease.

Hemochromatosis and Iron Overload

Hemochromatosis is a disorder of iron metabolism that is characterized by excess iron deposits throughout the body, including the liver, where they can cause cirrhosis. Once believed to be rare, hereditary hemochromatosis is now considered to be one the most common genetic diseases among Caucasians. Between 2% and 4% of people of European ancestry are believed to carry the gene, and the disease itself is estimated to occur in between 1.5 and three Caucasians per 1,000. Early symptoms of hemochromatosis include:

• Fatigue.
• Joint pain (arthralgia).
• Impotence in men.
• Arthritis.

A 2000 study further suggested that both hemochromatosis patients and their relatives who carry the trait are at higher risk for cirrhosis. Elevated iron levels, even in the absence of this disease, have been associated with liver scarring, particularly when accompanied by other risk factors for cirrhosis, including hepatitis, NASH, and alcoholism.

Other Causes of Cirrhosis

Inherited Diseases. Cirrhosis can be caused by a number of 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.

Changes That Resemble Cirrhosis

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 three million Americans a year. However, because an estimated 2.7 million to 4 million people harbor hepatitis C, experts expect the rates of cirrhosis to dramatically increase over the next few years. (Cirrhosis rates will then decline as the current fall in the prevalence of hepatitis C starts to take effect.)

Risk Factors in People with Alcoholism

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 role in increasing the risk for liver injury from alcoholism.

Risk Factors in People with Chronic Hepatitis

Risk Factors for Developing Cirrhosis from Hepatitis C. Overall, between 10% and 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% to 4%).
• Moderate to heavy alcohol users. (Even one or two alcoholic drinks a day increase the risk for liver injury in HCV 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 US. The other common forms are types 2 (15%) and 3 (7%), which are pose less danger. (Some evidence suggests that the genetic type is not a primary factor in disease progression, however.)
• 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% to 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, experts 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 HCV-related cirrhosis or liver cancer will double or triple over the next twenty years. Fortunately, improved therapies may significantly reduce these discouraging estimates.

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% and 10%, however, become carriers of the virus and 5% to 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 which patients may have a better outlook than others. Genotype C is the most common and is more aggressive than genotype B, which also responds better to treatment.

Risk Factors for Cirrhosis in Autoimmune Liver Diseases

Primary biliary cirrhosis accounts for only 0.6% to 2% of deaths from cirrhosis. And 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 treated, since untreated the five-year survival rates are 50%.

Obesity and Other Risk Factors for Cirrhosis

A 2003 study of more than 11,000 patients, published in the journal Gastroenterology, revealed that obesity increased the risk of death from cirrhosis in those who drank little or no alcohol, but not in alcoholics. Previous evidence has suggested that severe obesity and diabetes are major risk factors for cirrhosis in nonalcoholic steatohepatitis (NASH) patients. (Severe obesity in any case is a risk factor for liver damage and in one study, 2.3% of patients with severe obesity had signs of cirrhosis.) Men are at higher risk than women and African Americans have a higher risk than Caucasians. Patients with NASH-associated cirrhosis generally do better than patients with alcohol-related liver damage, however.

Symptoms

Many people experience few symptoms at the onset of cirrhosis.

Early symptoms include the following:

• 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 is a yellowish cast to the skin and eyes, which 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 blood stream 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.

Symptoms of Primary Biliary Cirrhosis

People with primary biliary cirrhosis are subject to 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, for alcoholics with cirrhosis who abstain, a survival rate of five years or more can be as high as 85%. For those who continue drinking, the chance for living beyond five years is no higher than 60%.
• In patients with hepatitis B or C, the five-year survival rate after a diagnosis of cirrhosis ranges between 71% to 85%.
• About two-thirds of patients with primary biliary cirrhosis never develop symptoms and can have a normal life span. 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, physicians are usually unable to determine when cirrhosis first occurred, which makes it difficult to determine prognosis.

Portal Hypertension

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 and legs and in the spleen. Although ascites itself is not fatal, it is a marker for severe progression. Once ascites occurs, only half of patients survive after two years. In fact, some experts refer to the phases of cirrhosis as preascitic and ascitic. Some physicians 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, which are 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 (the "food pipe"). They 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% to 30% of cirrhosis patients. The risk of death from a single episode can reach 70%.

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

Factors that predict variceal bleeding in general include the following:

• 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% and 40% of patients with cirrhosis experience bleeding, which carries a mortality rate of between 20% and 35%. Some experts 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.

Kidney Failure

Portal hypertension can cause a number of secondary complications including kidney failure. Non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen, may increase the risk for kidney failure.

Gastrointestinal Bleeding

Gastrointestinal (GI) bleeding can occur from abnormal blood clotting, which can be 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.

Infections

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 and Encephalopathy

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 effect the central nervous system.

Encephalopathy is often triggered by certain conditions, including the following:

• Gastrointestinal bleeding.
• Constipation.
• Excessive dietary protein.
• Infection.
• Surgery.
• Dehydration.

Alcoholics with cirrhosis are believed to be at higher risk for this complication than with 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

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.

Liver Cancer

Cirrhosis greatly increases the risk for liver cancer, regardless of the cause of cirrhosis. Although few studies have been conducted on the risk for liver cancer in patients with primary biliary cirrhosis, one study reported an incidence of 2.3%. About 4% of patients with cirrhosis caused by hepatitis C develop liver cancer. In Asia about 15% of people who have chronic hepatitis B develop liver cancer, but this high rate is not seen in other parts of the world. (One Italian study that followed a group of hepatitis B patients for 11 years found no liver cancer over that period of time.)

Osteoporosis

About 30% of patients with chronic liver disease develop osteoporosis (loss of bone density), which is twice the usual incidence Primary biliary cirrhosis poses 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 can reduce and even reverse loss of bone density.

Insulin Resistance

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.

Other Complications

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 findings 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 physician when pressing on the abdomen.

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

Specific Tests Used to Diagnosis Hepatitis

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 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 which 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 sufficient numbers of antibodies to be detectable by blood tests 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 HCV. In the March 16, 2004 issue of the Annals of Internal Medicine, the U.S. Preventive Services Task Force recommended against routine screening for the HCV 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 Task Force 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 CDC, NIH and other professional organizations. In response to the study, 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 which strongly emphasizes the need for screening in high-risk populations.

Biopsy

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 the following:

• 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 employs small abdominal incision through which the physician 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.

Tests for Determining Liver Function

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 physicians determine the severity of cirrhosis.

Specific Blood Tests for Primary Biliary 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.

Imaging Tests

A number of 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, enlarged spleen, 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 physician to measure portal vein pressure; this procedure is risky.

Hepatic Vein Wedge Pressure

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.

Other Tests Used to Detect Complications of Cirrhosis

Endoscopy. Some experts 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). This test involve inserting a fiber optic tube 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-fetoproetin (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.

Treatments for Chronic Hepatitis C

Interferons Alone and in Combination with Ribavirin. Pegylated (PEG) interferon combined with ribavirin (a nucleoside analogue), is now the gold standard for treating for chronic hepatitis C. Interferons are natural proteins that activate certain immune functions in the body and have antiviral properties. Ribavirin is poor at inducing initial responses alone but it can double sustained response rates when combined with an interferon. 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 number of natural and synthetic interferons are available:

• Natural interferons were the first used for HCV and include interferon alpha-2a (Intron) and Interferon alpha-2b (Roferon). Rebetron is the combination of interferon alpha-2b and ribavirin.
• Pegylated interferons (PegINF) are long-acting formulations of interferon. They include alfa-2b (Peg-Intron) or alfa 2a (Pegasys). Rebetol is a combination of alfa-2b and ribavarin.
• 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.

The combination of pegylated interferon alfa-2b with ribavirin (Rebetol) has achieved the best success rates to date of all interferons and their combinations. It has achieved responses of up to 51% with genotype 1 and nearly 80% with genotype 2 and 3. According to a 2002 comparison study, the Pegasys combination may even produce better results.

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.)

Investigative Drugs for Hepatitis C

The current drugs used for HCV 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. Some showing promise include the following:

• Nucleoside analogs. Several new nucleoside analogs are in clinical development. Viramidine is a drug related to ribavarin. It is being studied in Phase III trials alone and in combination with pegylated interferon-alfa. Valopicitabine (NM283) is being tested in Phase II trials as alone and in combination with pegylated interferons.
• 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 Phase II trials for patients who have not been treated with or have not responded to standard interferon-alfa.
• IMPDH Inhibitors. Mycophenylate mofetil and VX-497 are agents that inhibit an enzyme known by its brief name, IMPDH, which may block replication of the hepatitis C virus. If effective, they would most likely be used in combination with interferon and ribavirin.
• Amantadine (Symmetrel) is an anti-viral agent being investigated in various combinations. For example, triple therapy with amantadine, pegylated interferon, and ribavirin is showing particular promise. In some cases, the side effects of amantadine can be severe, and include vertigo, insomnia, nervousness, and depression. They are particularly disabling among older patients who receive inappropriately high doses.
• 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 call T-cells). It is being used for hepatitis B and is under investigation for hepatitis C in combinations with natural interferons and pegylated interferon.
• Protease Inhibitors. Novel protease inhibitors (similar to those used for HIV) are under investigation for hepatitis C patients who fail other treatments. These agents are based on molecular therapies that target proteins involved in viral reproduction.

Other agents under investigation include therapeutic vaccines and genetic therapies known as antisense oligonucleotides or monoclonal antibodies. InnoVac-C is one such vaccine undergoing Phase IIb clinical studies. In March 2004, Innogenetics reported 3-year histology data from an earlier InnoVac-C trial. After four courses of the vaccine, patients exhibited significant improvement in liver scarring, when compared to their baseline results. The HCV vaccine appeared to be well-tolerated. Even if successful, none of these agents would be available for some years.

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 possible slowed progression of cirrhosis.

Treatments for Chronic Hepatitis B

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 HBV is available. It can prevent hepatitis B and therefore, it can 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.

Four drugs are currently approved in the United States for treatment of chronic hepatitis B: interferon-alfa-2b (Intron), adefovir (Hepsera), lamivudine (Epivir), and entecavir (Baraclude) These drugs block the replication of HBV in the body. 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, and likelihood of drug resistance. A combination of drugs may also be prescribed.

Interferon Alpha. For many years, interferon alpha-2b (Intron) was the standard drug for hepatitis B. The drug is usually taken by injection every day for 16 weeks. Unfortunately, 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 and Entecavir. These two 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. Lamivudine has reduced viral count in over half of hepatitis B patients who have taken it as sole therapy for about a year. It is less expensive than interferon-alfa and has fewer side effects, but may not be as effective 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. In 2005, the FDA approved entecavir (Baraclude) for treatment of adults with chronic hepatitis B. In clinical trials, entecavir was more effective than lamivudine for treating HBV. However, questions have been raised about the drug’s possible cancer risks. Ongoing studies are assessing this risk.

Adefovir. Adefovir (Hepsera) belongs to a class of antiviral agents 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 HBV.

Drug Warnings. In 2004, the FDA issued two drug warnings for patients with HBV. The HIV drug tenofovir (Viread) should not be used to treat patients who are co-infected with HBV as the drug may increase hepatitis severity. The lymphoma drug rituximab (Rituxan) may reactivate HBV. Patients with lymphoma should be screened for HBV.

Investigative Drugs for Hepatitis B

• Telbivudine is a nucleoside analog drug in Phase III trials for treatment of chronic hepatitis B. A 2003 study, presented at a meeting of the American Association for the Study of Liver Diseases, found that telbivudine resulted in significantly better suppression of HBV and normalization of certain liver enzymes compared to lamivudine monotherapy.
• Pegylated interferon alfa-2b (Peg-Intron) is currently approved for treatment of chronic hepatitis C. It is being investigated alone and in combination with lamivudine for treatment of HBV. One 2005 study found that a third of patients treated solely with pegylated interferon-alfa-2b became negative for the hepatitis B antigen (HBeAg). Combining the drug with lamivudine did not improve effectiveness. Another 2005 trial tested a staggered drug regimen where pegylated interferon alfa-2b was administered alone and then later combined with lamivudine. Researchers compared the results with lamivudine single therapy and found that the combination group had better virologic response and less drug-resistance. However, there were more side effects in the combination drug group and the duration of the treatment regimen was longer.
• 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 call T-cells). It appears to be safe for hepatitis B patients when used alone or in combination. It is approved in many countries, but not the United States.
• Vaccines as Treatments. Hepatitis B vaccines are being investigated in combination with drugs, such as lamivudine, for treatment of HBV.

Treatments for Primary Biliary Cirrhosis

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. A number of 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 agents.

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

Agents 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. Agents called medium-chain triglycerides may be helpful for steatorrhea (in which the feces contain excessive fat).

Treatments for Other Causes of Cirrhosis

Treatment of Nonalcoholic Fatty Liver Disease (NASH). Weight loss is the most important component for managing NASH and preventing progression to liver disease. Investigators are studying various drugs, insulin-sensitizing drugs metformin, rosiglitazone, and pioglitazone, as well as the antioxidant vitamin E.

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 corticosteroids as standard agents and also possibly immunosuppressants, such as azathioprine and cyclosporine A.

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.

Treatments for Liver Scarring

Presently, there are no 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 agents that target the primary injury and/or inhibit abnormal cell mechanisms. Such agents, now in very early testing, could one day help prevent or reduce the progression of liver scarring or the progression to liver cancer.

Lifestyle Changes

A healthy lifestyle is particularly important for people with cirrhosis.

Dietary Factors

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

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 physician. 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 six months they showed significant improvement in many signs of overall health compared to those who didn't 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.

Limiting Fluids

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

Exercise

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 physician.

Preventing Influenza and Infections

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. Furthermore, they advise that patients who get the flu be treated immediately with rimantadine, but not a similar treatment called amantadine.

Treating Chronic Fatigue

A 2000 study of 15 patients with chronic liver disease concluded that methylphenidate (Ritalin) improves chronic fatigue symptoms in patients with cirrhosis and chronic hepatitis. All patients reported some improvement in fatigue, and no side effects were severe enough to warrant withdrawal from the study. The researchers recommended that treatment for chronic fatigue in patients with liver disease combine methylphenidate with physical therapy and nutritional counseling. Results of the study need to be confirmed in a randomized prospective trial.

Alternative Remedies

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). Two natural substances that may have some benefits for people with cirrhosis are discussed in the following paragraphs:

Silymarin. A 2001 review analyzed studies on 10 herbal remedies used for liver disease. None showed any benefits except silymarin. Furthermore, an analysis of five studies on cirrhosis patients reported an association between silymarin and a 7% reduced mortality rates from liver-related diseases. Known side effects from silymarin include rare reports of gastrointestinal problems and allergic skin rashes.

S-adenosylmethionine (SAMe). 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.

It should be strongly noted that herbal remedies are not necessarily harmless simply because they are natural (or marketed as natural), and their quality is not regulated except in clinical studies.

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 five days may be sufficient for certain patients. Some research indicates that the oral antibiotic ofloxacin may be as effective and is without complications, allowing patients to be treated at home.

Preventing Infections in Advanced Cirrhosis

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 found that preventive antibiotics were very cost effective in high-risk patients. Another study reported, however, that patients who took norfloxacin became susceptible to Staphylococcal infections, which are not ordinarily a problem in cirrhosis, and their survival rates were similar to patients who did not take the antibiotic. Long-term treatments with norfloxacin or similar antibiotics may increase the risk for fungal infections after liver transplantation. More research is needed.

Encephalopathy

The first step in managing encephalopathy (damage to the brain) is to treat any precipitating cause, if known, 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.

Eliminating Ammonia

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 may be beneficial in 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.
• Adding non-ammonia producing bacteria to the intestine, including L. acidophilus and E. faecium, is showing promise as a safe and effective treatment.

Investigative Agents. 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 can benefit form the following measures:

• Abstaining from alcohol. (Sometimes abstaining from alcohol is enough to reverse 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 rapid 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 or 2 pounds per day, but there is no limit for patients with massive swelling.

Physicians often recommend bed rest for patients with ascites, but many experts believe this is not necessary and say that studies do not support its benefits. Restricting fluid is not usually necessary unless sodium levels in the blood are very low.

Treatment for Recurring or Refractory Ascites

Patients with recurring ascites or ascites that does not respond to standard diuretics after a month 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 to 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 bleed vessels, may be as effective.
• If the ascites does not respond to treatments, paracentesis may need to be repeated every two weeks or more frequently, and up to 10 liters may need to be removed.

Patients who require this are probably not complying with dietary requirements.

Transjugular Intrahepatic Portosystemic Shunt (TIPS). 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 (LeVeen, Denver) 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.

Treatment of Hepatorenal Syndrome

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

Investigative Agents

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

Liver Transplantation

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.

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

Bleeding Episodes

Preventing an Initial Bleeding Episode. About half of patients with mild to moderate cirrhosis have esophageal varices (abnormal blood vessels in the esophagus). In such patients the risk for bleeding within two years is as high as 35%. Bleeding is fatal in half of these patients. In general, experts now recommend preventive drugs in 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 physicians should first be certain that bleeding is caused by portal hypertension and ruptured varices and not by other conditions. For example, cirrhosis patients 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 a normal blood flow (hemostasis) in order to stop the current bleeding episode and prevent early recurrence, which typically occurs three to five days after a bleeding episode.

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

• Drugs. The patient should be given drugs to reduce portal pressure and blood flow, typically octreotide or vasopressin.
• Endoscopy. Endoscopy employs an insertion of a thin tube containing a tiny camera and surgical instruments in order 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 of the existing evidence suggests that it is no more effective than agents used to stop 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. Investigation is ongoing concerning the most cost-efficient ways for preventing recurrence. At this time, beta-blockers are the best treatments available, although they are not effective in many patients. Drug combinations and endoscopic procedures are under investigation to determine if they offer any additional benefits.

Preventing Complications. The patients 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.

Drugs Used for Prevention of Bleeding

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 agent 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 two years and most likely longer to sustain a survival advantage.

Other Agents. Other agents 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 suggest appear to prevent rebleeding more effectively than beta-blockers alone. It is not clear if the combination improves any other aspects of the disease. (One study suggested that taking a low dose of before a meal might help reduce a rise in portal pressure that typically occurs after eating.) The nitrate has also been given as the alternative agent for patients who cannot tolerate beta-blockers. Studies have failed to show any survival advantage with isosorbide mononitrate when used alone, however.
• 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.

Drugs Used to Treat Bleeding Episodes

Somatostatinand Similar Agents. Somatostatin is a natural hormone that constricts blood vessels. This agent or synthetic derivatives (octreotide and vapreotide) may be more effective than the common procedure, endoscopic sclerotherapy, for controlling bleeding. No single agent is more effective than another. Their benefits for improving overall survival, however, are still uncertain, and a major 2002 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 2000 study, but it is short acting.
• Octreotide (Sandostatin) is a derivative of somatostatin and is longer acting. It has largely replaced the older agent. It is very safe, even for heart patients, and has few serious side effects.
• Vapreotide (Octastatin) also resembles somatostatin. A 2001 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 five 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 bridge for patients waiting for liver transplantation.

Endoscopic Procedures Used to Stop Bleeding and Prevent Recurrence

Endoscopic procedures employ a tube inserted down through the esophagus that contains 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 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 employs argon gas to deliver electric currents that coagulate and stop bleeding. In one small study, no recurrence of varices or bleeding occurred after APC, while recurrence occurred in 42% and bleeding in 7.2% of patients without the argon procedure. More work is warranted.

Endoscopic Sclerotherapy. Endoscopic sclerotherapy is only effective against bleeding in the esophagus. The endoscopic tube is inserted through the mouth. Agents are injected through what are called sclerosants (polidocanol and others). They toughen the tissue around the variceal blood vessels. The procedure is repeated over a period of two or three 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 for Uncontrolled Bleeding

Balloon tamponade has been available for years but is now used only for bleeding not controlled by drugs or endoscopy. It employs 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.

Shunt Procedures for Uncontrolled Bleeding

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. Experts do not recommend shunts as elective surgery for high-risk patients who are candidates for liver transplantation, since shunts makes this operation more difficult.

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

• 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

• www.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/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

Mas A, Rodes J, Sunyer L, Rodrigo L, Planas R, Vargas V, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol. 2003 Jan;38(1):51-8.

Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med. 2005 Jan 18;142(2):105-14.

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