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Cirrhosis

WHAT IS CIRRHOSIS?

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.  

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.

In response to the scarring, liver cells regenerate in abnormal 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, which relaxes and opens the blood vessels.

On the other hand, blood vessels in other organs, including the kidney, narrow.

The small blood vessels and bile ducts in the liver itself constrict.

Blood flow coming into the liver from the intestine, then, backs up through the portal vein and seeks other routes. One result is the development of new, abnormally twisted and swollen veins called varices that form in the stomach and lower part of the esophagus.

Bile also builds up in the blood stream, resulting in high levels of bilirubin, which causes a yellowish cast in the skin called jaundice.

Fluid build-up 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
The liver is the largest organ in the body. In the healthy adult, it weighs about three 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 is formed in the liver and helps the body absorb fats and fat-soluble vitamin. It is produced 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 gall bladder, 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 contributions to life is to render harmless potentially toxic substances, including alcohol, ammonia, nicotine, drugs, and harmful by-products of digestion.

Recycling Blood. Old red blood cells are removed from the blood by the liver and spleen, and the iron contained in them is recycled to 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 hierarchy 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 and formed from an intricate system of ducts and vessels.

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. [See The Liver's Blood Supply, below.]

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 gall bladder.

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 to the liver directly from the heart, and it is this blood that nourishes the liver.

The portal vein. The portal vein carries blood into the liver that has been circulating through the stomach, spleen, and intestine. This is the blood that the liver processes. The liver extracts nutrients and toxins from this blood.

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

WHAT CAUSES 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, theblood carries it directly into the liver, where it becomes the preferred energy source.

There, alcohol converts to toxic chemicals, such as acetaldehyde, which trigger the production of immune factors called cytokines. In large amounts, these agents cause inflammation and tissue injury and are proving to be major culprits in the destructive process in the liver. Over time, this process kills liver cells, a condition called alcoholic hepatitis.

The liver becomes 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 C. Chronic hepatitis C is the more dangerous form and accounts for one-third of all cirrhosis cases. 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.

Primary Biliary Cirrhosis
Primary biliary cirrhosis accounts for only 0.6% to 2% of deaths from cirrhosis. It is most likely an autoimmune disease; that is, the body’s immune system attacks its own liver cells mistaking them for foreign invaders (called antigens). In the case of primary biliary cirrhosis, the cells under attack are in the bile ducts. Liver cells are destroyed as the disease progresses.

Some research indicates that this autoimmune process may be triggered by a virus or an unknown intestinal microorganism. Other autoimmune diseases, such as scleroderma or Sjögren’s syndrome, may also accompany this form of cirrhosis.

Nonalcoholic Steatohepatitis (NASH)
Nonalcoholic steatohepatitis (NASH) is a form of liver damage characterized by fat deposits in an inflamed liver. NASH is similar to hepatitis caused by alcoholism, but is not related to alcohol and progresses more slowly than alcohol-related liver disease. (NASH is sometimes referred to as fatty liver hepatitis, nonalcoholic Laennec’s, steatonecrosis and diabetic hepatitis.)

The typical NASH patient is a middle-aged overweight woman with type 2 diabetes. Cirrhosis in NASH, then, is likely to be triggered by a combination of increased fatty deposits caused by obesity and impaired sugar (glucose) metabolism from diabetes. The disease has also developed in some people, including men and children, who are not overweight or diabetic, however, so other factors are at work. Certain medications, intestinal surgeries, and genetic diseases also increase the risk for NASH.

Evidence now suggests that NASH is an under-recognized cause of cirrhosis, and that 5% to 10% of people with this condition develop cirrhosis. Patients with NASH-associated cirrhosis generally do better than patients with alcohol-related liver damage.

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 among 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 3 Caucasians per 1,000. Early symptoms of hemochromatosis include:

Fatigue.

Joint pain (arthralgia).

Impotence.

Arthritis.

(It should be noted that elevated iron levels, even in the absence of this disease, have been associated with liver scarring caused by other disorders, 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, 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.

WHO GETS CIRRHOSIS?
Cirrhosis affects about three million Americans a year.

People with Alcoholism
About 10% to 35% of heavy drinkers develop alcoholic hepatitis, and 10% to 20% of these individuals develop cirrhosis. Not eating when drinking and consuming a variety of alcoholic beverages are also factors that increase the risk for liver damage. People with alcoholism are also at higher risk for hepatitis B and C.

People with Chronic Hepatitis
Risk Factors for Developing Cirrhosis from Hepatitis C. Between 20% and 30% of people with hepatitis C develop cirrhosis after twenty years. (It should be noted that even in patients with cirrhosis, survival rates in one study were nearly 80% at ten years in these patients.)

Although having a specific genetic type of the virus (mostly likely genotype 1) may be the strongest factor in predicting severity in chronic hepatitis C, patients in the following categories may also be at higher risk for developing severe liver damage than other patients:

Being male may pose a higher risk for severity than being female.

Developing hepatitis C at an older age.

Heavy alcohol users.

Co-infection with HIV or hepatitis B.

A history of transfusions. (One study reported that they are twice as likely as intravenous drug users to develop cirrhosis.)

Being overweight, particularly if fat is distributed in the abdomen (an apple-shape). This condition may pose a higher risk for a fatty liver, which in turn is more apt to become scarred and cirrhotic.

Having large iron stores in the liver.

Risk Factors for Developing Cirrhosis from Hepatitis B

The great majority of people with chronic persistent hepatitis B have a good long-term outlook, but between 5% and 10% 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. [ See also Well-Connected, Report #59, Hepatitis.]

Risk Factors for Primary Biliary Cirrhosis
Up to 95% of primary biliary cirrhosis cases occur in women, usually around age 50. Those with celiac sprue (an intestinal disorder associated with an allergy to wheat gluten) appear to have a higher risk. 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.

WHAT ARE THE SYMPTOMS OF CIRRHOSIS?
General 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.

The palms of the hands may be reddish and blotchy, a condition known as palmar erythema.

Loss of body hair. Patients may lose 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-build up and swelling (edema) in legs.

Encephalopathy. Forgetfulness, unresponsiveness, and trouble concentrating may be early symptoms of hepatic encephalopathy, which is damage to the brain caused by build-up of toxins. 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.

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.

HOW SERIOUS IS CIRRHOSIS?
General Outlook for Cirrhosis
Cirrhosis is the seventh leading cause of death by disease in the US, killing over 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 build-up (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 and blood pressure therefore increases. This pressure causes a back-up of blood through the portal vein, a condition called portal hypertension. The effects of portal hypertension can be widespread and serious.

Ascites and Fluid-Build-Up. Ascites is fluid build-up 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, blood vessels that enlarge to provide an alternative pathway for blood diverted from the liver. Varices often form in the stomach and esophagus (the tube connecting the mouth and stomach). 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: The greater risk in the evening. A lesser but still significant risk in the early morning.

Gastrointestinal Bleeding
Gastrointestinal (GI) bleeding can occur from abnormal blood clotting, often caused by deficiencies in vitamin K, low levels of clotting proteins, and low counts of platelets (the blood cells that normally initiate the clotting process).

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:

Build-up 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.

Hepatorenal Syndrome
Hepatorenal syndrome is a life-threatening complication of late-stage liver disease. In general, the kidneys fail in trying to compensate for altered blood flow in the liver by narrowing their own blood vessels.

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
Primary biliary cirrhosis is associated with reduced bone growth, partly because of the liver’s inability to process vitamin D and calcium and also from some of its treatments. As a result, osteoporosis occurs in 20% to 30% of these patients. Bone loss may also be a complication of liver disease in alcoholics and patients with hepatitis. 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.

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, a hormone that 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. 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.

HOW IS CIRRHOSIS DIAGNOSED?
Physical Examination
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.

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 procedure may employ different methods:

One approach uses a needle inserted through the abdomen to obtain a tissue sample from the liver.

Another uses peritoneoscopy, a procedure that uses small 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.

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 [ see above ].

Blood Tests
A number of blood tests can measure liver function and help determine the severity and cause of cirrhosis.

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.

Discriminant Function (DF). To help determine outlook, experts may use a calculation called a discriminant function (DF), which uses two important measurements:

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).

Liver Enzymes. Enzymes known as aminotransferases, particularly aspartate (AST) and alanine (ALT) are released when the liver is damaged. Measurements of these enzymes are important for determining the severity of liver damage and monitoring treatment effectiveness in some cases.

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.

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.

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:

For example, a cloudy fluid plus a high white blood cell count means an infection is present.

Bloody fluid suggests the presence of a tumor.

WHAT ARE THE TREATMENTS FOR CONDITIONS THAT CAUSE CIRRHOSIS?
Treating Alcoholism
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. Drugs under investigation for treating alcoholic cirrhosis include the following:

Propylthiouracil and colchicine, which inhibit deposits of collagen, the critical protein building block in connective and scar tissue.

Drugs that block factors in the immune system, called thromboxanes, may play an important role in the inflammatory process that kills liver cells in alcoholic cirrhoses.

A 2000 study on polyenylphosphatidylcholine (PPC), an antioxidant extract from soybeans, showed that it could halt, or perhaps even reverse, progression of liver fibrosis (scarring) in alcoholics. More research is warranted. [For more information, see Well-Connected, Report # 56, Alcoholism.]

Treating Chronic Hepatitis B or C
Drug treatments for chronic hepatitis B and C are aimed at reducing or preventing liver damage and boosting or modifying the immune system to promote its attack on the viruses. [For more information, see Well-Connected, Report # 59, Hepatitis.]

Primary Agents. The important agents for treating chronic hepatitis are the following:

Interferons (particularly interferon alpha). Of note, evidence suggests that interferon alpha reduces important factors that cause cirrhosis, inflammation and fibrosis (scarring), independent of its antiviral effects. It may even reverse fibrosis. If this evidence holds up, then even patients whose viral and liver enzyme counts remain high or steady may benefit from long-term use of these agents. Evidence is indicating that patients with hepatitis C and early stage (compensated) cirrhosis may be candidates for interferon combination treatments or from newer interferon forms, such as PEG-IFN. It is unclear if the drug improves survival in patients with advanced cirrhosis and, in any case, it may be dangerous for them.

Nucleoside Analogues (ribavirin, lamivudine, famciclovir, and adefovir) act directly against the virus. The nucleoside analogue lamivudine (Zeffix) has reduced viral count in over half of hepatitis B patients who have taken it as sole therapy for about a year. It also appears to significantly reduce the risk for liver damage and cirrhosis.

They are being used as sole therapy and in combinations. Some experts recommend that patients with cirrhosis caused by hepatitis C undergo interferon/ribavirin therapy for a year. These drugs are used differently depending on the specific hepatitis.

Immunotherapy. A number of drugs are being studied that boost the body's own immune system to fight the virus. For example, thymalfasin (Zadaxin) is a synthetic version of a peptide derived from the thymus gland (which produces immune factors call T-cells). It is showing some promise for patients with hepatitis B and C. Other vaccines, including Hepagene, are being investigated for treating as well as preventing hepatitis B.

Investigative Drugs for Hepatitis C.

Amantadine. Amantadine (Symmetrel) is a drug commonly used for Parkinson's disease, but which may have some antiviral effects. One 2000 study reported that in combination with interferon, it improves the quality of life more effectively than interferon alone. In another study, it was helpful in combination with interferon and ribavirin for hepatitis C patients who had failed interferon.

Ursodeoxycholic Acid. Ursodiol, or ursodeoxycholic acid, a drug ordinarily used for primary biliary cirrhosis, improves aminotransferase levels. It has no effect against the virus, but may be useful in combination with interferon.

Protease Inhibitors. Protease inhibitors (similar to those used for HIV) are under investigation for hepatitis C patients who fail other treatments.

Interleukin. Researchers are also looking at interleukins 10 and 12, immune factors that may enhance the immune response to hepatitis C.

Antioxidants. Antioxidants may help reduce liver injury from damaging particles known as oxygen free radicals. Among the antioxidants being investigated are an agent known as a histamine type-2 receptor agonist (Maxamime), N-acetylcysteine (an amino acid byproduct), and vitamin E. One very small study reported benefits from a combination of the antioxidants alpha lipoic acid (thioctic acid), silymarin (found in milk thistle), and selenium. In addition to protecting against free radical damage, these agents may have antiviral and immune boosting qualities.

Glycyrrhizin. Glycyrrhizin is a compound in licorice. Studies are reporting that it reduces liver enzymes (although has no effect on viral count).

Primary Biliary Cirrhosis
Ursodeoxycholic Acid (Actigall). Ursodiol or ursodeoxycholic acid (Actigall) is the standard drug used for primary biliary cirrhosis, but current studies are questioning its effectiveness, and, most recently, a 12-year study published in 2000 reported no survival advantages. An earlier 1999 European analysis of 11 studies also reported no improvement in survival and no effect from the drug on scarring, bleeding, or protein levels. Larger, controlled studies are needed. One study suggested that the doses used in most large trials are too low and that higher doses may have significant benefits. It may also be effective in combination with other agents, such as colchicine [ see below ]. Tauroursodeoxycholate, an agent similar to ursodeoxycholic acid, may prove to be more effective.

Colchicine. Colchicine, a drug that inhibits collagen (a protein in the body the makes up scar tissue) has produced some improvement in liver function and survival, but it does not appear to be as effective as methotrexate. Like methotrexate, colchicine can have severe side effects.

Corticosteroids (Budesonide) . Corticosteroids, such as budesonide, reduce inflammation and have been helpful in improving liver function and symptoms. Long-term use can produce bone loss and other severe side effects. One study of budesonide reported that it offered little additional benefits for patients who had failed ursodeoxycholic treatment, particularly in light of the risk for osteoporosis. Another study indicated that a combination of budesonide and ursodeoxycholic acid may be much more effective than either one and have minimal adverse effects.

Agents for Itching and Fatigue . Itching and fatigue are major problems with this disease and a number of agents have been used or investigated for these symptoms:

In one study an antioxidant compound (Bio-Antax) plus coenzyme Q10, another antioxidant, relieved itching and fatigue.

Itching can be relieved by taking cholestyramine with meals.

Low doses of the drug naltrexone relieved itching in one study; high doses of this drug are toxic to the liver.

Phototherapy, which uses light, may also reduce itching.

Methotrexate, an anti-inflammatory drug that suppresses elements of the immune system, has been shown to reduce itching. It was hoped that the drug might improve liver disease. A small 2000 study reported, however, that it improved liver tissue health in only 18% of patients and, in fact, the disease accelerated in 50% of the patients.

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. For steatorrhea, agents called medium-chain triglycerides may be helpful.

Treatments for Other Causes of Cirrhosis
Secondary Biliary Cirrhosis . Secondary biliary cirrhosis caused by blockage in the bile ducts can be relieved by surgery.

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.

WHAT LIFESTYLE FACTORS CAN HELP MANAGE CIRRHOSIS?
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.

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.

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.

HOW ARE ABDOMINAL INFECTIONS TREATED IN CIRRHOSIS?
Treating Abdominal Infection (Peritonitis)
Antibiotics are administered when fluid examination and tests for ascites [ see above ] 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. One study indicated that adding intravenous albumin (a protein) to this regimen reduced the risk of kidney damage and early death. 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.

HOW IS ENCEPHALOPATHY TREATED IN CIRRHOSIS?
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. Eliminate ammonia in the intestine. 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 flumazenil (Mazicon, Romazicon), are under investigation for treating encephalopathy. Flumazenil is typically administered to counteract the effects of sedatives.

WHAT ARE THE TREATMENTS FOR ASCITES IN CIRRHOSIS?
Diuretics and Lifestyle Changes
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 build-up. 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 one or two pounds a 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:

Albumin (protein) is administered intravenously.

At the same time large volumes of fluid are removed through a tube in the abdomen. Research indicates that four to six liters are usually effective and safe.

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). A small 2000 study reported that a procedure called transjugular intrahepatic portosystemic shunt (TIPS) improved survival without transplantation compared to large-volume paracentesis. The probability of survival in patients who had TIPs was 58% at two years and only 32% in the paracentesis group. This was a small study using mostly patients with alcoholic cirrhosis. More studies are needed to confirm these results in other groups. This procedure is not appropriate for patients with poor liver or kidney function. In general, paracentesis should still be used first for ascites that does not respond to diuretics. [For a description of TIPS, see How Are Portal Hypertension and Variceal Bleeding Treated?.]

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.

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 [ see Box Liver Transplantation].

HOW ARE PORTAL HYPERTENSION AND VARICEAL BLEEDING PREVENTED AND TREATED IN CIRRHOSIS?
Drugs Used to Prevent Initial and Recurring Bleeding

Ongoing research is being conducted to determine if agents or procedures can prevent a first bleeding episode. Drugs known as beta-blockers are the only therapies to date that may have some preventive effects. Candidates for these agents are patients who have large varices (twisted blood vessels) or other risk factors for bleeding.

Beta-blockers, typically propranolol (Inderal) or nadolol (Corgard), reduce the heart rate and can lower portal vein pressure and 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. It is not yet clear if these drugs are more effective against bleeding than procedures, such as sclerotherapy, but they are inexpensive and safe. They also appear to be more effective than procedures for preventing abdominal infection. Patients with diabetes type 1, asthma, emphysema, and chronic bronchitis should avoid them whenever possible.

Isosorbide mononitrate has been given as the alternative agent for patients who cannot tolerate beta-blockers. Studies have failed to show any survival advantage with this agent when used alone, however. Studies on combinations of isosorbide mononitrate with beta-blockers suggest that they prevent rebleeding more effectively than beta-blockers alone, but it is not clear if combination improves any other aspects of the disease.

Drugs known as angiotensin II receptor antagonists, including losartan (Cozaar), are being studied for lowering portal pressure.

Guidelines for Treating Bleeding Episodes
Determine Causes of Bleeding. The physicians should first be certain that bleeding is caused by portal hypertension and ruptured varices. Cirrhosis patients are also at higher than average risk for bleeding ulcers.

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

Achieve Normal Blood Flow. 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. [ See below. ]

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. [ See below. ]

Drugs Used to Treat Bleeding Episodes and Prevent Recurring Bleeding
Somatostatin and 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. Their benefits for improving overall survival, however, are still uncertain, and a major 2000 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. In one study terlipressin helped reverse a syndrome known as hepatorenal syndrome, a life-threatening condition in which kidneys fail in trying to compensate for altered blood flow in the liver. More research is warranted to determine if the drug has any effect on mortality.

Procedures Used to Treat Bleeding and Prevent Rebleeding
Different procedures may be required depending on the location of the bleeding.

Endoscopic Procedures. Those used stop bleeding in the esophagus primarily rely on endoscopy, which employs a tube inserted down through the esophagus that contains micro cameras and tiny instruments. It is used both to diagnose the disease and stop initial bleeding.

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.) The procedure is unpleasant and many patients cannot tolerate it.

Endoscopic Band Ligation . In endoscopic band ligation, latex bands are wrapped around the bleeding varices, shutting off the blood supply. There are few complications. In some studies it requires fewer sessions than sclerotherapy and may be more effective. One study found the procedure to be more protective than beta-blockers, the standard drugs used to prevent bleeding episodes, but other studies have not confirmed this. More research is needed, and studies on combinations of the procedure and drug therapy may be particularly useful.

Balloon Tamponade . Balloon tamponade has been available for years but is not 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 Used for Bleeding that Is Not Responsive to Other Treatments
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 (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 cave, a large vein that conducts blood back to the heart. This serves to widen the vein.

The needle then punctures the hepatic vein in the liver and a connection is then made to the portal vein.

A cylindrical wire-mesh stent is inserted into this vein to keep it open.

The shunt forces blood vessels to reroute around the scarred liver.

Blockage or closure of the shunt can develop over time.

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 for an initial bleeding episode, however, since it poses a much higher risk for encephalopathy than with endoscopic sclerotherapy and there is no survival advantage.

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 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 , also called the lienal vein. (The splenic vein returns blood from the spleen. It 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.

Liver Transplantation
Liver transplantation is indicated in 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 may also be candidates. Current five-year survival rates after liver transplantation are between 60% and 80%. Patients also report improved quality of life and mental functioning after liver transplantation. Patients should seek medical centers that have performed more than 50 transplants per year and produced better-than-average results.

Unfortunately, as of November 2000 there were more than 16,000 people waiting for a liver donation, with only about 4,500 donated livers available each year. The number of people waiting in 2000 is well over 10 times that of ten years ago. Given the large number of people with hepatitis C, this situation will almost certainly worsen in future years.

Liver Transplantation in Patients with Hepatitis . One of the primary problems with many hepatitis patients is recurrence of the virus after transplantation. It is a particular problem in hepatitis C. One study reported viral recurrence of 80% and cirrhosis of 10% within five years of the procedure. Recurrence in hepatits B has been significantly reduced using monthly infusions of hepatitis B immune globulin (HBIg), with or without lamivudine. Autoimmune hepatitis may also recur after liver transplantation, but only after several years.

Liver Transplantation in Primary Biliary Cirrhosis . Patients who require transplantation 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. Patients with primary biliary cirrhosis may be at higher risk for early rejection of the transplanted organ than patients with other forms of cirrhosis.

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.

WHERE ELSE CAN HELP FOR CIRRHOSIS BE FOUND?

American Association for the Study of Liver Diseases
1200 19th Street NW, Suite 300, Washington, DC 20036-2422.
Call (202 429-5179) or on the Internet (http://hepar-sfgh.ucsf.edu)
This group publishes the journal Hepatology. For good journal abstracts on the web (http://www.hepatology.org/) and (http://www.ltsjournal.org/)

American Liver Foundation
75 Maiden Lane, Suite 603, New York, NY 10038.
Call (800-GO LIVER) or (800-465-4837) or on the Internet (http://www.liverfoundation.org/)
The foundation has regional chapters, some with support groups. The hepatitis hotline provides patient information, brochures, and video and audio tapes.

American Gastrointestinal Association
7910 Woodmont Ave., Seventh Floor, Bethesda, MD 20814.
Call (301-654-2055) or on the Internet (http://www.gastro.org/).
This is an association for physicians and other professionals. They provide names of gastroenterologists in local areas.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Digestive Diseases
Information Clearinghouse, 2 Information Way, Bethesda, MD 20892-3570.
Call (301-654-3810) or on the Internet (http://www.niddk.nih.gov/)

Centers for Disease Control and Prevention, Hepatitis Branch
1600 Clifton Road NE., MS G37, Atlanta, GA 30333.
For a special number on hepatitis call (888-4HEPCDC) or (888-443-7232 ) or on the Internet (http://www.cdc.gov/ncidod/diseases/hepatitis/hepatitis.htm) This is an important source on hepatitis.

Hepatitis Foundation International
30 Sunrise Terrace, Cedar Grove, New Jersey 07009.
Call (800-891-0707) or on the Internet (http://www.hepfi.org)
This organization focuses just on viral hepatitis. It provides educational materials, offers support by phone, and gives referral to other physicians.

National Clearinghouse of Alcohol and Drug Information
PO Box 2345, Rockville, MD 20852.
Call (800-729-6686) or on the Internet (http://www.health.org/)
Offers many publications on alcohol and substance abuse.

Information on Alcoholism
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard - Willco Building, Bethesda, Maryland 20892-7003.
On the Internet (http://www.niaaa.nih.gov/)

National Council on Alcoholism
12 West 21 Street, New York, NY 10010.
Call (800-NCA-CALL) or on the Internet (http://www.ncadd.org/).
Their 800 number is a hotline that requires a touch-tone phone. A recorded message provides local numbers for counseling, help, and information after the caller keys in their zip code.

Information on Transplantation
United Network for Organ Sharing (http://www.unos.org/)
UNOS is the official US contractor for administering the national Organ Procurement and Transplantation Network (OPTN) and the US Scientific Registry on Organ Transplantation.

National Transplant Society
3340 Dundee Road, Unit 2C-3, Northbrook, IL 60062-2331.
Call 312-701-0700 or on the Internet (www.organdonor.org)
Nonprofit organization whose goal is to lobby and support people requiring transplants.

US government organ donor site (http://www.organdonor.gov/)

Information on Primary Biliary Cirrhosis
Primary Biliary Cirrhosis Organization (http://pbcers.org/)

Primary Biliary Cirrhosis Patient Support Network (http://www.superaje.com/~pbc/index.htm)

Other Web Sites:
Excellent site on liver diseases from Columbia-Presbyterian Medical Center (http://cpmcnet.columbia.edu/dept/gi/)
The Hepatitis Information Network (http://www.hepnet.com/)

ABOUT WELL-CONNECTED
Well-Connected reports are written and updated by experienced medical writers and reviewed and edited by the in-house editors and a board of physicians at Harvard Medical School and Massachusetts General Hospital. The reports are distinguished from other information sources available to patients and health care consumers by their quality, detail of information, and currency. These reports are not intended as a substitute for medical professional help or advice but are to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition. The reports may not be copied without the express permission of the publisher.

Board of Editors
Harvey Simon, MD, Editor-in-Chief, Massachusetts Institute of Technology; Physician, Massachusetts General Hospital

Stephen A. Cannistra, MD, Oncology, Associate Professor of Medicine, Harvard Medical School; Director, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center

Masha J. Etkin, MD, PhD, Gynecology, Harvard Medical School; Physician, Massachusetts General Hospital

John E. Godine, MD, PhD, Metabolism, Harvard Medical School; Associate Physician, Massachusetts General Hospital

Daniel Heller, MD, Pediatrics, Harvard Medical School; Associate Pediatrician, Massachusetts General Hospital; Active Staff, Children’s Hospital

Paul C. Shellito, MD, Surgery, Harvard Medical School; Associate Visiting Surgeon, Massachusetts General Hospital

Theodore A. Stern, MD, Psychiatry, Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital

Carol Peckham, Editorial Director

Cynthia Chevins, Publisher

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Please be aware that this information is provided to supplement the care provided by your physician. It is neither intended nor implied to be a substitute for professional medical advice. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with any questions you may have regarding a medical condition.

Predictors of Cirrhosis
Hepatitis C: Pathogenesis, Virology, and Immunology

Adrian M. Di Bisceglie, MD, FACP

Progression of liver disease due to hepatitis C is marked by progression of hepatic fibrosis. The degree of fibrosis is best assessed by liver biopsy. However, the search for a noninvasive means of assessing hepatic fibrosis has been a "holy grail" of hepatology for years.

Based on data from the HALT-C (Hepatitis C Antiviral Long-term Treatment Against Cirrhosis) trial, Lok and colleagues[15] developed a clinical model to predict cirrhosis in patients with chronic hepatitis C. They found that the use of routine laboratory tests such as platelet count, aspartate aminotransferase/alanine aminotransferase ratio, alkaline phosphatase level, and prothrombin time give a very good idea of the presence of cirrhosis, but are not yet accurate enough to replace the role of liver biopsy.

Myers and colleagues, in collaboration with Poynard,[16] evaluated the value of a panel of serum fibrosis markers to predict the presence of cirrhosis. This panel included alpha-2-macroglobulin, apolipoprotein A1, haptoglobin, gamma glutamyl transferase, and total serum bilirubin. Evaluation of this test was conducted using proprietary methods and the calculated score increased with worsening fibrosis and could predict cirrhosis with 87% sensitivity and a negative predictive value of 98%. It is clinically important to determine the presence of cirrhosis, not only because these patients are at greater risk of liver disease progression and therefore require aggressive antiviral therapy, but also because these individuals are targets for screening for esophageal varices and hepatocellular carcinoma.

Ref:
Schiff ER, Shiffman ML, McHutchison JG, et al. A clinical study of the VERSANT HCV RNA qualitative assays for detection of hepatitis C virus (HCV) RNA in patients at risk for or suspected of active HCV infection. Hepatology. 2002;36:347A. [Abstract #736]
Lunel F, Veillon P, Payan C. Evaluation of the Ortho total core antigen assay in comparison to methods of detection and quantitation for HCV RNA. Hepatology. 2002;36:353A. [Abstract #759]
Maynard M, Buti M, Esteban J, et al. High clinical relevance of total HCV core antigen testing for monitoring and predicting response to PEG-IFN/ribavirin combination. Hepatology. 2002;36:353A. [Abstract #761]
Lok ASF, Everhart J, Everson G, et al. Clinical model to predict cirrhosis in patients in the hepatitis c antiviral long-term therapy against cirrhosis (HALT-C) trial. Hepatology. 2002;36:315A. [Abstract #608]
Myers RP, Messous D, Thabut D, et al. The prediction of fibrosis with serum biochemical markers in patients with chronic hepatitis C: Prospective validation in 534 patients. Hepatology. 2002;36:351A. [Abstract #752]

http://www.medscape.com/viewarticle/444782
 

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