The liver is the second largest organ in the body (after the skin), and is essential in keeping the body functioning properly. The liver is located in the upper right-hand side of the abdomen. It performs many functions in the body, including processing the body's nutrients, manufacturing bile to help digest fats, synthesizing many important proteins, regulating blood clotting, and breaking down potentially toxic substances into harmless ones that the body can use or excrete. Inflammation of the liver may, in severe cases, interfere with these processes and allow potentially toxic substances to accumulate. Inflammation can occur while the liver is performing its functions, such as metabolizing drugs.

The liver is able to regenerate or repair up to two-thirds of injured tissue, including hepatocytes, biliary epithelial cells, and endothelial cells. Healthy cells take over the function of damaged cells, either indefinitely or until the damage is repaired.

There are many different types of liver disease. But no matter what type the individual has, the damage to the liver is likely to progress in a similar way. Viruses cause some of them, like hepatitis A, hepatitis B, and hepatitis C. Other types of liver damage can be the result of drugs (such as acetaminophen), poisons (such as the death cap mushroom), or drinking too much alcohol for a long period of time.

If the liver forms scar tissue because of an illness, it is called cirrhosis. Jaundice, or yellowing of the skin and eyes, can be one sign of liver disease. Cancer can also affect the liver. Individuals may inherit a liver disease such as hemochromatosis, which is a liver condition causing iron overload.

According to the U.S. Centers for Disease Control and Prevention (CDC), an estimated 1.25 million Americans have chronic hepatitis (liver inflammation). About 20-30% of hepatitis patients acquired their infection during childhood. The incidence per year has declined from an average of 260,000 in the 1980s to about 60,000 in 2004. The most significant decline has occurred among children and adolescents as a result of the routine hepatitis B vaccination.

STAGES OF LIVER TOXICITY

Fatty liver and inflammation: Fatty liver, also known as steatorrhoeic hepatosis, is the build-up of excess fat in the liver cells. It is normal for the liver to contain some fat. But, if fat accounts for more than 10% of the liver's weight, the individual has fatty liver. In countries where obesity is becoming a serious health issue, fatty liver is predicted to affect approximately 25% of the general population. Fatty liver occurs before inflammation is present.

Sometimes, inflammation from a fatty liver is linked to alcohol abuse, known as alcoholic steatohepatitis. Otherwise the condition is called nonalcoholic steatohepatitis, or NASH. NASH is very common in overweight persons over the age of 30. The liver is invaded by an excessive amount of fat and a normal healthy liver tissue is partially replaced with areas of unhealthy fats. In such a liver, the liver cells and the spaces in the liver are filled with fat so that the liver becomes slightly enlarged and heavier.

Hepatitis is an inflammation of the liver that can be caused by viruses, chemicals, drugs, alcohol, inherited diseases, or the individual's own immune system. This inflammation can be acute (short-term), flaring up and then resolving within a few weeks to months, or chronic (long-term), lasting many years. Chronic hepatitis may begin to damage the liver for 20 years or more before causing significant symptoms related to progressive liver damage such as cirrhosis (scarring and loss of function), liver cancer, or death.

In the early stage of any liver disease, the liver may become inflamed, tender, and enlarged. However, an inflamed liver may cause no discomfort at all.

Fibrosis: If left untreated, the inflamed liver will start to scar. As excess scar tissue (a type of fibrous tissue) grows, it replaces healthy liver tissue. This process is called fibrosis. Scar tissue cannot function as healthy liver tissue can. Scar tissue may keep blood from flowing through the liver. The healthy part of the liver now has to work harder. The liver can regenerate, however, and may heal itself from fibrosis.

Cirrhosis: If left untreated, the liver may become so seriously scarred that it can no longer heal itself. This stage, when the damage cannot be reversed, is called cirrhosis. Cirrhosis can lead to a number of complications, including liver cancer. In some individuals, the symptoms of cirrhosis may be the first signs of liver disease. Symptoms of cirrhosis include: easy bruising; fluid buildup in the legs and/or abdomen; the skin and eyes may take on a yellow color, a condition called jaundice; the skin may itch intensely; blood may back up in vessels leading to the liver because of blockage and may burst; increased sensitivity to medications and their side effects; developing insulin resistance and type-2 diabetes; or buildup of toxins in the brain, causing problems with concentration, memory, sleeping, or other mental functions.

Liver failure: Liver failure means that the liver is losing or has lost all of its function. It is a life-threatening condition that demands urgent medical care. The first symptoms of liver failure are often nausea, loss of appetite, fatigue, and diarrhea. Because these symptoms can have any number of causes, it may be hard to tell that the liver is failing.

As liver failure progresses, the symptoms become more serious. The individual may become confused and disoriented, and extremely sleepy. There is a risk of coma and death. Immediate treatment is needed. The medical team will try to save whatever part of the liver that still works. If this is not possible, the only option may be a liver transplant.

TYPES AND CAUSES OF LIVER TOXICITY

Hepatitis: Hepatitis is a condition that impairs liver function either temporarily or permanently, sometimes leading to death. It can be initiated by a host of factors but primarily by viruses. Drugs also can cause hepatitis. However, when the specific drug is discontinued, the liver usually returns to normal.

Drug-induced: The liver is responsible for the metabolism of alcohol, drugs, and environmental toxins. It breaks them down into substances that can be used and then excreted by the body. Some drugs may cause serious injuries to the livers of patients who take them. Injuries can lead to a loss of function leading to illness, disability, hospitalization, and even life threatening liver failure and death.

Many prescription and non-prescription drugs have the potential to cause hepatitis in people, in a seemingly random fashion. The effect of drugs cannot be foreseen and the causes are unknown, although drug-induced hepatitis rarely appears to be related to an allergic reaction to the medication. Drugs that have had this affect in some people include anesthetics, antibiotics, anabolic steroids, and seizure medications. In the United States, drug-induced liver injury (DILI) is now the leading cause of acute liver failure (ALF), exceeding all other causes combined.

Acetaminophen, which is found in many over-the-counter (OTC) and prescription medications, is an example of this. In therapeutic doses, acetaminophen is a useful pain reliever, but in very high dosages or in combination with alcohol, it has the potential to cause life-threatening acute liver failure. Acetaminophen produces toxic byproducts that the liver usually detoxifies by coupling them with other compounds and flushing them out through the bile.

An estimated 500 deaths per year are attributed to suicidal or unintentional overdoses of acetaminophen (Tylenol©) as well as more than 50,000 emergency room visits. This is the most common form of acute liver failure observed in the United States. While some are intentional, at least 50% of these are unintentional; the individual is consuming more than one product containing acetaminophen or simply using doses more than suggested by the package insert.

Alcohol: The liver can metabolize only a certain amount of alcohol per hour, regardless of the amount that has been consumed. The rate of alcohol metabolism depends, in part, on the amount of metabolizing enzymes in the liver, which varies among individuals. In general, after the consumption of one standard drink, the amount of alcohol in the drinker's blood peaks within 30-45 minutes. A standard drink is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof distilled spirits, all of which contain the same amount of alcohol. Alcohol is metabolized more slowly than it is absorbed. Since the metabolism of alcohol is slow, consumption needs to be controlled to prevent accumulation in the body and further intoxication. Excessive consumption of alcohol is toxic to the liver and is one of the most common causes of chemical hepatitis. Alcohol intake causes the body to overproduce an enzyme that boosts these byproducts further, while compromising the detoxification. Cirrhosis (replacement of normal tissue with scar tissue) of the liver, pancreatitis (inflammation of the pancreas), and damage to the brain and heart occur after years of heavy alcohol abuse. Heavy drinkers also are at risk of malnutrition because alcohol contains calories that may substitute for those in nutritious foods.

Fungal poisoning: When certain types of fungus grow on food, they produce minute amounts of toxins called mycotoxins. Most fungi-produced mycotoxins are harmless, and even helpful. For example, the antibiotic penicillin came from a fungus, and it is a mycotoxin. Some of these fungi (primarily Aspergillus flavus) produce the very lethal mycotoxins called aflatoxins. Aflatoxins are remarkably potent, often causing disease even when ingested in minute amounts. Aflatoxins can cause disease throughout the body, but are most commonly known for causing acute or chronic liver disease and liver cancer. Moisture, temperature, and composition of the substance the mold is on are the chief factors affecting fungal growth and aflatoxin production.

Amanita phalloides, commonly known as the death cap mushroom, is a deadly poisonous fungus (mushroom). The symptoms are slow to show themselves and often do not appear until 10-16 hours (or even longer) after eating, depending on the health of the individual and the stomach contents. Food in the stomach will increase the absorption of the toxin, causing symptoms to appear as early as six hours.

The first symptoms are stomach pains, vomiting, and diarrhea. These symptoms may continue for a day or two, after which there is typically an easing of symptoms and apparent recovery. The recovery period may last for two to three days. Then the terminal phase of three to five days starts with the re-occurrence of stomach pains, vomiting, and diarrhea accompanied by jaundice. Ingestion of the death cap mushroom can require urgent liver transplantation to save the individual's life in severe cases. Without effective, early medical intervention, coma and death occur between one and two weeks after eating the mushroom. Death is caused by liver failure, often accompanied by kidney failure.

Hepatic encephalopathy: Hepatic encephalopathy is a potentially reversible brain abnormality in the setting of liver failure, whether chronic (as in cirrhosis) or acute. It can be diagnosed only after exclusion of other neurological, psychiatric, infectious, and metabolic etiologies. Symptoms may be similar to other conditions, such as brain tumors and viral infections (including herpes simplex viruses).

With severe liver impairment, toxic substances normally removed by the liver accumulate in the blood and impair the function of brain cells. If there is also portal hypertension (high blood pressure in the portal vein inside the liver) and subsequent bypassing of the liver filtration system of blood flowing in from the intestines, these toxic substances can travel directly to the brain without being removed. Signs can include impaired cognition, a flapping tremor (asterixis), and a decreased level of consciousness including coma and, ultimately, death.

Hemochromatosis: Hemochromatosis is the most common form of iron overload disease. Primary hemochromatosis, also called hereditary hemochromatosis, is an inherited disease. Secondary hemochromatosis is caused by anemia, alcoholism, and other conditions causing liver damage. Hemochromatosis causes the body to absorb and store too much iron.

In healthy amounts, iron builds rich, red blood by helping form oxygen-carrying hemoglobin in red blood cells. Iron is also essential for a number of other body processes, including proper brain function, a strong immune system, and healthy muscles. However, excess iron stored in the body (such as in hemochromatosis) can cause health problems, such as fatigue, abdominal pain, and impotence. The extra iron can build up in the body's organs and damage them. Without treatment, the disease can cause the liver, heart, and pancreas to fail.

Juvenile hemochromatosis and neonatal hemochromatosis are two additional forms of the disease. Juvenile hemochromatosis leads to severe iron overload and liver and heart disease in adolescents and young adults between the ages of 15-30. The neonatal form causes rapid iron buildup in a baby's liver that can lead to death.

Viral hepatitis: Viruses cause most cases of hepatitis. The type of hepatitis is named for the virus that causes it, including hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E. The differences in each virus causing hepatitis include the method of transmission, symptoms, and severity.

Hepatitis A is transmitted primarily through food or water contaminated by feces from an infected person. In rare cases, it may spread via infected blood. Hepatitis A usually resolves without treatment in several weeks. However, there is a hepatitis A vaccine.

The Hepatitis B virus (HBV) causes a serious liver infection. The infection can become chronic in some people and lead to liver failure, liver cancer, cirrhosis (a condition that causes permanent scarring and damage to the liver), or death. The hepatitis B virus is transmitted through contact with bodily fluids, such as the blood and semen of someone who is infected. Even though HBV is transmitted the same way as the human immunodeficiency virus (HIV), the virus that causes AIDS, HBV is nearly 100 times as infectious as HIV. Individuals of any age, race, nationality, gender, or sexual orientation can become infected with HBV. Also, women who have HBV can transmit the infection to their babies during childbirth. When the infection is passed from mother to fetus, it is called vertical transmission. While there is no cure for HBV, the hepatitis B vaccine can prevent the disease. Also, infected individuals can take precautions to help prevent HBV from spreading to others by getting testing for the virus, abstaining from sex, using protection during sexual contact, and not sharing needles. Hepatitis B can be categorized into four different genetic groups (A through D). There is continuing research about the differences among the types. However, current findings suggest that genotype C, with its highest prevalence in Southeast Asia, is the most severe.

Hepatitis C is primarily spread via blood. It may also be transmitted through sexual contact and childbirth, although this occurs very rarely. Currently, there is no vaccine for hepatitis C. The only the way to prevent the disease is to reduce the risk of exposure to the virus. Individuals can minimize exposure to the virus by abstaining from sex, using protection during sexual contact, and not sharing needles. According to the U.S. Centers for Disease Control and Prevention (CDC), individuals who underwent hemodialysis or received blood clotting factors before 1987 are at a high risk of developing chronic hepatitis C because blood products were not tested for hepatitis C before then. Patients with acute hepatitis C should consult their healthcare providers if symptoms do not subside after two to three months.

Some evidence suggest that human leucocyte antigen (HLA) may be linked to hepatitis C. HLA are proteins that are on the outer surface of many cells in the body. The presence of two different genetic variations of HLA (HLA-DRB1*11 and HLA-DQB1*03) has been linked to a decreased incidence of developing hepatitis C-induced end-stage liver disease. In addition, a genetic marker, C4BQ0, relating to histocompatibility complex class III has been shown to be a positive risk factor for hepatitic C-related cirrhosis.

Anyone who has chronic hepatitis B is also susceptible to infection with another strain of viral hepatitis known as hepatitis D (formerly called delta virus). Hepatitis D virus can only infect cells if the hepatitis B virus (HBV) is present. Injection drug users with hepatitis B have the greatest risk of developing the infection. Individuals who are infected with both HBV and hepatitis D are more likely to develop cirrhosis or liver cancer than patients who only have HBV.

Hepatitis E is uncommon in the United States, and occurs mainly in tropical and subtropical areas. This disease is primarily spread through food or water that is contaminated by feces from an infected person. There is no vaccine for hepatitis E. The only way to prevent the disease is to reduce the risk of exposure to the virus. Hepatitis E usually resolves without treatment, within several weeks to months.

SIGNS AND SYMPTOMS

Jaundice is the yellowish staining of the skin and sclerae (the whites of the eyes) that is caused by high levels of the chemical bilirubin in the blood. Bilirubin is a brownish yellow substance found in bile. It is produced when the liver breaks down old red blood cells. Bilirubin is removed from the body through the stool (feces) and gives stool its normal brown color. The color of the skin and sclerae vary depending on the level of bilirubin. Excessive hemolysis or breakdown of red blood cells causes the formation of higher than normal amounts of bilirubin. When bilirubin levels increase, the liver may not be able to process the excess amounts. Jaundice then occurs. When the bilirubin level is mildly elevated, they are yellowish. When the bilirubin level is high, they tend to be brown. Icterus is the term for yellowing of the sclerae.

Other signs and symptoms of liver toxicity include: abdominal pain and swelling; chronic itchy skin; dark urine color; pale stool color; joint pain; bloody or tar-colored stool; chronic fatigue; nausea; and loss of appetite.

COMPLICATIONS

Edema and ascites: Fluid accumulation in the legs (edema) and in the abdomen (ascites) may occur when the liver loses its ability to make the protein albumin. Albumin, produced only in the liver, is the major plasma protein that circulates in the bloodstream.

Bruising and bleeding: Bruising and bleeding may occur when the liver slows or stops production of the proteins needed for blood clotting. The palms of the hands may be reddish and blotchy.

Itching: Bile products deposited in the skin may cause intense itching.

Gallstones: Gallstones are solid deposits of cholesterol or calcium salts that form in the gallbladder or nearby bile ducts. They often cause no symptoms and require no treatment. But some people with gallstones have a gallbladder attack (that can cause symptoms, such as nausea and an intense, steady ache in their upper middle or upper right abdomen). Gallbladder attacks include pain or tenderness under the rib cage on the right side, pain between shoulder blades, light or chalky colored stools, indigestion after eating, especially fatty or greasy foods, nausea, bloating, gas, burping or belching, and diarrhea or constipation. In some cases, the pain can be severe and intermittent. If cirrhosis blocks the tubes from the liver to the gallbladder and prevents bile from reaching the gallbladder, gallstones may develop.

Toxins in the blood or brain: A damaged liver cannot remove toxins from the blood, causing them to accumulate in the blood and eventually the brain. There, toxins can dull mental functioning and cause personality changes, coma, and even death. Signs of the buildup of toxins in the brain include neglect of personal appearance, unresponsiveness, forgetfulness, trouble concentrating, or changes in sleep habits.

Sensitivity to medication: Cirrhosis slows the liver's ability to filter medications from the blood. After a drug is taken, it is metabolized in the body. Metabolism is the enzymatic conversion of one chemical compound into another. Most drug metabolism occurs in the liver, although some processes occur in the gut wall, lungs, and blood plasma. Because the liver does not remove drugs from the blood at the usual rate when hepatitis is present, they act longer than expected and build up in the body. This causes a person to be more sensitive to medications and their side effects.

Portal hypertension: Normally, blood from the intestines and spleen is carried to the liver through the portal vein. But cirrhosis slows the normal flow of blood through the portal vein, which increases the pressure inside it. This condition is called portal hypertension. The portal vein may become weakened and damaged and hemorrhage (bleeding) may occur.

Varices: When blood flow through the portal vein slows, blood from the intestines and spleen backs up into blood vessels in the stomach and esophagus. These blood vessels may become enlarged because they are not meant to carry this much blood. The enlarged blood vessels, called varices, have thin walls and carry high pressure, and thus are more likely to burst. If they do burst, the result is a serious bleeding problem in the upper stomach or esophagus that requires immediate medical attention. Hemorrhages, or bleeding, may occur in damaged vessels.

Insulin resistance and type 2 diabetes: Cirrhosis causes resistance to insulin. Insulin is a hormone produced by the pancreas. Insulin enables blood glucose to be used as energy by the cells of the body. If an individual has insulin resistance, their muscle, fat, and liver cells do not use insulin properly. The pancreas tries to keep up with the demand for insulin by producing more. Eventually, the pancreas cannot keep up with the body's need for insulin, and type 2 diabetes develops as excess glucose builds up in the bloodstream.

Liver cancer: According to the National Cancer Institute (NCI), cancer of the liver is a rare malignancy in the United States, but in parts of Asia and Africa, it is one of the most common malignancies. In the United States, the average age of onset is 60-70 years, and the condition occurs more frequently in males than females by a ratio of 2:1. There is a strong association between chronic hepatitis B and C viral infections and the development of hepatocellular (liver cell) carcinoma, which account for about two-thirds of all liver cancers. People with cirrhosis also have an increased risk of liver cancer. Other possible hepatocarcinogens include aflatoxin, nitrosamines, oral estrogen compounds, and numerous other chemicals.

Ascites: Ascites is the accumulation of protein-containing (ascitic) fluid in the abdominal cavity. Ascites tends to occur in chronic (long-term) rather than in acute (short-lived) disorders. It occurs most commonly in cirrhosis (severe scarring of the liver), especially in cirrhosis caused by alcoholism or viral hepatitis. It may occur in other liver disorders, such as severe alcoholic hepatitis without cirrhosis and chronic hepatitis. Ascites can also occur in disorders unrelated to the liver, such as cancer, heart failure, kidney failure, pancreatitis (inflammation of the pancreas), and tuberculosis (a bacterial infection in the lungs) affecting the lining of the abdominal cavity. In people with a liver disorder, ascitic fluid leaks from the surface of the liver and intestine. A combination of factors is responsible. They include portal hypertension, decreased ability of the blood vessels to retain fluid, fluid retention by the kidneys, and alterations in various hormones and chemicals that regulate bodily fluids.

Problems in other organs: Cirrhosis can cause immune system dysfunction, leading to infection. Fluid in the abdomen (ascites) may become infected with bacteria normally present in the intestines. Cirrhosis can also lead to impotence, kidney dysfunction and failure, and osteoporosis.

DIAGNOSIS

Physical examination:

History: If an acetaminophen overdosage has occurred, the doctor will attempt to determine the time and amount of acetaminophen taken. It is important for the doctor to know what medications the individual has ingested and how much. Having access to all medication bottles that the person may have taken will help the doctor to determine the maximum amount taken. A sexual history will also be taken.

Physical: The doctor will look for signs and symptoms of liver toxicity. These signs may include jaundice (yellow skin), abdominal pain, vomiting, and ascites (fluid in the abdomen). On physical examination, a doctor looks for liver tenderness and enlargement using palpation. Palpation is a method of examination in which the examiner feels the body to determine its size, shape, firmness, or location.

Blood tests:

Albumin: Serum albumin levels measures the main protein made by the liver and tells how well the liver is making this protein. Low levels of albumin may indicate liver damage.

Ammonia: An ammonia test measures the amount of ammonia in the blood. Most ammonia in the body forms when protein is broken down by bacteria in the intestines. The liver normally converts ammonia into urea, which is then eliminated in urine. Ammonia levels in the blood rise when the liver is not able to convert ammonia to urea. This may be caused by cirrhosis or severe hepatitis.

Alpha-fetoprotein (AFP) test: Alpha-fetoprotein (AFP) is a type of protein produced in the developing embryo and fetus. In humans, AFP levels decrease gradually after birth, reaching adult levels by 8-12 months. If an individual has high levels of alpha-fetoprotein in the blood, it may be a sign of liver cancer. Healthy adult males and non-pregnant females typically have less than 40 micrograms of alpha-fetoprotein per liter of blood.

Bilirubin: Bilirubin is a waste product made from old blood cells; it is a yellow compound that causes jaundice and dark urine when present in increased amounts. Tests for bilirubin levels help determine if the liver is functioning appropriately.

INR: International normalized ratio (INR) is a blood-clotting test. It is used to measure how quickly blood forms a clot, compared with normal clotting time. The liver produces certain proteins (clotting factors) that help in blood clotting. If there is liver disease and cirrhosis, the liver may not produce the normal amount of proteins and then the blood is not able to clot normally. When a doctor is evaluating the function of the liver, a high INR usually means that the liver is not working as well as it could because it is not making the blood clot normally.

Liver biopsy: A liver biopsy may be performed to determine the extent of liver damage and to determine the best treatment option for the patient. During the procedure, a needle is inserted into the liver and a small tissue sample is removed. The tissue is then analyzed under a microscope in a laboratory.

Liver enzymes: Another blood test may be performed to check for elevated levels of liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). These enzymes leak into the bloodstream when liver cells are injured. Also, alkaline phosphatase (ALP) levels may be checked. ALP is an enzyme related to the bile ducts. ALP levels are often increased when they are blocked. Liver enzymes help catalyze or start chemical reactions in the liver cells. These enzymes are released into the bloodstream when the liver is damaged.

Transferrin saturation test: The transferrin saturation test reveals how much iron is bound to the protein that carries iron in the blood. Transferrin saturation tests are used in determining if hemochromatosis exists. Transferrin saturation values higher than 45% are considered too high. The total iron binding capacity test measures how well the blood can transport iron, and the serum ferritin test shows the level of iron in the liver. If either of these tests shows higher than normal levels of iron in the body, THEN doctors can order a special blood test to detect the genetic mutation for hemochromatosis, which will confirm the diagnosis. If the mutation is not present, hereditary hemochromatosis is not the reason for the iron buildup and the doctor will look for other causes.

Diagnostic tests:

In diagnosing liver toxicity, the doctor may use images of the liver obtained by an ultrasound test, a computerized tomography (CT) scan, or a magnetic resonance imaging (MRI) scan. These diagnostic tests can determine if the presence of liver damage exists. Evidence of fatty liver or liver damage can be viewed by the doctor as dark spots or abnormal images.

A liver scan is a diagnostic procedure to evaluate the liver for suspected disease. A harmless amount of a radioactive substance that concentrates in the liver is injected intravenously (IV or into the veins) and the image of its distribution in the liver is analyzed to diagnose abnormalities. Women who are pregnant or breastfeeding should not have this test.

TREATMENT

Therapies for liver toxicity focus on reducing the complications of the disease.

Individuals who knowingly have been exposed to the hepatitis B virus (HBV) should consult their healthcare providers as soon as possible. Patients who receive an injection of hepatitis B immune globulin within 24 hours of exposure to the virus may not develop HBV infection. Patients should also receive the first of three injections of the hepatitis B vaccine.

Diuretics: Diuretics, or fluid tablets, are used in the treatment of fluid retention in the legs (edema) or abdomen (ascites).

Laxatives: Laxatives, such as lactulose (Chronulac©), are used to prevent constipation and to reduce the chances of the poisonous substances, such as ammonia, from the bowel bypassing the liver and reaching the brain, causing drowsiness, confusion, and coma (hepatic encephalopathy).

Weight loss and exercise: If the individual's body mass index (BMI) is above 25, a diet and exercise program may reduce the amount of accumulated fat in the liver. BMI measures the amount of fat the body contains. The most effective diet is rich in fiber and low in calories and saturated fat, with total fat accounting for no more than 30% of total calories.

Diabetes control: Strict management of diabetes with diet, medications, or insulin lowers blood sugar, which may prevent further liver damage. Blood sugar control may also reduce the amount of accumulated fat in the liver.

Cholesterol control: Controlling elevated levels of cholesterol and triglycerides with diet, exercise, and cholesterol-lowering medications may help stabilize or reverse nonalcoholic fatty liver disease.

Avoidance of toxic substances: If an individual has nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), alcohol should not be consumed. Medications and other substances that can cause liver damage should also be avoided, such as acetaminophen (Tylenol©).

Ursodiol (Actigall©): Ursodiol (Actigall©) is a prescription medication most commonly used to treat gallstones. Ursodiol decreases production of bile acids, which may in theory help lower elevated levels of liver enzymes in individuals with liver disease.

Beta-blockers: For portal hypertension, the doctor may prescribe a beta blocker, such as propranolol (Inderal©). These drugs are normally used in hypertension or high blood pressure. Side effects include fatigue and loss of sexual desire.

N-acetyl cysteine (NAC): The antidote to acetaminophen overdose is N-acetylcysteine (NAC). NAC is most effective when given within eight hours of ingesting acetaminophen. Indeed, NAC can prevent liver failure if given early enough. For this reason, it is absolutely necessary that acetaminophen poisoning be recognized, diagnosed, and treated as early as possible. NAC can be purchase over-the-counter (OTC) as a dietary supplement, but when used for acetaminophen toxicity, NAC is a concentrated solution that is prescribed by a doctor and mixed appropriately by a pharmacist.

Other medications: Researchers are studying the effects of several medications on insulin resistance and nonalcoholic fatty liver disease in individuals with and without diabetes. These include metformin (Glucophage©, Glucophage XR©), pioglitazone (Actos©), rosiglitazone (Avandia©), and betaine (Cystadane©). Another drug being investigated is orlistat (Xenical©), a medication that blocks the absorption of some of the fat from food. Early results indicate that orlistat may reduce the amount of fat in the liver.

Interferon: Interferons are natural proteins produced by the cells of the immune system in response to challenges by foreign agents such as viruses, bacteria, parasites, and tumor cells. Administering additional synthetic interferon may stimulate the body's immune response to hepatitis B virus (HBV) and help prevent the virus from spreading. Two interferon medications are available: interferon alfa-2b (Intron A©) and peginterferon alfa-2a (Pegasys©). Intron A© is administered by injection several times a week. Pegasys© is given by injection once a week.

Not everyone is a candidate for interferon treatment. In a few cases, interferon has successfully eliminated the virus completely. However, the infection can return in the future. Several side effects are associated with interferon, including depression, fatigue, muscle pain, body aches, fever, and nausea. Interferon may also cause a decreased production of red blood cells. Symptoms are usually worse during the first two weeks of treatment and in the first four to six hours after receiving an injection of interferon.

Lamivudine (Epivir-HBV©): Lamivudine (Epivir-HBV©) is an antiviral medication that helps prevent HBV from replicating in the body's cells. The medication is usually taken in tablet form once daily. Side effects during treatment are generally mild, but some patients may experience a severe worsening of symptoms when they stop taking the medication. Patients should tell their healthcare providers if they have had any kidney problems or history of pancreatitis before starting this medication. Patients should call their healthcare providers immediately if they experience a worsening of jaundice (yellowing of the skin and eyes) or if they experience any unusual bruising, bleeding, or fatigue while taking the medication.

Adefovir dipivoxil (Hepsera©): Adefovir dipivoxil (Hepsera©) is a tablet taken orally once a day to help prevent HBV from replicating inside the body's cells. This drug is effective in patients who are resistant to lamivudine. Like lamivudine, side effects are generally mild, but symptoms may worsen when treatment is stopped. Hepsera© may cause kidney toxicity in patients with underlying kidney disease. A change in the amount of urine produced or blood in the urine may indicate kidney toxicity. Other side effects may include weakness, headache, fever, increased cough, nausea, vomiting, diarrhea, or gas.

Entecavir (Baraclude©): Entecavir (Baraclude©) is an antiviral medication that was approved by the U.S. Food and Drug Administration (FDA) in March 2005 for HPV (human papilloma virus). HPV infection is a sexually transmitted disease that may lead to cervical cancer in women. This medication is taken orally once a day. Studies comparing entecavir to lamivudine in hepatitis treatment found that entecavir was more effective. Baraclude© may cause symptoms of hepatitis to worsen once medication is discontinued.

Liver transplant: When the liver has been severely damaged, a liver transplant may be the only treatment option. Liver transplants are increasingly successful. However, there are not enough donor organs available for every patient who needs a transplant, and not all patients are suitable transplant candidates. It is estimated that more than 10,000 living donor transplants have been performed worldwide, and that the donor recipient death rate ranges from 0.1-0.3%.

INTEGRATIVE THERAPIES

Good scientific evidence:

Betaine: Betaine is found in most microorganisms, plants, and marine animals. Its main physiologic functions are to protect cells under stress and as a source of methyl groups needed for many biochemical pathways. Betaine is also found naturally in many foods and is most highly concentrated in beets, spinach, grain, and shellfish. Betaine raises S-adenosylmethionine (SAM) levels that may in turn play a role in improving hepatic steatosis, or fatty liver.

Avoid if allergic or hypersensitive to betaine or a type of betaine called cocamidopropylbetaine. Use cautiously with kidney disease, obesity, or psychiatric conditions. Avoid if pregnant or breastfeeding.

Choline: Choline, when given intravenously, has orphan drug status for TPN-associated hepatic steatosis. Additional research is needed in this area.

Avoid if allergic/hypersensitive to choline, lecithin, or phosphatidylcholine. Use cautiously with kidney or liver disorders or trimethylaminuria. Use cautiously with a history of depression. If pregnant or breastfeeding it seems generally safe to consume choline within the recommended adequate intake (AI) parameters; supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed.

Cordyceps: In traditional Chinese medicine, cordyceps has been used to support and improve liver function. Cordyceps may stimulate the immune system and improve serum gamma globulin levels in hepatitis B patients. Currently, there is insufficient evidence to recommend for or against the use of cordyceps for chronic hepatitis B. However, early study results are promising. Additional research of cordyceps and current hepatitis treatments is needed.

Avoid if allergic or hypersensitive to cordyceps, mold or fungi. Use cautiously with diabetes, bleeding disorders or taking anticoagulant medications, with prostate conditions, if taking immunosuppressive medications, or if on hormonal replacement therapy or oral contraceptives. Avoid with myelogenous type cancers. Avoid if pregnant or breastfeeding.

Milk thistle: Multiple studies from Europe suggest benefits of oral milk thistle for cirrhosis. In experiments up to five years long, milk thistle has improved liver function and decreased the number of deaths that occur in cirrhotic patients. Although these results are promising, most studies have been poorly designed. Further research is necessary before a strong recommendation can be made.

In addition, several studies of oral milk thistle for chronic hepatitis caused by viruses or alcohol report improvements in liver tests. However, most studies have been small and poorly designed. More research is needed before a recommendation can be made.

Use cautiously if allergic to plants in the aster family (Compositea, Asteraceae), daisies, artichoke, common thistle, or kiwi. Use cautiously with diabetes. Avoid if pregnant or breastfeeding.

Probiotics: Liver cirrhosis may be accompanied by an imbalance of intestinal bacteria flora. Probiotic supplementation in cirrhosis patients has been found to reduce the level of fecal acidity (pH) and fecal and blood ammonia, which are beneficial changes.

Probiotics are generally considered safe and well tolerated. Avoid if allergic or hypersensitive to probiotics. Use cautiously if lactose intolerant.

Zinc: Wilson's disease is an inherited disorder of copper metabolism characterized by a failure of the liver to excrete copper, which leads to its accumulation in the liver, brain, cornea, and kidney, with resulting chronic degenerative changes. Early research suggests that zinc treatment may be effective in the management of Wilson's disease. More well-designed trials are needed to confirm these early results.

Zinc is generally considered safe when taken at the recommended dosages. Avoid zinc chloride since studies have not been done on its safety or effectiveness. While zinc appears safe during pregnancy in amounts lower than the established upper intake level, caution should be used since studies cannot rule out the possibility of harm to the fetus.

Unclear or conflicting scientific evidence:

Alpha-lipoic acid: Alpha-lipoic acid (ALA) has been studied as a treatment for alcoholic liver disease. However, benefits have not been observed at this time. More research is needed in this area.

Avoid if allergic to ALA. Use cautiously with diabetes and thyroid diseases. Avoid with thiamine deficiency or alcoholism. Avoid if pregnant or breastfeeding.

Astragalus: Anti-viral activity has been reported with the use of astragalus in laboratory and animal studies. Limited human and animal research has examined the use of astragalus for viral infections in the liver (hepatitis B and C). However, most studies have been small and poorly designed. Due to a lack of well-designed research, no firm conclusions can be drawn. Clinical data suggests that astragalus may be effective in treating cirrhosis. Further research is needed to better understand the use of astragalus for liver protection.

Avoid if allergic to astragalus, peas, or any related plants or with a history of Quillaja bark-induced asthma. Avoid with aspirin or aspirin products or herbs or supplements with similar effects. Avoid with inflammation (swelling) or fever, stroke, transplant or autoimmune diseases (like HIV/AIDS). Stop use two weeks before surgery/dental/diagnostic procedures with a risk of bleeding and avoid use immediately after these procedures. Use cautiously with bleeding disorders, diabetes, high blood pressure, lipid disorders, or kidney disorders. Use cautiously with blood-thinners, blood sugar drugs, or diuretics or herbs and supplements with similar effects. Avoid if pregnant or breastfeeding.

Ayurveda: Ayurveda is an integrated system of specific theories and techniques employing diet, herbs, exercise, meditation, yoga and massage or bodywork. Clinical evidence suggests that the traditional herbal preparation Kamalahar may reduce clinical signs as well as indicators of liver damage in acute viral hepatitis. Kamalahar contains Tecoma undulate, Phyllanthus urinaria, Embelia ribes, Taraxacum officinale, Nyctanthes arbortistis, and Terminalia arjuna. The root powder from the herb Picrorhiza kurroa has also been shown to improve levels of bilirubin, SGOT (serum glutamic-oxaloacetic transaminase) and serum glutamic pyruvic transaminase (SGPT) in viral hepatitis. Further research is needed before a firm conclusion can be made.

Ayurvedic herbs should be used cautiously because they are potent and some constituents can be potentially toxic if taken in large amounts or for a long time. Some herbs imported from India have been reported to contain high levels of toxic metals. Ayurvedic herbs can interact with other herbs, foods and drugs. A qualified healthcare professional should be consulted before taking.

Biotin: Biotin is an essential water-soluble B vitamin. Antioxidant therapy with biotin, vitamins A-E, selenium, zinc, manganese, copper, magnesium, folic acid, and coenzyme Q10 was not shown to improve survival rates for hepatitis. More research with biotin alone is needed. Avoid if hypersensitive to constituents of biotin supplements.

Bupleurum: For more than 2,000 years bupleurum has been used in Asia to treat hepatitis, cirrhosis and other conditions associated with inflammation. A high-quality clinical trial and several small recent clinical reports suggest that bupleurum and/or an herbal combination formula containing bupleurum may be helpful in the treatment of chronic hepatitis. However, studies to date are small and not all well controlled. Further research is warranted to determine whether bupleurum can effectively treat hepatitis.

Avoid if allergic or hypersensitive to bupleurum, Apiaceae or Umbelliferae (carrot) families, snakeroot, cow parsnip, or poison hemlock. Use cautiously if operating motor vehicles or hazardous machinery. Use cautiously with low blood pressure, diabetes, or edema. Use cautiously with a history of bleeding, hemostatic disorders, or drug-related hemostatic disorders. Use cautiously if taking blood thinners. Avoid if pregnant or breastfeeding.

Capers: There is limited evidence of the effect of capers alone on cirrhosis. Additional studies are needed.

Capers are generally considered to be safe. Avoid with allergy or sensitivity to capers or mustard oil. There are limited reports of side effects with capers. Use cautiously with diabetes or low blood sugar or in those taking drugs, herbs, or supplements that lower blood sugar. Use cautiously with low blood pressure or if taking drugs, herbs, or supplements that lower blood pressure. Use cautiously in patients prone to iron overload. Use cautiously if taking diuretics. Use cautiously if pregnant or breastfeeding.

Chicory: Chicory (Chichorium intybus) has been suggested as a possible treatment for chronic hepatitis. However, further research is needed before a definitive conclusion can be made.

Avoid if allergic/hypersensitive to chicory or members of the Asteraceae or Compositae family, including ragweed, chrysanthemums, marigolds, and daisies. Use cautiously if taking drugs or herbs metabolized by cytochrome P450 enzymes. Use cautiously with gallstones. Avoid if pregnant or breastfeeding.

Chlorophyll: Chlorophyll is a chemoprotein commonly known for its contribution to the green pigmentation in plants, and is related to protoheme, the red pigment of blood. It can be obtained from green leafy vegetables (broccoli, Brussel sprouts, cabbage, lettuce, and spinach), algae (Chlorella and Spirulina), wheat grass, and numerous herbs (alfalfa, damiana, nettle, and parsley). Laboratory evidence suggests chlorophyll may be of use as a chemopreventative agent due to its potential ability to inhibit the tumor-promoting effects of carcinogens. Chlorophyll may act to improve the detoxification of toxins involved in cancer promotion. However, more research is needed in regard to protection from aflatoxins. It may also inhibit the absorption of dietary heterocyclic aromatic amines, which may act as potential carcinogens. The results of one clinical trial suggest that prophylactic interventions with chlorophyllin or diet supplementation with chlorophyll-rich foods may be a practical means to prevent the development of hepatocellular carcinoma or other environmentally-induced cancers. Additional large scale clinical research is needed in this area before a clinical recommendation can be made.

Avoid if allergic or hypersensitive to chlorophyll or any of its metabolites. Use cautiously with photosensitivity, compromised liver function, diabetes or gastrointestinal conditions or obstructions. Use cautiously if taking immunosuppressant agents or antidiabetic agents. Avoid if pregnant or breastfeeding.

Choline: Studies have assessed the use of choline for acute viral hepatitis, many of which have been poorly designed. There is currently insufficient evidence available to determine whether choline can effectively treat hepatitis.

Avoid if allergic/hypersensitive to choline, lecithin, or phosphatidylcholine. Use cautiously with kidney or liver disorders or trimethylaminuria. Use cautiously with a history of depression. If pregnant or breastfeeding it seems generally safe to consume choline within the recommended adequate intake (AI) parameters; supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed.

Clay: Phyllosilicate clay has been shown to adhere to aflatoxins in laboratory study, and HSACS clay in animal diets may diminish or block exposure to aflatoxins. However, the risks of chronic clay exposure likely do not justify the potential benefit of protection from aflatoxins.