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.
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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.