Drug-induced liver diseases are diseases of the liver that are caused by physician-prescribed medications, over-the-counter medications, vitamins, hormones, herbs, illicit ("recreational") drugs, and environmental toxins.
The liver is an organ that is located in the upper right hand side of the abdomen, mostly behind the rib cage. The liver of an adult normally weighs close to three pounds and has many functions.
Illustration of the Liver
When drugs injure the liver and disrupt its normal function, symptoms, signs, and abnormal blood tests of liver disease develop. Abnormalities of drug-induced liver diseases are similar to those of liver diseases caused by other agents such as viruses and immunologic diseases. For example, drug-induced hepatitis (inflammation of the liver cells) is similar to viral hepatitis; they both can cause elevations in blood levels of aspartate amino transferase (AST) and alanine aminotransferase (ALT) (enzymes that leak from the injured liver and into the blood) as well as anorexia (loss of appetite), fatigue, and nausea. Drug-induced cholestasis (interference with the flow of bile that is caused by injury to the bile ducts) can mimic the cholestasis of autoimmune liver disease (e.g., primary biliary cirrhosis or PBC) and can lead to elevations in blood levels of bilirubin (causing jaundice), alkaline phosphatase (an enzyme that is leaked from injured bile ducts), and itching.
Patients with mild liver disease may have few or no symptoms or signs. Patients with more serious disease develop symptoms and signs that may be nonspecific or specific.
Nonspecific symptoms (symptoms that also can be seen in other disorders) include:
Symptoms and signs that are specific for liver disease include:
Severe, advanced liver disease with cirrhosis can produce symptoms and signs related to cirrhosis; these symptoms include:
Drugs can cause liver disease in several ways. Some drugs are directly injurious to the liver; others are transformed by the liver into chemicals that can cause injury to the liver directly or indirectly. (This may seem strange in light of the liver's important role in transforming toxic chemicals into nontoxic chemicals, but it happens.) There are three types of liver toxicity; dose-dependent toxicity, idiosyncratic toxicity, and drug allergy.
Drugs that cause dose-dependent toxicity can cause liver disease in most people if enough of the drug is taken. The most important example of dose-dependent toxicity is acetaminophen (Tylenol) overdose (discussed later in this article.).
Drugs that cause idiosyncratic toxicity cause disease in only those few patients who have inherited specific genes that control the chemical transformation of that specific drug, causing accumulation of the drug or products of their transformation (metabolites) that are injurious to the liver. These inherited idiosyncratic toxicities usually are rare, and depending on the drug, typically occur in less than 1 to10 per 100,000 patients who are taking that drug; however, with some drugs the prevalence of toxicity is much higher. Even though the risk of developing drug-induced idiosyncratic liver disease is low, idiosyncratic liver disease is the most common form of drug-induced liver disease because tens of millions of patients are using drugs, and many of them are using several drugs.
Idiosyncratic drug toxicity is difficult to detect in early clinical trials that usually involve, at most, only a few thousand patients. Idiosyncratic toxicity will surface only after millions of patients begin to receive the drug after the drug is approved by the FDA.
Drug allergy also may cause liver disease, though it is uncommon. In drug allergy, the liver is injured by the inflammation that occurs when the body's immune system attacks the drugs with antibodies and immune cells.
Drugs and chemicals can cause a wide spectrum of liver injury. These include:
Many drugs cause mild elevations in blood levels of liver enzymes without symptoms or signs of hepatitis. AST, ALT, and alkaline phosphatase are enzymes that normally reside within the cells of the liver and bile ducts. Some drugs can cause these enzymes to leak from the cells and into the blood, thus elevating the blood levels of the enzymes. Examples of drugs that more commonly cause elevations of liver enzymes in the blood include the statins (used in treating high blood cholesterol levels) some antibiotics, some antidepressants (used in treating depression), and some medications used for treating diabetes, tacrine (Cognex), aspirin, and quinidine (Quinaglute, Quinidex).
Since these patients typically experience no symptoms or signs, the elevations of liver enzymes usually are discovered when blood tests are performed as a part of an annual physical examination, as pre-operative screening, or as a part of periodic monitoring for drug toxicity. Typically, these abnormal levels will become normal shortly after stopping the drug, and there usually is no long-term liver damage. With some drugs, low levels of abnormal liver enzymes are common and don't appear to be associated with important (severe or progressive) liver disease, and the patient may continue taking the drug.
Certain drugs can cause acute and chronic hepatitis (inflammation of liver cells) that can lead to necrosis (death) of the cells. Acute drug-induced hepatitis is defined as hepatitis that lasts less than 3 months, while chronic hepatitis lasts longer than 3 months. Acute drug-induced hepatitis is much more common than chronic drug-induced hepatitis.
Typical symptoms of drug-induced hepatitis include:
In more serious cases, patients can develop dark urine, fever, light-colored stool, and jaundice (a yellow appearance to the skin and white portion of the eyes). Patients with hepatitis usually have high blood levels of AST, ALT, and bilirubin. Both acute and chronic hepatitis typically resolve after stopping the drug, but sometimes acute hepatitis can be severe enough to cause acute liver failure (see discussion later in this article), and chronic hepatitis can on rare occasions, lead to permanent liver damage and cirrhosis.
Examples of drugs that can cause acute hepatitis include acetaminophen (Tylenol), phenytoin(Dilantin), aspirin, isoniazid (Nydrazid, Laniazid), diclofenac (Voltaren), and amoxicillin/clavulanic acid (Augmentin).
Examples of drugs that can cause chronic hepatitis include minocycline (Minocin), nitrofurantoin(Furadantin, Macrodantin), phenytoin (Dilantin), propylthiouracil, fenofibrate (Tricor), and methamphetamine ("ecstasy")..
Rarely, drugs cause acute liver failure (fulminant hepatitis). These patients are extremely ill with the symptoms of acute hepatitis and the additional problems of confusion or coma (encephalopathy) and bruising or bleeding (coagulopathy). In fact, 40% to 70% of people with fulminant hepatitis die, depending upon the cause. In the U. S., acetaminophen (Tylenol) is the most common cause of acute liver failure.
Cholestasis is a condition in which the secretion and/or flow of bile is reduced. Bilirubin and bile acids normally secreted by the liver into bile and eliminated from the body via the intestine, collect in the body leading to jaundice and itching, respectively. Drugs causing cholestasis typically interfere with the liver cell's secretion of bile without causing hepatitis or liver cell necrosis (death). Patients with drug-induced cholestasis typically have elevated blood levels of bilirubin but have normal or mildly elevated AST and ALT levels. Blood levels of alkaline phosphate (an enzyme made by bile ducts) increase because the cells of the bile ducts also are dysfunctional and leak the enzyme. Aside from itching and jaundice, patients usually are not as sick as patients with acute hepatitis.
Examples of drugs that have been reported to cause cholestasis include erythromycin (E-Mycin, Ilosone), chlorpromazine (Thorazine), sulfamethoxazole and trimethoprim (Bactrim; Septra), amitriptyline (Elavil, Endep), carbamazepine (Tegretol), ampicillin (Omnipen; Polycillin; Principen), ampicillin/clavulanic acid (Augmentin), rifampin (Rifadin), estradiol (Estrace; Climara; Estraderm; Menostar), captopril (Capoten), birth control pills (oral contraceptives), anabolic steroids, naproxen(Naprosyn), amiodarone (Cordarone), haloperidol (Haldol), imipramine (Tofranil), tetracycline(Achromycin), and phenytoin (Dilantin).
Most patients with drug-induced cholestasis will recover fully within weeks after stopping the drug, but in some patients, jaundice, itching, and abnormal liver tests can last months after stopping the drug. An occasional patient can develop chronic liver disease and liver failure. Drug-induced jaundice and cholestasis lasting longer than 3 months is called chronic cholestasis.
The most common causes of accumulation of fat in the liver are alcoholism and non-alcoholic fatty liver disease (NAFLD) associated with obesity and diabetes. Drugs may cause fatty liver with or without associated hepatitis. Patients with drug-induced fatty liver may have only a few symptoms, or none. They typically have mild to moderate elevations in blood levels of ALT and AST, and also may develop enlarged livers. In severe cases, drug-induced fatty liver can lead to cirrhosis and liver failure.
Drugs reported to cause fatty liver include total parenteral nutrition, methotrexate (Rheumatrex), griseofulvin (Grifulvin V), tamoxifen (Nolvadex), steroids, valproate (Depakote), and amiodarone(Cordarone).
In certain situations, fatty liver alone can be life threatening. For example, Reye's syndrome is a rare liver disease that can cause fatty liver, liver failure, and coma. It is believed to occur in children and teenagers with influenza when they are given aspirin. Another example of serious fatty liver is caused by high doses of intravenous tetracycline or amiodarone. Certain herbs (for example, the Chinese herb Jin Bu Huan, used as a sedative and pain reliever) also can cause serious fatty liver.
Chronic liver diseases such as hepatitis, fatty liver, or cholestasis can lead to the necrosis (death) of liver cells. Scar tissue forms as part of the healing process that is associated with the dying liver cells, and severe scarring of the liver can lead to cirrhosis.
The most common example of drug-induced cirrhosis is alcoholic cirrhosis . Examples of drugs that can cause chronic liver diseases and cirrhosis include methotrexate (Rheumatrex), amiodarone (Cordarone), and methyldopa (Aldomet). Please read the article on Cirrhosis for more information.
Normally, blood from the intestines is delivered to the liver via the portal vein, and the blood leaving the liver for the heart is carried via the hepatic veins into the inferior vena cava (the large vein that drains into the heart). Certain drugs can cause blood clots to form (thrombosis) in the hepatic veins and in the inferior vena cava. Thrombosis of the hepatic vein and inferior vena cava can lead to an enlarged liver, abdominal pain, fluid collection in the abdomen (ascites), and liver failure. This syndrome is called the Budd Chiari syndrome. The most important drugs that cause Budd-Chiari syndrome are birth control pills (oral contraceptives). Birth control pills also can cause a related disease called veno-occlusive disease in which blood clots only in the smallest hepatic veins. Pyrrolizidine alkaloids found in certain herbs (e.g., borage, comfrey) also can cause veno-occlusive disease.
The diagnosis of drug-induced liver diseases often is difficult. Patients may not have symptoms of liver disease or may have only mild, nonspecific symptoms. Patients may be taking multiple drugs, which makes it difficult to identify the offending drug. Patients also may have other potential causes of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and alcoholism.
The diagnosis of liver disease is based on a patient's symptoms (such as loss of appetite, nausea, fatigue, itching, and dark urine), findings on the physical examination (such as jaundice, enlarged liver), and abnormal laboratory tests (such as blood levels of liver enzymes or bilirubin and blood clotting times). If a patient has symptoms, signs, and abnormal liver tests, doctors then try to decide whether drug(s) are causing the liver disease by:
The most important treatment for drug-induced liver disease is stopping the drug that is causing the liver disease. In most patients, signs and symptoms of liver disease will resolve and blood tests will become normal and there will be no long-term liver damage. There are exceptions, however. For example, Tylenol overdoses are treated with oral N-acetylcysteine to prevent severe liver necrosis and failure. Liver transplantation may be necessary for some patients with acute liver failure. Some drugs also can cause irreversible liver damage and cirrhosis.
An overdose of acetaminophen can damage the liver. The probability of damage as well as the severity of the damage depends on the dose of acetaminophen ingested; the higher the dose, the more likely it is that there will be damage and the more likely it is that the damage will be severe. (The reaction to acetaminophen is dose-dependent and predictable; it is not idiosyncratic - peculiar to the individual.) The liver injury from an overdose of acetaminophen is a serious matter since the damage can be severe and result in liver failure and death. In fact, acetaminophen overdose is the leading cause of acute (rapid onset) liver failure in the U.S. and the United Kingdom.
For the average healthy adult, the recommended maximum dose of acetaminophen during a 24-hour period is 4 grams (4000 mg) or eight extra-strength tablets. (Each extra-strength tablet contains 500 mg, while each regular strength tablet contains 325 mg.) Among children, the dose of acetaminophen is determined on the basis of each child's weight and age, explicitly stated in the package insert. If these guidelines for adults and children are followed, acetaminophen is safe and carries essentially no risk of liver injury. A person who drinks more than two alcoholic beverages per day, however, should not take more than 2 grams (2000 mg) of acetaminophen over 24 hours, as discussed below, since alcohol makes the liver susceptible to damage from lower doses of acetaminophen.
A single dose of 7 to 10 grams (7000 - 10,000 mg) of acetaminophen (14 to 20 extra-strength tablets), twice the recommended dose, can cause liver injury in the average healthy adult. Among children, a single dose of 140 mg/kg (body weight) of acetaminophen can result in liver injury. Nevertheless, 3 to 4 grams ((3000 to 4000 mg) taken in a single dose or 4 to 6 grams (4000 to 6000 mg) over 24 hours have been reported to cause severe liver injury in some people, sometimes even resulting in death. It seems that certain individuals, for example, those who regularly drink alcohol, are more prone than others to developing acetaminophen-induced liver damage. Other factors that increase a person's risk for damage from acetaminophen include the fasting state, malnutrition, and concomitant administration of some other drugs such as phenytoin (Dilantin), phenobarbital, carbamazepine [(Tegretol) (anti-seizure medications)] or isoniazid [(Nydrazid, Laniazid) (anti-TB drug)].
Please read the Tylenol Liver Damage article for a detailed discussion of the symptoms, mechanisms of acetaminophen toxicity, treatment (early use of N-acetylcysteine), and prevention.
Statins are the most widely used medications to lower "bad" (LDL) cholesterol in order to prevent heart attacks and strokes. Most doctors believe that statins are safe for long-term use, and important liver injury is rare. Nevertheless, statins can injure the liver. The most common liver-related problem caused by statins is mild elevations in blood levels of liver enzymes (ALT and AST) without symptoms. These abnormalities usually improve or completely resolve upon stopping the statin or reducing the dose. There is no permanent liver damage.
Patients with obesity have an increased chance of developing diabetes, non-alcoholic fatty liver disease (NFALD), and elevated blood cholesterol levels. Patients with fatty liver often have no symptoms, and the abnormal tests are discovered when routine blood testing is done. Recent studies have found that statins can be used safely to treat high blood cholesterol in patients who already have fatty liver and mildly abnormal liver blood tests when the statin is started. In these patients, doctors may choose to use statins at lower doses and monitor liver enzyme levels regularly during treatment.
Nevertheless, idiosyncratic liver toxicity capable of causing severe liver damage (including liver failure leading to liver transplantation) has been reported with statins. The frequency of severe liver disease caused by satins is likely in the range of 1-2 per million users. As a precaution, the FDA labeling information advises that liver enzyme blood tests should be performed before and 12 weeks following the initiation of statin treatment or increase in dose, and periodically thereafter (for example, every six months).
Nicotinic acid (Niacin)
Niacin, like the statins, has been used to treat elevated blood cholesterol levels as well as elevated triglyceride levels. Also like the statins, niacin can damage the liver. It can cause mild transient elevations in blood levels of AST and ALT, jaundice, and, in rare instances, liver failure. Liver toxicity with niacin is dose-dependent; toxic doses usually exceed 2 grams per day. Patients with pre-existing liver diseases and those who drink alcohol regularly are at higher risk for developing niacin toxicity. The sustained-release preparations of niacin also are more likely to cause liver toxicity than the immediate-release preparations.
Amiodarone (Cordarone) is an important medication that is used to treat irregular heart rhythms such as atrial fibrillation and ventricular tachycardia. Amiodarone can cause liver damage ranging from mild and reversible liver blood enzyme abnormalities, to acute liver failure and irreversible cirrhosis. Mild liver blood test abnormalities are common and typically resolve weeks to months after stopping the drug. Serious liver damage occurs in less than 1% of patients.
Amiodarone differs from most other drugs because a substantial amount of amiodarone is stored in the liver. The stored drug is capable of causing fatty liver, hepatitis, and, more importantly, it can continue to damage the liver long after the drug is stopped. Serious liver damage can lead to acute liver failure, cirrhosis, and the need for liver transplantation.
Methotrexate (Rheumatrex, Trexall)
Methotrexate (Rheumatrex, Trexall) has been used for the long-term treatment of patients with severe psoriasis, rheumatoid arthritis, psoriatic arthritis, and some patients with Crohn's disease. Methotrexate has been found to be a cause of liver cirrhosis in a dose-dependent fashion. Patients with pre-existing liver diseases, obese patients, and those who drink alcohol regularly are particularly at risk of developing methotrexate-induced cirrhosis. In recent years, doctors have substantially decreased methotrexate liver damage by using low doses of methotrexate (5-15 mg) given once a week and by carefully monitoring liver blood tests during therapy. Some doctors also perform liver biopsies on patients without liver symptoms after two years (or after a cumulative dose of 4 grams of methotrexate) to look for early liver cirrhosis.
Isoniazid (Nydrazid, Laniazid). Isoniazid has been used for decades to treat latent tuberculosis(patients with positive skin tests for tuberculosis, without signs or symptoms of active tuberculosis). Most patients with isoniazid-induced liver disease only develop mild and reversible elevations in blood levels of AST and ALT without symptoms, but approximately 0.5% to 1% of the patients develop isoniazid-induced hepatitis. The risk of developing isoniazid hepatitis occurs more commonly in older patients than younger patients. The risk of serious liver disease is 0.5% in healthy young adults, and rises to more than 3% in patients older than 50. At least 10% of the patients who develop hepatitis go on to develop liver failure and require liver transplantation. The risk of isoniazid liver toxicity is increased with chronic regular alcohol intake, and with concomitant use of other medications such as Tylenol and rifampin (Rifadin, Rimactane).
Early symptoms of isoniazid hepatitis are fatigue, poor appetite, nausea, and vomiting. Jaundice may then follow. Most patients with isoniazid hepatitis recover fully and promptly after stopping the drug. Severe liver disease and liver failure mostly occur in patients who continue to take isoniazid after the onset of hepatitis. Therefore, the most important treatment for isoniazid liver toxicity is early recognition of hepatitis and discontinuation of the isoniazid before serious liver injury has occurred.
Nitrofurantoin. Nitrofurantoin is an anti-bacterial drug that is used to treat urinary tract infectionscaused by many gram-negative and some gram-positive bacteria. (Nitrofurantoin was approved by the FDA in 1953.) There are three forms of nitrofurantoin available: a microcrystalline form (Furadantin), a macrocrystalline form (Macrodantin), and a sustained release, macrocrystalline form used twice daily (Macrobid).
Nitrofurantoin can cause acute and chronic liver disease. Most commonly, nitrofurantoin causes mild and reversible elevations in blood levels of liver enzymes without symptoms. In rare instances, nitrofurantoin can cause hepatitis.
Symptoms of nitrofurantoin hepatitis include:
Some patients with hepatitis also have a rash, enlarged lymph glands, and nitrofurantoin-induced pneumonia (with symptoms of cough and shortness of breath). Blood tests usually show elevated liver enzymes and bilirubin. Recovery from hepatitis and other skin, joint, and lung symptoms is usually rapid once the drug is stopped. Serious liver disease such as acute liver failure and chronic hepatitis with cirrhosis mostly occur in patients who continue the drug despite developing hepatitis.
Augmentin. Augmentin is a combination of amoxicillin and clavulanic acid. Amoxicillin is an antibiotic that is related to penicillin and ampicillin. It is effective against many bacteria such as H. influenzae, N. gonorrhea, E. coli, Pneumococci, Streptococci, and certain strains of Staphylococci, Addition of clavulanic acid to amoxicillin in Augmentin enhances the effectiveness of amoxicillin against many other bacteria that are ordinarily resistant to amoxicillin.
Augmentin has been reported to cause cholestasis with or without hepatitis. Augmentin-induced cholestasis is uncommon, but has been implicated in hundreds of cases of clinically apparent acute liver injury. Symptoms of cholestasis (jaundice, nausea, itching) usually occur 1-6 weeks after starting Augmentin, but the onset of liver disease can occur weeks after stopping the Augmentin. Most patients recover fully in weeks to months after stopping the medication, but rare cases of liver failure, cirrhosis, and liver transplantation have been reported.
Other antibiotics have been reported to cause liver disease. Some examples include minocycline (an antibiotic related to tetracycline), and Cotrimoxazole (a combination of sulfamethoxazole and trimethoprim).
Nonsteroidal antiinflammatory drugs (NSAIDs)
Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed for the bone and joint-related inflammation such as arthritis, tendinitis and bursitis. Examples of NSAIDs include aspirin, indomethacin (Indocin), ibuprofen (Motrin), naproxen (Naprosyn), piroxicam (Feldene), and nabumetone(Relafen). Approximately 30 million Americans take NSAIDs regularly!
NSAIDs are safe when used properly and as prescribed by doctors; however, patients with cirrhosis and advanced liver disease should avoid NSAIDs since they can worsen liver function (and cause kidney failure as well).
Serious liver disease (such as hepatitis) from NSAIDs, occur rarely (in approximately 1-10 patients per 100,000 who use prescriptions). Diclofenac (Voltaren) is an example of an NSAID that has been reported to cause hepatitis slightly more frequently, in approximately 1-5 per 100,000 users of the drug. Hepatitis usually resolves completely after stopping the drug. Acute liver failure and chronic liver disease, such as cirrhosis, have been reported rarely.
Tacrine (Cognex) is an oral medication used for treating Alzheimer's disease. (The FDA approved tacrine in 1993.) Tacrine has been reported to cause abnormal elevations in blood liver enzymes commonly. Patients may report nausea, but hepatitis and serious liver disease are rare. Abnormal tests usually become normal after tacrine is stopped.
Disulfiram (Antabuse) is a medication occasionally prescribed to treat alcoholism. It discourages drinking by causing nausea, vomiting, and other unpleasant physical reactions when alcohol is ingested. Disulfiram has been reported to cause acute hepatitis. In rare cases, disulfiram-induced hepatitis can lead to acute liver failure and liver transplantation.
Excess intake of vitamin A, taken for years, can damage the liver. It is estimated that more than 30% of the U. S. population takes supplements of vitamin A, and some individuals are taking vitamin A at high doses that may be toxic to the liver (greater than 40,000 units/ day). Vitamin A-induced liver disease includes mild and reversible elevation in blood liver enzymes, hepatitis, chronic hepatitis with cirrhosis, and liver failure.
The symptoms of vitamin A toxicity may include bone and muscle aches, orange discoloration of skin, fatigue, and headache. In advanced cases, patients will develop enlarged livers and spleens, jaundice, and ascites (abnormal buildup of fluid in the abdomen). Patients who drink alcohol heavily and have other preexisting liver disease are at increased risk of liver damage from vitamin A. Gradual improvement in the liver disease usually occurs after stopping vitamin A, but progressive liver damage and failure may occur in severe vitamin A toxicity with cirrhosis.
Liver toxicity also has been reported with herbal teas. Examples include Ma Huang, Kava Kava , pyrrolizidine alkaloids in Comfrey, germander, and chaparral leaf. Amanita phylloides is a liver-toxic chemical found in poisonous mushrooms. Consumption of a single poisonous mushroom can lead to acute liver failure and death.