MEDICATIONS AND THE LIVER/HEPATITIS

There are over 1,000 drugs and chemicals that are capable of causing injury to the liver. The terms drug-induced liver disease, drug hepatotoxicity, and drug-induced hepatitis are used to describe those instances in which a medication or chemical substance has caused injury to the liver. Drug-induced liver injury may account for as many as 10 percent of hepatitis cases in adults overall, 40 percent of hepatitis cases in adults over fifty years old, and 25 percent of cases of fulminant liver failure.

    There is a rigorous process - known as clinical trials, that a drug must go through before it is determined to be safe for the public. These clinical trails are conducted on a carefully selected group of people who have met a long list of criteria in order to be able to participate in the testing of the medication. However, after the FDA has approved a particular drug, a larger and more varied group of people will be taking  the drug. This more diverse group of people may have additional medical problems that were not encountered  during the testing of the medication.  This is why occasionally, a drug originally thought to be safe, may be discovered to cause severe liver injury. In fact, drug-induced liver injury is the most common reason for the withdrawal from the market of an already FDA approved drug. Two examples of drugs withdrawn from the market due to severe liver injury include Duract (bromfenac), a nonsteroidal anti-inflammatory medication, and Rezulin (troglitasone) a diabetic medication.

Since all medications are processed through the liver at least to some degree, people with liver disease must become aware of which medications can cause liver damage, which medications can worsen preexisting liver disease, and which medications are safe to take. It is the liver’s job to detoxify any substances that are potentially harmful to the body. An already damaged and weakened liver must work much harder than a healthy liver in order to accomplish this task. When a person with liver disease ingests a potentially hepatotoxic drug, this puts an additional strain on the liver and can result in further liver injury or possibly even liver failure. Even people with a healthy liver can develop liver disease as a consequence of ingesting a toxic medication or drug.

In general, people with liver disease should avoid medications known to be hepatotoxic. People who must be treated with a medication that is potentially hepatotoxic should have their LFTs closely monitored by their doctors. If a person’s LFTs become greater than three times baseline values, the medication causing these elevations should be discontinued. Also, it is essential that people with liver disease inform their liver specialists of every medication or drug that they are taking—including herbs, over-the-counter drugs and/or recreational drugs. There is no reason for the patient to expect the doctor to be judgmental. Her goal is the same as the patient’s. Therefore, complete information should be provided to the doctor concerning prescription medications, over-the-counter medications, and herbal and alternative therapies. Remember, a doctor’s objective is to help her patient get better and to help protect her patient from unintentional additional liver damage. 

     People with cirrhosis must be particularly aware of which drugs are hepatotoxic, as they are typically more sensitive to drugs side effects due to the inability of the liver to clear the drug from the body ( excretion rate).  Even drugs that are not known to be hepatotoxic may have a prolonged excretion rate.  This means that the drug and its metabolites will stay in the body longer.  Therefore, usual dosages of these drugs should not be taken - the dosage of these drugs should be decreased.  Examples of such drugs that require a decrease in the dosage when used for a prolonged period of time in people with cirrhosis include

How Drugs Cause Liver Disease

A particular drug may cause liver damage for many reasons. First, there are some drugs that are intrinsically toxic to the liver. These drugs can cause liver injury when the drug is taken in a dosage that exceeds the recommended dosage. This form of drug hepatotoxicity is what is known as “dose-dependent.” The greater the amount by which the dosage taken exceeds the recommended dose, the more likely it is that the drug will cause liver injury. Drugs in this category are usually broken down by the cytochrome P450 enzyme system, discussed in Chapter 1. Under normal circumstances, the cytochrome P450 enzyme system usually converts toxic substances into nontoxic ones. However, in situations of drug hepatotoxicity, the reverse happens. A nonhepatotoxic drug is broken down into hepatotoxic byproducts. These byproducts cause liver damage as they begin to accumulate. An example of a drug in this category is the headache and minor pain reliever acetaminophen (Tylenol), which is discussed on page xx. The drugs in this category may also cause liver injury if taken in excess in combination with another hepatotoxic substance, such as alcohol.

Second, there are some drugs that can trigger an idiosyncratic reaction (an abnormal, unexpected hypersensitivity), to a normal dose of the drug similar to an allergic reaction, even though a normal dose may have been taken. Such a reaction is not related to the quantity of the drug ingested, and, furthermore, the ensuing liver injury is unpredictable. This type of drug hepatotoxicity is often accompanied by fatigue, fever, and rash. It usually develops after a person has already been taking the drug for a few weeks. An example of a drug in this category is the anticonvulsant phenytoin (Dilantin).

Finally, a person’s susceptibility to a potentially hepatotoxic drug is enhanced by many factors. Some of these factors are within the person’s control, such as cigarette smoking and excessive alcohol intake. But other factors cannot be altered. These include advancing age and being of the female gender. Many of the relevant factors, both alterable as well as permanent, are listed below. (See Table 24.1 on page 380 for more information concerning most of the medications mentioned in this list.)

• Age. Adults are more prone to liver injury from certain hepatotoxic drugs. such as isoniazide (INH), a drug used to treat tuberculosis.

• Gender. Females are more susceptible than males are to most forms of drug-induced liver disease—especially drugs that can cause chronic hepatitis, such as methyldopa (Aldomet)- a drug used to treat hypertension (high blood pressure).

• Genetics. Some people have a genetically based impaired ability to break down potentially hepatotoxic drugs into safe byproducts, such as phenytoin (Dilantin)—a drug used to treat seizures.

• Dose. The higher the dose the greater the risk of liver toxicity. This applies to drugs, such as acetaminophen (Tylenol), which are by nature, potentially toxic to the liver.

• Duration. For some drugs, such as methotrexate (a type of chemotherapy), the longer it is used, the greater the likelihood of liver damage or even cirrhosis.

• Kidney damage. People with poorly functioning kidneys are more prone to the hepatotoxicity of some drugs, such as tetracycline- an antibiotic.

• Alcohol. Alcohol consumption enhances the hepatotoxicity of certain drugs, such as acetaminophen.

• Cigarettes. Cigarette smoking enhances the hepatotoxicity of certain drugs, such as acetaminophen.

• Drug interactions. Taking two hepatotoxic drugs in combination can greatly increase the likelihood of liver damage compared with taking one hepatotoxic drug alone.

-  Hepatitis C.  The presence of hepatitis C may increase the hepatotoxic potential of certain drugs such as the nonsteroidal anti-inflammatory (NSAID) ibuprofen (Motrin), and certain medications used in the treatment of HIV.

• HIV. The presence of HIV (the virus which causes AIDS), increases the likelihood of hepatotoxicity from certain drugs, such as sulfamethoxazole-trimethoprim (Septra).

• Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). People with these autoimmune disorders are more prone to the hepatotoxic effects of aspirin than people without these disorders.

• Obesity. Obesity increases the susceptibility of halothane-induced liver injury. (Halothane is a type of anesthesia.)

• Nutritional status. Either fasting or a high protein diet can increase a person’s susceptibility to acetaminophen-induced liver injury. 

Characteristics of Drug-Induced Liver Disease

Many drugs have the ability to cause any form of liver disease, including acute and chronic hepatitis as well as a fatty liver and nonalcoholic fatty liver disease (NAFLD).  And, many drugs can cause cirrhosis, liver failure, or even liver tumors. People with drug-induced liver disease may be asymptomatic with only mildly elevated LFTs, or they may be severely ill with liver failure and consequently in need of a liver transplant. Or they may be somewhere in between. Drug-induced liver disease can result in exactly the same symptoms and signs as those that characterize the same disease when not induced by drugs. It is essential for both the patient and the doctor to consider the potential hepatotoxicity of all drugs that the patient is ­taking and to promptly discontinue the use of such medications whenever an ad­verse effect on the liver is suspected. Continuing to use a drug after liver-related symptoms and signs have appeared greatly increases the chances of serious liver damage.

Drug-induced liver injury may be diagnosed through blood work. Some medications may cause hepatocellular liver injury. This is manifested by elevations in the transaminases AST and ALT. Other medications may cause cholestatic liver injury. This is manifested by elevations in AP and GGTP. And some medications may cause both types of liver injury. In addition, there are medications that may cause elevated bilirubin levels. Patients with elevated bilirubin levels exhibit signs of jaundice, including yellowing of the skin and eyes, and a darkening of the urine.

Drug-induced liver disease can be expected to occur in most, but not all cases, within the time frame of between five and ninety days from initial exposure to the hepatotoxic drug. Thus, people taking potentially hepatotoxic drugs should be monitored with blood tests during this time period. If a greater than threefold increase from baseline LFT levels occurs, the medication should be discontinued. LFTs should improve within two to four weeks from when the medication was discontinued.

Since more than 1,000 drugs are potentially hepatotoxic, a comprehensive list detailing every hepatotoxic drug is beyond the scope of this book. However, Table 24.1 on page xx lists some commonly used medications that may cause liver injury in some people. It is important to remember that not everyone will sustain liver injury as a result of using one of these drugs. And it is important to keep in mind that, as discussed on page xx, there are numerous variables that increase a person’s susceptibility to the hepatotoxicity of these medications. Still, any person with liver disease who is using one or more of these medications needs to be carefully monitored. Careful monitoring is particularly crucial when such a person is using two or more hepatotoxic drugs in combination with alcohol. People with liver disease are best advised to use an alternative to one of these potentially hepatotoxic medications whenever possible.

All contents of this article are Copyright © Melissa Palmer, MD

Melissa Palmer, MD is the author of " Dr. Melissa Palmer's Guide of Hepatitis and Liver Disease". (Published 2004. Penguin Putnam).

The offices of Melissa Palmer, M.D. are located at:

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