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Chronic drug-induced hepatitis
Last reviewed: 12.07.2025
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Symptoms of chronic active hepatitis may be caused by medications. Such medications include oxyphenisatin, methyldopa, isoniazid, ketoconazole, and nitrofurantoin. Elderly women are most often affected. Clinical manifestations include jaundice and hepatomegaly. Serum transaminase activity and serum globulin levels increase, and lupus cells may be detected in the blood. Liver biopsy reveals chronic active hepatitis and even cirrhosis. Bridging necrosis is not as pronounced in this group.
Clinical and biochemical improvement occurs after drug withdrawal. Exacerbations of hepatitis follow their repeated administration. Drug reactions should be excluded in every patient with symptoms of chronic hepatitis.
The liver is actively involved in the metabolism of drugs, especially those taken orally. To penetrate the intestinal wall, they must be fat-soluble. Then, when they enter the liver, the drugs are transformed into water-soluble (more polar) products and excreted in the urine or bile.
In humans, drug-induced liver damage can resemble almost all existing liver diseases. In about 2% of patients hospitalized for jaundice, the cause is drugs. In the United States, 25% of cases of fulminant liver failure (FLF) are caused by drugs. Therefore, when collecting anamnesis from patients with liver diseases, it is necessary to find out what drugs they have taken in the last 3 months. The doctor has to conduct a real investigation for this.
It is important to diagnose drug-induced liver damage as early as possible. If the medication is continued after transaminase activity increases or symptoms appear, the severity of the damage increases many times over. This may serve as grounds for accusing doctors of negligence.
The liver's response to medication depends on the interaction of environmental and hereditary factors.
The same drug may cause several types of reactions. Hepatitis, cholestasis, and hypersensitivity reactions may overlap. For example, halothane may cause necrosis of zone 3 of the acinus and at the same time a picture similar to acute hepatitis. The reaction to promazine derivatives consists of hepatitis and cholestasis. Methyldopa may cause acute or chronic hepatitis, cirrhosis, liver granulomatosis, or cholestasis.
[ Risk factors for drug-induced liver injury
Impaired drug metabolism depends on the degree of hepatocellular insufficiency; it is most pronounced in cirrhosis. T 1/2 of the drug correlates with prothrombin time (PT), serum albumin level, hepatic encephalopathy and ascites.
Pharmacokinetics
The elimination of orally administered drugs by the liver is determined by the activity of enzymes that destroy them, hepatic clearance, hepatic blood flow, and the degree of drug binding to plasma proteins. The pharmacological effect of a drug depends on the relative role of each of these factors.
If a drug is actively absorbed by the liver (high hepatic clearance), it is said to be metabolized by the first pass. The absorption of the drug is limited by the rate of blood flow in the liver, so clearance can be used to judge the hepatic blood flow. An example of such a drug is indocyanine green. Such drugs are usually well soluble in lipids. If the blood flow in the liver is reduced, for example in cirrhosis of the liver or heart failure, the systemic effect of drugs metabolized by the first pass is enhanced. Drugs that slow hepatic blood flow, such as propranolol or cimetidine, have a similar effect.
Drugs that are metabolized in the liver during the first pass should be administered bypassing the portal vein. Thus, glycerol trinitrate is administered sublingually, and lidocaine is administered intravenously.
The elimination of a drug with low hepatic clearance, such as theophylline, is influenced mainly by enzyme activity. The role of hepatic blood flow is small.
Plasma protein binding limits the drug's delivery to liver enzymes. This process depends on the formation and breakdown of plasma proteins.
Drug metabolism in the liver
The major drug metabolizing system is located in the microsomal fraction of hepatocytes (in the smooth endoplasmic reticulum). It includes mixed-function monooxygenases, cytochrome C reductase, and cytochrome P450. The cofactor is reduced NADP in the cytosol. Drugs undergo hydroxylation or oxidation, which enhances their polarization. An alternative phase 1 reaction is the conversion of ethanol to acetaldehyde by alcohol dehydrogenases, found mainly in the cytosol.
Medicines that affect bilirubin metabolism
Medicines can affect any stage of bilirubin metabolism. Such reactions are predictable, reversible, and mild in adults. However, in newborns, increased levels of unconjugated bilirubin in the brain can lead to bilirubin encephalopathy (kernicterus). This is aggravated by drugs such as salicylates or sulfonamides, which compete with bilirubin for binding sites on albumin.
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Diagnosis of drug-induced liver damage
Drug-induced liver damage is most often caused by antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), cardiovascular, neuro- and psychotropic drugs, i.e., virtually all modern drugs. It should be assumed that any drug can cause liver damage, and if necessary, contact the manufacturers and organizations responsible for the safety of the drugs used.
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