Medical expert of the article
New publications
Acute drug-induced hepatitis
Last reviewed: 04.07.2025
All iLive content is medically reviewed or fact checked to ensure as much factual accuracy as possible.
We have strict sourcing guidelines and only link to reputable media sites, academic research institutions and, whenever possible, medically peer reviewed studies. Note that the numbers in parentheses ([1], [2], etc.) are clickable links to these studies.
If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please select it and press Ctrl + Enter.
Acute drug-induced hepatitis develops in only a small proportion of patients taking the drugs and occurs approximately 1 week after the start of treatment. The likelihood of developing acute drug-induced hepatitis is usually impossible to predict. It does not depend on the dose, but increases with repeated use of the drug.
Isoniazid
Severe liver damage has been described in 19 of 2231 healthy employees who were prescribed isoniazid because of a positive tuberculin test. Symptoms of damage appeared within 6 months of starting the drug; jaundice developed in 13 patients, and 2 patients died.
After acetylation, isoniazid is converted into hydrazine, from which, under the action of lysing enzymes, a powerful acetylating substance is formed, causing necrosis in the liver.
The toxic effect of isoniazid is enhanced when taken simultaneously with enzyme inducers, such as rifampicin, as well as with alcohol, anesthetics and paracetamol. Mortality increases significantly when isoniazid is combined with pyrazinamide. At the same time, PAS slows down enzyme synthesis and, perhaps, this explains the relative safety of the combination of PAS and isoniazid previously used to treat tuberculosis.
In people who are "slow" acetylators, the activity of the enzyme N-acetyltransferase is reduced or absent. It is unknown how the ability to acetylate affects the hepatotoxicity of isoniazid, however, it has been established that in the Japanese, "fast" acetylators are more sensitive to isoniazid.
Liver damage may occur with the participation of immune mechanisms. However, allergic manifestations are not observed, and the frequency of subclinical liver damage is very high - from 12 to 20%.
During the first 8 weeks of treatment, an increase in transaminase activity is often observed. It is usually asymptomatic, and even with continued administration of isoniazid, their activity subsequently decreases. However, transaminase activity should be determined before and after the start of treatment after 4 weeks. If it increases, the tests are repeated at 1-week intervals. If transaminase activity continues to increase, the drug should be discontinued.
Clinical manifestations
Severe hepatitis most often develops in people over 50 years of age, especially in women. After 2-3 months of treatment, non-specific symptoms may appear: anorexia and weight loss. Jaundice develops after 1-4 weeks.
After stopping the drug, hepatitis usually resolves quickly, but if jaundice develops, the mortality rate reaches 10%.
The severity of hepatitis increases significantly if the drug is continued after clinical manifestations or increased transaminase activity develop. If more than 2 months have passed since the start of treatment, hepatitis is more severe. Malnutrition and alcoholism worsen liver damage.
Liver biopsy reveals acute hepatitis. Continued use of the drug promotes the transition of acute hepatitis to chronic. Discontinuation of the drug apparently prevents further progression of the lesion.
[ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ]
Rifampicin
Rifampicin is usually used in combination with isoniazid. Rifampicin itself can cause mild hepatitis, but it usually occurs as a manifestation of a general allergic reaction.
Methyldopa
During treatment with methyldopa, an increase in transaminase activity, which usually disappears even with continued use of the drug, has been described in 5% of cases. This increase may be due to the action of a metabolite, since methyldopa can be converted into a powerful arylating agent in human microsomes.
In addition, immune mechanisms of drug hepatotoxicity associated with the activation of metabolites and the production of specific antibodies are possible.
The lesion is more often observed in postmenopausal women taking methyldopa for more than 1-4 weeks. Hepatitis usually develops during the first 3 months of treatment. Hepatitis may be preceded by a short-term fever. Liver biopsy reveals bridging and multilobular necrosis. In the acute stage, a fatal outcome is possible, but the condition of patients usually improves after discontinuation of the drug.
Other antihypertensive drugs
The metabolism of other antihypertensive drugs, like debrisoquine, is determined by genetic polymorphism of cytochrome P450-II-D6. Hepatotoxicity of metoprolol, atenolol, labetalol, acebutolol and hydralazine derivatives has been established.
Enalapril (an angiotensin-converting enzyme inhibitor) can cause hepatitis with eosinophilia. Verapamil can also cause a reaction resembling acute hepatitis.
Halothane
Liver damage caused by halothane is very rare and is either mild, manifested only by an increase in transaminase activity, or fulminant (usually in patients already exposed to halothane).
Mechanism
The hepatotoxicity of the products of reduction reactions increases with hypoxemia. The products of oxidation reactions are also active. Active metabolites cause lipid peroxidation and inactivation of enzymes that ensure drug metabolism.
Halothane accumulates in adipose tissue and is excreted slowly; halothane hepatitis often develops in the context of obesity.
Considering the development of halothane hepatitis, as a rule, with repeated administration of the drug, as well as the nature of the fever and the development of eosinophilia and skin rashes in some cases, it is possible to assume the involvement of immune mechanisms. In halothane hepatitis, specific antibodies to liver microsomal proteins, which bind halothane metabolites, are detected in the serum.
Increased lymphocyte cytotoxicity is observed in patients and their family members. The extreme rarity of fulminant hepatitis suggests that predisposed individuals may biotransform the drug by an unusual mechanism and/or have a pathological tissue reaction to polar halothane metabolites.
Clinical manifestations
In patients who undergo repeated halothane anesthesia, halothane hepatitis develops significantly more often. The risk is especially high in obese elderly women. Liver damage is also possible in children.
If a toxic reaction develops with the first administration of halothane, fever, usually with chills, accompanied by malaise, nonspecific dyspeptic symptoms and pain in the right upper quadrant of the abdomen, appears no earlier than 7 days (from 8 to 13 days) after the operation. In case of multiple halothane anesthesia, an increase in temperature is noted on the 1-11th day after the operation. Jaundice develops soon after the fever, usually 10-28 days after the first administration of halothane and 3-17 days in case of repeated halothane anesthesia. The time interval between fever and the appearance of jaundice, approximately equal to 1 week, is of diagnostic value and allows to exclude other causes of postoperative jaundice.
The white blood cell count is usually normal, with occasional eosinophilia. Serum bilirubin levels may be very high, particularly in fatal cases, but in 40% of patients they do not exceed 170 μmol/L (10 mg%). Halothane hepatitis may also occur without jaundice. Transaminase activity is similar to that seen in viral hepatitis. Serum alkaline phosphatase activity may sometimes increase significantly. Mortality increases significantly with jaundice. One study found that 139 (46%) of 310 patients with halothane hepatitis died. If coma develops and IIb levels increase significantly, there is virtually no chance of recovery.
Changes in the liver
Liver changes may not differ from those characteristic of acute viral hepatitis. Drug etiology can be suspected based on leukocyte infiltration of sinusoids, the presence of granulomas and fatty changes. Necrosis can be submassive and confluent or massive.
In addition, in the first week, the pattern of liver damage may be consistent with direct damage by metabolites with massive necrosis of zone 3 hepatocytes, covering two-thirds or more of each acinus.
If there is the slightest suspicion of even a mild reaction after the first halothane anesthesia, re-administration of halothane is inadmissible. Before administering any other anesthetic, the patient's medical history should be carefully analyzed.
Repeated halothane anesthesia may be administered no earlier than 6 months after the first one. If surgery is required before this period, another anesthetic should be used.
Enflurane and isoflurane are metabolized to a much lesser extent than halothane, and their poor solubility in blood results in their rapid excretion in exhaled air. Consequently, fewer toxic metabolites are formed. However, with repeated use of isoflurane, the development of FPN has been noted. Although cases of liver injury have been described after the administration of enflurane, they are still extremely rare. Despite their high cost, these drugs are preferable to halothane, but they should not be used at short intervals. After halothane hepatitis, antibodies remain that can "recognize" the metabolites of enflurane. Therefore, replacing halothane with enflurane during repeated anesthesia will not reduce the risk of liver injury in patients with a predisposition.
[ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ], [ 20 ]
Ketoconazole (nizoral)
Clinically significant liver reactions during treatment with ketoconazole are very rare. However, reversible increases in transaminase activity are observed in 5-10% of patients taking this drug.
The lesion is observed mainly in elderly patients (average age 57.9 years), more often in women, usually with a treatment duration of more than 4 weeks; taking the drug for less than 10 days does not cause a toxic reaction. Histological examination often reveals cholestasis, which can cause death.
The reaction is idiosyncratic but not immune-mediated, as fever, rash, eosinophilia, or granulomatosis are rarely present. Two deaths have been reported from massive liver necrosis, primarily of zone 3 acinus.
Hepatotoxicity may also be characteristic of more modern antifungal agents - fluconazole and itraconazole.
Cytotoxic drugs
The hepatotoxicity of these drugs and the VOB have already been discussed above.
Flutamide, an antiandrogen drug used to treat prostate cancer, can cause both hepatitis and cholestatic jaundice.
Acute hepatitis can be caused by cyproterone and etoposide.
[ 21 ], [ 22 ], [ 23 ], [ 24 ]
Drugs affecting the nervous system
Tacrine, a drug used to treat Alzheimer's disease, causes hepatitis in up to 13% of patients. Increased transaminase activity, usually within the first 3 months of treatment, is observed in half of patients. Clinical manifestations are rare.
When the drug is discontinued, transaminase activity decreases, and when it is resumed, it usually does not exceed the norm, which suggests the possibility of liver adaptation to tacrine. No cases of death from the hepatotoxic effect of the drug have been described; however, transaminase activity should be monitored during the first 3 months of tacrine treatment.
Pemoline, a central nervous system stimulant used in children, causes acute hepatitis (probably due to a metabolite) that can be fatal.
Disulfiram, used to treat chronic alcoholism, causes acute hepatitis, sometimes fatal.
Glafenine. The liver reaction to this analgesic develops within 2 weeks to 4 months after the start of treatment. Clinically, it resembles the reaction to cinchophen. Of the 12 patients with a toxic reaction to glafenine, 5 died.
Clozapine: This drug used to treat schizophrenia can cause FP.
Extended-release nicotinic acid preparations (niacin)
Extended-release nicotinic acid preparations (unlike crystalline forms) may have a hepatotoxic effect.
A toxic reaction develops 1-4 weeks after the start of treatment at a dose of 2-4 mg/day, manifests itself as psychosis and can be fatal.
Symptoms of acute drug-induced hepatitis
In the pre-icteric period, non-specific symptoms of gastrointestinal tract damage, observed in acute hepatitis, appear. This is followed by jaundice, accompanied by discolored stool and dark urine, as well as an enlarged and painful liver. Biochemical testing reveals increased activity of liver enzymes, indicating the presence of hepatocyte cytolysis. The level of γ-globulins in the serum increases.
In recovering patients, the serum bilirubin level begins to decrease from the 2nd-3rd week. In an unfavorable course, the liver shrinks and the patient dies of liver failure. Mortality among people with an established diagnosis is high - higher than among patients with sporadic viral hepatitis. With the development of hepatic precoma or coma, mortality reaches 70%.
Histological changes in the liver may not differ in any way from the picture observed in acute viral hepatitis. With moderate activity, variegated necrosis is detected, the zone of which expands and can diffusely cover the entire liver with the development of its collapse. Bridge necrosis often develops; inflammatory infiltration is expressed to varying degrees. Sometimes chronic hepatitis develops subsequently.
The mechanism of such liver damage may be either the direct damaging effect of toxic drug metabolites or their indirect action, when these metabolites, acting as haptens, bind to cell proteins and cause immune damage to the liver.
Drug-induced hepatitis can be caused by many drugs. Sometimes this property of a drug is discovered after it has been marketed. Information on individual drugs can be found in special manuals. Toxic reactions to isoniazid, methyldopa, and halothane are described in detail, although they can occur with other drugs. Each individual drug can cause several types of reactions, and manifestations of acute hepatitis, cholestasis, and allergic reaction can be combined.
Reactions are usually severe, especially if the medication is not stopped. Liver transplantation may be required if FPN develops. The effectiveness of corticosteroids has not been proven.
Acute drug-induced hepatitis is especially common in older women, while it is rare in children.
What's bothering you?
What do need to examine?
Who to contact?