Antituberculosis drug‐induced hepatotoxicity: Concise up‐to‐date review

Abstract

The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis druginduced hepatotoxicity. The reported incidence of antituberculosis drug-induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.

Clinical and Biochemical Profile of Tuberculosis in Patients with Liver Cirrhosis

“…4,5 Common risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. 15 However predictive model for identification of DILI is not available. Patients with cirrhosis have been shown to have a longer half-life of isoniazid and rifampicin, thus leading to their accumulation in the plasma.…”

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

“…INHinduced hepatotoxicity is seen mainly as hepatocellular steatosis and necrosis, and it has been suggested that toxic INH metabolites may bind covalently to cell macromolecules. 27 Approximately 0.5% of all patients treated with INH monotherapy develop clinically important increases in aminotransferase levels. 28 In patients who are receiving combination therapies that include INH but not RIF, the incidence of hepatotoxic effects is around 1.6%; the corresponding value for regimens containing both INH and RIF is 2.5%.…”

“…23 Asymptomatic, self-limited increase in aminotransferase levels is observed in the majority of patients treated with INH, which does not progress to more serious forms of liver injury. 27 Presence of jaundice, encephalopathy and the presence of severe hepatitis (aminotransferase levels >10-fold) are associated with a poor outcome. 30 Approximately 5-10% of patients who have clinical symptoms of severe hepatitis including jaundice develop acute liver failure.…”

“…Hepatic damage is rare in patients less than 20 years old; it is observed in 0.3% of those in the 20-34 years age group, increasing to 1.2% in the 35-49 years age group and 2.3% in those older than 50 years of age. 26,27,[32][33][34] Up to 12% of patients receiving INH may have elevated plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. 32,33 Recent treatment studies have reported significant transaminase elevation in 1-4% of those treated with INH for latent tuberculosis infection.…”

The Risk of Hepatotoxicity Associated with HAART/Anti-Tb Co-Treatment: A Case Control Study in a Central Ethiopian Referral Hospital

“…Therefore, these tests could be used as markers of hepatocellular injury [12]. Hepatocellular injury has different grading scale from mild to severe based on the concentration of the ALT or AST [13,14]. Studies have revealed that 14-20% of adults on ART had elevated serum liver enzymes as a marker of hepatocellular injury [15].…”