Isoniazid Liver Injury: Clinical Spectrum, Pathology, and Probable Pathogenesis

Abstract

The clinical spectrum of isoniazid-induced liver injury seems to be clinically, biochemically, and histologically indistinguishable from viral hepatitis, except that the injury occurs primarily in persons older than 35 years. A possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug has been found. Examination of isoniazid metabolites showed that patients with rapid acetylator phenotype hydrolyze much more isoniazid to isonicotinic acid and the free hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazid is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. It seems likely that formation of chemically reactive metabolites is also the biochemical event initiating isoniazid liver injury in man. Recognition of the seriousness of isoniazid hepatic injury, not readily accepted at first, has led to revisions in the uses of isoniazid prophylaxis.

Cytochrome P450 2E1 Genotype and the Susceptibility to Antituberculosis Drug–Induced Hepatitis

“…The elderly appear to be vulnerable to antituberculosis drugs. 5,6,[12][13][14][15] Nevertheless, after adjustment for age, we found that CYP2E1 remained a significant independent risk factor for antituberculosis drug-induced hepatotoxicity.…”

“…10,[13][14][15][16][17] Alcohol consumption, advanced age, acetylator status, and existing chronic liver disease have been reported to increase the risk of antituberculosis drug-induced hepatitis. [3][4][5][6][7][8][9][10][11][12][13][14][15] However, the exact mechanism for this hepatotoxicity remains unclear.…”

“…3,4 Therefore, a better understanding of the metabolism of isoniazid may be of help in understanding the mechanisms underlying hepatotoxicity and obviate its occurrence. In the liver, isoniazid first is metabolized into acetylisoniazid via Nacetyltransferase (NAT), 5 followed by hydrolysis to acetylhydrazine (Fig. 1).…”

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15] Metabolic intermediates of isoniazid, instead of isoniazid per se, are incriminated as the cause of hepatotoxicity. 3,4 Therefore, a better understanding of the metabolism of isoniazid may be of help in understanding the mechanisms underlying hepatotoxicity and obviate its occurrence.…”

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15] The incidence of antituberculosis drug-induced hepatitis ranges from 1% to 36%, depending on different regimens and definitions of hepatic injury. [3][4][5][6][7][8][9][10][11][12][13][14][15] This hepatotoxicity is also the most prevalent drug-induced hepatic injury in Taiwan and many other countries, and its associated mortality is not rare. 10,[13][14][15][16][17] Alcohol consumption, advanced age, acetylator status, and existing chronic liver disease have been reported to increase the risk of antituberculosis drug-induced hepatitis.…”