Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases.

Fifty cases of nitrofurantoin-associated hepatic injury and two cases of nifurtoinol (hydroxymethylnitrofurantoin)-associated hepatic injury reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs were analyzed in detail. In 38 cases, a causal relationship was considered likely [i.e., "highly probable" (n = 4), "probable" (n = 23) or "possible" (n = 11)]. In 25 cases, hepatic injury was of the acute type whereas 13 cases presented a chronic type of reaction. Both types were more common in the elderly. Eighty per cent of the acute reactions appeared within the first 6 weeks of treatment and were sometimes accompanied by fever (28%), rash (12%) and eosinophilia (16%). Biochemically, the pattern was mainly hepatocellular (32%), whereas mixed cholestatic-hepatocellular (4%) and cholestatic (4%) patterns were uncommon. Although mild to moderate liver enzyme elevations (60%) were common, these were primarily symptomatic. The reaction was fatal in one "acute" and one "chronic" case. In the chronic cases, nuclear (82%) and smooth muscle (73%) antibodies and LE cells (50%) were frequently present. HLA typing showed no increase of the HLA B8 or HLA DRw3 haplotype. HLA DR2 (56%) and HLA DRw6 (56%) were more frequent than in controls (both 29%), but this was not statistically significant. Histology showed mainly necrosis, varying from spotty to massive, in the acute cases and a pattern consistent with chronic active hepatitis in the chronic cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketoconazole-associated hepatic injury. A clinicopathological study of 55 cases.

Fifty-five cases of ketoconazole-associated hepatic injury, reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs, were analysed in detail. In 50 cases a causal relationship was considered likely, i.e. 'probable' (27 cases) or 'possible' (23 cases). Eighty-four % of individuals were women. Forty-six % of patients were over 50 years of age which suggests that, considering the lower prescription rate in this age group, the elderly are more vulnerable to ketoconazole. In 60% of all cases hepatic injury appeared within the first 6 weeks of therapy but in the group of 'probable'-cases the onset was mostly later. Jaundice was present in 44% of all cases but in 63% of the group of 'probable'-cases. Eosinophilia (10%), fever (6%) and rash (2%) were uncommon. Biochemically the pattern was hepatocellular in 54%, cholestatic in 16% and mixed cholestatic-hepatocellular in 30%. Histology (14 cases) showed a predominantly hepatocellular pattern in 57% with extensive centrilobular necrosis and mild to moderate bridging. In 43% cholestasis predominated. None of the cases had a fatal course. The incidence of symptomatic hepatic injury may be estimated at approximately 1:2000 but is probably higher. The mechanism of ketoconazole-induced hepatic injury seems to be based on metabolic idiosyncrasy although it is not excluded that in some patients an immunoallergic mechanism is causative.