Phenotypic characterization of idiosyncratic drug-induced liver injury: The influence of age and sex

Abstract

Increased age and female sex are suggested risk factors for drug-induced hepatotoxicity (DILI). We studied the influence of these variables on the propensity to develop DILI, as well as its clinical expression and outcome. All cases of DILI submitted to the Spanish Registry between April 1994 and August 2007 were analyzed. Six hundred three DILI cases (310 men; mean age, 54 years) showed a similar sex distribution, reaching two peaks in the 40-to 49-year-old and 60-to 69-year-old age groups. No cases were recorded in the 20-to 29-year-old group. Patients aged >60 years accounted for 46% of the cases, with a male predominance (158 males, 118 females; P ‫؍‬ 0.009), as opposed to younger patients. Older age was independently associated with cholestatic type of injury (odds ratio for an age interval for 1 year: 1.024 [95% confidence interval: 1.010-1.038]; male/female ratio, 1:2; P ‫؍‬ 0.001) and younger age with hepatocellular damage (odds ratio: 0.983 [95% confidence interval: 0.972-0.994]; female/male ratio, 1:2; P ‫؍‬ 0.002). In the mixed group, no age effect was evident. Outcome with fulminant liver failure/liver transplantation was more frequently encountered in women (P < 0.01). Conclusion: Neither older age nor female sex are predisposing factors to overall DILI. However, older age is a determinant for cholestatic damage with a male predominance, whereas younger age is associated with cytolytic damage and a female overrepresentation. Women distinctly exhibit the worst outcome. Knowledge of these phenotypic associations could guide differential diagnosis and attribution of causality in

Single-Center Experience With Drug-Induced Liver Injury From India: Causes, Outcome, Prognosis, and Predictors of Mortality

“…Our patients were much younger, with a mean age of 39 years compared with 53 and 58 years from Spain and Sweden, respectively ( 10 ). A similar observation was made in a recent study ( 29 ). Th e male-to-female gender ratio of 1.4:1 in our series is in contrast to the demographics in the United States and other Western countries where the incidence of DILI is higher in females compared with males.…”

“…Similar reasons may also have played a role in DILI caused by non-tuberculous drugs, although this needs further evaluation. Interestingly, even in Western series when DILI is split according to age, a ratio of 1.3:1 (M:F) is noted in men over 60 years ( 29 ) or in those < 39 years ( 11 ) whereas a male / female gender ratio of 1:8 is noted in DILI secondary to disulfi ram ( 31 ).…”

Idiosyncratic drug‐induced liver injury: A short review

“…Interestingly, drugs whose daily dose is over 50 mg account for over 70% to 80% of iDILI cases 11. These data suggest that iDILI may still have a dose‐dependent component similar to APAP 12, 13. The lipophilicity of drugs has also been shown to be a strong predictor of iDILI.…”

“Drug-Induced Liver Injury Clinical Consortia: a global research response for a worldwide health challenge”

“…Interestingly, the phenotypes of liver damage as characterized by liver biochemistry (hepatocellular, cholestatic and mixed) overlap among registries as does the severity. [9][10][11] New clinical findings provided by statistical analysis of the large DILI cohorts from the consortia include the recognition of female sex, hepatocellular type of damage and high bilirubin levels as risk factors for fulminant liver failure and death, [9,15] the influence of age and sex on the phenotypic expression of hepatotoxicity [16] and the higher mortality risk in patients with preexisting liver disease. [11] DILI Registries have also provided consistent figures on the therapeutic group of drugs most commonly implicated (Table 2) [9][10][11] and the growing problem with herbals and dietary supplements in the US.…”