Drug-induced liver injury in the elderly.

Historically, the elderly have been considered to be at increased risk for drug-induced liver injury (DILI). Animal studies have demonstrated changes in hepatic physiology that affect drug metabolism in the aging liver; however, there is no evidence that this leads to any appreciable deterioration of liver function in healthy older humans. Updated data from international DILI registries give us pause to consider whether the elderly are truly at increased risk to develop hepatic injury. Instead, hepatotoxicity in the elderly appears to be more a function of drug exposure, polypharmacy and drug-drug interactions. Isoniazid and benoxaprofen are the only two agents with a well-studied correlation between increasing age and risk of DILI. Nevertheless, given the increasing proportion of patients over age 65 in the U.S. and abroad, the influence of age on the risk of DILI is the focus of this review.

A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome.

Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities, has several features in common with hand-foot-genital syndrome (HFGS), including hypoplastic first digits and hypospadias. The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2(nd) toes with absent nails, suggests that it represents a distinct entity. HFGS is caused by mutations in the HOXA13 gene. We have therefore re-investigated the original Guttmacher syndrome family, and have found that affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L), which arose on an allele already carrying a novel 2-bp deletion (-78-79delGC) in the gene's highly conserved promoter region. This deletion produces no detectable abnormalities on its own, but may contribute to the phenotype in the affected individuals. The missense mutation, which alters a key residue in the recognition helix of the homeodomain, is likely to perturb HOXA13's DNA-binding properties, resulting in both a loss and a specific gain of function.