MITOCHONDRIAL-FUNCTION REFLECTED BY THE DECARBOXYLATION OF [C-13]KETOISOCAPROATE IS IMPAIRED IN ALCOHOLICS

Mitochondria of patients with alcoholic liver disease exhibit structur al abnormalities, and mitochondria isolated from animals exposed to et hanol are functionally deficient when studied in vitro. To assess poss ible functional consequences of these ethanol-associated alterations i n vivo, we measured mitochondrial function in alcoholics noninvasively with a breath test. A mitochondrial function, the decarboxylation of ketoisocaproate (KICA), was assessed by measuring the exhalation of (C O2)-C-13 following the administration of 1 mg/kg 2-keto[1-C-13]isocapr oic acid, the decarboxylation of which occurs in mitochondria. The res ults of the KICA breath test in 12 alcoholic subjects were compared wi th the results in healthy controls and patients with nonalcoholic live r disease. The peak exhalation of (CO2)-C-13 and the fraction of the a dministered dose decarboxylated in 120 min were both significantly low er in alcoholics than in healthy controls and patients with nonalcohol ic liver disease. In alcoholics, KICA decarboxylation was impaired in the presence of normal quantitative liver function tests such as the a minopyrine breath test and galactose elimination capacity, indicating that KICA decarboxylation does not simply reflect a decreased function al hepatic mass. The enrichment of circulating KICA with [C-13]KICA wa s similar in alcoholics and controls, indicating that a decreased bioa vailability or an increased dilution of labeled KICA cannot account fo r the decreased exhalation of (CO2)-C-13. It is concluded that mitocho ndrial function as reflected by KICA decarboxylation is impaired in ch ronic alcoholics. The functional impairment is specific for ethanol ab use and not a reflection of decreased global hepatic function. KICA de carboxylation could thus be useful as a marker for excessive ethanol c onsumption.