Mitochondrial function reflected by the decarboxylation of [13C]ketoisocaproate is impaired in alcoholics.
Mitochondria of patients with alcoholic liver disease exhibit structural abnormalities, and mitochondria isolated from animals exposed to ethanol are functionally deficient when studied in vitro. To assess possible functional consequences of these ethanol-associated alterations in 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 13CO2 following the administration of 1 mg/kg 2-keto[1-13C]isocaproic acid, the decarboxylation of which occurs in mitochondria. The results of the KICA breath test in 12 alcoholic subjects were compared with the results in healthy controls and patients with nonalcoholic liver disease. The peak exhalation of 13CO2 and the fraction of the administered dose decarboxylated in 120 min were both significantly lower in alcoholics than in healthy controls and patients with nonalcoholic liver disease. In alcoholics, KICA decarboxylation was impaired in the presence of normal quantitative liver function tests such as the aminopyrine breath test and galactose elimination capacity, indicating that KICA decarboxylation does not simply reflect a decreased functional hepatic mass. The enrichment of circulating KICA with [13C]KICA was similar in alcoholics and controls, indicating that a decreased bioavailability or an increased dilution of labeled KICA cannot account for the decreased exhalation of 13CO2. It is concluded that mitochondrial function as reflected by KICA decarboxylation is impaired in chronic alcoholics. The functional impairment is specific for ethanol abuse and not a reflection of decreased global hepatic function. KICA decarboxylation could thus be useful as a marker for excessive ethanol consumption.
Department of Clinical Pharmacology, University of Bern, Switzerland.
A
A
Witschi
S
S
Mossi
B
B
Meyer
E
E
Junker
B H
BH
Lauterburg
D000328:Adult; D000368:Aged; D001944:Breath Tests; D003653:Decarboxylation; D005260:Female; D006801:Humans; D007651:Keto Acids / Q000493:pharmacokinetics*; D008104:Liver Cirrhosis, Alcoholic / Q000175:diagnosis / Q000503:physiopathology / Q000534:rehabilitation; D008108:Liver Diseases, Alcoholic / Q000175:diagnosis / Q000503:physiopathology* / Q000534:rehabilitation; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000502:physiology*; D012016:Reference Values
D007651:Keto Acids; C013082:alpha-ketoisocaproic acid