Liver biopsies from 9 out of every 10 obese individuals exhibit pathological changes of unknown aetiology and 3 out of every 10 reflect severe injury in the form of periportal
fibrosis. To examine the hypothesis that excessive
fibrosis in
obesity arises in part from a predisposition to injury of the liver by drugs and
xenobiotics, we administered 5, 10 and 25 mg/kg doses of the model periportal hepatotoxin,
allyl alcohol, to obese Sprague-Dawley rats and age-matched non-obese controls.
Alanine aminotransferase activity (ALT) in plasma was ten-fold more elevated in obese animals than in non-obese animals given the 25 mg/kg dose (P < 0.05). On fitting the ALT results to a non-linear, parametric model by iterative non-linear least squares regression, we found that the slope of the log dose ALT curve was similar for obese and non-obese rats. However, the minimum dose required to produce elevated ALT (DMIN) was 50% lower for obese animals (DMIN 6.47 +/- 2.75 vs. 13.3 +/- 0.96 mg
allyl alcohol; P < 0.05). In a subsequent experiment,
allyl alcohol was administered to obese rats based on ideal body weight, which is defined as the mean total
body weight of an age-matched non-obese animal. With this dosing normalization, the 25 mg/kg ideal body weight doses translated to administration of a fixed dose of 13.5 mg
allyl alcohol to obese rats. Obese rats treated in this fashion exhibited more severe
necrosis in the periportal zone (median
necrosis score 2 versus 0-1, P < 0.05) and increased mortality over controls (44% versus 0%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)