Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese.
OBJECTIVE
Insulin resistance and systemic hypertension are predictors of advanced fibrosis in obese patients with non-alcoholic fatty liver disease (NAFLD). Genetic factors may also be important. We hypothesize that high angiotensinogen (AT) and transforming growth factor-beta1 (TGF-beta1) producing genotypes increase the risk of liver fibrosis in obese subjects with NAFLD.


METHODS
One hundred and five of 130 consecutive severely obese patients having a liver biopsy at the time of laparoscopic obesity surgery agreed to have genotype analysis. Influence of specific genotype or combination of genotypes on the stage of hepatic fibrosis was assessed after controlling for known risk factors.


RESULTS
There was no fibrosis in 70 (67%), stages 1-2 in 21 (20%) and stages 3-4 fibrosis in 14 (13%) of subjects. There was no relationship between either high AT or TGF-beta1 producing genotypes alone and hepatic fibrosis after controlling for confounding factors. However, advanced hepatic fibrosis occurred in five of 13 subjects (odds ratio 5.7, 95% confidence interval 1.5-21.2, P=0.005) who inherited both high AT and TGF-beta1 producing polymorphisms.


CONCLUSIONS
The combination of high AT and TGF-beta1 producing polymorphisms is associated with advanced hepatic fibrosis in obese patients with NAFLD. These findings support the hypothesis that angiotensin II stimulated TGF-beta1 production may promote hepatic fibrosis.
Dixon
John B
JB
Monash University Department of Surgery, Alfred Hospital, Melbourne, Vic. 3181, Australia. john.dixon@med.monash.edu.au
Bhathal
Prithi S
PS
Jonsson
Julie R
JR
Dixon
Andrew F
AF
Powell
Elizabeth E
EE
O'Brien
Paul E
PE
D000328:Adult; D005234:Fatty Liver / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012307:Risk Factors; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1