Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.
OBJECTIVE
The pathogenesis of nonalcoholic steatohepatitis (NASH) remains poorly understood. Although apoptosis is a common mechanism of liver injury, the extent and clinical significance of apoptosis in NASH has not been examined. Thus, the aims of this study were to quantify hepatocyte apoptosis in NASH, correlate it with disease severity, and identify possible mechanisms of apoptosis induction.


METHODS
Hepatocyte apoptosis was assessed in NASH, simple steatosis, alcoholic hepatitis, and controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspases 3 and 7. Liver specimens were also graded according to the magnitude of inflammation and fibrosis.


RESULTS
TUNEL-positive cells were significantly increased in liver biopsy specimens from patients with NASH compared with simple steatosis and controls. Unexpectedly, TUNEL-positive cells were also greater in NASH vs. alcoholic hepatitis. Immunohistochemistry demonstrated active caspases 3 and 7 in NASH specimens, confirming the occurrence of apoptosis in this disease. A positive correlation was observed between hepatocyte apoptosis and hepatic fibrosis and inflammatory activity, respectively. The Fas receptor was strongly expressed in hepatocytes in liver specimens from NASH patients as compared with controls.


CONCLUSIONS
Hepatocyte apoptosis is significantly increased in patients with NASH and correlates with disease severity, suggesting that antiapoptotic therapy may be useful in this syndrome.
Feldstein
Ariel E
AE
Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905 USA.
Canbay
Ali
A
Angulo
Paul
P
Taniai
Makiko
M
Burgart
Lawrence J
LJ
Lindor
Keith D
KD
Gores
Gregory J
GJ
D000328:Adult; D000368:Aged; D017209:Apoptosis; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D005260:Female; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D019014:fas Receptor / Q000032:analysis*
D019014:fas Receptor