Gastroenterology

Gastroenterology

Volume 125, Issue 2, August 2003, Pages 437-443
Gastroenterology

Clinical-liver, pancreas, and biliary tract
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis

https://doi.org/10.1016/S0016-5085(03)00907-7Get rights and content

Abstract

Background & Aims:

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.

Section snippets

Patient population

The study was approved by the Mayo Institutional Review Board, and all patients gave written informed consent for participation in medical research. Demographic, clinical, and laboratory data from 34 untreated consecutive patients with NASH were collected prospectively. All these patients were seen at the Mayo Clinic, Rochester, Minnesota. The diagnosis of NASH was established based on the following criteria: (1) persistent abnormal liver tests for more than 3 months, (2) liver biopsy

Clinical and laboratory features for the NASH population

The main demographic and clinical and laboratory data of the NASH population are summarized in Table 1. Among the 34 patients, 11 (32%) were male and 23 (68%) were female. The mean age at the time of liver biopsy was 46.2 ± 11 years. The mean body mass index (BMI) was 32.5 ± 4.4, with 21 patients having a BMI higher than 30. Four (12%) patients had cirrhosis, all Childs-Turcotte-Pugh class A. Seven (21%) patients had associated type 2 diabetes, with all 7 patients being treated with oral

Discussion

The principal findings of this study relate to the occurrence and significance of apoptosis in NASH. The observations demonstrate the following in NASH as compared with controls: (1) hepatocyte apoptosis is prominent; (2) hepatocytes apoptosis is associated with advanced stages of the disease, implicating a role for hepatocytes apoptosis in disease progression; and (3) Fas expression is enhanced, suggesting a mechanistic role for this death receptor in this disease process. Taken together,

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    Supported by grant DK41876 from the National Institute of Health, the Palumbo Foundation, and the Mayo Foundation.

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