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Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis
S Natori1, C Rust, L M Stadheim
1Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, MN 55905, USA.
Insights
Hepatocyte apoptosis is significantly increased in human alcoholic hepatitis (AH), correlating with disease severity. This finding supports therapeutic strategies targeting apoptosis inhibition in AH patients.
Area of Science:
- Hepatology
- Cell Biology
- Pathogenesis of Liver Disease
Background:
- The precise mechanisms driving liver injury in alcoholic hepatitis (AH) are not fully understood.
- While apoptosis is a known mechanism of liver damage, its role and induction pathways in human AH require elucidation.
Purpose of the Study:
- To quantify hepatocyte apoptosis in patients with AH.
- To correlate apoptosis levels with AH disease severity.
- To identify the molecular mechanisms responsible for apoptosis induction in AH.
Main Methods:
- TUNEL assay and immunohistochemistry for activated caspase 3 were used to assess hepatocyte apoptosis in 26 AH patients and 27 controls.
- Liver specimens were graded for disease severity.
- Expression of death receptors Fas and tumor necrosis factor-alpha receptor 1 (TNF-R1) was evaluated via immunohistochemistry.
Main Results:
- Hepatocyte apoptosis was significantly elevated in AH livers compared to controls.
- Apoptosis levels correlated positively with serum bilirubin levels (> 3 mg/dl) and grade 4 steatohepatitis.
- Strong expression of the Fas receptor was observed in AH hepatocytes, while TNF-R1 expression was similar between groups.
Conclusions:
- Hepatocyte apoptosis is markedly increased in human alcoholic hepatitis.
- These findings provide a rationale for developing therapies aimed at inhibiting apoptosis in AH.
Background/Aims:
The pathogenesis of alcoholic hepatitis (AH) remains poorly understood. Although apoptosis is now recognized as a mechanism of liver injury, the extent and mechanisms of apoptosis in human AH remain unknown. Thus, our aims were to quantify hepatocyte apoptosis in patients with AH, correlate it with disease severity, and identify the mechanisms of apoptosis induction.
Methods:
Hepatocyte apoptosis was assessed in 26 patients with AH and 27 controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspase 3. Liver specimens were also graded for disease severity. The expression of the death receptors, Fas and tumor necrosis factor-alpha receptor 1 (TNF-R1), was assessed by immunohistochemistry.
Results:
In contrast to normal livers, TUNEL- and caspase 3-positive hepatocytes were readily observed in the livers of patients with AH. In the AH group, hepatocyte apoptosis was significantly higher in patients with a serum bilirubin of > 3 mg/dl. Apoptosis was also greater in grade 4 steatohepatitis. The Fas receptor was strongly expressed in hepatocytes in AH, but not in normal livers; the TNF-R1 expression was comparable in both groups.
Conclusions:
The present results demonstrate that hepatocyte apoptosis is significantly increased in human AH and justify therapeutic strategies aimed at inhibiting apoptosis in this disease.