Abstract
Objective
Alcohol-related liver disease (ALD) is a global healthcare problem with limited
treatment options. Alpha-1 antitrypsin (AAT, encoded by
SERPINA1) shows potent anti-inflammatory activities in
many preclinical and clinical trials. In our study, we aimed to explore the role of
AAT in ALD.
Design
An unselected cohort of 512 patients with cirrhosis was clinically
characterised. Survival, clinical and biochemical parameters including AAT serum
concentration were compared between patients with ALD and other aetiologies of liver
disease. The role of AAT was evaluated in experimental ALD models.
Results
Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a
significantly higher risk for death/liver transplantation as compared with patients
with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression
analysis showed that low AAT serum concentration was a NaMELD-independent predictor of
survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant
decline in hepatic AAT compared with pair-fed mice. Therefore,
hAAT-Tg mice were ethanol-fed, and these mice displayed
protection from liver injury associated with decreased steatosis, hepatic neutrophil
infiltration and abated expression of proinflammatory cytokines. To test the
therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT.
Administration of AAT ameliorated hepatic injury, neutrophil infiltration and
steatosis.
Conclusion
Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an
increased risk for death/liver transplantation. Both
hAAT-Tg mice and AAT-treated wt animals showed protection
from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD,
especially for alcoholic hepatitis.
Cited by
5 articles.
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