Alpha 1 antitrypsin ameliorates experimental alcoholic liver disease and determines patient outcome

Background & Aims:

Alcoholic liver disease (ALD) is a substantial global health care problem, encompassing a broad spectrum of phenotypes including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis or even HCC (hepatocellular carcinoma). Pro-inflammatory cytokines (TNF-α, IL-1β), gut-barrier dysfunction and toxicity of ethanol and its metabolites (namely acetaldehyde) have been suggested as critical factors in the development of ALD, resulting in hepatocyte damage and cellular infiltration of immune cells (e.g. neutrophils). The acute-phase-protein Alpha-1 antitrypsin (A1AT) is a serin-proteinase inhibitor with anti-inflammatory properties (e.g. neutrophil elastase inhibition). In the present study we aimed to investigate the role of A1AT in ALD.

Methods:

In a cohort of 512 cirrhotic patients, biochemical and clinical parameters were compared between individuals with cirrhosis due to ALD and other etiologies, respectively. In a second step, the potential protective role of A1AT was evaluated in a murine binge-drinking model.

Results:

Low A1AT serum concentrations (≤120 mg/dL) were significantly associated with poorer survival of cirrhotic ALD patients (p < 0.001), however, this finding could not be found in patients with liver disease of other etiologies (p = 0.18). Multivariate Cox-regression analysis revealed that low A1AT serum concentration (< 120 mg/dL) was a NaMELD (Natrium model for end-stage liver disease)-independent predictor of transplantation/survival (HR = 2.17; 95% CI 1.20 – 3.92, p < 0.01). In a murine model of acute ALD a single ethanol gavage was associated with distinctive liver injury, inflammation and increased expression of hepatic Serpina1 (p < 0.05). Moreover, simultaneous ethanol gavage and supplementation of A1AT ameliorated ethanol-induced hepatic injury exemplified by decreased Tnfα transcription (p < 0.05) and hepatic infiltration by MPO⁺ cells (p < 0.001). Additionally, A1AT reduced hepatic microscopic steatosis (p < 0.05) upon acute ethanol exposure.

Conclusion:

A1AT concentrations > 120 mg/dL are associated with increased survival in patients with alcoholic liver cirrhosis. A1AT supplementation might potentially serve as a novel therapeutic option in ALD.