The results of the study “Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis” by Strnad et al. were published in August 2018 in the journal Gut (DOI:10.1136/gutjnl-2018-316228). Alpha1-antitrypsin (AAT) deficiency is among the most common genetic diseases. Homozygous carriers of the ‘Pi*Z’ variant of AAT are highly susceptible to develop liver cirrhosis due to ‘gain-of-function’ toxicity of the mutant protein in hepatocytes. Up to 10% of Caucasians carry an AAT variant but the relevance of heterozygous carriage of the two most common AAT variants, ‘Pi*Z’ and ‘Pi*S’, for developing cirrhosis remains controversial.
In two case–control cohorts with a total of 1184 individuals with biopsy-proven non-alcoholic fatty liver disease (NAFLD) as well as in two case–control cohorts with a total of 2462 individuals with long-term alcohol misuse, the presence of the Pi*Z variant was strongly associated with the development of cirrhosis (odds ratios of about 6–7). This study was also the first to systematically investigate the role of the Pi*S variant and revealed that it may represent a minor risk factor for developing cirrhosis in alcohol misusers. The authors concluded that the Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals. Moreover, as measuring the AAT serum level represents an easy and affordable screening test for AAT deficiency, physicians should incorporate it into the routine workup of chronic liver disease, especially in the setting of ALD and NAFLD.
More information on the European Alpha1 Liver Study group can be found at www.alpha1-liver.eu
Karim Hamesch & Pavel Strnad
Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany