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DOI: 10.1055/s-0037-1612696
Heterozygous carriage of the alpha1-antitrypsin PiZ variant increases the risk to develop liver fibrosis
Publication History
Publication Date:
03 January 2018 (online)
Background:
Homozygous carriers of the alpha1-antitrypsin (AAT) “PiZ” variant are at risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. We evaluated (i) the prevalence of liver disease in heterozygous carriers of the PiZ variant (“PiMZ”); and (ii) the impact of the PiZ variant on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.
Methods:
(i) 176 PiMZ carriers without known liver disease (German-Austrian-Dutch-Belgian; mean 47 years, 59% female, BMI 25.7 kg/m2) and 176 non-carriers without AAT mutations were prospectively examined by laboratory investigation and transient elastography (TE). (ii) Genotyping for the most relevant AAT variant “PiZ” was undertaken in 2462 alcohol misusers (German-Swiss & British-Irish) and in 643 biopsy-proven NAFLD patients (German-Austrian) with/without cirrhosis. Data were analyzed by logistic regression and were adjusted for age, sex, BMI, and diabetes mellitus.
Results:
(i) PiMZ carriers had higher serum ALT, AST and GGT levels as well as transient elastography (TE) values than non-carriers (all p<.05). The PiMZ genotype and obesity acted as independent risk factors for increased TE values suggesting significant liver fibrosis. (ii) The PiMZ genotype was present in 13.2% of NAFLD patients with cirrhosis but only in 2.5% of patients without histological fibrosis (p<.0001). In line, carriage of the PiZ variant predisposed NAFLD subjects to cirrhosis (unadjusted OR = 5.76 [1.82 – 18.24]; adjusted OR = 6.73 [1.46 – 30.99]). Likewise, the PiMZ genotype was present in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<.0001). Accordingly, alcohol misusers carrying the PiZ variant were prone to develop cirrhosis (unadjusted OR = 5.22 [2.75 – 9.91]; adjusted OR = 5.79 [2.87 – 11.68]). In the NAFLD and alcohol misuser cohorts, these odds remained significant after further adjustment for the well-established risk variants in the PNPLA3, TM6SF2 and MBOAT7 genes.
Conclusion:
The PiZ variant is the hitherto strongest single nucleotide polymorphism-based risk factor for liver fibrosis. This finding needs to be incorporated into genetic counseling of affected individuals. As 2 – 4% of Caucasians are heterozygous PiZ carriers these data advocate for AAT testing as a routine part of liver workup.