Abstract
BACKGROUND: The natural history of adult liver disease due to α1-antitrypsin deficiency (A1AD) remains poorly understood. OBJECTIVE: We investigated whether heterozygosity for the Z-allele predisposes for the development of clinically significant portal hypertension (CSPH). Moreover, we aimed to non-invasively assess the prevalence of liver fibrosis and hepatic steatosis in adults with A1AD treated by pulmonologists. METHODS: SERPINA1 rs28929474 (Z-allele) was genotyped in 315 patients with CSPH (hepatic venous pressure gradient ≥10 mmHg; cases) and 248 liver donors (controls). In addition, 31 adults with A1AD (Pi*ZZ/Pi*SZ) and 11 first-degree relatives (Pi*MZ/Pi*MS) underwent liver stiffness and controlled attenuation parameter (CAP) measurement. RESULTS: Heterozygosity for the Z-allele was observed in 6.7% of patients with CSPH and 2.8% of liver donors. Thus, harboring the Z-allele was associated with increased odds of CSPH (odds ratio: 2.47; 95% confidence interval: 1.03-5.9; P = 0.042). Among Pi*ZZ/Pi*SZ patients, 23%/3% had liver stiffness values indicative of liver fibrosis ( ≥F2/ ≥F3). Interestingly, 65%/52% of Pi*ZZ/Pi*SZ patients had CAP values indicative of hepatic steatosis ( ≥S1/ ≥S2). CONCLUSIONS: Heterozygosity for the Z-allele predisposes for the development of CSPH, confirming its role as a genetic (co)factor in liver disease. Pi*ZZ/SZ patients rarely develop liver fibrosis ≥F3 during adulthood; however, liver fibrosis ≥F2 is common. Elevated CAP values hint at underlying hepatic steatosis, which might promote liver fibrosis progression.