Meta‐Analysis: Redefining Liver Disease Risk in Heterozygous Alpha‐1 Antitrypsin Deficiency

BACKGROUND: Heterozygous SERPINA1 genotypes (MZ, SZ) have historically been regarded as carrier states with limited liver relevance. Emerging evidence suggests increased liver injury, but the magnitude of risk remains uncertain. We synthesized evidence on heterozygous SERPINA1 liver phenotypes to quantify this risk. METHODS: We performed a systematic review of bibliographic databases from inception to 21 October 2025 for studies reporting liver outcomes in MZ or SZ genotypes. Outcomes were grouped into metabolic comorbidities, biochemical markers, and clinical liver disease. Random-effects meta-analyses pooled mean differences (MDs) and odds ratios (ORs); risk of bias was assessed with established tools (PROSPERO CRD420251165586). RESULTS: Twenty-six studies including 27,933 heterozygotes and 547,961 controls met inclusion criteria. BMI (MD -0.09 [-0.20-0.02]) and steatosis risk (OR 1.09 [0.74-1.60]) were comparable between groups. Heterozygotes had modestly higher liver enzymes (ALT MD 1.03 [0.41-1.66]; AST MD 0.68 [0.51-0.85]; ALP MD 2.58 [1.58-3.58]) and higher odds of abnormal ALT (OR 1.18 [1.11-1.25]), AST (OR 1.16 [1.07-1.26]), and ALP (OR 1.41 [1.18-1.68]). They had significantly increased odds of fibrosis (OR 2.14 [1.52-3.02]), cirrhosis (OR 2.24 [1.73-2.91]), and liver transplantation (OR 2.28 [1.45-3.59]). CONCLUSIONS: Heterozygous SERPINA1 genotypes are bona fide liver risk states, with effect sizes comparable to established genetic and environmental determinants. MZ/SZ heterozygosity should be recognized as moderate-penetrance liver susceptibility genotypes in chronic liver disease risk assessment.