Alpha-1 antitrypsin Pi*MZ variant increases the risk of liver disease progression in MASLD and MASH
Year: 2025
Type: article
Abstract: INTRODUCTION AND OBJECTIVES: Most investigational treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) show modest anti-fibrotic effects, likely due to a multifactorial aetiology. The Pi*Z mutation in SERPINA1 can lead to proteotoxic liver injury and progressive chronic liver disease. Here, we investigate whether the SERPINA1 Z mutation is associated with disease progression in MASLD/MASH. PATIENTS AND METHODS: A population of MASLD/MASH patients of European ancestry was identified in the UK Biobank using ICD-10 codes (N = 6319). We estimated odds ratios (OR) for advanced liver disease (composite of incident cirrhosis, hepatic decompensation, and liver-related death/transplant) with the MZ genotype. ORs were compared with metabolic risk factors (RFs; obesity, dyslipidaemia, hypertension, and type 2 diabetes) and established genetic RFs (PNPLA3, HSD17B13, and TM6SF2). RESULTS: Some individuals (7.9%) experienced advanced liver disease. The MZ genotype prevalence was greater in individuals who experienced advanced liver disease (7.6% vs 3.9%). After adjustment for established metabolic and genetic RFs, advanced liver disease was significantly associated with the MZ genotype (OR 2.01; 95% CI, 1.38-2.92). We replicated known associations in all genetic and metabolic RFs. The MZ genotype (OR 1.90; 1.33-2.73) was a risk equivalent to ≥2 metabolic RFs (OR 1.74; 1.44-2.09) and PNPLA3 (OR 1.32; 1.15-1.51). CONCLUSIONS: Carriage of the Pi*Z mutation significantly affects the risk of future clinical outcomes among individuals with MASLD/MASH. The MZ genotype confers a risk equivalent to established RFs in MASLD/MASH, underscoring the importance of screening and further work to understand the underlying mechanisms.
Source: Annals of Hepatology
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,500
Awards: Non-invasive screening of diabetics for advanced fibrosis due to NAFLD, Ancillary Studies of NAFLD and NASH in HIV infected Adults, QUS Technology for Diagnosis and Grading of Hepatic Steatosis in NAFLD, Clinical Research on Nonalcoholic Fatty Liver Disease, San Diego Cirrhosis Clinical Research Network
OpenAlex ID: W4415436567