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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.
Jermy et al. (Wed,) studied this question.