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Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

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Schneider, Carolin V 
Pereira, Vitor 
Pons, Monica 


OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'PiZ' variant of AAT (PiZZ genotype) causes lung and liver disease, whereas heterozygous 'PiZ' carriage (PiMZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'PiS' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 PiZZ, 239 PiSZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, PiZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with PiMZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous PiS mutation (PiSS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. PiSZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.



cancer, fibrosis, liver, liver cirrhosis, Adult, Aged, Case-Control Studies, Cholelithiasis, Cohort Studies, Female, Humans, Liver Cirrhosis, Liver Neoplasms, Male, Middle Aged, Phenotype, Prevalence, United Kingdom, alpha 1-Antitrypsin Deficiency

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CSL Behring (N/A)
Deutsche Forschungsgemeinschaft (DFG) (consortium SFB/TRR57 “Liver fibrosis”, grant STR1095/6-1)
Arrowhead Pharmaceuticals (N/A)
EASL registry grant on alpha-1 antitrypsin-related liver disease (N/A)