Objective Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ 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 Pi*ZZ, 239 Pi*SZ, 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, Pi*ZZ 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 Pi*MZ 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 Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ 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.
- liver cirrhosis
Data availability statement
Data are available upon reasonable request. The deidentified participant data are available from the corresponding author upon request.
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MF and CVS contributed equally.
Correction notice This article has been corrected since it published Online First. The authors list has been updated.
Contributors Study concept and design: MF, CVS and PS. Acquisition of data: MF, CVS, VP, KH, MP, MCR, FB, PE, KT, MM, BB, VW, JC-W, JV, FN, JG, MM, AN, BS, HZ, SJ, NA, LJ, RG, CG, KMS, MT, AK, BG, DT, AM, JRH, DAL, FL, NTG, VC, WG, CT, AMT, NGM and PS. Analysis and interpretation of data: MF, CVS and PS. Drafting of the manuscript: MF, CVS and PS. Critical revision of the manuscript for important intellectual content: all authors. Figures and tables: MF, CVS and PS. Statistical analysis: MF and CVS. Obtained funding: CVS, KH, PE, MM, DAL, CT, AMT and PS. Study supervision: MF, CVS and PS. All authors had full access to all of the data and approved the final version of this manuscript. All authors take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was supported by the EASL registry grant on alpha-1 antitrypsin-related liver disease, the Deutsche Forschungsgemeinschaft (DFG) consortium SFB/TRR57 “Liver fibrosis” (both to PS and CT), the DFG grant STR1095/6-1 (to PS), unrestricted research grants from CSL Behring and Arrowhead Pharmaceuticals (to PS), the Peter-Scriba-MD-Scholarship (to CVS), the START program within the medical faculty at RWTH Aachen University (to KH), the German Liver Foundation (to KH), the Joseph-Skoda Award of the Austrian Society of Internal Medicine (to MM). DAL is supported by the Medical Research Council (UK), the Alpha-1 Foundation (USA), Alpha-1 Association (UK) and the NIHR UCLH Biomedical Research Centre. He is an NIHR Senior Investigator. BG is supported by the Alpha-1 Foundation (USA), Medical Research Council (UK) and the British Lung Foundation. AMT has current research grants from the Alpha 1 Foundation, ATS Foundation, NIHR, CSL Behring, AstraZeneca, Chiesi and Health Foundation. PE is supported by the Alpha 1 Foundation and ATS Foundation.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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