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Original research
Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency
  1. Malin Fromme1,
  2. Carolin V Schneider1,
  3. Vitor Pereira2,
  4. Karim Hamesch1,
  5. Monica Pons3,4,
  6. Matthias C Reichert5,
  7. Federica Benini6,
  8. Paul Ellis7,
  9. Katrine H Thorhauge8,
  10. Mattias Mandorfer9,
  11. Barbara Burbaum1,
  12. Vivien Woditsch1,
  13. Joanna Chorostowska-Wynimko10,
  14. Jef Verbeek11,
  15. Frederik Nevens11,
  16. Joan Genesca3,4,
  17. Marc Miravitlles12,
  18. Alexa Nuñez12,
  19. Benedikt Schaefer13,
  20. Heinz Zoller13,
  21. Sabina Janciauskiene14,
  22. Nélia Abreu2,
  23. Luís Jasmins2,
  24. Rui Gaspar15,
  25. Rodrigo Liberal15,
  26. Guilherme Macedo15,
  27. Ravi Mahadeva16,
  28. Catarina Gomes17,
  29. Kai Markus Schneider1,
  30. Michael Trauner9,
  31. Aleksander Krag8,
  32. Bibek Gooptu18,19,
  33. Douglas Thorburn19,20,
  34. Aileen Marshall19,20,
  35. John R Hurst19,21,
  36. David A Lomas19,21,
  37. Frank Lammert5,22,
  38. Nadine T Gaisa23,
  39. Virginia Clark24,
  40. William Griffiths25,
  41. Christian Trautwein1,
  42. Alice M Turner7,
  43. Noel G McElvaney26,
  44. Pavel Strnad1
  1. 1 Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
  2. 2 Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal
  3. 3 Liver Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Catalunya, Spain
  4. 4 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain
  5. 5 Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
  6. 6 Gastroenterology Unit, Department of Medicine, Spedali Civili and University, Brescia, Italy
  7. 7 Institute of Applied Health Research, University of Birmingham, Birmingham, UK
  8. 8 Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
  9. 9 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria
  10. 10 Department of Genetics and Clinical Immunology, National Tuberculosis and Lung Diseases Institute, Warszawa, Poland
  11. 11 Department of Gastroenterology & Hepatology, KU Leuven University Hospitals Leuven, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Leuven, Flanders, Belgium
  12. 12 Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
  13. 13 Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Tirol, Austria
  14. 14 Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
  15. 15 Gastroenterology Department, Centro Hospitalar de São João, Faculty of Medicine of Porto University, Porto, Portugal
  16. 16 Department of Respiratory Medicine, Cambridge University Hospitals, Cambridge, UK
  17. 17 Gastroenterology Department, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Porto, Portugal
  18. 18 NIHR Leicester BRC-Respiratory and Leicester Institute of Structural & Chemical Biology, University of Leicester, Leicester, Leicestershire, UK
  19. 19 London Alpha-1 Antitrypsin Deficiency Service, Royal Free Hospital, London, UK
  20. 20 Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
  21. 21 UCL Respiratory, Division of Medicine, University College London, London, UK
  22. 22 Hannover Medical School (MHH), Hannover, Germany
  23. 23 Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
  24. 24 Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida, USA
  25. 25 Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, Cambridgeshire, UK
  26. 26 Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
  1. Correspondence to Dr Pavel Strnad, Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, RWTH Aachen University, Aachen 52074, Germany; pstrnad{at}


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.

  • fibrosis
  • liver
  • liver cirrhosis
  • cancer

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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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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