Skip to main content
SpringerLink
Log in
Book cover

Liver Disorders pp 329–338Cite as

Metabolic and Genetic Liver Diseases: Alpha-1 Anti-trypsin Deficiency

  • Chapter
  • First Online:

Abstract

Alpha-1 antitrypsin deficiency (AATD) is a common genetic disorder characterized by a mutation in the SERPINA1 gene that codes for the alpha-1 antitrypsin protein. A homozygous mutation leads to the production of the Z protein, which takes an abnormal configuration that prevents its secretion from the hepatocyte, leading to a concomitant deficiency of the protein in the lung. The retained mutant Z protein in the endoplasmic reticulum of the hepatocyte activates a cascade of cell injury that leads to apoptosis, fibrosis, and in some individuals, cirrhosis. Clinical manifestations and progression of disease are highly variable even amongst Pi*ZZ homozygote individuals, suggesting a role from other genetic and environmental influences. Current treatment for liver disease from AATD consists mostly of supportive care and liver transplantation if indicated, but new and promising therapeutic approaches that include gene therapy, stem cell transplantation, and stimulation of autophagy are currently under investigation.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Laurell C, Eriksson S. The electrophoretic alpha 1 globulin pattern of serum in alpha 1 antitrypsin deficiency. Scan J Clin Lab Invest. 1963;15:132–40.

    Article  CAS  Google Scholar 

  2. Perlmutter DH. Alpha-1 antitrypsin deficiency. In: Suchy F, Sokol R, Balisteri W, editors. Liver disease in children. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2007.

    Google Scholar 

  3. Nelson DR, Teckman J, Di Bisceglie AM, Brenner DA. Diagnosis and management of patients with alpha1-antitrypsin (A1AT) deficiency. Clin Gastroenterol Hepatol. 2012;10(6):575–80.

    Article  PubMed  Google Scholar 

  4. Lindblad D, Blomenkamp K, Teckman J. Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatology. 2007;46(4):1228–35.

    Article  CAS  PubMed  Google Scholar 

  5. Eriksson S. Discovery of alpha 1-antitrypsin deficiency. Lung. 1990;168(Suppl):523–9.

    Article  CAS  PubMed  Google Scholar 

  6. Lomas DA, Elliott PR, Sidhar SK, Foreman RC, Finch JT, Cox DW, et al. alpha 1-Antitrypsin Mmalton (Phe52-deleted) forms loop-sheet polymers in vivo. Evidence for the C sheet mechanism of polymerization. J Biol Chem. 1995;270(28):16864–70.

    Article  CAS  PubMed  Google Scholar 

  7. Lomas DA, Finch JT, Seyama K, Nukiwa T, Carrell RW. Alpha 1-antitrypsin Siiyama (Ser53 → Phe). Further evidence for intracellular loop-sheet polymerization. J Biol Chem. 1993;268(21):15333–5.

    CAS  PubMed  Google Scholar 

  8. Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N Engl J Med. 1986;314(12):736–9.

    Article  CAS  PubMed  Google Scholar 

  9. Sveger T. The natural history of liver disease in alpha 1-antitrypsin deficient children. Acta Paediatr Scand. 1988;77(6):847–51.

    Article  CAS  PubMed  Google Scholar 

  10. Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med. 1976;294(24):1316–21.

    Article  CAS  PubMed  Google Scholar 

  11. Sveger T, Eriksson S. The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology. 1995;22(2):514–7.

    CAS  PubMed  Google Scholar 

  12. Lomas DA, Mahadeva R. Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest. 2002;110(11):1585–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Qu D, Teckman JH, Omura S, Perlmutter DH. Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J Biol Chem. 1996;271(37):22791–5.

    Article  CAS  PubMed  Google Scholar 

  14. Wu Y, Whitman I, Molmenti E, Moore K, Hippenmeyer P, Perlmutter DH. A lag in intracellular degradation of mutant alpha 1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha 1-antitrypsin deficiency. Proc Natl Acad Sci U S A. 1994;91(19):9014–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science. 2010;329(5988):229–32.

    Article  CAS  PubMed  Google Scholar 

  16. Kaushal S, Annamali M, Blomenkamp K, Rudnick D, Halloran D, Brunt EM, et al. Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model. Exp Biol Med. 2010;235(6):700–9.

    Article  CAS  Google Scholar 

  17. Perlmutter DH. Alpha-1-antitrypsin deficiency: diagnosis and treatment. Clin Liver Dis. 2004;8(4):839–59. viii–ix.

    Article  PubMed  Google Scholar 

  18. Hope PL, Hall MA, Millward-Sadler GH, Normand IC. Alpha-1-antitrypsin deficiency presenting as a bleeding diathesis in the newborn. Arch Dis Child. 1982;57(1):68–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. von Schonfeld J, Breuer N, Zotz R, Liedmann H, Wencker M, Beste M, et al. Liver function in patients with pulmonary emphysema due to severe alpha-1-antitrypsin deficiency (Pi ZZ). Digestion. 1996;57(3):165–9.

    Article  Google Scholar 

  20. Yunis EJ, Agostini Jr RM, Glew RH. Fine structural observations of the liver in alpha-1-antitrypsin deficiency. Am J Pathol. 1976;82(2):265–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Teckman JH, Jain A. Advances in alpha-1-antitrypsin deficiency liver disease. Curr Gastroenterol Rep. 2014;16(1):367.

    Article  PubMed  Google Scholar 

  22. Silverman EK, Sandhaus RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med. 2009;360(26):2749–57.

    Article  CAS  PubMed  Google Scholar 

  23. Morris H, Morgan MD, Wood AM, Smith SW, Ekeowa UI, Herrmann K, et al. ANCA-associated vasculitis is linked to carriage of the Z allele of alpha(1) antitrypsin and its polymers. Ann Rheum Dis. 2011;70(10):1851–6.

    Article  CAS  PubMed  Google Scholar 

  24. Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lyon MJ. Metabolic panniculitis: alpha-1 antitrypsin deficiency panniculitis and pancreatic panniculitis. Dermatol Ther. 2010;23(4):368–74.

    Article  PubMed  Google Scholar 

  26. Valverde R, Rosales B, Ortiz-de Frutos FJ, Rodriguez-Peralto JL, Ortiz-Romero PL. Alpha-1-antitrypsin deficiency panniculitis. Dermatol Clin. 2008;26(4):447–51. vi.

    Article  CAS  PubMed  Google Scholar 

  27. Turner AM. Alpha-1 antitrypsin deficiency: new developments in augmentation and other therapies. BioDrugs. 2013;27(6):547–58.

    Article  CAS  PubMed  Google Scholar 

  28. Lykavieris P, Ducot B, Lachaux A, Dabadie A, Broue P, Sarles J, et al. Liver disease associated with ZZ alpha1-antitrypsin deficiency and ursodeoxycholic acid therapy in children. J Pediatr Gastroenterol Nutr. 2008;47(5):623–9.

    Article  CAS  PubMed  Google Scholar 

  29. Kemmer N, Kaiser T, Zacharias V, Neff GW. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant Proc. 2008;40(5):1492–4.

    Article  CAS  PubMed  Google Scholar 

  30. Rudnick DA, Shikapwashya O, Blomenkamp K, Teckman JH. Indomethacin increases liver damage in a murine model of liver injury from alpha-1-antitrypsin deficiency. Hepatology. 2006;44(4):976–82.

    Article  CAS  PubMed  Google Scholar 

  31. Mueller C, Tang Q, Gruntman A, Blomenkamp K, Teckman J, Song L, et al. Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles. Mol Ther. 2012;20(3):590–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wilson AA, Kwok LW, Hovav AH, Ohle SJ, Little FF, Fine A, et al. Sustained expression of alpha1-antitrypsin after transplantation of manipulated hematopoietic stem cells. Am J Respir Cell Mol Biol. 2008;39(2):133–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, et al. Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature. 2011;478(7369):391–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci U S A. 2000;97(4):1796–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Teckman JH. Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with alpha-1-antitrypsin deficiency: a preliminary study. J Pediatr Gastroenterol Nutr. 2004;39(1):34–7.

    Article  CAS  PubMed  Google Scholar 

  36. Wise RA. Alpha-1 antitrypsin deficiency. In: Porter R, editor. Merck manual of diagnosis and therapy. Whitehouse Station, NJ: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.; 2014 [updated June 2014; cited 2015 January 2, 2015]. http://www.merckmanuals.com/professional/pulmonary_disorders/chronic_obstructive_pulmonary_disease_and_related_disorders/alpha-1_antitrypsin_deficiency.html. Accessed 2 Jan 2015.

Download references

Author information

Authors and Affiliations

  1. Center for Liver Diseases, University of Chicago Medicine, Chicago, IL, USA

    Helen S. Te M.D.

Authors
  1. Helen S. Te M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helen S. Te M.D. .

Editor information

Editors and Affiliations

  1. Division of Gastroenterology and Hepatology, Medical College of Wisconsin , Milwaukee, Wisconsin, USA

    Kia Saeian

  2. Division of Gastroenterology and Hepatology, Medicine Medical College of Wisconsin , Milwaukee, Wisconsin, USA

    Reza Shaker

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Te, H.S. (2017). Metabolic and Genetic Liver Diseases: Alpha-1 Anti-trypsin Deficiency. In: Saeian, K., Shaker, R. (eds) Liver Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-30103-7_19

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-30103-7_19

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-30101-3

  • Online ISBN: 978-3-319-30103-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation