SpringerLink
Log in

Alpha-1 Antitrypsin Deficiency in the Transition Period

  • Chapter
  • First Online:
Liver Disease in Adolescence

Part of the book series: In Clinical Practice ((ICP))

  • 333 Accesses

Abstract

Alpha-1 antitrypsin deficiency (A1ATD) is an intriguing condition causing liver disease in children and chronic obstructive pulmonary disease in young adult smokers. The pathogenesis of liver disease is related to retention of the abnormal PiZ polymers in the hepatocytes and their unexplained triggering of the chronic cellular injury, which in a proportion, but not all of the affected, could lead to progressive inflammation, fibrosis and cirrhosis. It appears that evolution of liver disease and development of portal hypertension are more aggressive in the ones who present with prolonged neonatal jaundice with more significant histological injury and more abnormal biochemical changes. At present the only treatment available is liver transplantation, despite several potential studied cellular mechanisms, such as abnormal polypeptide polymerisation or impaired cellular autophagy, which have been shown to be modifiable in the experimental models of A1ATD. Adolescents with this condition appear to have escaped severe liver disease and avoided liver transplantation, but need to be continuously monitored due to increased possibility of develo** respiratory complications and hepatic malignancies in comparison to general population. It remains unexplained why genotypically identical individuals have different clinical outcomes even in the same family, but it is hoped that better understanding of patophysiology would result in ability to modify the severe phenotypes in the future.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
EUR 29.95
Price includes VAT (Germany)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
EUR 85.59
Price includes VAT (Germany)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med. 2020;382(15):1443–55.

    Article  CAS  PubMed  Google Scholar 

  2. Miranda E, Pérez J, Ekeowa UI, Hadzic N, Kalsheker N, Gooptu B, Portmann B, Belorgey D, Hill M, Chambers S, Teckman J, Alexander GJ, Marciniak SJ, Lomas DA. A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency. Hepatology. 2010;52(3):1078–88.

    Article  CAS  PubMed  Google Scholar 

  3. Hadzic N, Francavilla R, Chambers SM, Castellaneta S, Portmann B, Mieli-Vergani G. Outcome of PiSS and PiSZ alpha-1-antitrypsin deficiency presenting with liver involvement. Eur J Pediatr. 2005;164(4):250–2.

    Article  PubMed  Google Scholar 

  4. Hinds R, Hadchouel A, Shanmugham NP, Al-Hussaini A, Chambers S, Cheeseman P, Mieli-Vergani G, Hadzić N. Variable degree of liver involvement in siblings with PiZZ alpha-1-antitrypsin deficiency-related liver disease. J Pediatr Gastroenterol Nutr. 2006;43(1):136–8.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. Mostafavi B, Diaz S, Tanash HA, Piitulainen E. Liver function in alpha-1-antitrypsin deficient individuals at 37 to 40 years of age. Medicine (Baltimore). 2017;96(12):e6180.

    Article  CAS  Google Scholar 

  7. Mostafavi B, Diaz S, Piitulainen E, Stoel BC, Wollmer P, Tanash HA. Lung function and CT lung densitometry in 37- to 39-year-old individuals with alpha-1-antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis. 2018;8(13):3689–98.

    Article  Google Scholar 

  8. Jaklin-Kekez A, Chambers SM, Hadzic N. Medium-term outcome of children with liver disease secondary to PiZ alpha-1- antitrypsin deficiency. Hepatology. 2013;58(4):813A.

    Google Scholar 

  9. Francavilla R, Castellaneta SP, Hadzic N, Chambers SM, Portmann B, Tung J, Cheeseman P, Rela M, Heaton ND, Mieli-Vergani G. Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation. J Hepatol. 2000;32(6):986–92.

    Article  CAS  PubMed  Google Scholar 

  10. Hadzic N. Therapeutic options in Alpha-1 antitrypsin deficiency: liver transplantation. Methods Mol Biol. 2017;1639:263–5.

    Article  CAS  PubMed  Google Scholar 

  11. Hadzic N, Quaglia A, Mieli-Vergani G. Hepatocellular carcinoma in a 12-year-old child with PiZZ alpha1-antitrypsin deficiency. Hepatology. 2006 Jan;43(1):194.

    Article  PubMed  Google Scholar 

  12. Hamesch K, Mandorfer M, Pereira VM, Moeller LS, Pons M, Dolman GE, Reichert MC, Schneider CV, Woditsch V, Voss J, Lindhauer C, Fromme M, Spivak I, Guldiken N, Zhou B, Arslanow A, Schaefer B, Zoller H, Aigner E, Reiberger T, Wetzel M, Siegmund B, Simões C, Gaspar R, Maia L, Costa D, Bento-Miranda M, van Helden J, Yagmur E, Bzdok D, Stolk J, Gleiber W, Knipel V, Windisch W, Mahadeva R, Bals R, Koczulla R, Barrecheguren M, Miravitlles M, Janciauskiene S, Stickel F, Lammert F, Liberal R, Genesca J, Griffiths WJ, Trauner M, Krag A, Trautwein C, Strnad P. European Alpha1-liver study group. Liver fibrosis and metabolic alterations in adults with alpha-1-antitrypsin deficiency caused by the pi*ZZ mutation. Gastroenterology. 2019;157(3):705–719.e18.

    Article  CAS  PubMed  Google Scholar 

  13. Clark VC, Marek G, Liu C, Collinsworth A, Shuster J, Kurtz T, Nolte J, Brantly M. Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol. 2018;69(6):1357–64.

    Article  CAS  PubMed  Google Scholar 

  14. Carey EJ, Iyer VN, Nelson DR, Nguyen JH, Krowka MJ. Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency–related cirrhosis. Liver Transpl. 2013;19(12):1370–6.

    Article  PubMed  Google Scholar 

  15. Roelandt P, Dobbels P, Komuta M, Corveleyn A, Emonds MP, Roskams T, Aerts R, Monbaliu D, Libbrecht L, Laleman W, Verslype C, Van Steenbergen W, van der Merwe S, Pirenne J, Nevens F, Cassiman D. Heterozygous α1-antitrypsin Z allele mutation in presumed healthy donor livers used for transplantation. Eur J Gastroenterol Hepatol. 2013;25(11):1335–9.

    Article  CAS  PubMed  Google Scholar 

  16. Antoury C, Lopez R, Zein N, Stoller JK, Alkhouri N. Alpha-1 antitrypsin deficiency and the risk of hepatocellular carcinoma in end-stage liver disease. World J Hepatol. 2015;7(10):1427–32.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lomas DA. New therapeutic targets for Alpha-1 antitrypsin deficiency. Chronic Obstr Pulm Dis. 2018;5(4):233–43.

    PubMed  PubMed Central  Google Scholar 

  18. Wewers MD, Casolaro MA, Sellers SE, Swayze SC, McPhaul KM, Wittes JT, Crystal RG. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med. 1987;316(17):1055–62.

    Article  CAS  PubMed  Google Scholar 

  19. Ordonez A, Perez J, Tan L, Dickens JA, Motamedi-Shad N, Irving JA, Haq I, Ekeowa U, Marciniak SJ, Miranda E, et al. A single-chain variable fragment intrabody prevents intracellular polymerization of Z alpha 1-antitrypsin while allowing its anti-proteinase activity. FASEB J. 2015;29:2667–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chang YP, Mahadeva R, Chang WS, Shukla A, Dafforn TR, Chu YH. Identification of a 4-mer peptide inhibitor that effectively blocks the polymerization of pathogenic Z alpha1-antitrypsin. Am J Respir Cell Mol Biol. 2006 Nov;35(5):540–8.

    Article  CAS  PubMed  Google Scholar 

  21. 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 Jul;39(1):34–7.

    Article  CAS  PubMed  Google Scholar 

  22. Li J, Pak SC, O'Reilly LP, Benson JA, Wang Y, Hidvegi T, Hale P, Dippold C, Ewing M, Silverman GA, Perlmutter DH. Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha-1-antitrypsin deficiency. PLoS One. 2014;9(1):e87260.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Cobanoglu MC, Li J, Hidvegi T, Hale P, Ewing M, Chu AS, Gong Z, Muzumdar R, Pak SC, Silverman GA, Bahar I, Perlmutter DH. An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z. PLoS One. 2019;14(1):e0209748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, Maurice N, Mukherjee A, Goldbach C, Watkins S, Michalopoulos G, Perlmutter DH. 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 

  25. Turner AM, Stolk J, Bals R, Lickliter JD, Hamilton J, Christianson DR, Given BD, Burdon JG, Loomba R, Stoller JK, Teckman JH. Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients. J Hepatol. 2018;69(2):378–84.

    Article  CAS  PubMed  Google Scholar 

  26. Wooddell CI, Blomenkamp K, Peterson RM, Subbotin VM, Schwabe C, Hamilton J, Chu Q, Christianson DR, Hegge JO, Kolbe J, Hamilton HL, Branca-Afrazi MF, Given BD, Lewis DL, Gane E, Kanner SB, Teckman JH. Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease. JCI Insight. 2020;5(12):e135348.

    Article  PubMed Central  Google Scholar 

  27. Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordóñez A, Hannan NR, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA, Bradley A, Vallier L. Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature. 2011;478(7369):391–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College Hospital NHS Foundation Trust, London, UK

    Nedim Hadžić

Authors
  1. Nedim Hadžić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nedim Hadžić .

Editor information

Editors and Affiliations

  1. Paediatric Centre for Hepatology, King's College Hospital, London, UK

    Nedim Hadžić

  2. Paediatric Centre for Hepatology Gastroenterology and Nutrition, King’s College Hospital NHS Foundation Trust, London, UK

    Marianne Samyn

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hadžić, N. (2022). Alpha-1 Antitrypsin Deficiency in the Transition Period. In: Hadžić, N., Samyn, M. (eds) Liver Disease in Adolescence. In Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-030-98808-1_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-98808-1_6

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-98810-4

  • Online ISBN: 978-3-030-98808-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation