Skip to main content

The Orphan Liver Disease

  • Chapter
  • First Online:
Liver Disease in Clinical Practice

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

  • 534 Accesses


Orphan diseases are typically very rare, making it challenging to develop novel treatments. This chapter covers three orphan liver diseases: (1) porphyria, (2) alpha-1 antitrypsin (A1AT) deficiency and (3) cystic fibrosis liver disease. Porphyrias are disorders of haem biosynthesis, with the resulting clinical features and treatments depending on which step of the metabolic pathway is impaired. In A1AT deficiency, patients develop lung and liver disease resulting from the inability of the liver to export A1AT. In patients with cystic fibrosis, viscous secretions can result in obstruction in the biliary tree and cause injury to cholangiocytes and hepatocytes. For each of these conditions, the chapter details the key pathogenetic mechanisms and disease management.

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

Access this chapter

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

USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
USD 37.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 37.99
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

Institutional subscriptions

Similar content being viewed by others


  1. Balwani M, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382(24):2289–301.

    Article  CAS  PubMed  Google Scholar 

  2. D’Avola D, et al. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol. 2016;65(4):776–83.

    Article  PubMed  Google Scholar 

  3. Jiang L, et al. Systemic messenger RNA as an etiological treatment for acute intermittent porphyria. Nat Med. 2018;24(12):1899–909.

    Article  CAS  PubMed  Google Scholar 

  4. Singal AK. Porphyria cutanea tarda: Recent update. Mol Genet Metab. 2019;128(3):271–81.

    Article  CAS  PubMed  Google Scholar 

  5. Singal AK, et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2012;10(12):1402–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Oustric V, et al. Antisense oligonucleotide-based therapy in human erythropoietic protoporphyria. Am J Hum Genet. 2014;94(4):611–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. de Serres FJ, Blanco I, Fernandez-Bustillo E. Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America. Clin Genet. 2003;64(5):382–97.

    Article  PubMed  Google Scholar 

  8. Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol. 2008;103(8):2136–41; quiz 2142.

    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. 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 

  11. de Serres F, Blanco I. Role of alpha-1 antitrypsin in human health and disease. J Intern Med. 2014;276(4):311–35.

    Article  PubMed  Google Scholar 

  12. Kok KF, et al. Heterozygous alpha-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review. Neth J Med. 2007;65(5):160–6.

    CAS  PubMed  Google Scholar 

  13. Bartlett JR, et al. Genetic modifiers of liver disease in cystic fibrosis. JAMA. 2009;302(10):1076–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818–900.

    Article  Google Scholar 

  15. Esquivel CO, et al. Indications for pediatric liver transplantation. J Pediatr. 1987;111(6 Pt 2):1039–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Prachalias AA, et al. Liver transplantation for alpha-1-antitrypsin deficiency in children. Transpl Int. 2000;13(3):207–10.

    Article  CAS  PubMed  Google Scholar 

  17. Greene CM, et al. alpha1-Antitrypsin deficiency. Nat Rev Dis Primers. 2016;2:16051.

    Article  PubMed  Google Scholar 

  18. Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005;365(9478):2225–36.

    Article  CAS  PubMed  Google Scholar 

  19. Debray D, et al. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. J Cyst Fibros. 2011;10(Suppl 2):S29–36.

    Article  PubMed  Google Scholar 

  20. Siano M, et al. Ursodeoxycholic acid treatment in patients with cystic fibrosis at risk for liver disease. Dig Liver Dis. 2010;42(6):428–31.

    Article  CAS  PubMed  Google Scholar 

  21. Lewindon PJ, et al. The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. Am J Pathol. 2002;160(5):1705–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Salvatore F, Scudiero O, Castaldo G. Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes. Am J Med Genet. 2002;111(1):88–95.

    Article  PubMed  Google Scholar 

  23. Herrmann U, Dockter G, Lammert F. Cystic fibrosis-associated liver disease. Best Pract Res Clin Gastroenterol. 2010;24(5):585–92.

    Article  CAS  PubMed  Google Scholar 

  24. Stonebraker JR, et al. Features of severe liver disease with portal hypertension in patients with cystic fibrosis. Clin Gastroenterol Hepatol. 2016;14(8):1207–15.e3.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hillaire S, et al. Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy. Liver Transpl. 2017;23(10):1342–7.

    Article  PubMed  Google Scholar 

  26. Mendizabal M, et al. Liver transplantation in patients with cystic fibrosis: analysis of United Network for Organ Sharing data. Liver Transpl. 2011;17(3):243–50.

    Article  PubMed  Google Scholar 

  27. Milkiewicz P, et al. Transplantation for cystic fibrosis: outcome following early liver transplantation. J Gastroenterol Hepatol. 2002;17(2):208–13.

    Article  PubMed  Google Scholar 

  28. Heijerman HGM, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019;394(10212):1940–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Middleton PG, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Philip Newsome .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Khan, R., Newsome, P. (2022). The Orphan Liver Disease. In: Cross, T. (eds) Liver Disease in Clinical Practice. In Clinical Practice. Springer, Cham.

Download citation

  • DOI:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-10011-6

  • Online ISBN: 978-3-031-10012-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics