Skip to main content
SpringerLink
Log in

α1-antitrypsin deficiency and liver disease: Clinical presentation, diagnosis and treatment

  • Published:
Journal of Inherited Metabolic Disease

Summary

The α1-antitrypsin deficient subject (protease inhibitor (PI) phenotype ZZ) has an increased susceptibility to liver disease. The condition is most commonly identified in early infancy as a conjugated hyperbilirubinaemia with hepatitis (11%) or a bleeding state due to vitamin K malabsorption (2%). 50% of cases have cirrhosis and 25% die in the first decade of life. A further 2% present with cirrhosis in later childhood. Adult males are at risk of hepatoma development with or without cirrhosis. Diagnosis is by isoelectric focussing or allele-specific oligonucleotide hybridization. The treatment is that of cholestasis and cirrhosis including transplantation. The pathobiology of the deficiency state, the mechanism of liver damage and the vulnerability of the newborn liver are discussed in this review. A plea is made for a trial of infusions of α1-antitrypsin in early infancy, as is used safely but without proven efficacy in the emphysematous PIZZ subject. Prospects of therapy by gene modification are also reviewed.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Brantly, M., Courtney, M. and Crystal, R. G. Repair of the secretion defect in the Z form of α1-antitrypsin by the addition of a second mutation.Science 242 (1988a) 1700–1702

    Google Scholar 

  • Brantly, M., Nukiwa, T. and Crystal, R. G. Molecular basis of α1-antitrypsin deficiency.Am. J. Med. 84 (1988b) 13–31

    Google Scholar 

  • Carrell, R. W. α1-antitrypsin: molecular pathology, leukocytes and tissue damage.J. Clin. Invest. 78 (1986) 1427–1431

    Google Scholar 

  • Cohen, A., O'Grady, J., Mowat, A. P. and Williams, R. Liver transplantation for metabolic disorders. In:Baillière's Clinical Gastroenterology 3 (1989) 767–786

    Google Scholar 

  • Corney, G., Whitehouse, D. B., Hopkinson, D. A., Rodeck, C. H., Nicolaides, K., Norman, M. and Mowat, A. P. Prenatal diagnosis of α1-antitrypsin deficiency by fetal blood sampling.Prenatal Diagnosis 7 (1987) 101–108

    Google Scholar 

  • Cox, D. W. α1-antitrypsin deficiency. In: Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D. (eds.),The Metabolic Basis of Inherited Disease, 6th edn., McGraw-Hill, New York, 1989, pp. 2409–2437

    Google Scholar 

  • Crystal, R. G. α1-antitrypsin deficiency, emphysema and liver disease. Genetic basis and strategies for therapy.J. Clin. Invest. 85 (1990) 1343–1351

    Google Scholar 

  • Crystal, R. G., Brantly, M. L., Hubbard, R. C., Curiel, D. T., States, D. J. and Holmes, M. D. The α1-antitrypsin gene and its mutations. Clinical consequences and strategies for therapy.Chest 95 (1989) 196–208

    Google Scholar 

  • Curiel, D. T., Holmes, M. D., Okayama, H.et al. Molecular basis of the liver and lung disease associated with α1-antitrypsin deficiency allele Mmalton.J. Biol. Chem. 264 (1989) 13938–13945

    Google Scholar 

  • Dick, M. C. and Mowat, A. P. Hepatitis syndrome in infancy. An epidemiological survey with 10-year follow-up.Arch. Dis. Child. 60 (1985) 512–516

    Google Scholar 

  • Doherty, D. G., Donaldston, P. T., Whitehouse, D. B., Mieli-Vergani, G., Duthie, A., Hopkinson, D. A. and Mowat, A. P. HLA phenotypes and gene polymorphisms in juvenile liver disease associated with α1-antitrypsin deficiency.Hepatology 12 (1990) 218–223

    Google Scholar 

  • Eriksson, S., Carlson, J. and Velez, R. The risk of cirrhosis and primary liver cancer in α1-antitrypsin deficiency.N. Engl. J. Med. 314 (1986) 736–739

    Google Scholar 

  • Freier, E., Sharp, H. L. and Bridges, R. A. α1-antitrypsin deficiency associated with familial infantile liver disease.Clin. Chem. 14 (1968) 782

    Google Scholar 

  • George, P. M., Travis, J., Vissers, M. C. M., Winterbourn, C. C. and Carrell, R. W. A genetically engineered mutant of α1-antitrypsin protects connective tissue from neutrophil damage and may be useful in lung disease.Lancet 2 (1984) 1426–1428

    Google Scholar 

  • Ghishan, F. K., Greene, H. L. Liver disease in children with PIZZ α1-antitrypsin deficiency.Hepatology 8 (1988) 307–310

    Google Scholar 

  • Ghishan, F. K., Gray, G. F. and Greene, H. L. α1-antitrypsin deficiency presenting with ascites and cirrhosis in the neonatal period.Gastroenterology 85 (1983) 435–439

    Google Scholar 

  • Greenough, A., Pool, J. B., Ball, C., Mieli-Vergani, G. and Mowat, A. P. Functional residual capacity related to hepatitic disease.Arch. Dis. Child. 63 (1988) 850–852

    Google Scholar 

  • Hope, P. L., Hall, M. A., Millward-Sadler, G. H. and Normand, I. C. S. α1-antitrypsin deficiency presenting as a bleeding diathesis in the newborn.Arch. Dis. Child. 57 (1982) 68–70

    Google Scholar 

  • Johnston, D. I., Mowat, A. P., Orr, H. and Kohn, J. Serum alpha-fetoprotein levels in extrahepatic biliary atresia, idiopathic neontal hepatitis and α1-antitrypsin PIZZ.Acta Paediatr. Scand. 65 (1976) 623–628

    Google Scholar 

  • Kelly, C. P., Tyrell, D. N. M., McDonald, G. S. A., Whitehouse, D. B. and Prichard, J. S. Heterozygous FZ α1-antitrypsin deficiency associated with severe emphysema and hepatic disease: case report and family study.Thorax 44 (1989) 758–759

    Google Scholar 

  • Krivit, W., Miller, J., Nowicki, M. and Freier, E. Contribution of monocyte-macrophage system to serum α1-antitrypsin.J. Lab. Clin. Med. 112 (1988) 437–442

    Google Scholar 

  • Labrune, P., Odievre, M. and Alagille, D. Influence of sex and breastfeeding on liver disease in α1-antitrypsin deficiency.Hepatology 10 (1989) 122

    Google Scholar 

  • Levy, M. Severe deficiency of α1-antitrypsin associated with cutaneous vasculitis, rapidly progressive glomerular nephritis and colitis.Am. J. Med. 81 (1986) 363

    Google Scholar 

  • Malone, M., Mieli-Vergani, G., Mowat, A. P. and Portmann, B. The fetal liver in PIZZ α1-antitrypsin deficiency: A report of 5 cases.Pediatr. Pathol. 9 (1989) 623–631

    Google Scholar 

  • Mondelli, M., Mieli-Vergani, G., Eddleston, A. L. W. F., Williams, R. and Mowat, A. P. Lymphocyte cytotoxicity to autologous hepatocytes in α1-antitrypsin deficiency.Gut 25 (1984) 1044–1049

    Google Scholar 

  • Mowat, A. P. α1-antitrypsin deficiency in liver disease. In: Williams, R. and Madre, W. C. (eds.),Gastroenterology, Volume 4, 1 (Butterworths International Medical Reviews), Butterworths, London, 1984, pp. 57–75

    Google Scholar 

  • Mowat, A. P.Liver Disorders in Childhood, 2nd edn., Butterworths, London, 1987

    Google Scholar 

  • Nebbia, G., Hadchouel, M. and Alagille, D. Early assessment of evolution of liver disease associated with α1-antitrypsin deficiency in childhood.Pediatr. 102 (1983) 661–668

    Google Scholar 

  • Noble-Jamieson, G., Barnes, N., Thiru, S. and Mowat, A. P. Severe hypertension after liver transplantation in children with α1-antitrypsin deficiency.Arch. Dis. Child. 65 (1990) 1217–1221

    Google Scholar 

  • Parham, D. M., Paterson, J. R., Gunn, A. and Guthrie, W. Cholangiocarcinoma in two siblings with emphysema and α1-antitrypsin deficiency.Q.J. Med. 71 (1989) 359–367

    Google Scholar 

  • Perlmutter, D. H., Schlesinger, M. J., Pierce, J. A., Punsal, P. I. and Schwartz, A. L. Synthesis of stress proteins is increased in individuals with PIZZ α1-antitrypsin deficiency and liver disease.J. Clin. Invest. 84 (1989) 1551–1561

    Google Scholar 

  • Peters, R. L. Early development of the liver: a review. In: Fischer, M. and Roy, C. C. (eds.),Paediatric Liver Disorders, Plenum Press, New York, 1983, pp. 1–19

    Google Scholar 

  • Povey, S. The genetics of α1-antitrypsin deficiency in relation to neonatal liver disease.Mol. Biol. Med. 7 (1990) 161–172

    Google Scholar 

  • Psacharopoulos, H. T. and Mowat, A. P. Incidence and early history of obstructive jaundice in infancy in SE England. In:Neonatal Hepatitis and Biliary Atresia, DHEW Publication (NIH) 79; 1296, US Government Printing Office, Washington, 1979, pp. 167–171

    Google Scholar 

  • Psacharopoulos, H. T., Mowat, A. P., Cooke, P. J. L., Carlile, P. A., Portmann, B. and Rodeck, C. H. Outcome of liver disease associated with α1-antitrypsin deficiency. Implications for genetic counselling and antenatal diagnosis.Arch. Dis. Child. 58 (1983) 882–887

    Google Scholar 

  • Ruoslahti, E. and Pierschbacher, M. D. Molecular basis of cell-extracellular matrix interactions. In: Arias, I. M., Jakoby, W.P., Popper, H., Schachter, D. and Shafritz, D. A. (eds.),The Liver: Biology and Pathobiology, 2nd edn., Raven Press, New York, pp. 739–745

  • Schultz, H. E., Gollner, I., Heide, K., Schonberger, M. and Schwick, G. Zur Kenntis der alpha globuline des menschlichen normalserums.Z. Naturforsch. 10 (1955) 463–469

    Google Scholar 

  • Schwarzenberg, S. J. and Sharp, H. L. Pathogenesis of α1-antitrypsin deficiency associated liver disease.J. Pediatr. Gastroenterol. Nutr. 10 (1990) 5–12

    Google Scholar 

  • Sharp, H. L., Bridges, R. A., Krivit, W. and Friere, E. R. Cirrhosis associated with α1-antitrypsin deficiency: a previously unrecognized disorder.J. Lab. Clin. Med. 73 (1969) 934–939

    Google Scholar 

  • Sokal, E., Trivedi, P., Portmann, B. and Mowat, A. P. Developmental changes in the intra-acinar distribution of succinate dehydrogenase, glutamate dehydrogenase, glucose-6-phosphatase and NADPH dehydrogenase in rat liver.J. Pediatr. Gastroenterol. Nutr. 8 (1989) 522–527

    Google Scholar 

  • Starzyl, T. E., Demetris, J. and Van Thield, D. Medical progress: liver transplantation.N. Engl. J. Med. 321 (1989) 1014–1022, 1092–1099

    Google Scholar 

  • Strife, C. F., Hug, G., Chuck, G., McAdams, A. J., Davis, C.A. and Kline, J.J. Membranoproliferative glomerulonephritis and α1-antitrypsin deficiency in children.Pediatrics 71 (1983) 88–92

    Google Scholar 

  • Sveger, T. The natural history of liver disease in α1-antitrypsin deficient children.Acta Paediatr. Scand. 77 (1988) 847–51

    Google Scholar 

  • Talbot, I. C. and Mowat, A. P. Liver disease in infancy: Histological features in relationship to α1-antitrypsin phenotype.J. Clin. Pathol. 28 (1975) 559–63

    Google Scholar 

  • Travis, J. Structure, function and control of neutrophil proteinases.Am. J. Med. 84 (1988) 37–42

    Google Scholar 

  • Trivedi, P., Hindmarsh, P., Risteli, J., Risteli, L., Mowat, A. P. and Brook, C. G. D. Growth velocity, growth hormone therapy and serum concentrations of the aminoterminal propeptide of type III procollagen.J. Pediatr. 114 (1989) 225–230

    Google Scholar 

  • Udall, I. N., Dixon, M., Newman, A. P., Wright, J. A., James, B. and Block, K. I. Liver disease in α1-antitrypsin deficiency. A retrospective analysis of the influence of early breast versus bottle feeding.J. Am. Med. Assoc. 253 (1985) 2679–2682

    Google Scholar 

  • Wall, M., Moe, E., Eisenberg, J., Powers, M., Buist, N. and Buist, S. Long-term follow-up of a cohort of children with α1-antitrypsin deficiency.J. Pediatr. 116 (1990) 248–251

    Google Scholar 

  • Wewers, M. Pathogenesis of emphysema.Chest 95 (1989) 190–195

    Google Scholar 

  • Whitehouse, D. B., Abbott, C. M., Lovegrove, J. U., McIntosh, I., McMahon, C. J., Mieli-Vergani, G., Mowat, A. P. and Hopkinson, D. A. Genetic studies on a new deficiency gene (PI* Ztun) at the PI locus.J. Med. Genet. 26 (1989) 744–749

    Google Scholar 

  • Whitehouse, D. B., Lovegrove, J. U., Mieli-Vergani, G., Mowat, A. P. and Hopkinson, D. A. ‘SZ-like’ α1-antitrypsin phenotypes in PIZZ children with cirrhosis. Submitted for publication

  • Wu, W. J., Wilson, J. M. and Wu, C. H. Targeting genes: detection of targeted human albumin gene expression in genetically analbuminaemic rats.Hepatology 10 (1989) 618

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Child Health, King's College Hospital, Denmark Hill, SE5 8RX, London, UK

    M. Hussain, G. Mieli-Vergani & A. P. Mowat

Authors
  1. M. Hussain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Mieli-Vergani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. P. Mowat
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hussain, M., Mieli-Vergani, G. & Mowat, A.P. α1-antitrypsin deficiency and liver disease: Clinical presentation, diagnosis and treatment. J Inherit Metab Dis 14, 497–511 (1991). https://doi.org/10.1007/BF01797920

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01797920

Keywords

Search

Navigation