Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-76fb5796d-22dnz Total loading time: 0 Render date: 2024-04-27T07:13:03.527Z Has data issue: false hasContentIssue false

Chapter 25 - α1-Antitrypsin deficiency

from Section IV - Metabolic liver disease

Published online by Cambridge University Press:  05 March 2014

By
David H. Perlmutter
Edited by
Frederick J. Suchy ,
Ronald J. Sokol  and
William F. Balistreri
David H. Perlmutter
Affiliation:
Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
Frederick J. Suchy
Affiliation:
University of Colorado Medical Center
Ronald J. Sokol
Affiliation:
University of Colorado Medical Center
William F. Balistreri
Affiliation:
University of Cincinnati College of Medicine
Get access

Summary

Introduction

Homozygous (PiZZ phenotype) α1-antitrypsin (α1-AT) deficiency is a relatively common genetic disorder, affecting 1 in 3000 live births [1]. It is an autosomal codominant disorder associated with 85–90% reduction in serum concentrations of α1-AT. A single amino acid substitution results in an abnormally folded protein that is unable to traverse the secretory pathway. The mutant α1-antitrypsin Z (α1-ATZ) protein is retained in the endoplasmic reticulum (ER) rather than secreted into the blood and body fluids.

α1-Antitrypsin is an approximately 55kDa secretory glycoprotein that inhibits destructive neutrophil proteases, elastase, cathepsin G, and proteinase 3. Plasma α1-AT is derived predominantly from the liver and increases three- to five-fold during the host response to tissue injury or inflammation. It is the archetype of a family of structurally related circulating serine protease inhibitors called serpins.

Nationwide prospective screening studies by Sveger and coworkers [2,3] in Sweden have shown that only 8–10% of the PiZZ population develops clinically significant liver disease over the first 20 years of life. Nevertheless, this deficiency is the most frequent genetic cause of liver disease in children and the most frequent genetic disease for which children undergo orthotopic liver transplantation. It also causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in adults [4].

Type
Chapter
Information
Liver Disease in Children , pp. 400 - 418
Publisher: Cambridge University Press
Print publication year: 2014

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Silverman, EK, Sandhaus, RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 2009;360:2749–2757.CrossRefGoogle ScholarPubMed
Sveger, T. Liver disease in α1-antitrypsin deficiency detected by screening of 200000 infants. N Engl J Med 1976;294:1216–1221.CrossRefGoogle ScholarPubMed
Piitulainen, E, Carlson, J, Ohlsson, K, et al. Alpha-1-antitrypsin deficiency in 26-year-old subjects: lung, liver and protease/protease inhibitor studies. Chest 2005;128:2076–2081.CrossRefGoogle ScholarPubMed
Eriksson, S, Carlson, J, Velez, R. Risk of cirrhosis and primary liver cancer in alpha-1-antitrypsin deficiency. N Engl J Med 1986;314:736–739.CrossRefGoogle ScholarPubMed
Crystal, RG. Alpha-1-antitrypsin deficiency, emphysema and liver disease: genetic basis and strategies for therapy. J Clin Invest 1990;95:1343–1352.CrossRefGoogle Scholar
Hidvegi, T, Ewing, M, Hale, P, et al. An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science 2010;329:229–232.CrossRefGoogle Scholar
Marcus, NY, Brunt, EM, Blomenkamp, K, et al. Characteristics of hepatocellular carcinoma in a murine model of alpha-1-antitrypsin deficiency. Hepatol Res 2010;40:641–653.CrossRefGoogle Scholar
Carlson, JA, Rogers, BB, Sifers, RN, et al. Accumulation of PiZ antitrypsin causes liver damage in transgenic mice. J Clin Invest 1988;83:1183–1190.CrossRefGoogle Scholar
Teckman, JH, Qu, D, Perlmutter, DH. Molecular pathogenesis of liver disease in α1-antitrypsin deficiency. Hepatology 1996;24:1504–1516.Google ScholarPubMed
Zhou, H, Fischer, H-P. Liver carcinoma in PiZ alpha-1-antitrypsin deficiency. Am J Surg Pathol 1998;22:742–748.CrossRefGoogle ScholarPubMed
Volpert, D, Molleston, JP, Perlmutter, DH. Alpha1-antitrypsin deficiency-associated liver disease progresses slowly in some children. J Pediatr Gastro Nutr 2000;31:258–263.CrossRefGoogle ScholarPubMed
Perlmutter, DH. Alpha-1-antitrypsin deficiency. In Schiff, ER, Sorrell, MF, Maddrey, WC (eds.) Schiff's Diseases of the Liver, 11th edn. Oxford: Wiley-Blackwell, 2011, pp. 835–867.Google Scholar
Schonfeld, JV, Brewer, N, Zotz, R, et al. Liver function in patients with pulmonary emphysema due to severe alpha-1-antitrypsin deficiency (PiZZ). Digestion 1996;57:165–169.CrossRefGoogle Scholar
Carrell, RW, Evans, DL, Steen, DE. Mobile reactive centre of serpins and the control of thrombosis. Nature 1991;353:376.CrossRefGoogle ScholarPubMed
Owen, MC, Brennan, SO, Lewis, JH, et al. Mutation of antitrypsin to antithrombin: alpha-1-antitrypsin Pittsburgh (358 Met-Arg), a fatal bleeding disorder. N Engl J Med 1983;309:694–698.CrossRefGoogle Scholar
Hafeez, W, Ciliberto, G, Perlmutter, DH. Constitutive and modulated expression of the human alpha-1-antitrypsin gene: different transcriptional initiation sites used in three different cell types. J Clin Invest 1992;89:1214–1222.CrossRefGoogle ScholarPubMed
Ogushi, F, Fells, GA, Hubbard, RC, et al. Z-type α1-antitrypsin is less competent than M1-type α1-antitrypsin as an inhibitor of neutrophil elastase. J Clin Invest 1987;89:1366–1374.CrossRefGoogle Scholar
Camussi, G, Tetta, C, Bussolino, F, et al. Synthesis and release of platelet-activating factor is inhibited by plasma α1-proteinase inhibitor or α1-antichymotrypsin and is stimulated by proteinases. J Exp Med 1988;168:1293–1306.CrossRefGoogle ScholarPubMed
Munch, J, Standker, L, Adermann, K, et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the g41 fusion peptide. Cell 2007;129:263–275.CrossRefGoogle Scholar
Forssmann, WG, The, H-K, Stoll, K, et al. Short-term monotherapy in HIV-infected patients with a virus entry inhibitor against the gp41 fusion peptide. Sci Transl Med 2010;2:63–66.CrossRefGoogle ScholarPubMed
Janciauskiene, SM, Bals, R, Koczulla, R, et al. The discovery of α1-antitrypsin and its role in health and disease. Resp Med 2011;105:1129–1139.CrossRefGoogle ScholarPubMed
Perlmutter, DH, Cole, FS, Kilbridge, P, et al. Expression of the α1-proteinase inhibitor gene in human monocytes and macrophages. Proc Natl Acad Sci USA 1985;82:795–799.CrossRefGoogle ScholarPubMed
Koopman, P, Povey, S, Lovel-Badge, RH. Widespread expression of human alpha-1-antitrypsin in transgenic mice revealed by in situ hybridization. Genes Dev 1989;3:16–25.CrossRefGoogle ScholarPubMed
Carlson, JA, Rogers, BB, Sifers, RN, et al. Multiple tissues express alpha-1-antitrypsin in transgenic mice and man. J Clin Invest 1988;82:26–36.CrossRefGoogle ScholarPubMed
Yamasaki, M, Li, W, Johnson, DJD, et al. Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature 2008;455:1255–1258.CrossRefGoogle ScholarPubMed
Sidhar, SK, Lomas, DA, Carrell, RW, et al. Mutations which impede loop-sheet polymerization enhance the secretion of human α1-antitrypsin deficiency variants. J Biol Chem 1995;270:8393–8396.CrossRefGoogle Scholar
Lin, L, Schmidt, B, Teckman, J, Perlmutter, DH. A naturally occurring non-polymerogenic mutant of α1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum. J Biol Chem 2001;276:33893–33898.CrossRefGoogle Scholar
Schmidt, BZ, Perlmutter, DH. GRP78, GRP94 and GRP170 interact with α1 AT mutants that are retained in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 2005;289:G444–G455.CrossRefGoogle ScholarPubMed
Kuznetsov, G, Nigam, SK. Folding of secretory and membrane proteins. N Engl J Med 1998;339:1688–1695.CrossRefGoogle ScholarPubMed
Davis, RL, Shrimpton, AE, Holohan, PD, et al. Familial dementia caused by polymerization of mutant neuroserpin. Nature 1999;401:376–379.CrossRefGoogle ScholarPubMed
Perlmutter, DH. Alpha-1-antitrypsin deficiency: Importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu Rev Med 2011;62:4.1–4.13.CrossRefGoogle ScholarPubMed
Wu, Y, Whitman, I, Molmenti, E, et al. A lag in intracellular degradation of mutant α1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ α1-antitrypsin deficiency. Proc Natl Acad Sci USA 1994;91:9014–9018.CrossRefGoogle Scholar
Teckman, JH, Perlmutter, DH. Retention of mutant α1-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol 2000;279:G961–G974.Google Scholar
Kamimoto, T, Shoji, S, Mizushima, N, et al. Intracellular inclusions containing mutant α1 ATZ are propagated in the absence of autophagy. J Biol Chem 2006;281:4467–4476.CrossRefGoogle Scholar
Kruse, KB, Brodsky, JL, McCracken, AA. Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble α1 PiZ and another for aggregates of α1 PiZ. Mol Biol Cell 2006;17:203–212.CrossRefGoogle Scholar
Kruse, K, Dear, A, Kaltenbrun, ER, et al. Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol 2006;168:1300–1308.CrossRefGoogle ScholarPubMed
Cabral, CM, Choudhury, P, Liu, Y, Sifers, RN. Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J Biol Chem 2000;275:25015–25022.CrossRefGoogle ScholarPubMed
Hidvegi, T, Mirnics, K, Hale, P, et al. Regulator of G signaling 16 is a marker for the distinct endoplasmic reticulum stress state associated with aggregated mutant α1-antitrypsin Z in the classical form of α1-antitrypsin deficiency. J Biol Chem 2007;282:27769–27780.CrossRefGoogle Scholar
Hidvegi, T, Schmidt, BZ, Hale, P, Perlmutter, DH. Accumulation of mutant α1-antitrypsin Z in the ER activates caspases-4 and -12, NFκB and BAP31 but not the unfolded protein response. J Biol Chem 2005;280:39002–39015.CrossRefGoogle Scholar
Teckman, JH, An, JK, Blomenkamp, K, et al. Mitochondrial autophagy and injury in the liver in α1-antitrypsin deficiency. Am J Physiol 2004;286:G851–G862.Google Scholar
Pan, S, Huang, L, McPherson, J, et al. Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha-1-antitrypsin deficiency. Hepatology 2009;50:275–281.CrossRefGoogle Scholar
Chappell, S, Hadzic, N, Stockley, R, et al. A polymorphism of the alpha-1-antitrypsin gene represents a risk factor for liver disease. Hepatology 2008;47:127–132.CrossRefGoogle ScholarPubMed
Geller, SA, Nichols, WS, Dycacio, MJ, et al. Histopathology of α1-antitrypsin liver disease in a transgenic mouse model. Hepatology 1990;12:40–47.CrossRefGoogle Scholar
Geller, SA, Nichols, WS, Kim, SS, et al. Hepatocarcinogenesis is the sequel to hepatitis in Z#2 α1-antitrypsin transgenic mice: histopathological and DNA ploidy studies. Hepatology 1994;19:389–397.CrossRefGoogle Scholar
Hubner, RH, Leopold, PL, Kiura, M, et al. Dysfunctional glycogen storage in a mouse model of α1-antitrypsin deficiency. Am J Respir Cell Mol Biol 2009;40:239–247.CrossRefGoogle Scholar
Mahadeva, R, Chang, W-SW, Dafforn, TR, et al. Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis. J Clin Invest 1999;103:999–1006.CrossRefGoogle Scholar
Teckman, JH, Perlmutter, DH. Conceptual advances in the pathogenesis and treatment of childhood metabolic liver disease. Gastroenterology 1995;108:1263–1279.CrossRefGoogle ScholarPubMed
Teckman, JH, An, J-K, Loethen, S, Perlmutter, DH. Effect of fasting on liver in a mouse model of α1-antitrypsin deficiency: constitutive activation of the autophagic response. Am J Physiol 2002;283:61117–61124.Google Scholar
Rudnick, DA, Liao, Y, An, JK, et al. Analyses of hepatocellular proliferation in a mouse model of α1-antitrypsin deficiency. Hepatology 2004;39:1048–1055.CrossRefGoogle Scholar
An, JK, Blomenkamp, K, Lindlbad, D, et al. Quantitative isolation of alpha-1-AT mutant Z protein polymers from human and mouse livers and the effect of heat. Hepatology 2005;41:160–167.CrossRefGoogle Scholar
Hadzic, N, Quaglia, A, Mieli-Vergani, G. Hepatocellular carcinoma in a 12-year-old child with PiZZ α1-antitrypsin deficiency. Hepatology 2006;43:194.CrossRefGoogle Scholar
Zhou, H, Ortiz-Pallardo, ME, Ko, Y, Fischer, H-P. Is heterozygous alpha-1-antitrypsin deficiency type PiZ a risk factor for primary liver cancer. Cancer 2000;88:2668–2676.3.0.CO;2-G>CrossRefGoogle Scholar
Rudnick, DA, Perlmutter, DH. Alpha-1-antitrypsin deficiency: A new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology 2005;42:514–521.CrossRefGoogle ScholarPubMed
Lindblad, DA, Blomenkamp, K, Teckman, J. Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatology 2007;46:1228–1235.CrossRefGoogle Scholar
Ding, J, Yannam, GR, Roy-Chowdhury, N, et al. Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes. J Clin Invest 2011;121:1930–1934.CrossRefGoogle ScholarPubMed
Kemmer, N, Kaiser, T, Zacharias, V, Neff, GW. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant Proc 2008;40:1492–1494.CrossRefGoogle ScholarPubMed
Burrows, JAJ, Willis, LK, Perlmutter, DH. Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency. Proc Natl Acad Sci USA 2000;97:1796–1801.CrossRefGoogle Scholar
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;39:34–37.CrossRefGoogle ScholarPubMed
Marcus, NY, Perlmutter, DH. Glucosidase and mannosidase inhibitors mediate increased secretion of mutant α1-antitrypsin Z. J Biol Chem 2000;275:1987–1992.CrossRefGoogle ScholarPubMed
Gosai, SJ, Kwak, JH, Luke, CJ, et al. Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z. PLOS one 2010;5:e15460.CrossRefGoogle ScholarPubMed
Abboud, RT, Ford, GT, Chapman, KR. Emphysema in alpha1antitrypsin deficiency: Does replacement therapy affect outcome?Treat Respir Med 2005;4:1–8.CrossRefGoogle Scholar
Burton, CM, Milman, N, Carlsen, J, et al. The Copenhagen National Lung Transplant group: survival after single lung, double lung and heart-lung transplantation. J Heart Lung Transplant 2005;24:1834–1843.CrossRefGoogle Scholar
Cruz, PE, Mueller, C, Cossette, TL, et al. In vivo post-transcriptional gene silencing of alpha-1-antitrypsin by adeno-associated virus vectors expressing siRNA. Lab Invest 2007;87:893–902.CrossRefGoogle ScholarPubMed
Li, C, Xiao, P, Gray, SJ, et al. Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins. Proc Natl Acad Sci USA 2011;108:14258–4263.CrossRefGoogle ScholarPubMed
Yusa, K, Rashid, T, Strick-Marchand, H, et al. Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature 2011;478:391–394.CrossRefGoogle ScholarPubMed
Psacharopoulos, HT, Mowat, AP, Cook, PJL, et al. Outcome of liver disease associated with alpha-1-antitrypsin deficiency (PiZ). Arch Dis Child 1983;58:882–887.CrossRefGoogle Scholar
Wall, M, Moe, E, Eisenberg, J, et al. Long-term follow-up of a cohort of children with alpha-1-antitrypsin deficiency. J Pediatr 1990;116:248–251.CrossRefGoogle ScholarPubMed
Sveger, T, Thelin, T, McNeil, TF. Young adults with α1-antitrypsin deficiency identified neonatally: their health, knowledge about and adaptation to the high-risk condition. Acta Paediatr 1997;86:37–40.CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×