Abstract
Alpha-1-antitrypsin deficiency is a relatively common but under-recognized genetic disease in which individuals homozygous for the mutant Z disease-associated allele are at risk for the development of liver disease and emphysema. The protein product of the mutant Z gene is synthesized in hepatocytes but accumulates intracellularly rather than being appropriately secreted. The downstream effects of the intracellular accumulation of the mutant Z protein include the formation of unique protein polymers, activation of autophagy, mitochondrial injury, endoplasmic reticulum stress, and caspase activation, which subsequently progress in a cascade, causing chronic hepatocellular injury. The variable clinical presentations among affected individuals suggest an important contribution of genetic and environmental disease modifiers, which are only now being identified. The heterozygous carrier state for the mutant Z gene, found in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modifier gene for other liver diseases.
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References and Recommended Reading
Perlmutter DH: Alpha-1-antitrypsin deficiency: diagnosis and treatment. Clin Liver Dis 2004, 8:839–859, viii–ix.
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, 168:818–900. This encyclopedic and exhaustively referenced position paper was compiled by an international team of physicians and scientists to review the state of medical knowledge with regard to this genetic disease. Although the adult lung disease and protein replacement therapy is emphasized, genetics, testing, and liver disease issues are included.
Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ 1997, 75:397–415.
Sveger T: Liver disease in alpha1-antitr ypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976, 294:1316–1321.
Sveger T: alpha 1-antitr ypsin deficiency in early childhood. Pediatrics 1978, 62:22–25.
Sveger T, Piitulainen E, Arborelius M, Jr: Lung function in adolescents with alpha 1-antitr ypsin deficiency. Acta Paediatr 1994, 83:1170–1173.
Mowat AP: Alpha 1-antitr ypsin deficiency (PiZZ): features of liver involvement in childhood. Acta Paediatr Suppl 1994, 393:13–7.
Pittschieler K, Massi G: Alpha 1 antitr ypsin deficiency in two population groups in north Italy. Padiatr Padol 1988, 23:307–311.
Sveger T, Eriksson S: The liver in adolescents with alpha 1-antitr ypsin deficiency. Hepatology 1995, 22:514–517.
Eriksson S: Alpha-1-antitr ypsin deficiency: natural course and therapeutic strategies. In Falk Symposium 115: Liver Cirrhosis and Its Development. Edited by Boyer JL, Blum HE, Maier HE, et al. Dordrecht: Kluwer Academic Publishers; 2001:307–315. This review, authored by the co-discoverer of the disease, includes data on an extensive retrospective autopsy series from Sweden that illustrates the progression of liver disease in older adults.
Eriksson S: Alpha 1-antitr ypsin deficiency. J Hepatol 1999, 30(Suppl 1):34–39.
An JK, Blomenkamp K, Lindblad D, Teckman JH: Quantitative isolation of alphalAT mutant Z protein polymers from human and mouse livers and the effect of heat. Hepatology 2005, 41:160–167.
Perlmutter DH: Alpha-1-antitrypsin deficiency: biochemistry and clinical manifestations. Ann Med 1996, 28:385–394.
Wu Y, Whitman I, Molmenti E, et al.: 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, 91:9014–9018.
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, 271:22791–22795.
Lomas DA, Parfrey H: Alpha1-antitrypsin deficiency. 4: Molecular pathophysiology. Thorax 2004, 59:529–535. An excellent review of the complex topic of the protein polymerization in á1AT deficiency. One of the authors is the co-discoverer of á1AT protein polymerization. How this basic science data might be applied to rational therapies is also discussed.
Dafforn TR, Mahadeva R, Elliott PR, et al.: A kinetic mechanism for the polymerization of alpha1-antitrypsin. J Biol Chem 1999, 274:9548–9555.
Lomas DA, Evans DL, Finch JT, Carrell RW: The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992, 357:605–607.
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.
Teckman JH, Burrows J, Hidvegi T, et al.: The proteasome participates in degradation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. J Biol Chem 2001, 276:44865–44872.
Teckman JH, Perlmutter DH: Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol Gastrointest Liver Physiol 2000, 279:G961-G974.
Sifers RN: Cell biology. Protein degradation unlocked. Science 2003, 299:1330–1331. A fine review of the mechanics of intracellular protein degradation processes and their role in the pathophysiology of á1AT deficiency.
Teckman JH, An JK, Blomenkamp K, et al.: Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 2004, 286:G851-G862. In this paper, the authors present the initial data linking mitochondrial injury and caspase activation to the pathophysiology of liver injury in á1AT deficiency.
Perlmutter DH: Alpha1-antitrypsin deficiency: liver disease associated with retention of a mutant secretory glycoprotein in the endoplasmic reticulum. Methods Mol Biol 2003, 232:39–56.
Lomas DA, Evans DL, Stone SR, et al.: Effect of the Z mutation on the physical and inhibitor y properties of alpha 1-antitr ypsin. Biochemistry 1993, 32:500–508.
Lomas DA, Mahadeva R: Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest 2002, 110:1585–1590.
Lin L, Schmidt B, Teckman J, Perlmutter DH: A naturally occurring nonpolymerogenic mutant of alpha 1-antitr ypsin characterized by prolonged retention in the endoplasmic reticulum. J Biol Chem 2001, 276:33893–3898.
Carrell RW, Lomas DA: Alpha1-antitrypsin deficiency--a model for conformational diseases. N Engl J Med 2002, 346:45–53.
Cabrita LD, Dai W, Bottomley SP: Different conformational changes within the F-helix occur during serpin folding, polymerization, and proteinase inhibition. Biochemistry 2004, 43:9834–9839.
Rudnick DA, Liao Y, An JK, et al.: Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Hepatology 2004, 39:1048–1055.
Wu Y, Swulius MT, Moremen KW, Sifers RN: Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation. Proc Natl Acad Sci U S A, 2003, 100:8229–8234.
Lawless MW, Greene CM, Mulgrew A, et al.: Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency. J Immunol, 2004, 172:5722–5726.
Teckman JH, An JK, Loethen S, Perlmutter DH: Fasting in alpha1-antitrypsin deficient liver: constitutive [correction of consultative] activation of autophagy. Am J Physiol Gastrointest Liver Physiol 2002, 283:G1156-GG165.
Teckman JH, Gilmore R, Perlmutter DH: Role of ubiquitin in proteasomal degradation of mutant alpha(1)-antitrypsin Z in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 2000, 278:G39-G48.
Teckman JH, Perlmutter DH: The endoplasmic reticulum degradation pathway for mutant secretory proteins alpha1-antitrypsin Z and S is distinct from that for an unassembled membrane protein. J Biol Chem 1996, 271:13215–13220.
Marcus NY, Perlmutter DH: Glucosidase and mannosidase inhibitors mediate increased secretion of mutant alpha1 antitrypsin Z. J Biol Chem 2000, 275:1987–1992.
Lomas DA, Lomas DA, Finch JT, et al.: Alpha 1-antitrypsin Siiyama (Ser53-->Phe). Further evidence for intracellular loop-sheet polymerization. J Biol Chem 1993, 268:15333–15335.
Lomas DA, Elliott PR, Sidhar SK, 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, 270:16864–16870.
Rodriguez F, Jardi R, Costa X, et al.: Rapid screening for alpha1-antitrypsin deficiency in patients with chronic obstructive pulmonary disease using dried blood specimens. Am J Respir Crit Care Med 2002, 166:814–817.
Piitulainen E, Sveger T: Respiratory symptoms and lung function in young adults with severe alpha(1)-antitrypsin deficiency (PiZZ). Thorax 2002, 57:705–708.
Sveger T, Thelin T, McNeil TF: Young adults with alpha 1-antitrypsin deficiency identified neonatally: their health, knowledge about and adaptation to the high-risk condition. Acta Paediatr 1997, 86:37–40.
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.
Duan YY, Wu J, Zhu JL, et al.: Gene therapy for human alpha1-antitrypsin deficiency in an animal model using SV40-derived vectors. Gastroenterology 2004, 127:1222–1232.
Eigenbrodt ML, McCashland TM, Dy RM, et al.: Heterozygous alpha 1-antitr ypsin phenotypes in patients with end stage liver disease. Am J Gastroenterol 1997, 92:602–607.
Fischer HP, Ortiz-Pallardo ME, Ko Y, et al.: Chronic liver disease in heterozygous alpha1-antitr ypsin deficiency PiZ. J Hepatol 2000, 33:883–892.
Pittschieler K: Liver disease and heterozygous alpha-1-antitr ypsin deficiency. Acta Paediatr Scand 1991, 80:323–327.
Kaserbacher R, Propst T, Propst A, et al.: Association between heterozygous alpha 1-antitr ypsin deficiency and genetic hemochromatosis. Hepatology 1993, 18:707–708.
Propst T, Propst A, Dietze O, et al.: High prevalence of viral infection in adults with homozygous and heterozygous alpha 1-antitr ypsin deficiency and chronic liver disease. Ann Intern Med 1992, 117:641–645.
Hodges JR, Millward-Sadler GH, Barbatis C, Wright R: Heterozygous MZ alpha 1-antitr ypsin deficiency in adults with chronic active hepatitis and cr yptogenic cirrhosis. N Engl J Med 1981, 304:557–560.
Zhou H, Ortiz-Pallardo ME, Ko Y, Fischer HP: Is heterozygous alpha-1-antitr ypsin deficiency type PIZ a risk factor for primar y liver carcinoma? Cancer 2000, 88:2668–2676.
Banner BF, Karamitsios N, Smith L, Bonkovsky HL: Enhanced phenotypic expression of alpha-1-antitr ypsin deficiency in an MZ heterozygote with chronic hepatitis C. Am J Gastroenterol 1998, 93:1541–1545.
Mahadeva R, Chang WS, Dafforn TR, et al.: Heteropolymerization of S, I, and Z alpha1-antitr ypsin and liver cirrhosis. J Clin Invest 1999, 103:999–1006.
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Teckman, J.H., Lindblad, D. Alpha-1-antitrypsin deficiency: Diagnosis, pathophysiology, and management. Curr Gastroenterol Rep 8, 14–20 (2006). https://doi.org/10.1007/s11894-006-0059-8
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DOI: https://doi.org/10.1007/s11894-006-0059-8