Abstract
Classical alpha-1 antitrypsin (a1AT) deficiency is an autosomal recessive disease associated with an increased risk of liver disease in adults and children, and with lung disease in adults (Teckman and Jain, Curr Gastroenterol Rep 16(1):367, 2014). The vast majority of the liver disease is associated with homozygosity for the Z mutant allele, the so-called PIZZ. These homozygous individuals synthesize large quantities of a1AT mutant Z protein in the liver, but the mutant protein folds improperly during biogenesis and approximately 85% of the molecules are retained within the hepatocytes rather than appropriately secreted. The resulting low, or “deficient,” serum level leaves the lungs vulnerable to inflammatory injury from uninhibited neutrophil proteases. Most of the mutant Z protein molecules retained within hepatocytes are directed into intracellular proteolysis pathways, but some molecules remain in the endoplasmic reticulum for long periods of time. Some of these molecules adopt an unusual aggregated or “polymerized” conformation (Duvoix et al., Rev Mal Respir 31(10):992–1002, 2014). It is thought that these intracellular polymers trigger a cascade of intracellular injury which can lead to end-organ liver injury including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (Lindblad et al., Hepatology 46(4):1228–1235, 2007). The hepatocytes with the largest accumulations of mutant Z polymers undergo apoptotic death and possibly other death mechanisms. This intracellular death cascade appears to involve ER stress, mitochondrial depolarization, and caspase cleavage, and is possibly linked to autophagy and redox injury. Cells with lesser burdens of mutant Z protein proliferate to maintain the liver cell mass. This chronic cycle of cell death and regeneration activates hepatic stellate cells and initiates the process of hepatic fibrosis. Cirrhosis and hepatocellular carcinoma then result in some patients. Since not all patients with the same homozygous PIZZ genotype develop end-stage disease, it is hypothesized that there is likely to be a strong influence of genetic and environmental modifiers of the injury cascade and of the fibrotic response.
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References
Teckman JH, Jain A (2014) Advances in alpha-1-antitrypsin deficiency liver disease. Curr Gastroenterol Rep 16(1):367. doi:10.1007/s11894-013-0367-8
Duvoix A, Roussel BD, Lomas DA (2014) Molecular pathogenesis of alpha-1-antitrypsin deficiency. Rev Mal Respir 31(10):992–1002. doi:10.1016/j.rmr.2014.03.015
Lindblad D, Blomenkamp K, Teckman J (2007) Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatology 46(4):1228–1235. doi:10.1002/hep.21822
Teckman JH, Gilmore R, Perlmutter DH (2000) Role of ubiquitin in proteasomal degradation of mutant alpha(1)-antitrypsin Z in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 278(1):G39–G48
Teckman JH, Rosenthal P, Abel R, Bass LM, Michail S, Murray KF, Rudnick DA, Thomas DW, Spino C, Arnon R, Hertel PM, Heubi J, Kamath BM, Karnsakul W, Loomes KM, Magee JC, Molleston JP, Romero R, Shneider BL, Sherker AH, Sokol RJ (2015) Baseline analysis of a young alpha-1-antitrypsin deficiency liver disease cohort reveals frequent portal hypertension. J Pediatr Gastroenterol Nutr 61(1):94–101. doi:10.1097/MPG.0000000000000753
Teckman JH, Perlmutter DH (2000) Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol Gastrointest Liver Physiol 279(5):G961–G974
Sifers RN (2010) Medicine. Clearing conformational disease. Science 329(5988):154–155. doi:10.1126/science.1192681. 329/5988/154 [pii]
Sifers RN (2013) Resurrecting the protein fold for disease intervention. Chem Biol 20(3):298–300. doi:10.1016/j.chembiol.2013.03.002
Qu D, Teckman JH, Omura S, Perlmutter DH (1996) Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J Biol Chem 271(37):22791–22795
Teckman JH, Perlmutter DH (1996) 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 271(22):13215–13220
Perlmutter DH (2011) Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu Rev Med 62:333–345. doi:10.1146/annurev-med-042409-151920
Sifers RN (2010) Intracellular processing of alpha1-antitrypsin. Proc Am Thorac Soc 7(6):376–380. doi:10.1513/pats.201001-011AW. 7/6/376 [pii]
Pastore N, Blomenkamp K, Annunziata F, Piccolo P, Mithbaokar P, Maria Sepe R, Vetrini F, Palmer D, Ng P, Polishchuk E, Iacobacci S, Polishchuk R, Teckman J, Ballabio A, Brunetti-Pierri N (2013) Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency. EMBO Mol Med 5(3):397–412. doi:10.1002/emmm.201202046
Kaushal S, Annamali M, Blomenkamp K, Rudnick D, Halloran D, Brunt EM, Teckman JH (2010) Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model. Exp Biol Med (Maywood) 235(6):700–709. doi:10.1258/ebm.2010.009297. 235/6/700 [pii]
Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, Maurice N, Mukherjee A, Goldbach C, Watkins S, Michalopoulos G, Perlmutter DH (2010) An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 329(5988):229–232. doi:10.1126/science.1190354. science.1190354 [pii]
Marcus NY, Blomenkamp K, Ahmad M, Teckman JH (2012) Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency. Exp Biol Med (Maywood) 237(10):1163–1172. doi:10.1258/ebm.2012.012106
Teckman JH (2013) Liver disease in alpha-1 antitrypsin deficiency: current understanding and future therapy. COPD 10(Suppl 1):35–43. doi:10.3109/15412555.2013.765839
Teckman JH, Mangalat N (2015) Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions. Expert Rev Gastroenterol Hepatol 9(2):261–268. doi:10.1586/17474124.2014.943187
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Teckman, J.H., Blomenkamp, K.S. (2017). Pathophysiology of Alpha-1 Antitrypsin Deficiency Liver Disease. In: Borel, F., Mueller, C. (eds) Alpha-1 Antitrypsin Deficiency . Methods in Molecular Biology, vol 1639. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7163-3_1
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DOI: https://doi.org/10.1007/978-1-4939-7163-3_1
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