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Liver transplantation in alpha-1-antitrypsin defi ciency


Authors: S. Fraňková 1 ;  M. Holinka 1,2 ;  J. Šperl 1,3
Authors place of work: Klinika hepatogastroenterologie, Transplantcentrum, Institut klinické a experimentální medicíny, Praha 2 3. LF UK, Praha 3 1. LF UK, Praha 1
Published in the journal: Gastroent Hepatol 2024; 78(2): 129-135
Category: Hepatology
doi: https://doi.org/10.48095/ccgh2024129

Summary

Alpha-1-antitrypsin deficiency (AATD) is an autosomal codominant genetic condition which manifests with lung emphysema at young age and with liver disease. A point mutation in the SERPINA1 gene, which encodes a1-antitrypsin (AAT), causes a defective secondary structure of the protein, which subsequently accumulates in the endoplasmic reticulum of hepatocytes and is not transported into the blood and body fluids. Deficiency of AAT, which inhibits neutrophil elastase in the lung, thus allows proteolytic damage to the connective tissue of the lung, leading to the development of emphysema. Liver disease is caused by the accumulation of the mutant AAT in liver cells, contributing to proteotoxic liver injury that can lead to liver cirrhosis. Liver transplantation (LT) is the only curative method; after LT, the recipient has the phenotype of the donor organ and normal serum AAT concentrations. The indication for LT should be considered in all patients with AATD and end-stage liver disease. The patients should be referred to the transplant centre when severe complications of liver cirrhosis, such as variceal bleeding, ascites, encephalopathy, and hepatorenal syndrome. In patients with hepatocellular carcinoma, LT represents an optimal treatment modality in the case of an early, unresectable tumour. The timing of LT is crucial; LT should be performed before the patient develops life-threatening complications of end-stage liver disease. LT should be considered in patients of Child-Pugh classification B and C and MELD score of 15 points or higher. Survival of patients after LT for AADT is excellent.

Keywords:

alpha-1-antitrypsin – alpha-1-antitrypsin deficiency – liver cirrhosis – end-stage liver disease – hepatocellular carcinoma – live transplantation


Zdroje

1. Strnad P, McElvaney NG, Lomas DA. Alpha1- -Antitrypsin Deficiency. N Engl J Med 2020; 382 (15): 1443–1455. doi: 10.1056/NEJMra1910234.

2. Feldmann G, Martin JP, Sesboue R et al. The ultrastructure of hepatocytes in alpha-1-antitrypsin deficiency with the genotype Pi. Gut 1975; 16 (10): 796–799. doi: 10.1136/gut.16.10.796.

3. Remih K, Amzou S, Strnad P. Alpha1-antitrypsin deficiency: New therapies on the horizon. Curr Opin Pharmacol 2021; 59: 149–156. doi: 10.1016/j.coph.2021.06.001.

4. Rabekova Z, Frankova S, Jirsa M et al. Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk. Int J Mol Sci 2021; 22 (19). doi: 10.3390/ijms221910560.

5. Blanco I, Bueno P, Diego I et al. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update. Int J Chron Obstruct Pulmon Dis 2017; 12: 561–569. doi: 10.2147/COPD.S125389.

6. Janciauskiene S, Eriksson S, Callea F et al. Differential detection of PAS-positive inclusions formed by the Z, Siiyama, and Mmalton variants of alpha1-antitrypsin. Hepatology 2004; 40 (5): 1203–1210. doi: 10.1002/hep.20451.

7. Lomas DA, Evans DL, Finch JT et al. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992; 357 (6379): 605–607. doi: 10.1038/357605a0.

8. Silverman EK, Sandhaus RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 2009; 360 (26): 2749–2757. doi: 10.1056/NEJM cp0900449.

9. Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976; 294 (24): 1316–1321. doi: 10.1056/NEJM197606102942404.

10. Bernspang E, Carlson J, Piitulainen E. The liver in 30-year-old individuals with alpha (1) -antitrypsin deficiency. Scand J Gastroenterol 2009; 44 (11): 1349–1355. doi: 10.3109/003655 20903296669.

11. DeMeo DL, Silverman EK. Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha (1) -antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax 2004; 59 (3): 259–264. doi: 10.1136/thx.2003.006502.

12. Hope PL, Hall MA, Millward-Sadler GH et al. Alpha-1-antitrypsin deficiency presenting as a bleeding diathesis in the newborn. Arch Dis Child 1982; 57 (1): 68–70.

13. Ghishan FK, Gray GF, Greene HL. alpha 1-antitrypsin deficiency presenting with ascites and cirrhosis in the neonatal period. Gastroenterology 1983; 85 (2): 435–438.

14. Odievre M, Martin JP, Hadchouel M et al. Alpha1-antitrypsin deficiency and liver disease in children: phenotypes, manifestations, and prognosis. Pediatrics 1976; 57 (2): 226–231.

15. 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): 736–239. doi: 10.1056/NEJM198603203141202.

16. Fromme M, Schneider CV, Trautwein C et al. Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder. J Hepatol 2022; 76 (4): 946–958. doi: 10.1016/j.jhep.2021.11.022.

17. Tanash HA, Nilsson PM, Nilsson JA et al. Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ). Thorax 2008; 63 (12): 1091–1095. doi: 10.1136/thx.2008.095497.

18. Strnad P, Buch S, Hamesch K et al. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. Gut 2019; 68 (6): 1099–1107. doi: 10.1136/gutjnl-2018-316228.

19. McElvaney NG, Burdon J, Holmes M et al. Long-term efficacy and safety of alpha1 proteinase inhibitor treatment for emphysema caused by severe alpha1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med 2017; 5 (1): 51–60. doi: 10.1016/S2213-2600 (16) 30430-1.

20. Strnad P, Mandorfer M, Choudhury G et al. Fazirsiran for Liver Disease Associated with Alpha (1) -Antitrypsin Deficiency. N Engl J Med 2022; 387 (6): 514–524. doi: 10.1056/NEJMoa2205416.

21. Putnam CW, Porter KA, Peters RL et al. Liver replacement for alpha1-antitrypsin deficiency. Surgery 1977; 81 (3): 258–261.

22. Esquivel CO, Vicente E, Van Thiel D et al. Orthotopic liver transplantation for alpha-1-antitrypsin deficiency: an experience in 29 children and ten adults. Transplant Proc 1987; 19 (5): 3798–1802.

23. Vennarecci G, Gunson BK, Ismail T et al. Transplantation for end stage liver disease related to alpha 1 antitrypsin. Transplantation 1996; 61 (10): 1488–1495. doi: 10.1097/000 07890-199605270-00014.

24. Prachalias AA, Kalife M, Francavilla R et al. Liver transplantation for alpha-1-antitrypsin deficiency in children. Transpl Int 2000; 13 (3): 207–210. doi: 10.1007/s001470050688.

25. Francavilla R, Castellaneta SP, Hadzic N et al. Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation. J Hepatol 2000; 32 (6): 986–992. doi: 10.1016/s0168-8278 (00) 80103-8.

26. Bakula A, Socha P, Pawlowska J et al. Good and bad prognosis of alpha-1-antitrypsin deficiency in children: when to list for liver transplantation. Transplant Proc 2007; 39 (10): 3186–3188. doi: 10.1016/j.transproceed.2007.09.046.

27. Teckman JH, Rosenthal P, Abel R et al. Baseline Analysis of a Young alpha-1-Antitrypsin Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension. J Pediatr Gastroenterol Nutr 2015; 61 (1): 94–101. doi: 10.1097/MPG.0000000000000753.

28. Kemmer N, Kaiser T, Zacharias V et al. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant Proc 2008; 40 (5): 1492–1494. doi: 10.1016/j.transproceed. 2008. 02.075.

29. Hughes MG Jr., Khan KM, Gruessner AC et al. Long-term outcome in 42 pediatric liver transplant patients with alpha 1-antitrypsin deficiency: a single-center experience. Clin Transplant 2011; 25 (5): 731–736. doi: 10.1111/ j.1399-0012.2010.01371.x.

30. Strange C, Stoller JK, Sandhaus RA et al. Results of a survey of patients with alpha-1 antitrypsin deficiency. Respiration 2006; 73 (2): 185–190. doi: 10.1159/000088061.

31. Stoller JK, Tomashefski J Jr., Crystal RG et al. Mortality in individuals with severe deficiency of alpha1-antitrypsin: findings from the National Heart, Lung, and Blood Institute Registry. Chest 2005; 127 (4): 1196–1204. doi: 10.1378/chest.127.4.1196.

32. Chu AS, Chopra KB, Perlmutter DH. Is severe progressive liver disease caused by alpha-1-antitrypsin deficiency more common in children or adults? Liver Transpl 2016; 22 (7): 886–894. doi: 10.1002/lt.24434.

33. Carey EJ, Iyer VN, Nelson DR et al. Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency-related cirrhosis. Liver Transpl 2013; 19 (12): 1370–1376. doi: 10.1002/lt.23744.

34. European Association for the Study of the Liver. Electronic address eee. EASL Clinical Practice Guidelines: Liver transplantation. J Hepatol 2016; 64 (2): 433–485. doi: 10.1016/ j.jhep.2015.10.006.

35. Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334 (11): 693–699. doi: 10.1056/NEJM199603143341104.

36. Wiesner R, Edwards E, Freeman R et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003; 124 (1): 91–96. doi: 10.1053/gast.2003.50016.

37. Elzouki AN, Eriksson S. Risk of hepatobiliary disease in adults with severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma? Eur J Gastroenterol Hepatol 1996; 8 (10): 989–994. doi: 10.1097/00042737-199610000-00010.

38. Antoury C, Lopez R, Zein N et al. Alpha-1 antitrypsin deficiency and the risk of hepatocellular carcinoma in end-stage liver disease. World J Hepatol 2015; 7 (10): 1427–1432. doi: 10.4254/wjh.v7.i10.1427.

39. Krowka MJ, Wiesner RH, Heimbach JK. Pulmonary contraindications, indications and MELD exceptions for liver transplantation: a contemporary view and look forward. J Hepatol 2013; 59 (2): 367–374. doi: 10.1016/j.jhep.2013.03.026.

40. Doshi SD, Wood L, Abt PL et al. Outcomes of Living-donor Liver Transplantation Using Grafts Heterozygous for alpha-1 Antitrypsin Gene Mutations. Transplantation 2019; 103 (6): 1175–1180. doi: 10.1097/TP.0000000000002 493.

Poděkování

Děkujeme doc. MUDr. Evě Sticové, Ph.D., a doc. MUDr. Ondřeji Fabiánovi, Ph.D., za poskytnutí obrazové dokumentace.

ORCID autorů

S. Fraňková 0000-0002-1462-5920,

M. Holinka 0009-0007-2353-5189,

J. Šperl 0000-0001-8619-2610.

Doručeno/Submitted: 4. 1. 2024
Přijato/Accepted: 15. 1. 2024
doc. MUDr. Jan Šperl, CSc.
Klinika hepatogastroenterologie
Institut klinické a experimentální medicíny
Vídeňská 1958/9
140 21 Praha 4
jan.sperl@ikem.cz
Štítky
Paediatric gastroenterology Gastroenterology and hepatology Surgery

Článok vyšiel v časopise

Gastroenterology and Hepatology

Číslo 2

2024 Číslo 2
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