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Semin Liver Dis 2023; 43(03): 258-266
DOI: 10.1055/a-2122-7674
Review Article

Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

Mathias Ruiz
1   Hépatologie, Gastroentérologie et Nutrition Pédiatriques, Hôpital Femme Mère Enfant, Hospices civils de Lyon, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Lyon, France
,
Florence Lacaille
2   Service de Gastroentérologie-Nutrition Pédiatriques et Unité d'Hépatologie Pédiatrique Hôpital Universitaire Necker-Enfants Malades, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Paris, France
,
Christina Schrader
3   Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
,
Monica Pons
4   Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Barcelona, Spain
5   Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
,
Piotr Socha
6   The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, Al. Dzieci Polskich, Warszawa, Poland
,
Aleksander Krag
7   Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
,
Ekkehard Sturm
8   Pediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Member Center of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Tübingen, Germany
,
Marion Bouchecareilh
9   University of Bordeaux, CNRS, INSERM, BRIC, U1312, Bordeaux, France
,
Pavel Strnad
3   Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
› Author Affiliations Funding None.
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Abstract

Alpha-1 antitrypsin deficiency (AATD) arises due to inherited variants in SERPINA1, the AAT gene that impairs the production or secretion of this hepatocellular protein and leads to a gain-of-function liver proteotoxicity. Homozygous Pi*Z pathogenic variant (Pi*ZZ genotype) is the leading cause of severe AATD. It manifests in 2 to 10% of carriers as neonatal cholestasis and 20 to 35% of adults as significant liver fibrosis. Both children and adults may develop an end-stage liver disease requiring liver transplantation. Heterozygous Pi*Z pathogenic variant (Pi*MZ genotype) constitutes an established disease modifier. Our review summarizes the natural history and management of subjects with both pediatric and adult AATD-associated liver disease. Current findings from a phase 2 clinical trial indicate that RNA silencing may constitute a viable therapeutic approach for adult AATD. In conclusion, AATD is an increasingly appreciated pediatric and adult liver disorder that is becoming an attractive target for modern pharmacologic strategies.

Keywords

cirrhosis - hepatitis - children


Publication History

Accepted Manuscript online:
04 July 2023

Article published online:
09 August 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med 2020; 382 (15) 1443-1455
    CrossrefPubMedGoogle Scholar
  • 2 de Serres FJ, Blanco I, Fernández-Bustillo E. PI S and PI Z alpha-1 antitrypsin deficiency worldwide. A review of existing genetic epidemiological data. Monaldi Arch Chest Dis 2007; 67 (04) 184-208
    PubMedGoogle Scholar
  • 3 Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992; 357 (6379): 605-607
    CrossrefPubMedGoogle Scholar
  • 4 Fromme M, Schneider CV, Trautwein C, Brunetti-Pierri N, Strnad P. Alpha-1 antitrypsin deficiency: a re-surfacing adult liver disorder. J Hepatol 2022; 76 (04) 946-958
    CrossrefPubMedGoogle Scholar
  • 5 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 (05) G961-G974
    CrossrefPubMedGoogle Scholar
  • 6 Teckman JH, Mangalat N. Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions. Expert Rev Gastroenterol Hepatol 2015; 9 (02) 261-268
    CrossrefPubMedGoogle Scholar
  • 7 Mahadeva R, Chang WS, Dafforn TR. et al. Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis. J Clin Invest 1999; 103 (07) 999-1006
    CrossrefPubMedGoogle Scholar
  • 8 Miravitlles M, Dirksen A, Ferrarotti I. et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency. Eur Respir J 2017; 50 (05) 50
    CrossrefPubMedGoogle Scholar
  • 9 Ferrarotti I, Thun GA, Zorzetto M. et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax 2012; 67 (08) 669-674
    CrossrefPubMedGoogle Scholar
  • 10 Greene CM, Marciniak SJ, Teckman J. et al. α1-Antitrypsin deficiency. Nat Rev Dis Primers 2016; 2: 16051
    CrossrefPubMedGoogle Scholar
  • 11 Yang P, Sun Z, Krowka MJ. et al. Alpha1-antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk. Arch Intern Med 2008; 168 (10) 1097-1103
    CrossrefPubMedGoogle Scholar
  • 12 Chapman KR, Burdon JG, Piitulainen E. et al; RAPID Trial Study Group. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 386 (9991): 360-368
    CrossrefPubMedGoogle Scholar
  • 13 Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976; 294 (24) 1316-1321
    CrossrefPubMedGoogle Scholar
  • 14 Sveger T. The natural history of liver disease in alpha 1-antitrypsin deficient children. Acta Paediatr Scand 1988; 77 (06) 847-851
    CrossrefPubMedGoogle Scholar
  • 15 Sveger T, Eriksson S. The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology 1995; 22 (02) 514-517
    PubMedGoogle Scholar
  • 16 Nebbia G, Hadchouel M, Odievre M, Alagille D. Early assessment of evolution of liver disease associated with alpha 1-antitrypsin deficiency in childhood. J Pediatr 1983; 102 (05) 661-665
    CrossrefPubMedGoogle Scholar
  • 17 Wall M, Moe E, Eisenberg J, Powers M, Buist N, Buist AS. Long-term follow-up of a cohort of children with alpha-1-antitrypsin deficiency. J Pediatr 1990; 116 (02) 248-251
    CrossrefPubMedGoogle Scholar
  • 18 Ibarguen E, Gross CR, Savik SK, Sharp HL. Liver disease in alpha-1-antitrypsin deficiency: prognostic indicators. J Pediatr 1990; 117 (06) 864-870
    CrossrefPubMedGoogle Scholar
  • 19 Teckman JH, Rosenthal P, Abel R. et al; Childhood Liver Disease Research Network (ChiLDReN). Baseline analysis of a young α-1-antitrypsin deficiency liver disease cohort reveals frequent portal hypertension. J Pediatr Gastroenterol Nutr 2015; 61 (01) 94-101
    CrossrefPubMedGoogle Scholar
  • 20 Ruiz M, Lacaille F, Berthiller J. et al; Groupe Francophone d'Hépatologie Gastroentérologie et Nutrition Pédiatriques. Liver disease related to alpha1-antitrypsin deficiency in French children: the DEFI-ALPHA cohort. Liver Int 2019; 39 (06) 1136-1146
    CrossrefPubMedGoogle Scholar
  • 21 Guillaud O, Dumortier J, Couchonnal-Bedoya E, Ruiz M. Wilson disease and alpha1-antitrypsin deficiency: a review of non-invasive diagnostic tests. Diagnostics (Basel) 2023; 13 (02) 13
    PubMedGoogle Scholar
  • 22 Fawaz R, Baumann U, Ekong U. et al. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2017; 64 (01) 154-168
    CrossrefPubMedGoogle Scholar
  • 23 Bakula A, Pawlowska J, Niewiadomska O. et al. Liver transplantation in Polish children with α1-antitrypsin deficiency: a single-center experience. Transplant Proc 2016; 48 (10) 3323-3327
    CrossrefPubMedGoogle Scholar
  • 24 Hinds R, Hadchouel A, Shanmugham NP. et al. Variable degree of liver involvement in siblings with PiZZ alpha-1-antitrypsin deficiency-related liver disease. J Pediatr Gastroenterol Nutr 2006; 43 (01) 136-138
    CrossrefPubMedGoogle Scholar
  • 25 Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC. Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology 2007; 45 (05) 1313-1323
    CrossrefPubMedGoogle Scholar
  • 26 Perlmutter DH, Silverman GA. Hepatic fibrosis and carcinogenesis in α1-antitrypsin deficiency: a prototype for chronic tissue damage in gain-of-function disorders. Cold Spring Harb Perspect Biol 2011; 3 (03) 3
    CrossrefPubMedGoogle Scholar
  • 27 Joly P, Lachaux A, Ruiz M. et al. SERPINA1 and MAN1B1 polymorphisms are not linked to severe liver disease in a French cohort of alpha-1 antitrypsin deficiency children. Liver Int 2017; 37 (11) 1608-1611
    CrossrefPubMedGoogle Scholar
  • 28 Karatas E, Bouchecareilh M. Alpha 1-antitrypsin deficiency: a disorder of proteostasis-mediated protein folding and trafficking pathways. Int J Mol Sci 2020; 21 (04) 21
    CrossrefPubMedGoogle Scholar
  • 29 Leon C, Bouchecareilh M. The autophagy pathway: a critical route in the disposal of alpha 1-antitrypsin aggregates that holds many mysteries. Int J Mol Sci 2021; 22 (04) 22
    CrossrefPubMedGoogle Scholar
  • 30 Joly P, Ruiz M, Garin R. et al. A particular SORL1 micro-haplotype may prevent severe liver disease in a French cohort of alpha 1-antitrypsin-deficient children. J Pediatr Gastroenterol Nutr 2021; 73 (03) e68-e72
    CrossrefPubMedGoogle Scholar
  • 31 Kamp JC, Kappe NN, Moro CF. et al. Fibrosis-related gene profiling in liver biopsies of PiZZ α1-antitrypsin children with different clinical courses. Int J Mol Sci 2023; 24 (03) 24
    CrossrefPubMedGoogle Scholar
  • 32 Shneider BL, Goodrich NP, Ye W. et al; Childhood Liver Disease Research Network (ChiLDReN). Nonfasted liver stiffness correlates with liver disease parameters and portal hypertension in pediatric cholestatic liver disease. Hepatol Commun 2020; 4 (11) 1694-1707
    CrossrefPubMedGoogle Scholar
  • 33 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 (06) 986-992
    CrossrefPubMedGoogle Scholar
  • 34 Guillaud O, Jacquemin E, Couchonnal E. et al. Long term results of liver transplantation for alpha-1 antitrypsin deficiency. Dig Liver Dis 2021; 53 (05) 606-611
    CrossrefPubMedGoogle Scholar
  • 35 Doshi SD, Wood L, Abt PL. et al. Outcomes of living-donor liver transplantation using grafts heterozygous for α-1 antitrypsin gene mutations. Transplantation 2019; 103 (06) 1175-1180
    CrossrefPubMedGoogle Scholar
  • 36 Sood V, Lee EJ, Raghu V. et al. Liver transplantation for alpha 1 antitrypsin deficiency (A1ATD) using a heterozygous donor: outcomes and review of the literature. Pediatr Transplant 2023; 27 (04) e14488
    CrossrefPubMedGoogle Scholar
  • 37 Lykavieris P, Ducot B, Lachaux A. et al. Liver disease associated with ZZ alpha1-antitrypsin deficiency and ursodeoxycholic acid therapy in children. J Pediatr Gastroenterol Nutr 2008; 47 (05) 623-629
    CrossrefPubMedGoogle Scholar
  • 38 Cakir M, Sag E, Islek A, Baran M, Tumgor G, Aydogdu S. Liver involvement in children with alpha-1 antitrypsin deficiency: a multicenter study. Pediatr Gastroenterol Hepatol Nutr 2020; 23 (02) 146-153
    CrossrefPubMedGoogle Scholar
  • 39 Campbell KM, Arya G, Ryckman FC. et al. High prevalence of alpha-1-antitrypsin heterozygosity in children with chronic liver disease. J Pediatr Gastroenterol Nutr 2007; 44 (01) 99-103
    CrossrefPubMedGoogle Scholar
  • 40 Bartlett JR, Friedman KJ, Ling SC. et al; Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA 2009; 302 (10) 1076-1083
    CrossrefPubMedGoogle Scholar
  • 41 Boëlle PY, Debray D, Guillot L, Corvol H. French CF Modifier Gene Study Investigators. SERPINA1 Z allele is associated with cystic fibrosis liver disease. Genet Med 2019; 21 (09) 2151-2155
    CrossrefPubMedGoogle Scholar
  • 42 Lin HC, Kasi N, Quiros JA. Alpha1-antitrypsin deficiency: transition of care for the child with AAT deficiency into adulthood. Curr Pediatr Rev 2019; 15 (01) 53-61
    CrossrefPubMedGoogle Scholar
  • 43 Antonini TM, Girard M, Habes D, Goria O, Debray D. Optimization of the transition process of youth with liver disease in adulthood: a position paper from FILFOIE, the French network for paediatric and adult rare liver diseases. Clin Res Hepatol Gastroenterol 2020; 44 (02) 135-141
    CrossrefPubMedGoogle Scholar
  • 44 Janus ED, Phillips NT, Carrell RW. Smoking, lung function, and alpha 1-antitrypsin deficiency. Lancet 1985; 1 (8421): 152-154
    CrossrefPubMedGoogle Scholar
  • 45 Fromme M, Schneider CV, Pereira V. et al. Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency. Gut 2022; 71 (02) 415-423
    CrossrefPubMedGoogle Scholar
  • 46 Ferkingstad E, Oddsson A, Gretarsdottir S. et al. Genome-wide association meta-analysis yields 20 loci associated with gallstone disease. Nat Commun 2018; 9 (01) 5101
    CrossrefPubMedGoogle Scholar
  • 47 Clark VC, Marek G, Liu C. et al. Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol 2018; 69 (06) 1357-1364
    CrossrefPubMedGoogle Scholar
  • 48 Hamesch K, Mandorfer M, Pereira VM. et al; European Alpha1-Liver Study Group. Liver fibrosis and metabolic alterations in adults with alpha-1-antitrypsin deficiency caused by the Pi*ZZ mutation. Gastroenterology 2019; 157 (03) 705-719.e18
    CrossrefPubMedGoogle Scholar
  • 49 Kümpers J, Fromme M, Schneider CV. et al. Assessment of liver phenotype in adults with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype). J Hepatol 2019; 71 (06) 1272-1274
    CrossrefPubMedGoogle Scholar
  • 50 Mandorfer M, Bucsics T, Hutya V. et al. Liver disease in adults with α1-antitrypsin deficiency. United European Gastroenterol J 2018; 6 (05) 710-718
    CrossrefPubMedGoogle Scholar
  • 51 Guillaud O, Dumortier J, Traclet J. et al. Assessment of liver fibrosis by transient elastography (Fibroscan®) in patients with A1AT deficiency. Clin Res Hepatol Gastroenterol 2019; 43 (01) 77-81
    CrossrefPubMedGoogle Scholar
  • 52 Abbas SH, Pickett E, Lomas DA. et al. Non-invasive testing for liver pathology in alpha-1 antitrypsin deficiency. BMJ Open Respir Res 2020; 7 (01) 7
    CrossrefPubMedGoogle Scholar
  • 53 Pons M, Núñez A, Esquinas C. et al. Utility of transient elastography for the screening of liver disease in patients with alpha1-antitrypsin deficiency. J Clin Med 2021; 10 (08) 10
    CrossrefPubMedGoogle Scholar
  • 54 Hiller AM, Ekstrom M, Piitulainen E. et al. Cancer risk in severe alpha-1-antitrypsin deficiency. Eur Respir J 2022; 60 (04) 2103200
    CrossrefPubMedGoogle Scholar
  • 55 Fromme M, Strnad P. Liver cancer in severe alpha-1 antitrypsin deficiency: who is at risk?. Eur Respir J 2022; 60 (05) 60
    CrossrefPubMedGoogle Scholar
  • 56 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) 22
    CrossrefPubMedGoogle Scholar
  • 57 Chen VL, Burkholder DA, Moran IJ. et al. Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi. ∗MZ genotype. JHEP Rep 2022; 4 (06) 100483
    CrossrefPubMedGoogle Scholar
  • 58 Balcar L, Scheiner B, Urheu M. et al. Alpha-1 antitrypsin Pi. ∗Z allele is an independent risk factor for liver transplantation and death in patients with advanced chronic liver disease. JHEP Rep 2022; 4 (11) 100562
    PubMedGoogle Scholar
  • 59 Meister F, Lurje G, Neumann UP, Trautwein C, Strnad P. Heterozygosity for the alpha-1-antitrypsin Z allele in cirrhosis is associated with more advanced disease. Liver Transpl 2019; 25 (02) 342-343
    CrossrefPubMedGoogle Scholar
  • 60 Carey EJ, Iyer VN, Nelson DR, Nguyen JH, Krowka MJ. Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency–related cirrhosis. Liver Transpl 2013; 19 (12) 1370-1376
    CrossrefPubMedGoogle Scholar
  • 61 Clark VC. Liver transplantation in alpha-1 antitrypsin deficiency. Clin Liver Dis 2017; 21 (02) 355-365
    CrossrefPubMedGoogle Scholar
  • 62 Kemmer N, Kaiser T, Zacharias V, Neff GW. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant Proc 2008; 40 (05) 1492-1494
    CrossrefPubMedGoogle Scholar
  • 63 Schneider CV, Hamesch K, Gross A. et al; European Alpha-1 Liver Study Group. Liver phenotypes of European adults heterozygous or homozygous for Pi. ∗Z variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and noncarriers. Gastroenterology 2020; 159 (02) 534-548.e11
    CrossrefPubMedGoogle Scholar
  • 64 Gurbuz B, Guldiken N, Reuken P. et al. Biomarkers of hepatocellular synthesis in patients with decompensated cirrhosis. Hepatol Int 2023; 17 (03) 698-708
    CrossrefPubMedGoogle Scholar
  • 65 Townsend SA, Edgar RG, Ellis PR, Kantas D, Newsome PN, Turner AM. Systematic review: the natural history of alpha-1 antitrypsin deficiency, and associated liver disease. Aliment Pharmacol Ther 2018; 47 (07) 877-885
    CrossrefPubMedGoogle Scholar
  • 66 Rudnick DA, Liao Y, An JK, Muglia LJ, Perlmutter DH, Teckman JH. Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Hepatology 2004; 39 (04) 1048-1055
    CrossrefPubMedGoogle Scholar
  • 67 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 (06) 1099-1107
    CrossrefPubMedGoogle Scholar
  • 68 Remih K, Amzou S, Strnad P. Alpha1-antitrypsin deficiency: new therapies on the horizon. Curr Opin Pharmacol 2021; 59: 149-156
    CrossrefPubMedGoogle Scholar
  • 69 Hidvegi T, Ewing M, Hale P. et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 2010; 329 (5988): 229-232
    CrossrefPubMedGoogle Scholar
  • 70 Strnad P, Mandorfer M, Choudhury G. et al. Fazirsiran for liver disease associated with alpha1-antitrypsin deficiency. N Engl J Med 2022; 387 (06) 514-524
    CrossrefPubMedGoogle Scholar
  • 71 Rademacher L, Fromme M, Strnad P. Cleaning up alpha-1 antitrypsin deficiency related liver disease. Curr Opin Gastroenterol 2023; 39 (03) 163-168
    CrossrefPubMedGoogle Scholar
  • 72 Gardin A, Remih K, Gonzales E, Andersson ER, Strnad P. Modern therapeutic approaches to liver-related disorders. J Hepatol 2022; 76 (06) 1392-1409
    CrossrefPubMedGoogle Scholar
  • 73 Wooddell CI, Blomenkamp K, Peterson RM. et al. Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease. JCI Insight 2020; 5 (12) 5
    CrossrefPubMedGoogle Scholar
  • 74 Packer MS, Chowdhary V, Lung G. et al. Evaluation of cytosine base editing and adenine base editing as a potential treatment for alpha-1 antitrypsin deficiency. Mol Ther 2022; 30 (04) 1396-1406
    CrossrefPubMedGoogle Scholar
  • 75 Merkle T, Merz S, Reautschnig P. et al. Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides. Nat Biotechnol 2019; 37 (02) 133-138
    CrossrefPubMedGoogle Scholar