Aggiornamento
Il deficit di alfa1-antitripsina in età pediatrica
ALPHA 1-ANTITRYPSIN DEFICIENCY IN CHILDHOOD
LUISELLA GIGLIO, IRENE BERTI, CHIARA TREVISIOL
Centro Fibrosi Cistica, Clinica Pediatrica, IRCCS “Burlo Garofolo”, Trieste
Marzo 2003 - pagg. 155 -161
Abstract
Alpha 1-antitrypsin deficiency (AATD) is an autosomal recessive disease, with more than
70 genetic variants, and a frequency which varies from 1:1000 to 1:5000, depending on
genetic epidemiology and screening methods. The AATD involves primarily the liver, causing
about 15% of cases of neonatal cholestasis and, in 1 out of 35 affected newborns, the
onset of hemorrhagic disease. Cirrhosis may develop in a few cases as a consequence of
early liver involvment. Liver transplantation is indicated for severe cases. The lung is usually
involved only in adult age with late development of chronic lung disease. Conditions that
should lead to investigation of a possible AATD are listed and implications for counselling
and antenatal diagnosis of confirmed cases are discussed. Screening of AADT has been
proposed but so far cannot be recommended due to lack of effective treatment.
Classificazione MeSH
Bibliografia
1. Primhak RA, Tanner MS. Alpha-1-Antitrypsin
deficiency. Arch Dis Child 2001;85:2-5.
2. Campbell EJ. Alpha-1-Antitrypsin deficiency: incidence and detection program. Respir Med 2000;94(suppl C):S18-21.
3. Beckman L, Sikstrom C, Mikelsaar A, et al. Alpha 1-Antitrypsin (PI) alleles as markers of Westeuropean influence in Baltic Sea region. Hum Hered 1999;49:52-5.
4. Sveger T, Thelin T. A future for neonatal α- 1-Antitrypsin screening. Acta Paediatr 2000; 89:628-31.
5. Stoller Jk, Dodge JA, Boulyjenkov V. Alpha- 1-Antitrypsin deficiency: memorandum from a WHO meeting. Bull WHO 1997;75:397-415.
6. Fisher HP, Ortiz-Pallardo E, Ko Y,et al. Chronic liver disease in heterozygous α-1-antitrypsin deficiency PiZ. J Hepatol 2000; 33:883- 92.
7. O’Brien ML, Buist NR, Murphey WH. Neonatal screening for α-1-Antitrypsin deficiency. J Pediatr 1978;92:1006-10.
8. Sveger T. Liver disease in α-1-Antitrypsin deficiency detected by screening of 200,000 infants. NEJM 1976;294:1316-21.
9. Pittschieler K. Rare α-1-Antitrypsin phenotypes and liver-test abnormalities during infancy. Acta Paediatr 2001;90:406-8.
10. Carrell R, Lomas D. Alpha-1-Antitrypsin deficiency - A Model for Conformational Disease. N Engl J Med 2002;346:45-53.
11. Parmer JS, Mahadeva R, Reed BJ, et al. Polymers of α-1-Antitrypsin are chemotactic for human neutrophils. A new paradigm for pathogenesis of emphysema. Am J Respir Cell Mol Biol 2002; 26:723-30.
12. Carrell RW, Lomas DA. Conformational disease. Lancet 1997;350:134-8.
13. Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z α-1-Antitrypsin accumulation in the liver. Nature 1992;357:605-7.
14. Mahadeva R, Chang WS, Dafforn TR, et al. Heteropolymerization of S, I, and Z α-1-antitrypsin and liver cirrhosis. J Clin Invest 1999;103(7):999-1006.
15. Marcus N, Teckman JH, Perlmutter DH. Alpha-1-Antitrypsin deficiency: from genotype to childhood disease. J Pediatr Gastroenterol Nutr 1998;27:65-74.
16. Wu Y, Whitman I, Molmenti E, et al. A lag in intracellular degradation of mutant α-1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha-1-antitrypsin deficiency. Proc Natl Acad Sci USA 1994; 91:9014-8.
17. van Kries R. Neonatal vitamin K prophylaxis: the Gordian Knot still awaits untying. BMJ 1998;316:161-2.
18. Fischler B, Papadogiannakis N, Nemeth A. Aetiological factors in neonatal cholestasis. Acta Paediatr 2001;90:88-92.
19. Fischler B, Papadogiannakis N, Nemeth A. Clinical aspects on neonatal cholestasis based on observations at Swedish tertiary referral centre. Acta Paediatr 2001;90:171-8.
20. Mieli-Vergani G, Howard ER, Mowat AP. Liver disease in infancy: a 20 year perspective. Gut 1991;(suppl):S123-28.
21. Psacharopolous HT, Mowat AP, Cook PJ, et al. Outcome of liver disease associated with alpha-1-antitrypsin deficiency (PiZ). Implications for genetic counselling and antenatal diagnosis. Arch Dis Child 1983;58:882-7.
22. Ghishan FK, Greene HI. Liver disease in children with PiZZ α-1-antitrypsin deficiency. Hepathology 1988;8:307-10.
23. Nemeth A. Liver transplantation in Alpha- 1-Antitrypsin deficiency. Eur J Pediatr 1999; 158(suppl 2):S85-88.
24. Sveger T, Eriksson S. The liver in adolescents with α-1-Antitrypsin deficiency. Hepatology 1995;22:514-7.
25. Wall M, Moe E, Eisenberg J, et al. Longterm follow-up of a cohort of children with alpha-1-antitrypsin deficiency. J Pediatr 1990; 116:248-51.
26. Francavilla R, Castellaneta SP, Hadzic N, et al. Prognosis of alpha-1-antitrypsin deficiencyrelated liver disease in the era of pediatric liver transplantation. J Hepatol 2000;32:986-92.
27. Ibarguen E, Gross CR, Savik K, Sharp H. Liver disease in α-1-antitrypsin deficiency: prognostic indicators. J Pediatr 1990;117:864- 70.
28. Pittschieler K. Liver involvement in α-1-antitrypsin deficient phenotypes PiSZ and PiMZ. Acta Paediatr 2002;91:239-40.
29. Graziadei IW, Joseph JJ, Wiesner RH, et al. Increased risk of chronic liver failure in adults with heterozygous alpha1-antitrypsin deficiency. Hepatology 1998;28:1058-63.
30. Yoon D, Kueppers F, Genta RM, et al. Role of alpha-1-antichymotrypsin deficiency in promoting cirrhosis in two siblings with heterozygous α-1-antitrypsin deficiency phenotype SZ. Gut 2002;50:730-2.
31. Sveger T, Piitulainen E, Arborelius M. Clinical feature and lung function in 18-year-old adolescents with alpha1-antitrypsin deficiency. Acta Paediatr 1995;84:815-6.
32. Piitulainen E, Sveger T. Effect of environmental and clinical factors on lung function and respiratory symtoms in adolescents with alpha1-antitrypsin deficiency. Acta Paediatr 1998;87:1120-4.
33. Piitulainen E, Sveger T. Respiratory symptoms and lung function in young adults with severe α-1-antitrypsin deficiency (PiZZ). Thorax 2002;57:705-8.
34. Hird MF, Greenough A, Mieli-Vergani G, Mowat AP. Hyperinflation in children with liver disease due to α-1-antitrypsin deficiency. Pediatr Pulmonol 1991;11:212-6.
35. Davis ID, Burke B, Frese D, Sharp HL, Kim Y. The pathologic spectrum of the nephropathy associated with alpha 1-antitrypsin deficiency. Hum Pathol 1992;23:57-62.
36. Whitehouse DB, Lovegrove JU, Mieli-Vergani G. “SZ like” α-1-antitrypsin phenotypes in PiZZ children with liver disease. Ann Hum Genet 1994;58:1-7.
37. Pennesi M, Lepore L, Fains S, et al. Difetto di α-1-antitripsina. Medico e Bambino 1992; 7:17-22.
38. Udall JN, Dixon M, Newman AP, et al. Liver disease in Alpha-1-Antitrypsin deficiency: a retrospective analysis of the influence of early breast vs bottle-feeding. JAMA 1985;253:2679- 82.
39. Sveger T. Breast-feeding, Alpha-1-Antitrypsin deficiency and liver disease. JAMA (letter) 1985;245:3036.
40. Pittschieler K. Il deficit di alfa-1-antitripsina e malattia epatica. In: Aggiornamenti in Pediatria, 1996:3-32.
41. Mahadeva R, Dafforn TR, Carrell RW, Lomas DA. 6-mer peptide selectively anneals to a pathogenic serpin conformation and bloks polymerisation. Implications for the prevention of Z α-1-antitrypsin-related cirrhosis. J Biol Chem 2002;277:6771-4.
42. Devlin GL, Parfrey H, Tew DJ, et al. Prevention of polymerisation of M and Z α-1-antitrypsin with trimethylamine N-oxide. Implications for the treatment of alpha1-at deficiency. Am J Respir Cell Mol Biol 2001;24:727-32
43. Dirksen A, Dijkman JL, Madsen F, et al. A randomised clinical trial of alpha1-antitrypsin augmentation therapy. Am J Resp Crit Care Med 1999;160:1468.
44. Lieberman J. Augmentation therapy reduces frequency of lung infections in antitrypsin deficiency. Chest 2000;118:1480-5.
45. Wencker M, Fuhrmann B, Banik N, Konietzko N. Longitudinal follow-up of patients with α-1-protease inhibitor deficiency before and during therapy with α-1-protease inhibitor. Chest 2001;119:737-44.
46. Stockley RA, Bayley DL, Unsal I, Dowson LJ. The effect of augmentation therapy on bronchial inflammation in α-1-Antitrypsin deficiency. Am J Resp Crit Care Med 2002; 165:1494-8.
47. Metz R, DiCola M, Kurihara T, et al. Mode of action of RNA/DNA oligonucleotides: Progress in the development of gene repair as therapy for α-1-Antitrypsin deficiency. Chest 2002;121;91S-97S.
48. Seerolm N, Kok-Jensen A. Clinical features and prognosis of life time non-smokers with severe Alpha-1-Antitrypsin deficiency. Thorax 1998;53:265-8.
49. Piitulainen E, Eriksson S. Decline in FEV1 related to smoking status in individuals with severe α-1-Antitrypsin deficiency (PiZZ). Eur Respir J 1999;13:247-51.
50. Sveger T, Piitulainen E, Arborelius M. Lung function in adolescents with α-1-antitripsin deficiency. Acta Paediatr 1994;83:1170-3.
2. Campbell EJ. Alpha-1-Antitrypsin deficiency: incidence and detection program. Respir Med 2000;94(suppl C):S18-21.
3. Beckman L, Sikstrom C, Mikelsaar A, et al. Alpha 1-Antitrypsin (PI) alleles as markers of Westeuropean influence in Baltic Sea region. Hum Hered 1999;49:52-5.
4. Sveger T, Thelin T. A future for neonatal α- 1-Antitrypsin screening. Acta Paediatr 2000; 89:628-31.
5. Stoller Jk, Dodge JA, Boulyjenkov V. Alpha- 1-Antitrypsin deficiency: memorandum from a WHO meeting. Bull WHO 1997;75:397-415.
6. Fisher HP, Ortiz-Pallardo E, Ko Y,et al. Chronic liver disease in heterozygous α-1-antitrypsin deficiency PiZ. J Hepatol 2000; 33:883- 92.
7. O’Brien ML, Buist NR, Murphey WH. Neonatal screening for α-1-Antitrypsin deficiency. J Pediatr 1978;92:1006-10.
8. Sveger T. Liver disease in α-1-Antitrypsin deficiency detected by screening of 200,000 infants. NEJM 1976;294:1316-21.
9. Pittschieler K. Rare α-1-Antitrypsin phenotypes and liver-test abnormalities during infancy. Acta Paediatr 2001;90:406-8.
10. Carrell R, Lomas D. Alpha-1-Antitrypsin deficiency - A Model for Conformational Disease. N Engl J Med 2002;346:45-53.
11. Parmer JS, Mahadeva R, Reed BJ, et al. Polymers of α-1-Antitrypsin are chemotactic for human neutrophils. A new paradigm for pathogenesis of emphysema. Am J Respir Cell Mol Biol 2002; 26:723-30.
12. Carrell RW, Lomas DA. Conformational disease. Lancet 1997;350:134-8.
13. Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z α-1-Antitrypsin accumulation in the liver. Nature 1992;357:605-7.
14. Mahadeva R, Chang WS, Dafforn TR, et al. Heteropolymerization of S, I, and Z α-1-antitrypsin and liver cirrhosis. J Clin Invest 1999;103(7):999-1006.
15. Marcus N, Teckman JH, Perlmutter DH. Alpha-1-Antitrypsin deficiency: from genotype to childhood disease. J Pediatr Gastroenterol Nutr 1998;27:65-74.
16. Wu Y, Whitman I, Molmenti E, et al. A lag in intracellular degradation of mutant α-1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha-1-antitrypsin deficiency. Proc Natl Acad Sci USA 1994; 91:9014-8.
17. van Kries R. Neonatal vitamin K prophylaxis: the Gordian Knot still awaits untying. BMJ 1998;316:161-2.
18. Fischler B, Papadogiannakis N, Nemeth A. Aetiological factors in neonatal cholestasis. Acta Paediatr 2001;90:88-92.
19. Fischler B, Papadogiannakis N, Nemeth A. Clinical aspects on neonatal cholestasis based on observations at Swedish tertiary referral centre. Acta Paediatr 2001;90:171-8.
20. Mieli-Vergani G, Howard ER, Mowat AP. Liver disease in infancy: a 20 year perspective. Gut 1991;(suppl):S123-28.
21. Psacharopolous HT, Mowat AP, Cook PJ, et al. Outcome of liver disease associated with alpha-1-antitrypsin deficiency (PiZ). Implications for genetic counselling and antenatal diagnosis. Arch Dis Child 1983;58:882-7.
22. Ghishan FK, Greene HI. Liver disease in children with PiZZ α-1-antitrypsin deficiency. Hepathology 1988;8:307-10.
23. Nemeth A. Liver transplantation in Alpha- 1-Antitrypsin deficiency. Eur J Pediatr 1999; 158(suppl 2):S85-88.
24. Sveger T, Eriksson S. The liver in adolescents with α-1-Antitrypsin deficiency. Hepatology 1995;22:514-7.
25. Wall M, Moe E, Eisenberg J, et al. Longterm follow-up of a cohort of children with alpha-1-antitrypsin deficiency. J Pediatr 1990; 116:248-51.
26. Francavilla R, Castellaneta SP, Hadzic N, et al. Prognosis of alpha-1-antitrypsin deficiencyrelated liver disease in the era of pediatric liver transplantation. J Hepatol 2000;32:986-92.
27. Ibarguen E, Gross CR, Savik K, Sharp H. Liver disease in α-1-antitrypsin deficiency: prognostic indicators. J Pediatr 1990;117:864- 70.
28. Pittschieler K. Liver involvement in α-1-antitrypsin deficient phenotypes PiSZ and PiMZ. Acta Paediatr 2002;91:239-40.
29. Graziadei IW, Joseph JJ, Wiesner RH, et al. Increased risk of chronic liver failure in adults with heterozygous alpha1-antitrypsin deficiency. Hepatology 1998;28:1058-63.
30. Yoon D, Kueppers F, Genta RM, et al. Role of alpha-1-antichymotrypsin deficiency in promoting cirrhosis in two siblings with heterozygous α-1-antitrypsin deficiency phenotype SZ. Gut 2002;50:730-2.
31. Sveger T, Piitulainen E, Arborelius M. Clinical feature and lung function in 18-year-old adolescents with alpha1-antitrypsin deficiency. Acta Paediatr 1995;84:815-6.
32. Piitulainen E, Sveger T. Effect of environmental and clinical factors on lung function and respiratory symtoms in adolescents with alpha1-antitrypsin deficiency. Acta Paediatr 1998;87:1120-4.
33. Piitulainen E, Sveger T. Respiratory symptoms and lung function in young adults with severe α-1-antitrypsin deficiency (PiZZ). Thorax 2002;57:705-8.
34. Hird MF, Greenough A, Mieli-Vergani G, Mowat AP. Hyperinflation in children with liver disease due to α-1-antitrypsin deficiency. Pediatr Pulmonol 1991;11:212-6.
35. Davis ID, Burke B, Frese D, Sharp HL, Kim Y. The pathologic spectrum of the nephropathy associated with alpha 1-antitrypsin deficiency. Hum Pathol 1992;23:57-62.
36. Whitehouse DB, Lovegrove JU, Mieli-Vergani G. “SZ like” α-1-antitrypsin phenotypes in PiZZ children with liver disease. Ann Hum Genet 1994;58:1-7.
37. Pennesi M, Lepore L, Fains S, et al. Difetto di α-1-antitripsina. Medico e Bambino 1992; 7:17-22.
38. Udall JN, Dixon M, Newman AP, et al. Liver disease in Alpha-1-Antitrypsin deficiency: a retrospective analysis of the influence of early breast vs bottle-feeding. JAMA 1985;253:2679- 82.
39. Sveger T. Breast-feeding, Alpha-1-Antitrypsin deficiency and liver disease. JAMA (letter) 1985;245:3036.
40. Pittschieler K. Il deficit di alfa-1-antitripsina e malattia epatica. In: Aggiornamenti in Pediatria, 1996:3-32.
41. Mahadeva R, Dafforn TR, Carrell RW, Lomas DA. 6-mer peptide selectively anneals to a pathogenic serpin conformation and bloks polymerisation. Implications for the prevention of Z α-1-antitrypsin-related cirrhosis. J Biol Chem 2002;277:6771-4.
42. Devlin GL, Parfrey H, Tew DJ, et al. Prevention of polymerisation of M and Z α-1-antitrypsin with trimethylamine N-oxide. Implications for the treatment of alpha1-at deficiency. Am J Respir Cell Mol Biol 2001;24:727-32
43. Dirksen A, Dijkman JL, Madsen F, et al. A randomised clinical trial of alpha1-antitrypsin augmentation therapy. Am J Resp Crit Care Med 1999;160:1468.
44. Lieberman J. Augmentation therapy reduces frequency of lung infections in antitrypsin deficiency. Chest 2000;118:1480-5.
45. Wencker M, Fuhrmann B, Banik N, Konietzko N. Longitudinal follow-up of patients with α-1-protease inhibitor deficiency before and during therapy with α-1-protease inhibitor. Chest 2001;119:737-44.
46. Stockley RA, Bayley DL, Unsal I, Dowson LJ. The effect of augmentation therapy on bronchial inflammation in α-1-Antitrypsin deficiency. Am J Resp Crit Care Med 2002; 165:1494-8.
47. Metz R, DiCola M, Kurihara T, et al. Mode of action of RNA/DNA oligonucleotides: Progress in the development of gene repair as therapy for α-1-Antitrypsin deficiency. Chest 2002;121;91S-97S.
48. Seerolm N, Kok-Jensen A. Clinical features and prognosis of life time non-smokers with severe Alpha-1-Antitrypsin deficiency. Thorax 1998;53:265-8.
49. Piitulainen E, Eriksson S. Decline in FEV1 related to smoking status in individuals with severe α-1-Antitrypsin deficiency (PiZZ). Eur Respir J 1999;13:247-51.
50. Sveger T, Piitulainen E, Arborelius M. Lung function in adolescents with α-1-antitripsin deficiency. Acta Paediatr 1994;83:1170-3.