perinatologyРоссийский вестник перинатологии и педиатрииRossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)1027-40652500-2228Ltd. “The National Academy of Pediatric Science and Innovation”10.21508/1027-4065-2020-65-1-11-21perinatology-1052Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWSПатофизиологические аспекты поражения печени у детей при недостаточности альфа-1-антитрипсинаPathophysiological aspects of liver damage in children with alpha-1-antitrypsin deficiencyhttps://orcid.org/0000-0002-5413-9599ВолынецГ. В.VolynetsG. V.

Волынец Галина Васильевна – д.м.н., гл. науч. сотр. отдела гастроэнтерологии 

125412 Москва, ул. Талдомская, д. 2

Moscow

volynec_g@mail.ruhttps://orcid.org/0000-0001-8837-9243НикитинА. В.NikitinA. V.

Никитин Артем Вячеславович – к.м.н., вед. науч. сотр. отдела гастроэнтерологии, асс. кафедры гастроэнтерологии 

125412 Москва, ул. Талдомская, д. 2

Moscow

ОСП «Научно-исследовательский клинический институт педиатрии им. академика Ю.Е. Вельтищева»; ФГАОУ ВО РНИМУ им. Н.И. Пирогова Минздрава РоссииРоссияVeltischev Research and Clinical Institute for Pediatrics of the Pirogov; Russian National Research Medical UniversityRussian Federation2020050320206511121Copyright © Ltd. “The National Academy of Pediatric Science and Innovation”, 20202020Ltd. “The National Academy of Pediatric Science and Innovation”Ltd. “The National Academy of Pediatric Science and Innovation”https://www.ped-perinatology.ru/jour/about/submissions#copyrightNoticehttps://www.ped-perinatology.ru/jour/article/view/1052

Дефицит альфа-1-антитрипсина представляет собой аутосомно-рецессивное заболевание, характеризующееся поражением печени у детей и взрослых, а также заболеванием легких, обусловленным снижением соответствующего содержания белка в сыворотке вследствие мутаций в гене PI (proteinase inhibitor). Большинство заболеваний печени связано с гомозиготной мутацией по аллелю Z. У детей с генотипом PI*ZZ клинические проявления заболевания печени могут сильно варьировать. В неонатальном периоде заболевание печени обычно носит холестатический характер и сопровождается длительной холестатической желтухой, кожным зудом, определить который объективно можно лишь в более старшем возрасте (после 6 мес), снижением аппетита и отставанием в прибавке массы тела, гепато- и спленомегалией. В статье представлен обзор патофизиологии поражения печени при дефиците альфа-1-антитрипсина у детей. Изложены рекомендации по ведению детей с подозрением и подтвержденным дефицитом альфа-1-антитрипсина.

Alpha-1-antitrypsin deficiency is an autosomal recessive disease characterized by both liver damage and lung disease in children and adults because of a decrease in the serum protein content due to the mutations in the PI (proteinase inhibitor) gene. The majority of liver diseases are associated with a homozygous mutation of the Z allele. There are many variations of clinical manifestations of the liver disease in children with the PI*ZZ genotype.  In the neonatal period, liver disease is usually cholestatic; and it is accompanied by a prolonged cholestatic jaundice, skin itching, which can be determined only later (after 6 months), decreased appetite and bad weight gain, hepato- and splenomegaly. The article describes the pathophysiology of liver damage in children with alpha-1-antitrypsin deficiency. The authors provide their recommendations for the management of children with suspected and confirmed alpha-1-antitrypsin deficiency.

детидефицит альфа-1-антитрипсинапатофизиология поражения печенихолестазфиброзциррозгепатоцеллюлярная карциномаchildrenalfa-1-antitrypsin deficiencypathophysiology of liver damagecholestasisfibrosiscirrhosishepatocellular carcinomaReferencesLaurell C.B., Eriksson S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. 1963. COPD 2013; 10 Suppl 1: 3–8. DOI: 10.3109/15412555.2013.771956Laurell C.B., Eriksson S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. 1963. COPD 2013; 10 Suppl 1: 3–8. DOI: 10.3109/15412555.2013.771956Sveger 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/NEJM197606102942404Sveger 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/NEJM197606102942404Campos M.A., Wanner A., Zhang G., Sandhaus R.A. Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest 2005; 128 (3): 1179–1186. DOI: 10.1378/chest.128.3.1179Campos M.A., Wanner A., Zhang G., Sandhaus R.A. Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest 2005; 128 (3): 1179–1186. DOI: 10.1378/chest.128.3.1179Duvoix A., Roussel B.D., Lomas D.A. Molecular pathogenesis of alpha-1-antitrypsin deficiency. Rev Mal Respir 2014; 31 (10): 992–1002. DOI: 10.1016/j.rmr.2014.03.015Duvoix A., Roussel B.D., Lomas D.A. Molecular pathogenesis of alpha-1-antitrypsin deficiency. Rev Mal Respir 2014; 31 (10): 992–1002. DOI: 10.1016/j.rmr.2014.03.015Ильченко А.А. Болезни желчного пузыря и желчных путей. Руководство для врачей. 2-е изд., перераб. и доп. М.: Медицинское информационное агентство, 2011; 880. [Il’chenko A.A. Diseases of the gallbladder and biliary tract. A guide for doctors. Moscow: Meditsinskoe informatsionnoe agentstvo, 2011; 880. (in Russ.)]Ильченко А.А. Болезни желчного пузыря и желчных путей. Руководство для врачей. 2-е изд., перераб. и доп. М.: Медицинское информационное агентство, 2011; 880. [Il’chenko A.A. Diseases of the gallbladder and biliary tract. A guide for doctors. Moscow: Meditsinskoe informatsionnoe agentstvo, 2011; 880. (in Russ.)]Жигальцова-Кучинская О.А., Сивицкая Л.Н., Даниленко Н.Г., Жигальцов А.М., Нагорнов И.В., Метельский С.М. Дефицит альфа-1-антитрипсина: генетические основы, эпидемиология, значение в развитии бронхолегочной патологии. Вестник Витебского государственного медицинского университета 2015; 14 (6): 39-52. [Zhigaltsova-Kuchinskaya O.A., Sivitskaya L.N., Danilenko N.G., Zhigaltsov A.M., Nagornov I.V., Metelsky S.M. Alpha-1-antitrypsin deficiency: genetic basis, epidemiology, significance in the development of bronchopulmonary pathology. Vestnik Vitebskogo gosudarstvennogo meditsinskogo universiteta 2015; 14 (6): 39–52. (in Russ.)] 7. Колесникова Е.В. Альфа-1-антитрипсиновая недостаточность: Современный взгляд на проблему. Сучасна гастроентерологія 2008; 2: 93–98. [Kolesnikova E.V. Alpha-1-antitrypsin deficiency: A modern view of the problem. Suchasna gastroenterologіya 2008; 2: 93–98. (in Russ.)]Жигальцова-Кучинская О.А., Сивицкая Л.Н., Даниленко Н.Г., Жигальцов А.М., Нагорнов И.В., Метельский С.М. Дефицит альфа-1-антитрипсина: генетические основы, эпидемиология, значение в развитии бронхолегочной патологии. Вестник Витебского государственного медицинского университета 2015; 14 (6): 39-52. [Zhigaltsova-Kuchinskaya O.A., Sivitskaya L.N., Danilenko N.G., Zhigaltsov A.M., Nagornov I.V., Metelsky S.M. Alpha-1-antitrypsin deficiency: genetic basis, epidemiology, significance in the development of bronchopulmonary pathology. Vestnik Vitebskogo gosudarstvennogo meditsinskogo universiteta 2015; 14 (6): 39–52. (in Russ.)] 7. Колесникова Е.В. Альфа-1-антитрипсиновая недостаточность: Современный взгляд на проблему. Сучасна гастроентерологія 2008; 2: 93–98. [Kolesnikova E.V. Alpha-1-antitrypsin deficiency: A modern view of the problem. Suchasna gastroenterologіya 2008; 2: 93–98. (in Russ.)]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 (7): 818–900. DOI: 10.1164/rccm.168.7.818American 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 (7): 818–900. DOI: 10.1164/rccm.168.7.818McLean C., Greene C.M., McElvaney N.G. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency. Biologics 2009; 3: 63–75.McLean C., Greene C.M., McElvaney N.G. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency. Biologics 2009; 3: 63–75.Teckman J.H., Jain A. Advances in alpha-1-antitrypsin deficiency liver disease. Curr Gastroenterol Rep 2014; 16 (1): 367. DOI: 10.1007/s11894-013-0367-8Teckman J.H., Jain A. Advances in alpha-1-antitrypsin deficiency liver disease. Curr Gastroenterol Rep 2014; 16 (1): 367. DOI: 10.1007/s11894-013-0367-8Stoller J.K., Aboussouan L.S. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med 2012; 185 (3): 246–259. DOI: 10.1164/rccm.201108-1428CIStoller J.K., Aboussouan L.S. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med 2012; 185 (3): 246–259. DOI: 10.1164/rccm.201108-1428CIAlpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ 1997; 75 (5): 397–415.Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ 1997; 75 (5): 397–415.Crowther D.C., Belorgey D., Miranda E., Kinghorn K.J., Sharp L.K., Lomas D.A. Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. Eur J Hum Genet 2004; 12 (3): 167–172. DOI: 10.1038/sj.ejhg.5201127Crowther D.C., Belorgey D., Miranda E., Kinghorn K.J., Sharp L.K., Lomas D.A. Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. Eur J Hum Genet 2004; 12 (3): 167–172. DOI: 10.1038/sj.ejhg.5201127Davis I.D., Burke B., Freese D., Sharp H.L., Kim Y. The pathologic spectrum of the nephropathy associated with alpha 1-antitrypsin deficiency. Hum Pathol 1992; 23 (1): 57– 62. DOI: 10.1016/0046-8177(92)90012-rDavis I.D., Burke B., Freese D., Sharp H.L., Kim Y. The pathologic spectrum of the nephropathy associated with alpha 1-antitrypsin deficiency. Hum Pathol 1992; 23 (1): 57– 62. DOI: 10.1016/0046-8177(92)90012-rFregonese L., Stolk J., Frants R.R., Veldhuisen B. Alpha-1 antitrypsin Null mutations and severity of emphysema. Respir Med 2008; 102 (6): 876–884. DOI: 10.1016/j. rmed.2008.01.009Fregonese L., Stolk J., Frants R.R., Veldhuisen B. Alpha-1 antitrypsin Null mutations and severity of emphysema. Respir Med 2008; 102 (6): 876–884. DOI: 10.1016/j. rmed.2008.01.009Fairbanks K.D., Tavill A.S. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol 2008; 103 (8): 2136–2141. DOI: 10.1111/j.1572-0241.2008.01955.xFairbanks K.D., Tavill A.S. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol 2008; 103 (8): 2136–2141. DOI: 10.1111/j.1572-0241.2008.01955.xMolloy K., Hersh C.P., Morris V.B., Carroll T.P., O’Connor C.A., Lasky-Su J.A. et al. Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes. Am J Respir Crit Care Med 2014; 189 (4): 419–427. DOI: 10.1164/rccm.201311-1984OCMolloy K., Hersh C.P., Morris V.B., Carroll T.P., O’Connor C.A., Lasky-Su J.A. et al. Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes. Am J Respir Crit Care Med 2014; 189 (4): 419–427. DOI: 10.1164/rccm.201311-1984OCLomas D.A., Evans D.L., Finch J.T., Carrell R.W. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992; 357 (6379): 605–607. DOI: 10.1038/357605a0Lomas D.A., Evans D.L., Finch J.T., Carrell R.W. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992; 357 (6379): 605–607. DOI: 10.1038/357605a0Lomas D.A. Twenty years of polymers: A personal perspective on alpha-1 antitrypsin deficiency. COPD 2013; 10 (Suppl 1): 17–25. DOI: 10.3109/15412555.2013.764401Lomas D.A. Twenty years of polymers: A personal perspective on alpha-1 antitrypsin deficiency. COPD 2013; 10 (Suppl 1): 17–25. DOI: 10.3109/15412555.2013.764401Teckman J.H. Liver disease in alpha-1 antitrypsin deficiency: current understanding and future therapy. COPD 2013; 10 (Suppl 1): 35–43. DOI: 10.3109/15412555.2013.765839Teckman J.H. Liver disease in alpha-1 antitrypsin deficiency: current understanding and future therapy. COPD 2013; 10 (Suppl 1): 35–43. DOI: 10.3109/15412555.2013.765839Rakela J., Goldschmiedt M., Ludwig J. Late manifestation of chronic liver disease in adults with alpha-1-antitrypsin deficiency. Dig Dis Sci 1987; 32 (12): 1358–1362. DOI: 10.1007/bf01296661Rakela J., Goldschmiedt M., Ludwig J. Late manifestation of chronic liver disease in adults with alpha-1-antitrypsin deficiency. Dig Dis Sci 1987; 32 (12): 1358–1362. DOI: 10.1007/bf01296661de Serres F., Blanco I. Role of alpha-1 antitrypsin in human health and disease. J Intern Med 2014; 276 (4): 311–335. DOI: 10.1111/joim.12239de Serres F., Blanco I. Role of alpha-1 antitrypsin in human health and disease. J Intern Med 2014; 276 (4): 311–335. DOI: 10.1111/joim.12239Sharp H.L., Bridges R.A., Krivit W., Freier E.F. Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder. J Lab Clin Med 1969; 73 (6): 934–939.Sharp H.L., Bridges R.A., Krivit W., Freier E.F. Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder. J Lab Clin Med 1969; 73 (6): 934–939.Sharp H.L. History of the first description of childhood liver disease in AATD. COPD 2013; 10 (Suppl 1): 13–16. DOI: 10.3109/15412555.2013.766165Sharp H.L. History of the first description of childhood liver disease in AATD. COPD 2013; 10 (Suppl 1): 13–16. DOI: 10.3109/15412555.2013.766165Francavilla R., Castellaneta S.P., Hadzic N., Chambers S.M., Portmann B., Tung J. 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)80103-8Francavilla R., Castellaneta S.P., Hadzic N., Chambers S.M., Portmann B., Tung J. 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)80103-8Kemmer N., Kaiser T., Zacharias V., Neff G.W. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant Proc 2008; 40 (5): 1492–1494. DOI: 10.1016/ j.transproceed.2008.02.075Kemmer N., Kaiser T., Zacharias V., Neff G.W. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant Proc 2008; 40 (5): 1492–1494. DOI: 10.1016/ j.transproceed.2008.02.075Sveger T., Eriksson S. The liver in adolescents with alpha 1- antitrypsin deficiency. Hepatol 1995; 22 (2): 514–517. DOI: 10.1002/hep.1840220221Sveger T., Eriksson S. The liver in adolescents with alpha 1- antitrypsin deficiency. Hepatol 1995; 22 (2): 514–517. DOI: 10.1002/hep.1840220221Teckman J.H., Gilmore R., Perlmutter D.H. Role of ubiquitin in proteasomal degradation of mutant alpha(1)-antitrypsin Z in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 2000; 278 (1): G39–48. DOI: 10.1152/ajpgi.2000.278.1.G39Teckman J.H., Gilmore R., Perlmutter D.H. Role of ubiquitin in proteasomal degradation of mutant alpha(1)-antitrypsin Z in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 2000; 278 (1): G39–48. DOI: 10.1152/ajpgi.2000.278.1.G39Lindblad D., Blomenkamp K., Teckman J. Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatol 2007; 46 (4): 1228–1235. DOI: 10.1002/hep.21822Lindblad D., Blomenkamp K., Teckman J. Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatol 2007; 46 (4): 1228–1235. DOI: 10.1002/hep.21822Teckman J.H., Rosenthal P., Abel R., Bass L.M., Michail S., Murray K.F. 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. 0000000000000753 31. Teckman J.H., Perlmutter D.H. Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol Gastrointest Liver Physiol 2000; 279 (5): 961–974. DOI: 10.1152/ajpgi.2000.279.5.G961Teckman J.H., Rosenthal P., Abel R., Bass L.M., Michail S., Murray K.F. 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. 0000000000000753 31. Teckman J.H., Perlmutter D.H. Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol Gastrointest Liver Physiol 2000; 279 (5): 961–974. DOI: 10.1152/ajpgi.2000.279.5.G961Sifers R.N. Medicine. Clearing conformational disease. Science 2010; 329 (5988): 154–5. DOI: 10.1126/science.1192681Sifers R.N. Medicine. Clearing conformational disease. Science 2010; 329 (5988): 154–5. DOI: 10.1126/science.1192681Sifers R.N. Resurrecting the protein fold for disease intervention. Chem Biol 2013; 20 (3): 298–300. DOI: 10.1016/j. chembiol.2013.03.002Sifers R.N. Resurrecting the protein fold for disease intervention. Chem Biol 2013; 20 (3): 298–300. DOI: 10.1016/j. chembiol.2013.03.002Perlmutter D.H. Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu Rev Med 2011; 62: 333–345. DOI: 10.1146/annurev-med-042409-151920Perlmutter D.H. Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu Rev Med 2011; 62: 333–345. DOI: 10.1146/annurev-med-042409-151920Teckman J.H., Perlmutter D.H. 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 (22): 13215–13220. DOI: 10.1074/jbc.271.22.13215Teckman J.H., Perlmutter D.H. 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 (22): 13215–13220. DOI: 10.1074/jbc.271.22.13215Sifers R.N. Intracellular processing of alpha1-antitrypsin. Proc Am Thorac Soc 2010; 7 (6): 376–380. DOI: 10.1513/ pats.201001-011AWSifers R.N. Intracellular processing of alpha1-antitrypsin. Proc Am Thorac Soc 2010; 7 (6): 376–380. DOI: 10.1513/ pats.201001-011AWHidvegi T., Ewing M., Hale P., Dippold C., Beckett C., Kemp C. et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 2010; 329 (5988): 229–232. DOI: 10.1126/science.1190354Hidvegi T., Ewing M., Hale P., Dippold C., Beckett C., Kemp C. et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 2010; 329 (5988): 229–232. DOI: 10.1126/science.1190354Kaushal S., Annamali M., Blomenkamp K., Rudnick D., Halloran D., Brunt E.M. et al. Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model. Exp Biol Med (Maywood) 2010; 235 (6): 700–709. DOI: 10.1258/ebm.2010.009297Kaushal S., Annamali M., Blomenkamp K., Rudnick D., Halloran D., Brunt E.M. et al. Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model. Exp Biol Med (Maywood) 2010; 235 (6): 700–709. DOI: 10.1258/ebm.2010.009297Pastore N., Blomenkamp K., Annunziata F., Piccolo P., Mithbaokar P., Maria Sepe R. et al. 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 2013; 5 (3): 397–412. DOI: 10.1002/emmm.201202046Pastore N., Blomenkamp K., Annunziata F., Piccolo P., Mithbaokar P., Maria Sepe R. et al. 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 2013; 5 (3): 397–412. DOI: 10.1002/emmm.201202046Marcus N.Y., Blomenkamp K., Ahmad M., Teckman J.H. Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency. Exp Biol Med (Maywood) 2012; 237 (10): 1163–1172. DOI: 10.1258/ebm.2012.012106Marcus N.Y., Blomenkamp K., Ahmad M., Teckman J.H. Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency. Exp Biol Med (Maywood) 2012; 237 (10): 1163–1172. DOI: 10.1258/ebm.2012.012106Teckman J.H., Mangalat N. Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions. Expert Rev Gastroenterol Hepatol 2015; 9 (2): 261–268. DOI: 10.1586/17474124.2014.943187.Teckman J.H., Mangalat N. Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions. Expert Rev Gastroenterol Hepatol 2015; 9 (2): 261–268. DOI: 10.1586/17474124.2014.943187.Kalsheker N.A. alpha1-Antitrypsin deficiency: best clinical practice. J Clin Pathol 2009; 62: (10): 865–869. DOI: 10.1136/jcp.2008.063495Kalsheker N.A. alpha1-Antitrypsin deficiency: best clinical practice. J Clin Pathol 2009; 62: (10): 865–869. DOI: 10.1136/jcp.2008.063495Moyer V., Freese D.K., Whitington P.F., Olson A.D., Brewer F., Colletti R.B. et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39 (2): 115–128. DOI: 10.1097/00005176-200408000-00001Moyer V., Freese D.K., Whitington P.F., Olson A.D., Brewer F., Colletti R.B. et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39 (2): 115–128. DOI: 10.1097/00005176-200408000-00001Dawwas M.F., Davies S.E., Griffiths W.J., Lomas D.A., Alexander G.J. Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease. Am J Respir Crit Care Med 2013; 187 (5): 502–508. DOI: 10.1164/rccm.201204-0739OCDawwas M.F., Davies S.E., Griffiths W.J., Lomas D.A., Alexander G.J. Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease. Am J Respir Crit Care Med 2013; 187 (5): 502–508. DOI: 10.1164/rccm.201204-0739OCClark V.C., Dhanasekaran R., Brantly M., Rouhani F., Schreck P., Nelson D.R. Liver test results do not identify liver disease in adults with α(1)-antitrypsin deficiency. Clin Gastroenterol Hepatol 2012; 10 (11): 1278–1283. DOI: 10.1016/j.cgh.2012.07.007Clark V.C., Dhanasekaran R., Brantly M., Rouhani F., Schreck P., Nelson D.R. Liver test results do not identify liver disease in adults with α(1)-antitrypsin deficiency. Clin Gastroenterol Hepatol 2012; 10 (11): 1278–1283. DOI: 10.1016/j.cgh.2012.07.007Rudnick D.A., Perlmutter D.H. Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatol 2005; 42 (3): 514–521. DOI: 10.1002/ hep.20815Rudnick D.A., Perlmutter D.H. Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatol 2005; 42 (3): 514–521. DOI: 10.1002/ hep.20815Ebell M.H., Siwek J., Weiss B.D., Woolf S.H., Susman J., Ewigman B. et al. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004; 69 (3): 548–556.Ebell M.H., Siwek J., Weiss B.D., Woolf S.H., Susman J., Ewigman B. et al. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004; 69 (3): 548–556.De Tommaso A.M., Rossi C.L., Escanhoela C.A., Serra H.G., Bertuzzo C.S., Hessel G. Diagnosis of alpha-1-antitrypsin deficiency by DNA analysis of children with liver disease. Arq Gastroenterol 2001; 38 (1): 63–68.De Tommaso A.M., Rossi C.L., Escanhoela C.A., Serra H.G., Bertuzzo C.S., Hessel G. Diagnosis of alpha-1-antitrypsin deficiency by DNA analysis of children with liver disease. Arq Gastroenterol 2001; 38 (1): 63–68.Filipponi F., Soubrane O., Labrousse F., Devictor D., Bernard O., Valayer J. et al. Liver transplantation for end-stage liver disease associated with alpha-1-antitrypsin deficiency in children: pretransplant natural history, timing and results of transplantation. J Hepatol 1994; 20 (1): 72–78. DOI: 10.1016/s0168-8278(05)80469-6Filipponi F., Soubrane O., Labrousse F., Devictor D., Bernard O., Valayer J. et al. Liver transplantation for end-stage liver disease associated with alpha-1-antitrypsin deficiency in children: pretransplant natural history, timing and results of transplantation. J Hepatol 1994; 20 (1): 72–78. DOI: 10.1016/s0168-8278(05)80469-6Stoller J.K., Brantly M. The challenge of detecting alpha-1 antitrypsin deficiency. COPD 2013; 10 (Suppl 1): 26–34. DOI: 10.3109/15412555.2013.763782Stoller J.K., Brantly M. The challenge of detecting alpha-1 antitrypsin deficiency. COPD 2013; 10 (Suppl 1): 26–34. DOI: 10.3109/15412555.2013.763782Silverman E.K., Sandhaus R.A. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 2009; 360 (26): 2749– 2757. DOI: 10.1056/NEJMcp0900449Silverman E.K., Sandhaus R.A. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 2009; 360 (26): 2749– 2757. DOI: 10.1056/NEJMcp0900449Sveger T., Thelin T., McNeil T.F. Young adults with alpha 1-antitrypsin deficiency identified neonatally: their health,Sveger T., Thelin T., McNeil T.F. Young adults with alpha 1-antitrypsin deficiency identified neonatally: their health,knowledge about and adaptation to the high-risk condition. Acta Paediatr 1997; 86 (1): 37–40. DOI: 10.1111/j.16512227.1997.tb08828.xknowledge about and adaptation to the high-risk condition. Acta Paediatr 1997; 86 (1): 37–40. DOI: 10.1111/j.16512227.1997.tb08828.xCoors M.E., Moseley R., McGorray S. Informed consent process in Alpha-1 testing of atrisk children: views of parents and adults tested as children. COPD 2011; 8 (1): 30–38. DOI: 10.3109/15412555.2010.541958Coors M.E., Moseley R., McGorray S. Informed consent process in Alpha-1 testing of atrisk children: views of parents and adults tested as children. COPD 2011; 8 (1): 30–38. DOI: 10.3109/15412555.2010.541958Harada K., Ohba K., Ozaki S., Isse K., Hirayama T., Wada A. et al. Peptide antibiotic human beta-defensin-1 and -2 contribute to antimicrobial defense of the intrahepatic biliary tree. Hepatol 2004; 40 (4): 925–932. DOI: 10.1002/hep.20379Harada K., Ohba K., Ozaki S., Isse K., Hirayama T., Wada A. et al. Peptide antibiotic human beta-defensin-1 and -2 contribute to antimicrobial defense of the intrahepatic biliary tree. Hepatol 2004; 40 (4): 925–932. DOI: 10.1002/hep.20379Sveger T., Thelin T., McNeil T.F. Neonatal alpha1-antitrypsin screening: parents’ views and reactions 20 years after the identification of the deficiency state. Acta Paediatr 1999; 88 (3): 315–318. DOI: 10.1080/08035259950170097 56. Bakula A., Socha P., Pawlowska J., Teisseyre M., Jankowska I., Kalicinski P. 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.2007.09.046Sveger T., Thelin T., McNeil T.F. Neonatal alpha1-antitrypsin screening: parents’ views and reactions 20 years after the identification of the deficiency state. Acta Paediatr 1999; 88 (3): 315–318. DOI: 10.1080/08035259950170097 56. Bakula A., Socha P., Pawlowska J., Teisseyre M., Jankowska I., Kalicinski P. 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.2007.09.046Jain A.B., Patil V., Sheikh B., Apostolakos M., Ryan C., Kashyap R. et al. Effect of liver transplant on pulmonary functions in adult patients with alpha 1 antitrypsin deficiency: 7 cases. Exp Clin Transplant 2010; 8 (1): 4–8.Jain A.B., Patil V., Sheikh B., Apostolakos M., Ryan C., Kashyap R. et al. Effect of liver transplant on pulmonary functions in adult patients with alpha 1 antitrypsin deficiency: 7 cases. Exp Clin Transplant 2010; 8 (1): 4–8.Vennarecci G., Gunson B.K., Ismail T., Hübscher S.G., Kelly D.A., McMaster P. et al. Transplantation for end stage liver disease related to alpha 1 antitrypsin. Transplant 1996; 61 (10): 1488–1495. DOI: 10.1097/00007890199605270-00014Vennarecci G., Gunson B.K., Ismail T., Hübscher S.G., Kelly D.A., McMaster P. et al. Transplantation for end stage liver disease related to alpha 1 antitrypsin. Transplant 1996; 61 (10): 1488–1495. DOI: 10.1097/00007890199605270-00014Fromer L. Improving diagnosis and management of alpha-1 antitrypsin deficiency in primary care: translating knowledge into action. COPD 2010; 7 (3): 192–198. DOI: 10.3109/15412555.2010.482577Fromer L. Improving diagnosis and management of alpha-1 antitrypsin deficiency in primary care: translating knowledge into action. COPD 2010; 7 (3): 192–198. DOI: 10.3109/15412555.2010.482577Taliercio R.M., Chatburn R.L., Stoller J.K. Knowledge of alpha-1 antitrypsin deficiency among internal medicine house officers and respiratory therapists: results of a survey. Respir Care 2010; 55 (3): 322–327.Taliercio R.M., Chatburn R.L., Stoller J.K. Knowledge of alpha-1 antitrypsin deficiency among internal medicine house officers and respiratory therapists: results of a survey. Respir Care 2010; 55 (3): 322–327.Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014; 4 (1): 25–36. DOI: 10.1016/j. jceh.2013.10.005Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014; 4 (1): 25–36. DOI: 10.1016/j. jceh.2013.10.005Campos M., Shmuels D., Walsh J. Detection of alpha-1 antitrypsin deficiency in the US. Am J Med 2012; 125 (7): 623– 624. DOI: 10.1016/j.amjmed.2011.12.014Campos M., Shmuels D., Walsh J. Detection of alpha-1 antitrypsin deficiency in the US. Am J Med 2012; 125 (7): 623– 624. DOI: 10.1016/j.amjmed.2011.12.014Aboussouan L.S., Stoller J.K. Detection of alpha-1 antitrypsin deficiency: a review. Respir Med 2009; 103 (3): 335–341. DOI: 10.1016/j.rmed.2008.10.006 64. Bals R., Koczulla R., Kotke V., Andress J., Blackert K., Vogelmeier C. Identification of individuals with alpha-1-antitrypsin deficiency by a targeted screening program. Respir Med 2007; 101 (8): 1708–1714. DOI: 10.1016/j. rmed.2007.02.024Aboussouan L.S., Stoller J.K. Detection of alpha-1 antitrypsin deficiency: a review. Respir Med 2009; 103 (3): 335–341. DOI: 10.1016/j.rmed.2008.10.006 64. Bals R., Koczulla R., Kotke V., Andress J., Blackert K., Vogelmeier C. Identification of individuals with alpha-1-antitrypsin deficiency by a targeted screening program. Respir Med 2007; 101 (8): 1708–1714. DOI: 10.1016/j. rmed.2007.02.024Hogarth D.K., Rachelefsky G. Screening and familial testing of patients for alpha 1-antitrypsin deficiency. Chest 2008; 133 (4): 981–988. DOI: 10.1378/chest.07-1001Hogarth D.K., Rachelefsky G. Screening and familial testing of patients for alpha 1-antitrypsin deficiency. Chest 2008; 133 (4): 981–988. DOI: 10.1378/chest.07-1001Thelin T., Sveger T., McNeil T.F. Primary prevention in a high risk group: smoking habits in adolescents with homozygous alpha1antitrypsin deficiency (ATD). Acta Paediatr 1996; 85 (10): 1207–1212. DOI: 10.1111/j.1651-2227.1996.tb18230.xThelin T., Sveger T., McNeil T.F. Primary prevention in a high risk group: smoking habits in adolescents with homozygous alpha1antitrypsin deficiency (ATD). Acta Paediatr 1996; 85 (10): 1207–1212. DOI: 10.1111/j.1651-2227.1996.tb18230.xSeersholm N., Wencker M., Banik N., Viskum K., Dirksen A., Kok-Jensen A. et al. Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group. Eur Respir J 1997; 10 (10): 2260–2263. DOI: 10.1183/09031936.97.10102260Seersholm N., Wencker M., Banik N., Viskum K., Dirksen A., Kok-Jensen A. et al. Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group. Eur Respir J 1997; 10 (10): 2260–2263. DOI: 10.1183/09031936.97.10102260Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 1998; 158L (1): 49–59. DOI: 10.1164/ajrccm.158.1.9712017Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 1998; 158L (1): 49–59. DOI: 10.1164/ajrccm.158.1.9712017Wencker M., Banik N., Buhl R., Seidel R., Konietzko N. Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1-ATstudy group. Eur Respir J 1998; 11 (2): 428–433. DOI: 10.1183/09031936.98.11020428Wencker M., Banik N., Buhl R., Seidel R., Konietzko N. Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1-ATstudy group. Eur Respir J 1998; 11 (2): 428–433. DOI: 10.1183/09031936.98.11020428Dimmick J.E. Intrahepatic bile duct paucity and cytomegalovirus infection. Pediatr Pathol 1993; 13 (6): 847–852.Dimmick J.E. Intrahepatic bile duct paucity and cytomegalovirus infection. Pediatr Pathol 1993; 13 (6): 847–852.Dirksen A., Piitulainen E., Parr D.G., Deng C., Wencker M., Shaker SB. et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur Respir J 2009; 33 (6): 1345–1353. DOI: 10.1183/09031936.00159408Dirksen A., Piitulainen E., Parr D.G., Deng C., Wencker M., Shaker SB. et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur Respir J 2009; 33 (6): 1345–1353. DOI: 10.1183/09031936.00159408

The authors declare that there are no conflicts of interest present.