16,423 research outputs found

    Liver Transplantation for Advanced Liver Disease with Alpha-1antitrypsin Deficiency

    Get PDF
    ALPHA-1-antitrypsin deficiency associated with chronic obstructive airway disease was recognized in 1963 by Laurell and Ericksson.1 In 1969, Sharp2 described the first cases of alpha-1-antitrypsin-deficiency disease in children with cirrhosis. Since then, this inborn error has been recognized as one of the more common factors in cirrhosis of infancy and childhood,3 including “neonatal hepatitis.”4 Alpha-1-antitrypsin is a glycoprotein that accounts for a major portion of the alpha-1 globulin fraction of the serum.5 It is responsible for approximately 90 per cent of the antitrypsin activity6 of the serum, and it also inhibits several other plasma enzymes, including plasmin,7 elastase,8 collagenase,9 and. © 1980, Massachusetts Medical Society. All rights reserved

    REVERSAL OF HEPATIC ALPHA-1-ANTITRYPSIN DEPOSITION AFTER PORTACAVAL SHUNT

    Get PDF
    End-to-side portacaval shunts were carried out in three children with the liver disease of alpha-1-antitrypsin deficiency and complications of portal hypertension. Their clinical courses have been stable for 31/2 to almost 7 years. Postoperative liver biopsy material from two of the patients showed the typical histopathological changes caused by portal diversion, as well as an apparent reduction in the quantity of alpha-1-antitrypsin particles in the hepatocytes. The metabolic changes caused by portal diversion have apparently created a more favourable equilibrium between the synthesis and excretion of the abnormal alpha-1-antitrypsin. © 1983

    Alpha-1 antitrypsin deficiency

    Get PDF
    α-1 antitrypsin is synthesised in the liver and protects lung alveolar tissues from destruction by neutrophil elastase. α-1 antitrypsin deficiency is a common autosomal recessive condition (1:1600 to 1:1800) in which liver disease results from retention of abnormal polymerised α-1 antitrypsin in the endoplasmic reticulum of hepatocytes, and emphysema results from alveolar wall damage. The clinical consequences of α-1 antitrypsin deficiency in childhood are haemorrhagic disease in infancy, cholestasis in infancy, or chronic liver disease. Lung disease attributable to α-1 antitrypsin deficiency does not occur in childhood, but is closely linked to smoking in adults. Membranoproliferative glomerulonephritis, panniculitis, and necrotising vasculitis are associations with α-1 antitrypsin deficiency in adult life

    Diagnosis Of Alpha-1-antitrypsin Deficiency By Dna Analysis Of Children With Liver Disease

    Get PDF
    Background - Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. Objective - The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. Patients and Methods - Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genoma through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele) and Taq 1 (Z allele). Results - Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ) and two had the S allele with another allele (*S) different from Z. Conclusion - These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6%). A correct diagnosis is important for effective clinical follow-up and for genetic counseling.3816368Alagille, D., Cholestasis in the first three months of life (1979) Prog Liver Dis, 6, pp. 471-485Andresen, B.S., Knudsen, I., Jensen, P.K.A., Gregersen, N., Two novel nonradioactive polymerase chain reaction-based assays of dried blood spots, genomic DNA, or whole cells for fast, reliable detection of Z and S mutations in the alpha-1-antitrypsin gene (1992) Clin Chem, 38, pp. 2100-2107Balistreri, W.F., Schubert, W.K., Liver disease in infancy and childhood (1993) Diseases of the Liver. 7.ed., pp. 1099-1203. , Schiff L, Schiff ER, editors. Philadelphia: LippincottBillingsley, G.D., Cox, D.W., Functional assessment of genetic variants of alpha 1-antitrypsin (1982) Hum Genet, 61, pp. 118-122Brantly, M., Nukiwa, T., Crystal, R.G., Molecular basis of alpha-1-antitrypsin deficiency (1988) Am J Med, 84, pp. 13-31Carlson, J.A., Rogers, R.B., Sifers, R., Acumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice (1989) J Clin Invest, 83, pp. 1183-1190Carrel, R.W., Alpha 1-antitrypsin: Molecular pathology, leukocytes and tissue damage (1986) J Clin Invest, 78, pp. 1427-1431Cox, D.W., Woo, S.L., Mansfield, T., DNA restriction fragments associated with alpha 1-antitrypsin indicate a single origin for deficiency allele PI Z (1985) Nature, 316, pp. 79-81Crystal, R.G., Brantly, M.L., Hubbard, R.C., Curiel, D.T., States, D.J., Holmes, M.D., The alpha 1-antitrypsin gene and its mutations. Clinical consequences and strategies for therapy (1989) Chest, 95, pp. 196-208Crystal, R.G., Ferrans, V.J., Basset, F., Biologic basis of pulmonary fibrosis (1991) The Lung: Scientific Foundations, pp. 2031-2046. , Crystal RG, West JB, Barnes PJ, Cherniack S, editors. New YorkRaven PressCuriel, D., Brantly, M., Curiel, E., Crystal, R.G., Alpha-1-antitrypsin deficiency caused by the alpha-1-antitrypsin Nullmattawa gene. An insertion mutation rendering the alpha-1-antitrypsin gene incapable of producing alpha-1-antitrypsin (1989) J Clin Invest, 83, pp. 1144-1152Dermer, S.J., Johnson, E.M., Rapid DNA analysis of alpha 1-antitrypsin deficiency: Application of an improved method for amplifying mutated gene sequence (1988) Lab Invest, 59, pp. 403-408Deutsch, J., Becker, H., Auböck, L., Histopathological features of liver disease in alpha 1-antitrypsin deficiency (1994) Acta Paediatr, 393 (SUPPL.), pp. 8-12Dubel, J.R., Finwick, R., Hejtmancik, J.F., Denaturing gradient gel electrophoresis of the alpha 1-antitrypsin gene: Application to prenatal diagnosis (1991) Am J Med Genet, 41, pp. 39-43Evans, H.E., Levi, M., Mandl, I., Serum enzyme inhibitor concentrations in the respiratory distress syndrome (1970) Am Rev Resp Dis, 101, pp. 359-363Fagerhol, M.K., Cox, D.W., The PI polimorphism: Genetic, biochemical and clinical aspects of human alpha-1-antitrypsin (1981) Human Genetic, pp. 1-62. , Harris H, Hirchorn, K, editors. New York: PlenumGartner, J.C., Zitelli, B.J., Malatak, J.J., Shaw, B.W., Iwatsuki, S., Starzl, T.E., Orthotopic liver transplantation in children: Two-year experience with 47 patients (1984) Pediatrics, 74, pp. 140-145Ishak, K.G., Hepatic morphology in inherited metabolic diseases (1986) Sem Liver Dis, 6, pp. 246-258Jeppsson, J.O., Laurell, C.B., Fagerhol, M.K., Properties of isolated alpha-1-antitrypsin of Pi types M, S and Z (1978) Eur J Biochem, 83, pp. 143-153Lai, E.C., Kao, F.T., Law, M.L., Woo, S.L., Assignment of the alpha 1-antitrypsin gene and a sequence-related gene to human chromossome 14 by molecular hybridization (1983) Am J Hum Genet, 35, pp. 385-392Laurell, C.B., Eriksson, S., The electrophoretic alpha-1-globulin pattern of serum in alpha-1-antitrypsin deficiency (1963) Scand J Clin Lab Invest, 15, pp. 132-140Laurell, C.B., Kullander, S., Thorell, J., Effect of administration of a combined strogen-progestin contraceptive on the level of individual plasma proteins (1968) Scand J Clin Lab Invest, 21, pp. 337-343Massi, G., Chiarelli, C., Alpha 1-antitrypsin: Molecular and the Pi system (1994) Acta Paediatr, 393 (SUPPL.), pp. 1-4Mowat, A.P., Avaliação laboratorial das afecções hepatobiliares (1991) Doenças Hepáticas Em Pediatria. 2.ed., pp. 410-430. , Mowat AP. Rio de Janeiro: RevinterNukiwa, T., Brantly, M., Ogushi, F., Crystal, R.G., Characterization of the M1(ala 213) type of alpha-1-antitrypsin, a newly recognized common "normal" alpha-1-antitrypsin haplotype (1987) Biochemistry, 26, pp. 5259-5267Okayama, H., Curiel, D.T., Brantly, M.L., Holmes, M.D., Crystal, R.G., Rapid nonradioactive detection of mutations in the human genome by allele-specific amplification (1989) J Lab Clin Med, 114, pp. 105-113Perlmutter, D.H., The cellular basis for liver injury in alpha-1-antitrypsin deficiency (1991) Hepatology, 13, pp. 172-185Perlmutter, D.H., Clinical manifestations of alpha 1-antitrypsin deficiency (1995) Gastroenterol Clin North Am, 24, pp. 27-43Schroeder, W.T., Miller, M.F., Woo, S.L., Saunders, G.F., Chromosomal localization of the human alpha 1-antitrypsin gene (PI) to 14q31-32 (1985) Am J Hum Genet, 37, pp. 868-872Serra, H.G., (1998) Identificação Molecular Dos Alelos S e Z Do Gene Da Alfa-1-antitripsina Em Um Grupo de Pacientes Portadores de Doença Pulmonar Crônica [tese de Doutorado], , Campinas, SP: Instituto de Biologia da Universidade Estadual de CampinasSilverman, E.K., Miletich, J.P., Pierce, J.A., Sherman, L.A., Endicott, S.K., Broze, G.J., Campbell, E.J., Alpha-1-antitrypsin deficiency. High prevalence in the St. Louis area determined by direct population screening (1989) Am Rev Respir Dis, 140, pp. 961-966Sveger, T., Liver disease in alpha 1-antitrypsin deficiency detected by screening of 200,000 infants (1976) N Engl J Med, 294, pp. 1316-1321Sveger, T., The natural history of liver disease in alpha 1-antitrypsin deficient children (1988) Acta Paediatr Scand, 77, pp. 847-851Sveger, T., Ericksson, S., The liver in adolescents with alpha 1-antitrypsin deficiency (1995) Hepatology, 22, pp. 514-517Talbot, I.C., Mowat, A.P., Liver disease in infancy. Histological features and relationship to alpha 1-antitrypsin phenotype (1975) J Clin Pathol, 28, pp. 559-563Travis, J., Salvesen, G.S., Human plasma proteinase inhibitors (1983) Annu Rev Biochem, 52, pp. 655-709Van Steenbergen, W., Alpha 1-antitrypsin deficiency: An overview (1993) Acta Clin Belg, 48 (3), pp. 171-189Wewers, M.D., Casolaro, M.A., Sellers, S.E., Swayze, S.C., McPhaul, K.M., Wittes, J.T., Crystal, R.G., Replacement therapy deficiency associated with emphysema (1987) N Engl J Med, 316, pp. 1055-1062Woodhead, J.L., Fallon, R., Figuered, H., Longdale, J., Malcom, A.D.B., Alternative methodology of gene diagnosis (1986) Human Genetic Diseases - a Pratical Approach, pp. 51-64. , Davies KE, editor. Oxford: IRL Pres

    5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency

    Get PDF
    Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%-3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%-2.5% of the target level from years 1-5 in these same patients without any additional recombinant adeno-associated virus serotype-1 alpha-1 antitrypsin vector administration. In addition, we observed partial correction of disease-associated neutrophil defects, including neutrophil elastase inhibition, markers of degranulation, and membrane-bound anti-neutrophil antibodies. There was also evidence of an active T regulatory cell response (similar to the 1 year data) and an exhausted cytotoxic T cell response to adeno-associated virus serotype-1 capsid. These findings suggest that muscle-based alpha-1 antitrypsin gene replacement is tolerogenic and that stable levels of M-AAT may exert beneficial neutrophil effects at lower concentrations than previously anticipated

    Alpha-1 antitrypsin deficiency in a French General Hospital: fortuitous detection rather than efficient screening

    Get PDF
    Introduction: We studied the characteristics of the screening procedure for alpha-1 antitrypsin at Nevers Hospital (France), together with the performance of serum protein gel electrophoresis for the fortuitous detection of patients with deficiency. Material and methods: We carried out a retrospective study of requests for alpha-1 antitrypsin determination referred to the laboratory during 3 years. We compared these requests with the numbers of patients seen at the hospital and requiring screening according to international recommendations. In parallel, we reviewed all the serum protein gel electrophoresis results obtained during the same period. Results: The laboratory received 102 direct requests for alpha-1 antitrypsin determination, whereas more than 1397 patients presented an indication for screening. No case of alpha-1 antitrypsin deficiency was detected among the 102 patients screened. In parallel, 5551 serum protein gel electrophoresis analyses were carried out at the laboratory. A decrease in the size of the alpha-1 globulin fraction was detected in 68 patients. Seventeen of these patients underwent alpha-1 antitrypsin determinations and 14 were found to have alpha-1 antitrypsin deficiency. Conclusion: Alpha-1 antitrypsin deficiency was more frequently detected fortuitously, by electrophoresis, than through efficient screening. The exploration of alpha-1 globulin deficiencies by serum protein gel electrophoresis thus appears to be still a particularly efficient approach to the detection of alpha-1 antitrypsin deficiency and should be carried out systematically. Furthermore, the testing of all patients with an indication for screening according to international recommendations should be encouraged

    Diagnosis Of Alpha-1-antitrypsin Deficiency By Dna Analysis Of Children With Liver Disease.

    Get PDF
    Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genome through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele) and Taq-1 (Z allele). Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ) and two had the S allele with another allele (*S) different from Z. These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6%). A correct diagnosis is important for effective clinical follow-up and for genetic counseling.3863-

    Therapeutic target-site variability in α1-antitrypsin characterized at high resolution

    Get PDF
    The intrinsic propensity of [alpha]1-antitrypsin to undergo conformational transitions from its metastable native state to hyperstable forms provides a motive force for its antiprotease function. However, aberrant conformational change can also occur via an intermolecular linkage that results in polymerization. This has both loss-of-function and gain-of-function effects that lead to deficiency of the protein in human circulation, emphysema and hepatic cirrhosis. One of the most promising therapeutic strategies being developed to treat this disease targets small molecules to an allosteric site in the [alpha]1-antitrypsin molecule. Partial filling of this site impedes polymerization without abolishing function. Drug development can be improved by optimizing data on the structure and dynamics of this site. A new 1.8 Ă… resolution structure of [alpha]1-antitrypsin demonstrates structural variability within this site, with associated fluctuations in its upper and lower entrance grooves and ligand-binding characteristics around the innermost stable enclosed hydrophobic recess. These data will allow a broader selection of chemotypes and derivatives to be tested in silico and in vitro when screening and developing compounds to modulate conformational change to block the pathological mechanism while preserving function

    Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies

    Get PDF
    Alpha-1-antitrypsin (alpha(1)-antitrypsin) is the archetypal member of the serine proteinase inhibitor or serpin superfamily. The most common severe deficiency variant is the Z allele, which results in the accumulation of mutant protein within hepatocytes. This 'protein overload' causes neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating plasma alpha(1)-antitrypsin results in early-onset panlobular emphysema. The mechanism underlying the deficiency of Z alpha(1)-antitrypsin is due to an aberrant conformational transition within the protein and the formation of chains of polymers that tangle within the secretory pathway of hepatocytes. This mechanism also underlies the plasma deficiency of other members of the serpin superfamily to cause a class of diseases called the serpinopathies. Specifically mutant alleles of antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin have been reported that favour the spontaneous formation of polymers and the retention of protein within hepatocytes. The consequent lack of plasma antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin results in thrombosis, angio-oedema and emphysema, respectively. Moreover, the polymerisation of mutants of neuroserpin results in the retention of polymers within neurones to cause the inclusion body dementia, familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the genetic and molecular basis and clinical features of alpha(1)-antitrypsin deficiency, and show how this provides a platform to understand the other serpinopathies
    • …
    corecore