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Hereditary alpha-1-antitrypsin deficiency and its clinical consequences

Fregonese L, Stolk J - Orphanet J Rare Dis (2008)

Bottom Line: For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended.Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids.The end-stage liver and lung disease can be treated by organ transplantation.

Affiliation: Alpha1 International Registry, c/o Department of Pulmology, Leiden University Medical Center, Leiden, The Netherlands. L.Fregonese@lumc.nl

ABSTRACT

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.

Structure of alpha-1-antitrypsin: 3 β-sheets and 8 α-helixes. The reactive loop site contains the neutrophil elastase binding site with a methionine residue. Reprinted from Janciauskiene S. Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. Biochim Biophys Acta, 2001, 1535:221-35. Copyright © 2001, with permission from Elsevier.
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Figure 5: Structure of alpha-1-antitrypsin: 3 β-sheets and 8 α-helixes. The reactive loop site contains the neutrophil elastase binding site with a methionine residue. Reprinted from Janciauskiene S. Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. Biochim Biophys Acta, 2001, 1535:221-35. Copyright © 2001, with permission from Elsevier.

Mentions: The alpha-1-antitrypsin molecule includes 394 amino acids and 3 glycosylated side chains coupled to asparagine [32]. The molecule has a globular tertiary structure, and its active site to inhibit enzymes is on a surface protrusion (Figure 5). Here is where the most important amino acid is present, a methionine in position 358, an aminoacid susceptible to conversion to methionine sulfoxide by oxidants from cigarette smoke, rendering it much less potent as an inhibitor of neutrophil elastase [33].

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Hereditary alpha-1-antitrypsin deficiency and its clinical consequences

Fregonese L, Stolk J - Orphanet J Rare Dis (2008)

Structure of alpha-1-antitrypsin: 3 β-sheets and 8 α-helixes. The reactive loop site contains the neutrophil elastase binding site with a methionine residue. Reprinted from Janciauskiene S. Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. Biochim Biophys Acta, 2001, 1535:221-35. Copyright © 2001, with permission from Elsevier.
© Copyright Policy
Figure 5: Structure of alpha-1-antitrypsin: 3 β-sheets and 8 α-helixes. The reactive loop site contains the neutrophil elastase binding site with a methionine residue. Reprinted from Janciauskiene S. Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. Biochim Biophys Acta, 2001, 1535:221-35. Copyright © 2001, with permission from Elsevier.
Mentions: The alpha-1-antitrypsin molecule includes 394 amino acids and 3 glycosylated side chains coupled to asparagine [32]. The molecule has a globular tertiary structure, and its active site to inhibit enzymes is on a surface protrusion (Figure 5). Here is where the most important amino acid is present, a methionine in position 358, an aminoacid susceptible to conversion to methionine sulfoxide by oxidants from cigarette smoke, rendering it much less potent as an inhibitor of neutrophil elastase [33].

Bottom Line: For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended.Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids.The end-stage liver and lung disease can be treated by organ transplantation.

Affiliation: Alpha1 International Registry, c/o Department of Pulmology, Leiden University Medical Center, Leiden, The Netherlands. L.Fregonese@lumc.nl

ABSTRACT

Background: Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.

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View Article: Medline Plus - Pubmed Central - HTML -  PubMed
Show All Figures - Show MeSH
getmorefigures.php?pmc=2441617&rFormat=json&query=null&req=5