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Review
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Hereditary alpha-1-antitrypsin Deficiency and Its Clinical Consequences

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Review

Hereditary alpha-1-antitrypsin Deficiency and Its Clinical Consequences

Laura Fregonese et al. Orphanet J Rare Dis.

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.

Figures

Figure 1
Figure 1
Serum alpha-1-antitrypsin (AAT) levels in various Pi phenotypes consisting of two alleles each, i.e. MM (left part of the figure). Serum iso-electric focusing (Pi) is one of the methods to determine the type of allele deficiency present in patients (right part of the figure). Each Pi type gives a characteristic set of bands from top to bottom on a polyacramide gel and is reported as Pi phenotype. These Pi types correlate to mean general serum AAT concentrations, but are dependent on the inflammatory status of the individual, as AAT is an acute-phase reactant protein. Clinical significant liver disease only occurs with Pi ZZ, clinical significant lung disease is associated with Pi Null, Pi SZ and PiZZ types.
Figure 2
Figure 2
The Z-allele is the most important genetic defect in alpha-1-antitrypsin deficiency. It is a single mutation in exon 5 of the gene, leading to substitution of the amino acid glutamine (G) in position 342 in the protein for a lysine (A) amino acid. Alpha-1-antitrypsin is an important protease inhibitor, in particular of neutrophil elastase. The Z allele results in hepatic polymerization in both hepatocyte inclusions and decreased serum concentration. Therefore, strategies to augment the inherited deficiency as well as the development of small peptides that can selectively inhibit polymerization of the Z allele of the AAT protein in the liver are central to therapeutic approach.
Figure 3
Figure 3
Computed tomography of the lung with thin slices (1 mm) showing emphysema and bullae in the lower lung lobes of a subject with type ZZ alpha-1-antitrypsin deficiency. There is also increased lung density in areas with compression of lung tissue by the bullae.
Figure 4
Figure 4
Computed tomography of the lung with thin slices (1 mm) showing bronchiectasis in the lower lung lobes of a subject with type ZZ alpha-1-antitrypsin deficiency. There are no signs of emphysema.
Figure 5
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.
Figure 6
Figure 6
Loop-sheet polymer of AAT molecules. Reproduced from Lomas DA, Mahadeva R. Alpha-1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest, 2002, 110:1585–90. Copyright © 2002, with permission from American Society for Clinical Investigation.
Figure 7
Figure 7
Alpha-1-antitrypsin testing algorithm. The first step is to measure the level in serum by radial immunodiffusion or nephelometry. If the serum level is below 11 μM or 50 mg/ml (by nephelometry) further analysis by either isoelectric focussing or genetyping is warranted. Very low serum levels or levels below the detection limit of the serum assay suggest the presence of a Null variant (no production by the hepatocytes, and therefore distinct from the Z deficiency). A Null variant may be further analysed by isoelectric focussing and/or gene sequencing (as described in Fregonese et al., Respir Med; in press).

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