α1-Antitrypsin Deficiency: Biological Answers to Clinical Questions

doi:10.1097/00000441-200101000-00006

The American Journal of the Medical Sciences

Volume 321, Issue 1, January 2001, Pages 33-41

https://doi.org/10.1097/00000441-200101000-00006 Get rights and content

ABSTRACT

α1-antitrypsin (α1AT) deficiency is a common lethal hereditary disorder of white persons of European descent. The condition is characterized by reduced serum levels of α1AT, a 52-kDa glycoprotein synthesized chiefly in the liver and, to a lesser extent, by macrophages and neutrophils. α1AT acts as an antiprotease and is the physiological inhibitor of neutrophil serine proteases such as neutrophil elastase cathepsin G and proteinase 3. The clinical manifestations of α1AT deficiency occur chiefly in the lung, with a high risk of emphysema occurring by the third or fourth decade of life. Cigarette smoking accelerates the development of emphysema in persons with α1AT deficiency. There is also an increased risk of liver disease in α1AT deficiency, which occurs mostly in childhood. In this review, we will define further the diagnosis of α1AT deficiency and its clinical manifestations and describe the therapeutic strategies that are currently being developed to treat the hepatic and pulmonary disease associated with this condition.

Section snippets

α1AT and Its Gene

The α1AT gene is located on the q arm of chromosome 14. It is a 12.2-kilobase-pair gene composed of 7 exons and 6 introns. It is a member of a family of serpins that also includes α-1 antichymotrypsin, α-2 antiplasmin, plasminogen activator I, thyroxine binding globulin, cortisol-binding globulin, angio-tensinogen, protease nexin I, kallistatin and leukocyte inhibitor.2., 3. It is likely that these genes had common ancestry; despite their structural homology, however, they have diverse

The Physiological Role of α1AT

The human lung marginates up to 80 million neutrophils from the pulmonary arterial circulation every second, returning a similar number to the pulmonary veins.⁹ As a result of this passage of neutrophils through the pulmonary connective tissues, the pulmonary parenchymal stroma is exposed to an array of proteolytic enzymes including NE, proteinase-3, and cathepsin G. The most important protease in relation to the development of pulmonary emphysema is NE, a 29-kDa, 220-amino-acid-residue,

The Mechanism of Lung Disease in α1AT Deficiency

In deficiency states, the lack of α1AT in the pulmonary interstitium results in the unopposed action of proteases, the gradual destruction of pulmonary connective tissue and the loss of alveolar units. The deficiency states arise because of mutations of the α1AT gene. These mutations have been categorized into 4 groups: base substitutions, in-frame deletions, frameshift mutations, and exon deletions. The molecular basis of most cases (> 90%), the Z mutation, seems to be a single amino acid

Mechanism of Hepatic Disease in α1AT Deficiency

Hepatic disease has been described in association with the Pi*Z and Pi*M_malton alleles.¹⁴ These mutations affect the uniquely flexible conformation of the active site loop region of α1AT. The Pi*Z mutation results in excessive transformation of the protein into its locking form and abnormalities of its folding at the time of synthesis.¹⁵ The abnormal intermediate forms of the protein undergo concentration- and temperature-dependent polymerization and intracellular degradation and accumulation.

Epidemiology of α1AT Deficiency

There are estimated to be more than 100,000 persons with α1AT deficiency in the United States.¹⁷ They are thought to account for 2% of cases of emphysema referred to pulmonary physicians. Many cases (as many as 95%), apparently, remain undiagnosed.¹⁸

More than 90% of clinical cases of α1AT deficiency are caused by the Pi*ZZ mutation, which occurs with an allelic frequency of 0.01 to 0.02 in North American white persons and 0.02 to 0.03 in Northern Europeans. The allelic frequency is lower in

The Laboratory Diagnosis of α1AT Deficiency

The numerous α1AT phenotypes are named according to their migration characteristics in a pH 4 to pH 5 isoelectric focusing (IEF) polyacrylamide gel.²⁰ Variants displaying a higher isoelectric point (PI), so-called anodal variants, are conferred with letters from the beginning of the alphabet, whereas those with a lower PI, cathodal variants, receive an alphabetical designation from the end of the alphabet. The major bands of α1AT seen on an IEF gel are the 4 and 6 bands, whereas the minor bands

Pulmonary Manifestations of α1AT Deficiency

Patients with α1AT deficiency characteristically develop pulmonary emphysema in the third and fourth decades of life. Seventy-five to 80% of patients develop chronic obstructive pulmonary disease (COPD).²² The majority of persons with α1AT deficiency have a history of cigarette smoking.²³ The apparent predominance of male patients, and the increasing frequency of symptomatic female patients, reflect the gender differences in smoking habits and underscore the importance of smoking in the

Hepatic Disease

Because the cause of the hepatic disease in α1AT deficiency is the pathological accumulation of abnormal α1AT in hepatocytes, no hepatic benefit of augmentation with exogenous α1AT levels in plasma is expected. Instead the only corrective therapy for α1AT-deficient patients with severe liver disease currently is liver transplantation.65., 66. This is associated with good results and survival in both children and adults (70–80% and 60–70%, respectively). In cases where transplantation is not

Conclusions

α1AT deficiency is a relatively common condition, being, along with cystic fibrosis, the commonest form of hereditary lung disease. Despite this, it is frequently underdiagnosed or misdiagnosed, as indicated in the National Heart, Lung, and Blood Institute registry. α1AT deficiency also serves as a template for our understanding of protease-antiprotease function in the lung and the biochemistry of pulmonary emphysema. Its study has also contributed to our knowledge of the regulation of gene

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