Saudi Journal of Gastroenterology
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Year : 1996  |  Volume : 2  |  Issue : 3  |  Page : 113-119
Alpha-1-antitrypsin deficiency: An overview of recent advances


Department of Medical Biochemistry and W.H.O. Collaborating Center for Hemoglobinopathies, Thalassaemias and Enzymopathies, College of Medicine and King Khaled University Hospital, King Saud University, Riyadh, Saudi Arabia

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Date of Submission14-May-1996
Date of Acceptance12-Jun-1996
 

   Abstract 

Alpha 1-antitrypsin (αl AT), a serpine, is one of the most important proteinase inhibitor in the serum and plays an essential role in protection of the lung tissues against the proteolytic attach of elastase. The gene for a1AT is located on chromosome 14 q 32 and is highly susceptible to mutations. A large number of variants of α 1 AT are known and some including PiZ and PiS result in a1AT deficiency. In patients with PiZ, the most severe and common α1AT deficient variant, the α1AT protein accumulates in the liver and results in severe hepatic diseases. Other clinical consequences of α1AT deficiency include emphysema in majority of the patients. This state is further aggravated in patients who smoke.
Several treatment strategies have been suggested, including replacement therapy by purified α1AT or recombinant α1AT given intravenously or as aerosol. Synthetic peptides. lung transplantation and volume reduction surgery are under investigation and evaluation. This paper updates the information on α1 AT and its deficiency state.

How to cite this article:
El Hazmi MA. Alpha-1-antitrypsin deficiency: An overview of recent advances. Saudi J Gastroenterol 1996;2:113-9

How to cite this URL:
El Hazmi MA. Alpha-1-antitrypsin deficiency: An overview of recent advances. Saudi J Gastroenterol [serial online] 1996 [cited 2019 Aug 22];2:113-9. Available from: http://www.saudijgastro.com/text.asp?1996/2/3/113/34015


Proteolytic activity of a vast number of protease, if uncontrolled, can lead to a variety of clinical consequences in the biological systems. The control of proteolytic activity is assigned to a group of naturally occurring small molecular weight proteins known as "protease inhibitors". These proteins maintain the necessary homeostasis and control tissue degradation by offsetting the degradative activity of the naturally occurring protease. Alpha-l-antitrypsin is one such antiprotease (out of 6-8 protease inhibitors) in the human plasma that has the ability to inactivate a number of different serine proteases including elastase, thrombin and trypsin with a variable degree of specificity. The α 1AT is the major antiprotease with a molecular weight of 52 Kd and contains approximately 12% carbohydrate. The α 1AT can readily diffuse into most tissue spaces and is found on pleural and alveolar surfaces. The clinical significance of this protein was demonstrated when it was shown that genetic deficiency can lead to emphysema and liver disease in the adults and children, respectively [1] .

Genetics and Molecular Biology of α 1AT

The α 1AT gene loci is located on chromosome 14q32 and is located within a 280 kb region. It resides among gene cluster which code for other proteins including some proteinase inhibitors. These genes are believed to arise from gene duplication and is remarkably conserved. The α 1AT gene is composed of seven exons and three introns which together span around 12 kb. The exons are numbered as la, lb, lc, 11, III, IV and V and contain different elements responsible for gene expression in the different tissues. Exon la and lb have elements responsible for macrophage specific transcription while exons la contains the promoter for hepatocyte directed transcription. In the other four exons the coding regions are located with the start codon (ATG) in exon II and the stop codon (TAA) and polyadenylation site (ATAA) in the exon V [2],[3],[4] .

The principal site of α 1AT gene expression is in the hepatocyte, but some α 1AT is also synthesized in the mononuclear phagocytes, neutrophils, intestinal epithelium, kidney parenchyma and several other sites. Several transcription factors are involved in modulation of transcription and IL-6 a major cytokine responsible for acute phase response up-regulates hepatocytes α 1AT transcription, while IL-1 and TNF are also involved in acute phase response but do not increase α 1AT level [5] . The entire process of synthesis and secretion takes about 90 minutes.

Variants of α1AT

The α 1AT gene seems to be highly susceptible to mutations and a large number of α 1AT variants of the normal antiprotease which differ in the charge, electrophoretic mobility, isoelectric point and functional activity, are known. The normal and most common type of α 1AT in all populations is PiM, which occurs in several subtypes referred to as PiMI, PiM2, PiM3, PiM4, PiM5 etc.

At least 49 α1AT gene alleles have so far been characterized by DNA sequencing. Most of the alleles result from a single point mutation (base substitution, deletions, insertions and large deletions) in the coding sequence [6] . The different variants differ in one or more amino acids or degree of glycosylation or degree of gene expression. In some variants most of the coding regions of α 1AT is deleted, thereby a severe α 1AT deficiency results. Some deficiency also results from abnormalities in mRNA splicing and stability, while several variants including PiZ are retained in the hepatocytes due to partial glycosylation and are degraded inthe cells [2],[7],[8],[9] .

The variants have been divided into four categories, depending on the level and activity in the serum, and include:

  • The normal variants - with normal activity. The most common one is PiM.
  • The deficient variants - with level lower than normal and mobility on isoelectric focusing different from normal e.g. the PiS and PiZ.
  • The Null variants - associated with complete absence of the protein e.g. PiNull granulate fall.
  • The dysfunctional variants - where the amount of a 1 -antitrypsin is normal, but the molecule does not function normally e.g. PiPittsburg.


The condition "α IAT deficiency" is inherited as an autosomal recessive (AR) disorder and is hence expressed in homozygous state.

Distribution of α 1AT variants in different populations

The variants of α1AT occur at a variable frequency in different populations [Table - 1] [10] . The commonly encountered deficient variants include PiZ and PiS, where the former is a cause of a severely deficient state compared to the latter. The frequency of S and Z variants differ among various populations and hence the disease risk associated with the α 1AT deficiency [11],[12],[13],[14] .

Distribution of α1AT variants among Arabs and their neighbors

In the W.H.O. Eastern Mediterranean regions a limited number of surveys have been reported which give the frequency of the various phenotypes. A detailed investigation on normal healthy Saudis revealed significant differences in plasma levels of a IAT in males and females of different age groups compared to results reported in literature [13],[14],[15],[16] . Population screening for α 1AT deficiency carried out in Saudi Arabia indicated the presence of α 1AT deficiency, caused mainly by PiZ and PiS alleles [17],[18] . These alleles have been identified both in homozygous and in heterozygous states in healthy individuals and in those suffering from various disease states [1],[17],[18] . The PiZ frequency reported in an earlier study was high in Saudis in relation to other populations. However, in a recent survey on 260 Saudi nationals the phenotypes identified included PiMM, PiMZ, PiFM and PiMS and the gene frequency of PiM, Z, S and F were found to be 0.95, 0.004, 0.002 and 0.03, respectively (personal observation).

In Jordanians the PiM exists at a frequency of 0.9937, possibly the highest frequency so far reported in any other population [19] . PiZ was not encountered in this study and PiS exists at a low frequency of 0.0083 [19],[20] .

Thus differences in the allele frequency of α 1AT are obvious in the Eastern Mediterranean populations. However, the few studies so far reported are in line with the frequency of other genetic disorders, which show a considerable diversity [21] .

Other reports from Pakistan, Iran and some Arab Druze populations indicated the presence of α 1AT deficiency caused by PiS and PiZ at variable frequency [10],[14],[20],[22] . In Egypt, pilot studies have been reported but the exact frequency is not known. [Table - 1] presents the gene frequency of the Pi alleles and the frequency of the various genotypes, hitherto reported from Eastern Mediterranean region.

When compared to the frequency reported in other Asian, African, European and American populations, the Eastern Mediterranean region of W.H.O. seem to follow a similar pattern of diversity [Table - 1].

This summation of the reports from the W.H.O. Eastern Mediterranean regions indicates that there is a need for investigations, involving population screening or neonatal screening, to determine the frequency of the various phenotypes and the magnitude of the genetic defects.

Alpha-1-antitrypsin deficiency state

Some of the α 1AT variants state including PiZ and PiS are associated with very low levels of α1AT in plasma and this condition is referred to as "α 1AT deficiency". The extensive interest in a 1AT deficiency arises from its involvement in several clinically abnormal states [Table - 2].

The pathogenesis of α1AT deficiency

Alpha 1-AT deficiency ranks as one of the most common lethal hereditary disease among the Caucasians and leads to liver injury, emphysema and a number of other conditions [23] .

The prime role of α 1AT is to inhibit elastases released by the principal inflammatory white cells i.e. the neutrophils. It can inhibit other protease and is also referred to as α 1 protease inhibitor (PI). It belongs to the "serpine family" of protease inhibitor, which are serine protease inhibitors. All serpines have complex template structure and have an unusual property of being able to change from one conformation form to another [24] . These inhibitors are predominant protease inhibitors in human plasma i.e. antithrombin control coagulation pathway, CI-esterase inhibitors control complement cascade, plasminogen inhibitors inhibit fibrinolysis etc.

The α 1AT binds its target protease, particular elastase, and tightly entraps it with a mechanism closely analogous to that of a mousetrap. The protease-inhibitor complex circulates in the blood stream and is finally catabolized and removed from the circulation. Mutations that effect the critical mobile domains of the molecule either prevent changes or produce inappropriate changes in the conformation and hence loss of the inhibitory activity [25],[26],[27] .

The most frequent cause of α 1AT deficiency is PiZ. The mutation producing this variant is a single base change GAG to AAG in exon V, hence resulting in a substitution of glutamyl residue at position 342 by lysyl residue. This does not influence the synthesis of the molecule, but results in decrease glycosylation and hence secretion in the plasma. The various mechanisms involved in producing α 1AT deficiency are outlined in [Figure - 1]. The α 1AT accumulates as large intracellular inclusions in the liver and the pathology results from (i) deficiency of α 1 AT in plasma and (ii) formation of hepatocyte inclusions [6],[7],[8] .

Pathogenesis of hepatic disease in α1AT deficiency

Some children suffering from α 1AT deficiency develop a severe hepatic disease. This is explained by the "Accumulation theory". According to this the accumulation and degree of polymerization α 1AT depend on rate of production and on temperature. Polymerization is concentration dependent and sensitive to body temperature, when it is greatly accelerated at 41° C. Children often develop high temperature due to infections. This results in at least four-fold increase in α 1AT synthesis and in children with PiZ the increased concentration of PiZ in the liver cells (due to decreased secretion into the plasma), under the influence of high temperature results in accumulation and polymerization leading to progressive infantile hepatitis and hepatocellular damage leading to cirrhosis [7],[23] .

α1AT deficiency and lung disease

Increased intracellular degradation of PiZ in the liver results in severe plasma α 1AT deficiency [7] . In adults major clinical consequence of a IAT deficiency is lung diseases, in particular, early onset emphysema. This is significantly aggravated under the influence of smoking. An outline of the mechanism leading to insult by smoking, pollution and infections is outlined in [Figure - 2]. The pathology results from destruction of the elastin in the alveolar walls of lungs by the elastases released from neutrophils, thus leading to decreased lung elasticity and hence emphysema. In a normal individual the neutrophil derived elastase is inhibited by the α 1AT, the major protein protecting alveolar structures, while in its deficiency the unimpeded neutrophil derived elastase destroys the lungs [8],[12],[23] . Smoking has two major effects. First, there is an increase in the lung neutrophils following smoking and hence an increase in the release of elastases, which are not inhibited due to the deficiency of α 1AT and cause destruction of the lung tissue, and secondly, the normal functional ability of the α 1AT is lost due to oxidation of a very essential salt-bridge at the active site methionine. Thus, people who are not α 1AT deficient, but are smokers also develop emphysema. Environmental factors that may lead to chronic obstructive pulmonary disease are listed in [Table - 3]. The major risk factors for development of emphysema in α 1AT deficiency include age, male sex, smoking and other associated lung disease such as asthma and pneumonia.

Clinical consequence of α1-antitrypsin deficiency

The association between α 1AT deficiency and emphysema in adults and neonatal liver disease in children is well established [23] . Several other diseases are reported to occur at a higher frequency in people with α 1AT deficiency, however, these reports have not been confirmed. A few interesting reports have studied the occurrence of α 1AT phenotypes in patients with various diseases [28],[29],[30],[31],[32],[33],[34],[35],[36] .

These include rheumatoid arthritis, connective tissue disorders, bronchiectasis, liver diseases and cancer [Table - 4]. An interesting finding is that α I-antitrypsin deficiency occurs at a high frequency in cancer patients and phenotype pattern in these patients is considerably different from the pattern in the normal population. PiZ and PiS occur at a higher frequency in these disease states compared to the normal population and possibly play a role in the pathogenesis of the disease state.

Genotype-Phenotype Correlations

The presence of so many variants of α 1AT has initiated considerable interest in the genotype­phenotype correlation studies. However, correlation is evident so far for the PiZ variant, as it occurs at a fairly high frequency in some populations [37] . Other severely deficient variants are rare and it has not been possible so far to document the exact genotype-phenotype correlation studies.

Population screening and counseling for α 1-antitrypsin deficiency

The question whether population screening for α 1AT deficiency will be of value is of relevance in the setting of the Arab population. It is of paramount importance that screening and counseling efforts should regard the religious and traditional values. The programs need to be orientated to the populations and made appropriately relevant to the prevailing lifestyle. In addition, the cost-effectiveness of the screening and counseling endeavors should be considered, as the frequency of the deficiency state may be negligible. On the other hand, advantages may prove too many. The diagnosis of α 1AT deficient patient early in life, followed by proper management as well as guarding against the harmful environmental factors such as smoking may play a role in decreasing the morbidity associated with this chronic condition.

Treatment of α1AT deficiency

The primary therapy of α 1AT deficiency in infants involves early detection, and early treatment of pyrexia to prevent the polymerization of α 1AT to occur. In adults avoidance of smoking can significantly delay and ameliorate the symptoms associated with α 1AT deficiency.

Replacement of α 1AT by IV administration of α 1AT purified from plasma in doses of 60 mg/kg/wk is used widely and last for up to six days. In 1988, the US Food and Drug Administration (FDA) approved the use of pooled plasma concentrate (Prolactin by Bayer) of α 1AT for treatment of hereditary a 1AT deficiency [38] . The use of prolactin is now approved in USA, Canada, Germany and Spain. Different intravenous infusion protocols for prolactin have been used with success [38] . The major drawbacks of replacement therapy include its time consuming nature, risk of blood born diseases and requirement of medical supervision.

Recombinant α 1AT has been prepared by recombinant DNA technology. However, its use is not yet very successful as it is a non-Glycosylated protein and has a half life of only a few hours due to its rapid renal clearance [39] . More recently, aerosol for direct delivery of α 1AT to the lungs have been prepared since lung is the major organ affected by a IAT deficiency. This protocol has shown efficacy in short term trials in animals and in α 1AT deficient patients. However, the trials are continuing and longer and larger studies are required to ascertain the safety of α 1AT aerosol [40] .

A few synthetic elastase inhibitors have been used for the treatment of α 1AT deficiency. These include a short synthetically prepared peptide which binds to the binding site in the elastase and makes it inactive.

Other treatment protocols include lung transplantation and volume reduction surgery. Lung transplantation has been undertaken in over 4300 patients until September 1995 and the survival rate was almost 54%. The survival rate was better if the patients were younger, had no systemic illness, were either non-smokers or had a shorter smoking history and had favorable psychosocial factors [41].

 
   References Top

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Correspondence Address:
Mohsen A.F El Hazmi
Department of Medical Biochemistry, College of Medicine & King Khalid University Hospital, P.O. Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


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