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{{Alpha 1-antitrypsin deficiency}}
{{Alpha 1-antitrypsin deficiency}}
{{CMG}}; {{AE}}{{Mazia}}{{CZ}}
{{CMG}}; {{AE}}{{Mazia}}
 
==Overview==
==Overview==
[[Alpha 1-antitrypsin]] (A1AT) is synthesized and secreted mainly by [[hepatocytes]]. However, other sources of the [[enzyme]] include [[macrophages]] and [[bronchial]] [[epithelial]] [[cells]].[[Alpha1 antitrypsin|Alpha1-antitrypsin]] [[enzyme]] is a member of the [[serine protease inhibitor]] ([[serpin]]) family of [[proteins]]. [[Alpha 1-antitrypsin]] (A1AT) protects the [[lungs]] from [[proteases]] like the [[elastase|neutrophil elastase]] enzyme.[[Genetic mutation]] in the [[SERPINA4|SERPINA1]] [[gene]] results in decreased levels of [[alveolar]] [[alpha1]] [[antitrypsin]]. [[Proteases]] accumulate in the [[alveoli]] causing a destruction of [[alveolar]] walls and resultant [[emphysema]]. Excess [[Alpha1 antitrypsin|alpha1-antitrypsin]] in [[hepatocytes]] results in [[chronic liver disease]].SERPINA1 gene mutation alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule.  This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency.On cut section of the lung, emphysematous process is evidenced by dilated air spaces and loss of lung parenchyma. Superimposed infections can result in scarring. Panacinar emphysema is commonly associated with AATD with loss of all portions of the acinus from the respiratory bronchiole to the alveoli.In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the lobule found more commonly in the basilar portions of the lung.  
[[Alpha 1-antitrypsin]] (A1AT) is synthesized and secreted mainly by [[hepatocytes]]. However, other sources of the [[enzyme]] include [[macrophages]] and [[bronchial]] [[epithelial]] [[cells]].[[Alpha1 antitrypsin|Alpha1-antitrypsin]] [[enzyme]] is a member of the [[serine protease inhibitor]] ([[serpin]]) family of [[proteins]]. [[Alpha 1-antitrypsin]] (A1AT) protects the [[lungs]] from [[proteases]] like the [[elastase|neutrophil elastase]] enzyme.[[Genetic mutation]] in the [[SERPINA4|SERPINA1]] [[gene]] results in decreased levels of [[alveolar]] [[alpha1]] [[antitrypsin]]. [[Proteases]] accumulate in the [[alveoli]] causing a destruction of [[alveolar]] walls and resultant [[emphysema]]. Excess [[Alpha1 antitrypsin|alpha1-antitrypsin]] in [[hepatocytes]] results in [[chronic liver disease]].SERPINA1 gene mutation alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule.  This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency.On cut section of the lung, emphysematous process is evidenced by dilated air spaces and loss of lung parenchyma. Superimposed infections can result in scarring. Panacinar emphysema is commonly associated with AATD with loss of all portions of the acinus from the respiratory bronchiole to the alveoli.In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the [[lobule]] found more commonly in the basilar portions of the [[lung]].  


== Pathophysiology ==
== Pathophysiology ==
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*The Z [[Mutations|mutation]] results in a [[conformational change]] in the [[Alpha antitrypsin|alpha 1 antitrypsin]] molecule. The β sheet opens leaving it susceptible to interaction with another [[Alpha antitrypsin|alpha 1 antitrypsin]] molecules to form a [[dimer]] or a [[polymer]]. These [[polymers]] get trapped in the [[endoplasmic reticulum]].The [[Z]] [[mutation]] causes most of the unstable [[protein]] to form [[polymers]].   
*The Z [[Mutations|mutation]] results in a [[conformational change]] in the [[Alpha antitrypsin|alpha 1 antitrypsin]] molecule. The β sheet opens leaving it susceptible to interaction with another [[Alpha antitrypsin|alpha 1 antitrypsin]] molecules to form a [[dimer]] or a [[polymer]]. These [[polymers]] get trapped in the [[endoplasmic reticulum]].The [[Z]] [[mutation]] causes most of the unstable [[protein]] to form [[polymers]].   
*[[Smoking]] is an important [[risk factor]] in the development of the [[lung disease]] associated with [[Alpha antitrypsin|alpha 1 antitrypsin]] [[deficiency]]. The [[Proteases|protease]]-antiprotease imbalance in the [[lung]] has major consequences, in addition to increasing the [[inflammation|inflammatory]] reaction in the [[airway]]s, [[cigarette]] smoke directly inactivates [[alpha 1-antitrypsin]] by [[oxidation|oxidizing]] essential [[methionine]] residues to [[sulfoxide]] forms, decreasing the [[enzyme]] activity by a rate of 2000.   
*[[Smoking]] is an important [[risk factor]] in the development of the [[lung disease]] associated with [[Alpha antitrypsin|alpha 1 antitrypsin]] [[deficiency]]. The [[Proteases|protease]]-antiprotease imbalance in the [[lung]] has major consequences, in addition to increasing the [[inflammation|inflammatory]] reaction in the [[airway]]s, [[cigarette]] smoke directly inactivates [[alpha 1-antitrypsin]] by [[oxidation|oxidizing]] essential [[methionine]] residues to [[sulfoxide]] forms, decreasing the [[enzyme]] activity by a rate of 2000.   
*The [[Proteases|protease]]-antiprotease imbalance in the [[lung]] has a major effect. In Z-variant of [[alpha1 antitrypsin]] deficiency, there is less [[alpha1 antitrypsin]] in the lung. The [[alpha1 antitrypsin]] that is present is 5 times less effective than normal [[alpha1 antitrypsin]]. The residual [[alpha1 antitrypsin]] is susceptible to inactivation by oxidation of the P1 methionine residue by free radicals from leukocytes or direct oxidation by cigarette smoke. The Z [[alpha1 antitrypsin]] also favors the formation of polymers in the lung. Z [[alpha1 antitrypsin]]-deficient patients have excess [[neutrophils]] in lavage fluid and in tissue sections of the lung possibly related to the [[chemoattractant]] effect of an excess of [[Leukotriene B4|leukotriene B4 (LTB4]]) and [[IL-8|interleukin (IL)-8]] and the [[polymers]] themselves. These circumstances of unopposed [[proteolytic]] [[enzyme activity]] and an increase in [[inflammatory]] conditions cause the trademark [[emphysema]] of this disease.   
*The [[Proteases|protease]]-antiprotease imbalance in the [[lung]] has a major effect. In Z-variant of [[alpha1 antitrypsin]] deficiency, there is less [[alpha1 antitrypsin]] in the lung. The [[alpha1 antitrypsin]] that is present is 5 times less effective than normal [[alpha1 antitrypsin]]. The residual [[alpha1 antitrypsin]] is susceptible to inactivation by [[oxidation]] of the P1 methionine residue by free [[radical]]s from [[leukocytes]] or direct [[oxidation]] by cigarette smoke. The Z [[alpha1 antitrypsin]] also favors the formation of polymers in the lung. Z [[alpha1 antitrypsin]]-deficient patients have excess [[neutrophils]] in lavage fluid and in [[tissue]] sections of the [[lung]] possibly related to the [[chemoattractant]] effect of an excess of [[Leukotriene B4|leukotriene B4 (LTB4]]) and [[IL-8|interleukin (IL)-8]] and the [[polymers]] themselves. These circumstances of unopposed [[proteolytic]] [[enzyme activity]] and an increase in [[inflammatory]] conditions cause the trademark [[emphysema]] of this [[disease]].   
===Genetics===
===Genetics===
*Alpha1-antitrypsin deficiency (AATD) is inherited in an autosomally-codominant pattern caused by mutations in the ''SERPINA1'' gene.
*Alpha1-antitrypsin deficiency (AATD) is inherited in an autosomally-codominant pattern caused by [[mutations]] in the ''SERPINA1'' [[gene]].
*Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 [[gram|gm]]/[[litre|l]].
*Normal [[blood]] levels of alpha-1 antitrypsin are 1.5-3.5 [[gram|gm]]/[[litre|l]].
*The alpha-1 AT gene is located on the long arm of chromosome 14 (gene locus:14q32.1). The SERPINA1 gene has six introns, seven axons and 12.2kb in length. There have been 120 different alleles for alpha-1 AT variants that have been described, but only 10-15 are associated with severe alpha-1 deficiency.
*The alpha-1 AT gene is located on the long arm of [[chromosome]] 14 (gene locus:14q32.1). The SERPINA1 gene has six [[introns]], seven [[axons]] and 12.2kb in length. There have been 120 different [[alleles]] for alpha-1 AT variants that have been described, but only 10-15 are associated with severe alpha-1 deficiency.
*Each allele has been given a letter code based upon electrophoretic mobility that varies according to protein charge from amino acid alterations on gel electrophoresis that is used to identify the PI phenotype.  
*Each allele has been given a letter code based upon electrophoretic mobility that varies according to [[protein]] charge from [[amino acid]] alterations on [[gel electrophoresis]] that is used to identify the PI [[phenotype]].  
*SERPINA1 gene mutation alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule.  This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency. The 75 alleles can basically be divided into four groups:
*SERPINA1 [[gene mutation]] alters the [[configuration]] of the alpha1-antitrypsin molecule and prevents its release from [[hepatocytes]]. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a [[lysine]] for [[glutamate]] at position 342 of the molecule.  This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency. The 75 alleles can basically be divided into four groups:


* Normal – M alleles (normal phenotype is MM), found in 90% of the U.S. population, patients have normal lung function.
* Normal – M alleles (normal [[phenotype]] is MM), found in 90% of the U.S. population, patients have normal [[lung]] function.
* Deficient – Z allele (carried by 2-3% of the U.S. Caucasian population), have plasma levels of alpha-1 AT that is < 35% of normal.
* Deficient – Z allele (carried by 2-3% of the U.S. [[Caucasian]] population), have [[plasma]] levels of alpha-1 AT that is < 35% of normal.
* Null – No detectable alpha-1 AT.  Least common and most severe form of the disease.
* Null – No detectable alpha-1 AT.  Least common and most severe form of the [[disease]].
* Dysfunctional – Patients have a normal alpha-1 AT level, but the enzyme does not function properly.
* Dysfunctional – Patients have a normal alpha-1 AT level, but the [[enzyme]] does not function properly.


In individuals with PiSS, PiMZ and PiSZ [[phenotype]]s, blood levels of A1AT are reduced to between 40 and 60 % of normal levels. This is sufficient to protect the lungs from the effects of [[elastase]] in people who do not [[tobacco smoking|smoke]]. However, in individuals with the PiZZ phenotype, A1AT levels are less than 15 % of normal, and patients are likely to develop [[emphysema]] at a young age; 50 % of these patients will develop [[cirrhosis|liver cirrhosis]], because the A1AT is not secreted properly and instead accumulates in the liver. A [[liver biopsy|liver]] [[biopsy]] in such cases will reveal Periodic acid-Shiff (PAS)-positive, [[diastase]]-negative granules.
In individuals with PiSS, PiMZ and PiSZ [[phenotype]]s, blood levels of A1AT are reduced to between 40 and 60 % of normal levels. This is sufficient to protect the [[lungs]] from the effects of [[elastase]] in people who do not [[tobacco smoking|smoke]]. However, in individuals with the PiZZ [[phenotype]], A1AT levels are less than 15 % of normal, and patients are likely to develop [[emphysema]] at a young age; 50 % of these patients will develop [[cirrhosis|liver cirrhosis]], because the A1AT is not secreted properly and instead accumulates in the [[liver]]. A [[liver biopsy|liver]] [[biopsy]] in such cases will reveal Periodic acid-Shiff (PAS)-positive, [[diastase]]-negative [[granules]].




Differences in speed of migration of different protein variants on gel electrophoresis have been used to identify the PI phenotype, and these differences in migration relate to variations in protein charge resulting from amino acid alterations (Fig. 1).43 The M allele results in a protein with a medium rate of migration; the Z form of the protein has the slowest rate of migration. Some individuals inherit null alleles that result in protein levels that are not detectable. Individuals with a Z pattern on serum isoelectric focusing are referred to as phenotype PIZ (encompassing both PIZZ and PIZnull genotype variants). The S variant occurs at a frequency of 0.02–0.03 and is associated with mild reductions in serum AAT levels. The Z variant is associated with a severe reduction in serum AAT levels. The most common alleles are the M variants with allele frequencies of greater than 0.95 and normal AAT levels
Differences in speed of [[migration]] of different [[protein]] variants on [[gel electrophoresis]] have been used to identify the PI [[phenotype]], and these differences in migration relate to variations in [[protein charge]] resulting from [[amino acid alterations]] (Fig. 1).43 The M [[allele]] results in a [[protein]] with a medium rate of migration; the Z form of the protein has the slowest rate of migration. Some individuals inherit null alleles that result in protein levels that are not detectable. Individuals with a Z pattern on serum isoelectric focusing are referred to as [[phenotype]] PIZ (encompassing both PIZZ and PIZnull [[genotype]] variants). The S variant occurs at a frequency of 0.02–0.03 and is associated with mild reductions in serum AAT levels. The Z variant is associated with a severe reduction in serum AAT levels. The most common [[alleles]] are the M variants with allele frequencies of greater than 0.95 and normal AAT levels.


===Molecular Biology===
===Molecular Biology===
*Crystal structure of alpha1-antitrypsin enzyme is composed of three β sheets (A, B, C) and an exposed mobile reactive loop with a peptide sequence as a pseudosubstrate for the target proteinase enzyme. This loop consists of amino acids within this loop are the PI–PI′ residues, methionine serine, as these are binding sites for neutrophil elastase.
*Crystal structure of alpha1-antitrypsin enzyme is composed of three β sheets (A, B, C) and an exposed mobile reactive loop with a [[peptide]] sequence as a pseudosubstrate for the target [[proteinase]] [[enzyme]]. This loop consists of [[amino acids]] within this loop are the PI–PI′ residues, methionine serine, as these are binding sites for [[neutrophil elastase]].
*The Alpha-1 antitrypsin molecule is an acute phase glycoprotein.
*The Alpha-1 antitrypsin molecule is an acute phase [[glycoprotein]].
*Alpha-1 AT is the protease inhibitor in highest concentration in human plasma.Its functions include inhibition of trypsin and neutrophil elastase. Alpha-1 antitrypsin is a part of serpin class of serine protease inhibitors characterized by their unique ability to undergo a conformational change. Other members of the serpin class of protease inhibitors include antithrombin, C1-inhibitor, and the many inhibitors of plasminogen.  An advantage of this molecular mobility is that it enables the inhibitor to trap its target protease form a complex that can remain stable for hours. A potential disadvantage, however, is that it makes the serpins more than usually vulnerable to dysfunctional mutations.
*Alpha-1 AT is the [[protease inhibitor]] in highest concentration in human [[plasma]].Its functions include inhibition of [[trypsin]] and [[neutrophil elastase]]. Alpha-1 antitrypsin is a part of serpin class of serine [[protease inhibitors]] characterized by their unique ability to undergo a conformational change. Other members of the serpin class of [[protease inhibitors]] include [[antithrombin]], [[C1-inhibitor]], and the many inhibitors of [[plasminogen]].  An advantage of this molecular mobility is that it enables the inhibitor to trap its target [[protease]] form a complex that can remain stable for hours. A potential disadvantage, however, is that it makes the serpins more than usually vulnerable to dysfunctional [[mutations]].


===Associated Conditions===
===Associated Conditions===
α<sub>1</sub>-antitrypsin deficiency has been associated with a number of diseases:
α<sub>1</sub>-antitrypsin deficiency has been associated with a number of [[diseases]]:
* [[COPD]]
* [[COPD]]
* [[Asthma]]
* [[Asthma]]
Line 61: Line 60:


===Gross Pathology===
===Gross Pathology===
On cut section of the lung, emphysematous process is evidenced by dilated air spaces and loss of lung parenchyma. Superimposed infections can result in scarring. Panacinar emphysema is commonly associated with AATD with loss of all portions of the acinus from the respiratory bronchiole to the alveoli.
On cut section of the [[lung]], [[emphysematous]] process is evidenced by dilated air spaces and loss of [[lung parenchyma]]. Superimposed infections can result in [[scarring]]. [[Panacinar emphysema]] is commonly associated with AATD with loss of all portions of the acinus from the respiratory [[bronchiole]] to the [[alveoli]].


===Microscopic Pathology===
===Microscopic Pathology===
Emphysema results in destruction of alveolar walls and permanent abnormal enlargement of the airspace distal to the terminal bronchiole.  
Emphysema results in destruction of alveolar walls and permanent abnormal enlargement of the airspace distal to the terminal [[bronchiole]].  
In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the lobule found more commonly in the basilar portions of the lung. This is in contrast emphysema resulting from cigarette smoking that characteristically involves the centrilobular lung and respiratory bronchioles in the central portion of the lobule, initially at the apex of the lung.
In alpha1-antitrypsin deficiency (AATD), the [[emphysematous]] areas are uniformly distributed throughout the [[lobule]] found more commonly in the [[basilar portions]] of the lung. This is in contrast emphysema resulting from cigarette smoking that characteristically involves the [[centrilobular lung]] and [[respiratory bronchioles]] in the central portion of the [[lobule]], initially at the apex of the [[lung]].


==References==
==References==

Revision as of 18:00, 13 December 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Overview

Alpha 1-antitrypsin (A1AT) is synthesized and secreted mainly by hepatocytes. However, other sources of the enzyme include macrophages and bronchial epithelial cells.Alpha1-antitrypsin enzyme is a member of the serine protease inhibitor (serpin) family of proteins. Alpha 1-antitrypsin (A1AT) protects the lungs from proteases like the neutrophil elastase enzyme.Genetic mutation in the SERPINA1 gene results in decreased levels of alveolar alpha1 antitrypsin. Proteases accumulate in the alveoli causing a destruction of alveolar walls and resultant emphysema. Excess alpha1-antitrypsin in hepatocytes results in chronic liver disease.SERPINA1 gene mutation alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule. This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency.On cut section of the lung, emphysematous process is evidenced by dilated air spaces and loss of lung parenchyma. Superimposed infections can result in scarring. Panacinar emphysema is commonly associated with AATD with loss of all portions of the acinus from the respiratory bronchiole to the alveoli.In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the lobule found more commonly in the basilar portions of the lung.

Pathophysiology

Genetics

  • Alpha1-antitrypsin deficiency (AATD) is inherited in an autosomally-codominant pattern caused by mutations in the SERPINA1 gene.
  • Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 gm/l.
  • The alpha-1 AT gene is located on the long arm of chromosome 14 (gene locus:14q32.1). The SERPINA1 gene has six introns, seven axons and 12.2kb in length. There have been 120 different alleles for alpha-1 AT variants that have been described, but only 10-15 are associated with severe alpha-1 deficiency.
  • Each allele has been given a letter code based upon electrophoretic mobility that varies according to protein charge from amino acid alterations on gel electrophoresis that is used to identify the PI phenotype.
  • SERPINA1 gene mutation alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule. This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency. The 75 alleles can basically be divided into four groups:
  • Normal – M alleles (normal phenotype is MM), found in 90% of the U.S. population, patients have normal lung function.
  • Deficient – Z allele (carried by 2-3% of the U.S. Caucasian population), have plasma levels of alpha-1 AT that is < 35% of normal.
  • Null – No detectable alpha-1 AT. Least common and most severe form of the disease.
  • Dysfunctional – Patients have a normal alpha-1 AT level, but the enzyme does not function properly.

In individuals with PiSS, PiMZ and PiSZ phenotypes, blood levels of A1AT are reduced to between 40 and 60 % of normal levels. This is sufficient to protect the lungs from the effects of elastase in people who do not smoke. However, in individuals with the PiZZ phenotype, A1AT levels are less than 15 % of normal, and patients are likely to develop emphysema at a young age; 50 % of these patients will develop liver cirrhosis, because the A1AT is not secreted properly and instead accumulates in the liver. A liver biopsy in such cases will reveal Periodic acid-Shiff (PAS)-positive, diastase-negative granules.


Differences in speed of migration of different protein variants on gel electrophoresis have been used to identify the PI phenotype, and these differences in migration relate to variations in protein charge resulting from amino acid alterations (Fig. 1).43 The M allele results in a protein with a medium rate of migration; the Z form of the protein has the slowest rate of migration. Some individuals inherit null alleles that result in protein levels that are not detectable. Individuals with a Z pattern on serum isoelectric focusing are referred to as phenotype PIZ (encompassing both PIZZ and PIZnull genotype variants). The S variant occurs at a frequency of 0.02–0.03 and is associated with mild reductions in serum AAT levels. The Z variant is associated with a severe reduction in serum AAT levels. The most common alleles are the M variants with allele frequencies of greater than 0.95 and normal AAT levels.

Molecular Biology

  • Crystal structure of alpha1-antitrypsin enzyme is composed of three β sheets (A, B, C) and an exposed mobile reactive loop with a peptide sequence as a pseudosubstrate for the target proteinase enzyme. This loop consists of amino acids within this loop are the PI–PI′ residues, methionine serine, as these are binding sites for neutrophil elastase.
  • The Alpha-1 antitrypsin molecule is an acute phase glycoprotein.
  • Alpha-1 AT is the protease inhibitor in highest concentration in human plasma.Its functions include inhibition of trypsin and neutrophil elastase. Alpha-1 antitrypsin is a part of serpin class of serine protease inhibitors characterized by their unique ability to undergo a conformational change. Other members of the serpin class of protease inhibitors include antithrombin, C1-inhibitor, and the many inhibitors of plasminogen. An advantage of this molecular mobility is that it enables the inhibitor to trap its target protease form a complex that can remain stable for hours. A potential disadvantage, however, is that it makes the serpins more than usually vulnerable to dysfunctional mutations.

Associated Conditions

α1-antitrypsin deficiency has been associated with a number of diseases:

Gross Pathology

On cut section of the lung, emphysematous process is evidenced by dilated air spaces and loss of lung parenchyma. Superimposed infections can result in scarring. Panacinar emphysema is commonly associated with AATD with loss of all portions of the acinus from the respiratory bronchiole to the alveoli.

Microscopic Pathology

Emphysema results in destruction of alveolar walls and permanent abnormal enlargement of the airspace distal to the terminal bronchiole. In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the lobule found more commonly in the basilar portions of the lung. This is in contrast emphysema resulting from cigarette smoking that characteristically involves the centrilobular lung and respiratory bronchioles in the central portion of the lobule, initially at the apex of the lung.

References


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