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{{Alpha 1-antitrypsin deficiency}}
{{Alpha 1-antitrypsin deficiency}}
{{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}
{{CMG}}; {{AE}}{{Mazia}}
==Overview==
[[Alpha 1-antitrypsin]] (A1AT) is synthesized and secreted mainly by [[hepatocytes]]. [[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. A [[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]]. Acculmulation of excess [[Alpha1 antitrypsin|alpha1-antitrypsin]] in [[hepatocytes]] results in [[chronic liver disease]]. [[SERPINA2|SERPINA1]] [[gene mutation]] alters the structure of the [[Alpha1 antitrypsin|alpha1-antitrypsin]] [[Molecules|molecule]] and prevents its release from [[hepatocytes]]. By far, the most common severe deficient variant is the [[Alleles|Z allele]], which is produced by [[lysine]] [[substitution]] for [[glutamate]] at 342 position in the [[alpha 1-antitrypsin]] [[Molecules|molecule]].  The [[Alleles|Z allele]] accounts for 95% of the [[Clinical|clinically]] recognized cases of severe alpha-1 AT deficiency. On cut section of the [[lung]], [[Emphysema|emphysematous process]] is evidenced by dilated air spaces and loss of [[lung]] [[Parenchyma|parenchyma.]] [[Infections|Superimposed infections]] can result in [[scarring]]. [[Emphysema|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 [[Emphysema|emphysematous areas]] are uniformly distributed throughout the [[lobule]] found more commonly in the basilar portions of the [[lung]].


==Overview==
== Pathophysiology ==
Alpha 1-antitrypsin deficiency (A1AD) is more common in people of Northern European, Iberian, and Saudi Arabian descent. Most researchers believe it is markedly underrecognized.
The pathophysiology of alpha 1-antitrypsin deficiency (AATD) may be described as follows:<ref name="pmid21960536">{{cite journal |vauthors=Stoller JK, Aboussouan LS |title=A review of α1-antitrypsin deficiency |journal=Am. J. Respir. Crit. Care Med. |volume=185 |issue=3 |pages=246–59 |year=2012 |pmid=21960536 |doi=10.1164/rccm.201108-1428CI |url=}}</ref><ref name="pmid23527684">{{cite journal |vauthors=Stoller JK, Brantly M |title=The challenge of detecting alpha-1 antitrypsin deficiency |journal=COPD |volume=10 Suppl 1 |issue= |pages=26–34 |year=2013 |pmid=23527684 |doi=10.3109/15412555.2013.763782 |url=}}</ref><ref name="pmid27399863">{{cite journal |vauthors=Stoller JK |title=Alpha-1 antitrypsin deficiency: An underrecognized, treatable cause of COPD |journal=Cleve Clin J Med |volume=83 |issue=7 |pages=507–14 |year=2016 |pmid=27399863 |doi=10.3949/ccjm.83a.16031 |url=}}</ref>
*[[Alpha 1-antitrypsin]] (A1AT) is synthesized and secreted mainly by [[hepatocytes]]. 
*Other sources of the [[enzyme]] include:
**[[Macrophage|Macrophages]]. 
**[[Bronchus|Bronchial]] [[epithelial]] [[cells]].
*[[Alpha1 antitrypsin|Alpha1-antitrypsin]] [[enzyme]] is a member of the [[serine protease inhibitor]] ([[serpin]]) family of [[proteins]].
*Functions of [[Alpha1 antitrypsin|alpha1-antitrypsin]] include:
**Inhibition of [[pancreatic]] [[trypsin]], and other [[Proteinase|proteinases]] including [[neutrophil elastase]], [[cathepsin G]] and [[proteinase 3]].
**Protection of 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]]. 
====Lung====
*[[Proteases]] accumulate in the [[alveoli]] causing a destruction of [[alveolar]] walls and resultant [[emphysema]]. 
*[[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. 
*In Z-variant of [[alpha1 antitrypsin]] deficiency, there is decreased levels of [[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 [[Radical (chemistry)|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 [[Gastric lavage|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 result in [[emphysema]]. 
====Liver====
*Excess [[Alpha1 antitrypsin|alpha1-antitrypsin]] in [[hepatocytes]] results in [[chronic liver disease]]. 
*The Z [[Mutations|mutation]] results in a [[conformational change]] in the [[Alpha antitrypsin|alpha 1 antitrypsin]] molecule and causes most of the unstable [[protein]] to form [[polymers]]. 
*Opening of the β sheet leaves 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]]. 
*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.
 
===Genetics===
*Alpha1-antitrypsin deficiency (AATD) is [[inherited]] in an [[autosomally-codominant]] pattern caused by [[mutations]] in the ''SERPINA1'' [[gene]].<ref name="urlThe genetics of α1-antitrypsin: a family study in England and Scotland - COOK - 1975 - Annals of Human Genetics - Wiley Online Library">{{cite web |url=http://onlinelibrary.wiley.com/doi/10.1111/j.1469-1809.1975.tb00611.x/full |title=The genetics of α1-antitrypsin: a family study in England and Scotland - COOK - 1975 - Annals of Human Genetics - Wiley Online Library |format= |work= |accessdate=}}</ref>
*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.
*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 (Z) – No detectable alpha-1 AT.  Least common and most severe form of the [[disease]].
** Dysfunctional (S) – Patients have a normal alpha-1 AT level, but the [[enzyme]] does not function properly.
*The most common allele is the M allele which codes for protease inhibitor (Pi) M protein.
*The most common severe deficiency allele is the Z allele which, in the homozygous state (PiZZ).
*The S allele is associated with AAT plasma levels approximately 60% of normal in the homozygous state.
* In individuals with PiSS, PiMZ and PiSZ [[phenotype]]s, blood levels of A1AT are reduced to between 40 and 60% of normal levels, sufficient to protect the [[lungs]] from the effects of [[elastase]] in people who do not [[tobacco smoking|smoke]].
* 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]] of affected 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]].
* 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.
* 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.
*The limitation is that it makes the serpins more than usually vulnerable to dysfunctional [[mutations]].


== Epidemiology and Demographics ==
===Associated Conditions===
People of northern European, Iberian and Saudi Arabian ancestry are at the highest risk for A1AD. Four percent carry the PiZ [[allele]]; between 1 in 625 and 1 in 2000 are [[homozygote|homozygous]].
α<sub>1</sub>-antitrypsin deficiency has been associated with a number of [[diseases]]:
* [[COPD]]
* [[Asthma]]
* [[Wegener's granulomatosis]]
* [[Pancreatitis]]
* [[Gallstone]]s
* [[Bronchiectasis]] (possibly)
* [[Prolapse]][http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14983422]
* [[Primary sclerosing cholangitis]]
* [[Autoimmune hepatitis]]
* [[Emphysema]]
* [[Cancer]]
** [[Hepatocellular carcinoma]] (liver)
** [[Bladder carcinoma]]
** [[Gallbladder cancer]]
** [[Lymphoma]]
** [[Lung cancer]]


[[Image:PiZZ Europe.png|center|thumb|Distribution of PiZZ in Europe.]]
===Gross Pathology===
* On cut section of the [[lung]], emphysematous process is evidenced by dilated air spaces and loss of [[lung]] [[parenchyma]].  
* Superimposed [[infection]]s may result in [[scarring]].
* [[Panacinar]] [[emphysema]] is commonly associated with [[alpha 1-antitrypsin deficiency]] with loss of all portions of the [[acinus]] from the respiratory [[bronchiole]] to the [[alveoli]].


It is estimated that between 80,000 – 1000,000 (~ 1 in 1,650 to 1 in 3,000) Americans have severe alpha-1 AT deficiency (PI ZZ phenotype). This is approximately the same prevalence as [[cystic fibrosis]].  Studies have also estimated that ~ 2-3% of patients with severe [[COPD]] ([[chronic obstructive pulmonary disease]]) have severe alpha-1 AT deficiency.  Given this relatively high prevalence, it is interesting to find that most clinicians perceive alpha-1 AT deficiency to be rare. In fact, only ~ 4% of patients with the PI ZZ phenotype were identified by the medical community in one study. The remaining 96% of PI ZZ patients must therefore be asymptomatic, or symptomatic but have escaped detection. In a recent survey, the average time interval between the onset of pulmonary symptoms and time of diagnosis was 7.2 years.  Additionally, 43% of patients see at least 3 physicians before the diagnosis is established, and 12% see between 6 and 10.  Thus, most authors believe that alpha-1 AT deficiency is markedly underrecognized.  Because there are genetic implications to the next generation, that diagnosis can assist in smoking prevention / cessation, and that treatment is now available, enhanced detection is essential.
===Microscopic Pathology===
* [[Emphysema]] results in destruction of [[alveolar]] walls and permanent abnormal enlargement of the airspace distal to the terminal [[bronchiole]]. <ref name="pmid23355203">{{cite journal |vauthors=Greene DN, Elliott-Jelf MC, Straseski JA, Grenache DG |title=Facilitating the laboratory diagnosis of α1-antitrypsin deficiency |journal=Am. J. Clin. Pathol. |volume=139 |issue=2 |pages=184–91 |year=2013 |pmid=23355203 |doi=10.1309/AJCP6XBK8ULZXWFP |url=}}</ref>
* In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the [[lobule]] found more commonly in the basilar portions of the [[lung]].  
* In contrast, [[emphysema]] resulting from [[cigarette]] [[smoking]] characteristically involves the centrilobular [[lung]] and [[respiratory bronchioles]] in the central portion of the [[lobule]], initially at the apex of the [[lung]].


==References==
==References==
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[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Genetic disorders]]
[[Category:Pulmonology]]
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[[Category:Hepatology]]
[[Category:Inborn errors of metabolism]]
[[Category:Metabolic disorders]]
[[Category:Mature chapter]]
[[Category:Disease state]]


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Latest revision as of 17:29, 15 February 2018

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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. 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. A 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. Acculmulation of excess alpha1-antitrypsin in hepatocytes results in chronic liver disease. SERPINA1 gene mutation alters the structure 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 lysine substitution for glutamate at 342 position in the alpha 1-antitrypsin molecule. The Z allele 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

The pathophysiology of alpha 1-antitrypsin deficiency (AATD) may be described as follows:[1][2][3]

Lung

Liver

Genetics

  • Alpha1-antitrypsin deficiency (AATD) is inherited in an autosomally-codominant pattern caused by mutations in the SERPINA1 gene.[4]
  • 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 (Z) – No detectable alpha-1 AT. Least common and most severe form of the disease.
    • Dysfunctional (S) – Patients have a normal alpha-1 AT level, but the enzyme does not function properly.
  • The most common allele is the M allele which codes for protease inhibitor (Pi) M protein.
  • The most common severe deficiency allele is the Z allele which, in the homozygous state (PiZZ).
  • The S allele is associated with AAT plasma levels approximately 60% of normal in the homozygous state.
  • In individuals with PiSS, PiMZ and PiSZ phenotypes, blood levels of A1AT are reduced to between 40 and 60% of normal levels, sufficient to protect the lungs from the effects of elastase in people who do not smoke.
  • 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 of affected 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.
  • 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.
  • 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

Associated Conditions

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

Gross Pathology

Microscopic Pathology

  • Emphysema results in destruction of alveolar walls and permanent abnormal enlargement of the airspace distal to the terminal bronchiole. [5]
  • In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the lobule found more commonly in the basilar portions of the lung.
  • In contrast, emphysema resulting from cigarette smoking characteristically involves the centrilobular lung and respiratory bronchioles in the central portion of the lobule, initially at the apex of the lung.

References

  1. ↑ Stoller JK, Aboussouan LS (2012). "A review of α1-antitrypsin deficiency". Am. J. Respir. Crit. Care Med. 185 (3): 246–59. doi:10.1164/rccm.201108-1428CI. PMID 21960536.
  2. ↑ Stoller JK, Brantly M (2013). "The challenge of detecting alpha-1 antitrypsin deficiency". COPD. 10 Suppl 1: 26–34. doi:10.3109/15412555.2013.763782. PMID 23527684.
  3. ↑ Stoller JK (2016). "Alpha-1 antitrypsin deficiency: An underrecognized, treatable cause of COPD". Cleve Clin J Med. 83 (7): 507–14. doi:10.3949/ccjm.83a.16031. PMID 27399863.
  4. ↑ "The genetics of α1-antitrypsin: a family study in England and Scotland - COOK - 1975 - Annals of Human Genetics - Wiley Online Library".
  5. ↑ Greene DN, Elliott-Jelf MC, Straseski JA, Grenache DG (2013). "Facilitating the laboratory diagnosis of α1-antitrypsin deficiency". Am. J. Clin. Pathol. 139 (2): 184–91. doi:10.1309/AJCP6XBK8ULZXWFP. PMID 23355203.


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