Alpha 1-antitrypsin deficiency
310757
223586551
2008-07-04T19:18:32Z
203.98.101.251
/* Associated diseases */
{{refimprove|date=July 2007}}
{{DiseaseDisorder infobox |
Name = Alpha 1-antitrypsin deficiency |
ICD10 = {{ICD10|E|88|0|e|70}} |
ICD9 = {{ICD9|273.4}} |
Image = A1AT.png |
Caption = Structure of [[Alpha 1-antitrypsin]] |
Width = 150 |
ICDO = |
OMIM = 107400 |
DiseasesDB = 434 |
MedlinePlus = 000120 |
eMedicineSubj = med |
eMedicineTopic = 108 |
MeshID = D019896 |
}}
'''Alpha 1-antitrypsin deficiency''' ('''α1-antitrypsin deficiency''', '''A1AD''' or '''Alpha-1''') is a [[genetic disorder]] caused by defective production of [[alpha 1-antitrypsin]] (A1AT), leading to decreased A1AT activity in the [[blood]] and [[lungs]], and deposition of excessive abnormal A1AT [[protein]] in [[liver]] cells.<ref name=Stoller_2005>{{cite journal | author = Stoller J, Aboussouan L | title = Alpha1-antitrypsin deficiency | journal = Lancet | volume = 365 | issue = 9478 | pages = 2225–36 | year = 2005| pmid = 15978931 | doi = 10.1016/S0140-6736(05)66781-5}}</ref> There are several forms and degrees of deficiency. Severe A1A deficiency causes [[emphysema]] and/or [[COPD]] in adult life in nearly all people with the condition, as well as various liver diseases in a minority of children and adults, and occasionally more unusual problems.<ref name=Needham_2004>{{cite journal | author = Needham M, Stockley RA | title = α1-antitrypsin deficiency 3: Clinical manifestations and natural history | journal = Thorax | volume = 59 | issue = | pages = 441–5 | year = 2004 | pmid = 15115878 | doi = 10.1136/thx.2003.006510}}</ref> It is treated by avoidance of damaging inhalants, by [[intravenous infusion]]s of the A1AT protein, by [[Organ transplant|transplantation]] of the [[liver transplant|liver]] or [[lung transplantation|lungs]], and by a variety of other measures, but it usually produces some degree of [[disability]] and reduced life expectancy.
== Signs and symptoms ==
Symptoms of alpha-1 antitrypsin deficiency include [[dyspnea|shortness of breath]], [[Wheeze|wheezing]], [[rhonchi]], and [[rales]]. The patient's symptoms may resemble recurrent respiratory infections or [[asthma]] that does not respond to treatment. Individuals with A1AD may develop [[emphysema]] during their thirties or forties even without a history of significant [[Tobacco smoking|smoking]], though smoking greatly increases the risk for emphysema. A1AD also causes impaired liver function in some patients and may lead to [[cirrhosis]] and [[liver failure]] (15%). It is the leading cause of [[liver transplantation]] in newborns.
== Pathophysiology ==
''Please see [[alpha 1-antitrypsin]] for a discussion of the various [[genotype]]s and [[phenotype]]s associated with A1AD.''
[[Alpha 1-antitrypsin]] (A1AT) is produced in the [[liver]], and one of its functions is to protect the lungs from the [[elastase|neutrophil elastase]] enzyme, which can disrupt connective tissue. Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 [[gram|gm]]/[[litre|l]]. 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.
[[Cigarette]] smoke is especially harmful to individuals with A1AD. 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 factor of 2000.
== Treatment ==
In the United States, Canada, and several European countries, lung-affected A1AD patients may receive intravenous infusions of alpha-1 antitrypsin, derived from donated human plasma. This augmentation therapy is thought to arrest the course of the disease and halt any further damage to the lungs. Long-term studies of the effectiveness of A1AT replacement therapy are not available. It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.
Augmentation therapy is not appropriate for liver-affected patients; treatment of A1AD-related liver damage focuses on alleviating the symptoms of the disease. In severe cases, liver transplantation may be necessary.
As α<sub>1</sub>-antitrypsin is an [[acute phase reaction|acute phase reactant]], its [[Transcription (genetics)|transcription]] is markedly increased during [[inflammation]] elsewhere in response to increased [[interleukin]]-1 and 6 and [[Tumor necrosis factor-alpha|TNFα]] production. Any treatment that blunts this response, specifically [[paracetamol]] (acetaminophen), can delay the accumulation of A1AT polymers in the liver and (hence) [[cirrhosis]]. A1AD patients are therefore encouraged to use paracetamol when slightly to moderately ill, even if they would otherwise not have used [[antipyretic]]s.
Treatments currently being studied include recombinant and inhaled forms of A1AT. Other experimental therapies are aimed at the prevention of [[polymer]] formation in the [[liver]].
== Epidemiology ==
[[Image:PiZZ Europe.png|right|thumb|Distribution of PiZZ in Europe.]]
People of northern [[European ethnic groups|European]], [[Iberian Peninsula|Iberian]] and [[Saudi Arabia]]n 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]].
== Associated diseases ==
α<sub>1</sub>-antitrypsin deficiency has been associated with a number of diseases:
* [[Cirrhosis]]
* [[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]]
==History==
A1AD was discovered in 1963 by Carl-Bertil Laurell (1919–2001), at the University of Lund, Sweden.<ref name=Laurell_1963>{{cite journal | author = Laurell CB, Eriksson S | title = The electrophoretic alpha 1-globulin pattern of serum in alpha 1-antitrypsin deficiency | journal = Scand J Clin Lab Invest | year = 1963 | volume = 15 | issue = | pages = 132–140 | url= | doi = 10.3109/00365516309051324}}</ref>
Laurell, along with a medical resident, Sten Eriksson, made the discovery after noting the absence of the α<sub>1</sub> band on protein [[electrophoresis]] in five of 1500 samples; three of the five patient samples were found to have developed emphysema at a young age.
The link with liver disease was made six years later, when Sharp ''et al'' described A1AD in the context of liver disease.<ref name=Sharp_1969>{{cite journal | author = Sharp H, Bridges R, Krivit W, Freier E | title = Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder | journal = J Lab Clin Med | volume = 73 | issue = 6 | pages = 934–9 | year = 1969 | pmid = 4182334}}</ref>
== See also ==
* [[COPD]]
* [[Emphysema]]
* [[Cirrhosis]]
==References==
<references />
==External links==
* [http://www.alphaone.org/alphas/?c=01-What-is-Alpha-1-Alphas Information] from the Alpha-1 Foundation
* [http://www.alphanet.org FAQ] from AlphaNet
* [http://www.alpha2alpha.net/whatisalpha1.htm Information] from Alpha2alpha
* {{MedlinePlusOverview|alpha1antitrypsindeficiency}}
{{Other metabolic pathology}}
[[Category:Gastroenterology]]
[[Category:Genetic disorders]]
[[Category:Pulmonology]]
[[Category:Hepatology]]
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