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| '''For patient information, click [[Alpha 1-antitrypsin deficiency (patient information)|here]] | | __NOTOC__ |
| | {{Alpha 1-antitrypsin deficiency}} |
| | {{CMG}}; {{AE}} {{Mazia}} |
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| | {{SK}}: Alpha-1-deficiency; Anti-protease deficiency; |
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| | '''For patient information, click [[Alpha 1-antitrypsin deficiency (patient information)|here]]''' |
| {{DiseaseDisorder infobox | | | {{DiseaseDisorder infobox | |
| Name = Alpha 1-antitrypsin deficiency | | | Name = Alpha 1-antitrypsin deficiency | |
| ICD10 = {{ICD10|E|88|0|e|70}} | | | ICD10 = {{ICD10|E|88|0|e|70}} | |
| ICD9 = {{ICD9|273.4}} | | | ICD9 = {{ICD9|273.4}} | |
| Image = A1AT.png |
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| Caption = Structure of [[Alpha 1-antitrypsin]] |
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| Width = 150 | | | Width = 150 | |
| ICDO = | | | ICDO = | |
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| DiseasesDB = 434 | | | DiseasesDB = 434 | |
| MedlinePlus = 000120 | | | MedlinePlus = 000120 | |
| eMedicineSubj = |
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| }} | | }} |
| {{SI}}
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| {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}
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| ==Overview==
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| '''Alpha 1-antitrypsin deficiency''' ('''A1AD''' or '''Alpha-1''') is a [[genetic disorder]] caused by defective production of [[alpha 1-antitrypsin]], deficient activity in the blood and [[lungs]], and deposition of excessive amounts of 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 = | id = PMID 15978931}}</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, 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 | id = PMID 15115878}}</ref> It is treated by avoidance of damaging inhalants, by [[intravenous infusion]]s of the A1AT protein, by [[transplantation]] of liver or lungs, and by a variety of other measures, but it usually produces some degree of [[disability]] and shortens life.
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| ==History==
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| 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= }}</ref>
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| 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.
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| 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 | id = PMID 4182334}}</ref>
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| == Epidemiology and Demographics ==
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| 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]].
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| [[Image:PiZZ Europe.png|center|thumb|Distribution of PiZZ in Europe.]]
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| 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.
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| == Pathophysiology ==
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| [[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. 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.
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| [[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 rate of 2000.
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| == Molecular Biology ==
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| Laurell and Eriksson first discovered alpha-1 antitrypsin (alpha-1 AT) deficiency at the General Hospital in Malmö, Sweden in 1963. Alpha-1 AT is the protease inhibitor in highest concentration in human plasma, and although it is a good inhibitor of trypsin, its primary physiologic target is neutrophil elastase. Alpha-1 AT belongs to the serpin class of serine protease inhibitors, and is synthesized and secreted primarily by hepatocytes, but also the mononuclear phagocytes. Other examples of the serpin class of protease inhibitors include antithrombin, C1-inhibitor, and the many inhibitors of plasminogen. The serine protease inhibitors have a unique ability to undergo a conformational change. An advantage of this molecular mobility is that it enables the inhibitor to snare its target protease and tightly entrap it, forming a complex that can remain stable for hours. A potential disadvantage, however, is that it makes the serpins more than usually vulnerable for dysfunctional mutations.
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| == Genetics == | | ==[[Alpha 1-antitrypsin deficiency overview|Overview]]== |
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| The alpha-1 AT gene has been located on the long arm of chromosome 14, and has been successfully been sequenced and cloned. There have been 75 different alleles for alpha-1 AT variants that have been described, but only 10-15 are associated with severe alpha-1 AT deficiency. Each allele has been given a letter code based upon electrophoretic mobility. 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:
| | ==[[Alpha 1-antitrypsin deficiency historical perspective|Historical Perspective]]== |
| * Normal – M alleles (normal phenotype is MM), found in 90% of the U.S. population, patients have normal lung function.
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| * Deficient – Z allele (carried by 2-3% of the U.S. Caucasian population), have plasma levels of alpha-1 AT that are < 35% of normal.
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| * Null – No detectable alpha-1 AT. Least common and most severe form of the disease.
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| * Dysfunctional – Patients have a normal alpha-1 AT level, but the enzyme does not function properly.
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| == Natural History == | | ==[[Alpha 1-antitrypsin deficiency classification|Classification]]== |
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| * Within the first two decades of life, liver dysfunction tends to dominate the clinical picture, while lung function is generally preserved.
| | ==[[Alpha 1-antitrypsin deficiency pathophysiology|Pathophysiology]]== |
| * Two prospective studies have followed newborns identified at birth with blood screening for up to 16 years, and both showed no difference in lung function compared with controls.
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| * After the first 20 years, however, lung function begins to deteriorate at the rate mentioned above. <br>
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| Respiratory failure accounts for ~ 62% of deaths, and complications of chronic liver disease for ~ 13%. The mean age of death in one study was 53 years old for nonsmokers and 40 years old for smokers, with only 16% surviving to 60 years old. This compares to ~ 85% surviving to 65 years old in the general population. Mortality is directly related to FEV1 (forced expiratory volume), and rises exponentially as FEV1 falls below 35% predicted.
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| In a Danish study, asymptomatic nonsmokers, who were identified as relatives of symptomatic patients with alpha-1 AT had a normal life expectancy. This is consistent with the presence of a subgroup of patients with severe deficiency in alpha-1 AT who escape medical attention.
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| == Diagnosis == | | ==[[Alpha 1-antitrypsin deficiency causes|Causes]]== |
| * The diagnosis of alpha-1 AT deficiency should be suspected in any patient who:
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| # Develops [[emphysema]] younger than 45 years old, if they are a non/minimal smoker, or if they have primarily basilar disease OR
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| # Has a history of [[panniculitis]] or
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| # Has or has a family history of unexplained liver disease (especially [[cirrhosis]] or [[hepatoma]]). <br>
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| In suspected individuals the initial step is to measure the serum alpha-1 AT concentration. In general, phenotyping should be reserved for patients who have low or borderline low alpha-1 AT levels. In addition, baseline PFTs-pulmonary function tests (spirometry pre and post bronchodilators, lung volumes and diffusing capacity), LFTs (liver function test), an ABG-arterial blood gases (usually) and a PA (posteroanterior) and lateral chest x-ray are recommended.
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| === Signs and Symptoms === | | ==[[Alpha 1-antitrypsin deficiency differential diagnosis|Differentiating Alpha 1-antitrypsin deficiency from other Diseases]]== |
| Symptoms of alpha-1 antitrypsin deficiency include [[dyspnea|shortness of breath]], wheezing, [[rhonchi]], rales may be present and appear to be recurring respiratory infections (but isn't), or obstructive [[asthma]] that does not respond to treatment. Individuals with alpha-1 may develop [[emphysema]] during their thirties or forties, without a history of significant smoking (although 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. <ref>American Thoracic Society, Guidelines for the approach to the patient with severe hereditary alpha-1-antitrypsin deficiency, Am Rev Respir Dis 1989; 140: 1494-1497.</ref> <ref>Eriksson, S. Alpha 1 – antitrypsin Deficiency: Lessons Learned from the Bedside to the Gene and Back Again: Historic Perspectives, Chest 1989; 95: 181-189. PMID 2642407</ref> <ref>Rovner, M.S., Stoller, J.K., Treatment of alpha-1 antitrypsin deficiency, in UpToDate, January 12, 1998.</ref> <ref>Stoller, J.K., Clinical Features and Natural History of Severe alpha-1 Antitrypsin Deficiency, Chest 1997; 111: 123s-128s. PMID 9184559</ref> <ref>Stoller, J.K., Extrapulmonary manifestations of alpha-1 antitrypsin deficiency, in UpToDate, March 13, 1997.</ref> <ref>Stoller, J.K., Clinical manifestations and natural history of alpha-1 antitrypsin deficiency, in UpToDate, January 3, 1997.</ref>
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| === Physical Examination === | | ==[[Alpha 1-antitrypsin deficiency epidemiology and demographics|Epidemiology and Demographics]]== |
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| === Lungs === | | ==[[Alpha 1-antitrypsin deficiency risk factors|Risk Factors]]== |
| * The primary pulmonary manifestation of alpha-1 AT deficiency is panacinar [[emphysema]] which is seen in 75-85% of patients with the PI ZZ phenotype. Although [[asthma]] and [[bronchiectasis]] have also been reported, their exact relationship with alpha-1 AT deficiency remains unclear.
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| * Emphysema results from an imbalance between neutrophil elastase, which destroys elastin, and the elastase inhibitor, alpha-1 AT, which protects against the proteolytic degradation of elastin.
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| * The risk of emphysema increases as the levels of alpha-1 AT fall below the ‘protective’ threshold level of 11 umol/L (80mg/dl), normal values being 20-53 umol/L (150-350 mg/dl).
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| * Patients with the PI ZZ phenotype have serum levels of alpha-1 AT that cluster ~ 5-6umol/L (35mg/dl).
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| * In patients with the PI ZZ phenotype, cigarette smoking, a history of pneumonia, and episodes of cough and sputum production, and a parental history of emphysema have been shown to increase the risk for developing airflow obstruction.
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| * Cigarette smoking can accelerate the onset of dyspnea in these patients by as much as 19 years. One study found the average age of onset of dyspnea to be ~ 48 – 56 years in nonsmokers, as compared to ~ 32 – 40 years in smokers.
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| * The FEV1 declines approximately 132 ml/yr in nonsmokers with alpha-1 AT. This compares to ~25-30 ml/yr in nonsmokers without any lung disease, and up to 317 ml/yr in patients with alpha-1 AT who smoke.
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| * The emphysematous changes in these patients are seen primarily at the bases of the lungs. This likely results from the increased blood flow, and hence neutrophil delivery to the basses as compared with the apices.
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| === Abdomen === | | ==[[Alpha 1-antitrypsin deficiency screening|Screening]]== |
| ==== Liver ==== | |
| * Liver disease occurs in approximately 12-16% of patients with the PI ZZ phenotype. As opposed to lung disease, which results from an increase in the relative amount of elastase, liver disease results from the accumulation of alpha-1 AT within the hepatocytes. Thus, patients who are null homozygotes do not get liver disease, since they do not get accumulation of alpha-1 AT.
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| * The primary diseases seen are neonatal hepatitis, cirrhosis in both adults and children, and hepatoma.
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| * It seems that of the 10-15% of newborns with neonatal hepatitis, 5% die of cirrhosis within the first year of life. Approximately 25% have complete resolution of hepatitis by ages 3-10 years, ~ 25% develop cirrhosis between 6 months and 17 years, ~ 25% have histologic evidence of cirrhosis but survive through the first decade without problems, and ~ 25% have persistent transaminitis without cirrhosis.
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| * The risk of hepatoma is greater in men, and hepatoma can develop in the absence of cirrhosis.
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| ==== Skin ==== | | ==[[Alpha 1-antitrypsin deficiency natural history, complications, and prognosis|Natural History, Complications and Prognosis]]== |
| Panniculitis is the primary dermatologic manifestation of alpha-1 AT deficiency. There have only been 26 reported cases in the English literature (up to 1991), and it is seen in < 1 in 1,000 patients with alpha-1 AT deficiency. It has been reported in patients with every phenotype (except null), and is thought to result from a relative excess of elastin.
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| == Differential Diagnosis == | | ==Diagnosis== |
| | [[Alpha 1-antitrypsin deficiency history and symptoms|History and Symptoms]] | [[Alpha 1-antitrypsin deficiency physical examination|Physical Examination]] | [[Alpha 1-antitrypsin deficiency laboratory tests|Laboratory Findings]] | [[Alpha 1-antitrypsin deficiency electrocardiogram |Electrocardiogram]] | [[Alpha 1-antitrypsin deficiency x ray|X Ray]] | [[Alpha 1-antitrypsin deficiency CT|CT]] | [[Alpha 1-antitrypsin deficiency MRI|MRI]] | [[Alpha 1-antitrypsin deficiency echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Alpha 1-antitrypsin deficiency other imaging findings|Other Imaging Findings]] | [[Alpha 1-antitrypsin deficiency other diagnostic studies|Other Diagnostic Studies]] |
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| * Adult [[hepatitis]] or [[cirrhosis]] of unclear origin
| | ==Treatment== |
| * Adult pulmonary [[emphysema]]
| | [[Alpha 1-antitrypsin deficiency medical therapy|Medical Therapy]] | [[Alpha 1-antitrypsin deficiency surgery|Surgery]] | [[Alpha 1-antitrypsin deficiency primary prevention|Primary Prevention]] | [[Alpha 1-antitrypsin deficiency secondary prevention|Secondary Prevention]] | [[Alpha 1-antitrypsin deficiency cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Alpha 1-antitrypsin deficiency future or investigational therapies|Future or Investigational Therapies]] |
| * [[Cachexia]]
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| * [[Hepatitis]] of unclear origin in children
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| * Hereditary, [[autosomal recessive]] [[Alpha-1 Antitrypsin Deficiency|alpha-1 antitrypsin deficiency]]
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| * [[Malnutrition]]
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| * [[Nephrotic Syndrome]]
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| * Nonphysiologic neonatal [[jaundice]]
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| == Associated diseases == | | ==Related Chapters== |
| α<sub>1</sub>-antitrypsin deficiency has been associated with a number of diseases:
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| * [[COPD]]
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| * [[Asthma]]
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| * [[Wegener's granulomatosis]]
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| * [[Pancreatitis]]
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| * [[Gallstone]]s
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| * [[Bronchiectasis]] (possibly)
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| * [[Prolapse]][http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14983422]
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| * [[Primary sclerosing cholangitis]]
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| * [[Autoimmune hepatitis]]
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| * [[Emphysema]]
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| * [[Cancer]]
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| ** [[Hepatocellular carcinoma]] (liver)
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| ** [[Bladder carcinoma]]
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| ** [[Gallbladder cancer]]
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| ** [[Lymphoma]]
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| ** [[Lung cancer]]
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| == Treatment ==
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| 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.
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| 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.
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| 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.
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| 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]].
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| '''Pitfalls of Therapy:'''
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| * Despite the isolation and cloning of the alpha-1 AT gene, the efficacy of augmentation therapy remains controversial due to the lack of large randomized trials that define the treatment regimens and target population. The current goal of therapy is to raise the level of alpha-1 AT in the plasma, and therefore the lung interstitium above the ‘protective’ threshold of 11 umol/L (80 mg/dl). There are basically two types of treatment for this disease, ‘augmentation’ therapy, and organ transplantation.
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| * Endogenous enhancement of alpha-1 AT production has been attempted pharmacologically with medications such as Danazol, Tamoxifen and estrogen/progesterone combinations based on the observation that alpha-1 AT levels increase as an acute phase reactant in times of stress (including pregnancy). Unfortunately, the alpha-1 AT levels do not increase enough to warrant therapy.
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| * Exogenous augmentation via aerosolization of either pooled human alpha-1 AT, or recombinant alpha-1 AT has been attempted, and both are thought to be safe and effective. Large clinical trials are currently underway.
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| * Gene therapy uses viruses that have been altered so they can not replicate to ‘infect’ and integrate their genome (with the cDNA of alpha-1 AT) into host cells with the goal of the host cell manufacturing endogenous alpha-1 AT. Unfortunately, in the initial studies, expression of the gene was limited, and the alpha-1 AT levels did not increase above the protective threshold.
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| * Exogenous augmentation via IV infusion of pooled human alpha-1 AT is the only approved method of augmentation therapy for patients with alpha-1 AT deficiency. Although being safe, well-tolerated, and without significant side effects, its clinical efficacy is still unproven. In addition, the goal plasma level is not known, especially since there is a cohort of patients with severe alpha-1 AT deficiency that are not symptomatic. Unfortunately, there has not been a randomized, double-blinded, placebo-controlled trial in patients with alpha-1 AT deficiency with and without symptoms.
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| *:* A recent observational study compared the rate of decline in FEV1 in 97 Danish ex-smokers to 198 German ex-smokers, both of whom had severe alpha-1 AT deficiency. The German subjects received weekly infusions of 60 mg/kg alpha-1 AT, and the Danish did not receive augmentation therapy. The Germans had a slower rate of decline in their FEV1 as compared with the Danes (-53 ml/yr vs. -75 ml/yr, p=0.002).
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| *:* Although weekly infusions are the only FDA approved regimen, monthly infusions (250 mg/kg) seem to have the same efficacy and safety and are widely used.
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| *:* The ATS recommends augmentation therapy for patients with alpha-1 AT phenotypes PI ZZ, PI Z null or PI null null with alpha-1 AT levels < 11 umol/L and airflow obstruction. Conversely, the Canadian Thoracic Society recommends waiting until the results of a large trial establish its efficacy. Additionally, although it is thought that severe COPD is associated with negligible benefit, a lower limit of FEV1 below which augmentation therapy should be withheld has not been proposed.
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| *:* It is crucial that these patients don’t smoke, and are treated with bronchodilators, just as other patients with airways obstruction. They should also receive pneumococcal and influenza vaccines.
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| *:* A years worth of IV augmentation therapy costs approximately $25,000 - $35,000 (90% of which is for the drug).
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| *:* There have not been any cases of HIV or hepatitis transmitted by pooled human alpha-1 AT.
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| *:* Transplantation of both lungs and liver has been offered to patients with end stage disease. Liver transplantation has the added benefit of correcting the underlying disorder, as the new liver will produce and secrete alpha-1 AT. There is no data to support the use of augmentation therapy after lung transplantation, although some authors suggest augmentation therapy during times of increased neutrophil burden in the lung.
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| ==References==
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| {{Reflist|2}}
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| == See also ==
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| * [[COPD]] | | * [[COPD]] |
| * [[Emphysema]] | | * [[Emphysema]] |
| * [[Cirrhosis]] | | * [[Cirrhosis]] |
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| ==External links==
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| * {{MedlinePlusOverview|alpha1antitrypsindeficiency}}
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| {{SIB}}
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| {{Endocrine, nutritional and metabolic pathology}} | | {{Endocrine, nutritional and metabolic pathology}} |
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| [[es:Deficiencia de alfa-1 antitripsina]]
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| [[fr:Déficit en alpha 1-antitrypsine]]
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| [[nl:Alpha-1-antitrypsine-deficiëntie]]
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| [[pt:Deficiência de alfa-1-antitripsina]]
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| [[Category:Inborn errors of metabolism]]
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