| Alpha 1-antitrypsin deficiency |
| Classification and external resources |
Structure of Alpha 1-antitrypsin |
| ICD-10 |
E88.0 |
| ICD-9 |
273.4 |
| OMIM |
107400 |
| DiseasesDB |
434 |
| MedlinePlus |
000120 |
| eMedicine |
med/108 |
| MeSH |
D019896 |
| GeneReviews |
Alpha1-Antitrypsin Deficiency |
Alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency, A1AD or simply Alpha-1) is a genetic disorder that causes 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.[1][2] There are several forms and degrees of deficiency, principally depending on whether the sufferer has one or two copies of the affected gene because it is a codominant trait. Severe A1AT deficiency causes panacinar emphysema or COPD in adult life in many people with the condition (especially if they are exposed to cigarette smoke), as well as various liver diseases in a minority of children and adults, and occasionally more unusual problems.[3] It is treated by avoidance of damaging inhalants, by intravenous infusions of the A1AT protein, by transplantation of the liver or lungs, and by a variety of other measures, but it usually produces some degree of disability and reduced life expectancy.[1]
|
Contents
- 1 Signs and symptoms
- 1.1 Associated conditions
- 2 Pathophysiology
- 3 Diagnosis
- 4 Treatment
- 5 Epidemiology
- 6 History
- 7 See also
- 8 References
- 9 External links
|
Signs and symptoms
Symptoms of alpha-1 antitrypsin deficiency include shortness of breath, 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 smoking, though smoking greatly increases the risk for emphysema.[1] A1AD also causes impaired liver function in some patients and may lead to cirrhosis and liver failure (15%). It is a leading indication for liver transplantation in newborns.
Associated conditions
Conditions associated with Alpha-1 Antitrypsin Deficiency, occurring due to paucity of AAT in circulation allowing uninhibited inflammation in lungs, and accumulation of mutated AAT in the Liver
|
|
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (December 2010) |
α1-antitrypsin deficiency has been associated with a number of diseases:
- Cirrhosis
- COPD
- Pneumothorax
- Asthma
- Wegener's granulomatosis
- Pancreatitis
- Gallstones
- Bronchiectasis
- Pelvic organ prolapse[4]
- Primary sclerosing cholangitis
- Autoimmune hepatitis
- Emphysema, predominantly involving the lower lobes and causing bullae
- Cancer
- Hepatocellular carcinoma (liver)
- Bladder carcinoma
- Gallbladder cancer
- Lymphoma
- Lung cancer
Pathophysiology
Photomicrograph of a liver biopsy from a patient with alpha-1 antitrypsin deficiency. The PAS with diastase stain shows the diastase-resistant pink globules that are characteristic of this disease.
See also: Alpha 1-antitrypsin
Alpha 1-antitrypsin (A1AT) is produced in the liver, and one of its functions is to protect the lungs from neutrophil elastase, an enzyme that can disrupt connective tissue.[1] Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 g/l. In individuals with PiSS, PiMZ and PiSZ phenotypes, blood levels of A1AT are reduced to between 40 and 60% of normal levels. This is usually 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 panacinar 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 PAS-positive, diastase-resistant granules.
Cigarette smoke is especially harmful to individuals with A1AD.[1] In addition to increasing the inflammatory reaction in the airways, cigarette smoke directly inactivates alpha 1-antitrypsin by oxidizing essential methionine residues to sulfoxide forms, decreasing the enzyme activity by a factor of 2000.
Diagnosis
Emphysema due to alpha-1-antitrypsin deficiency.
Computed tomography of the lung showing emphysema and bullae in the lower lung lobes of a subject with type ZZ alpha-1-antitrypsin deficiency. There is also increased lung density in areas with compression of lung tissue by the bullae.
A1AT deficiency remains undiagnosed in many patients. Patients are usually labelled as having COPD without an underlying cause. It is estimated that about 1% of all COPD patients actually have A1AT deficiency. Thus, testing should be performed for all patients with COPD, asthma with irreversible air-flow obstruction, unexplained liver disease, or necrotizing panniculitis. The initial test performed is serum A1AT level. A low level of A1AT confirms the diagnosis and further assessment with A1AT protein phenotyping and A1AT genotyping should be carried out subsequently.[5]
As protein electrophoresis does not completely distinguish between A1AT and other minor proteins at the alpha-1 position (agarose gel), antitrypsin can be more directly and specifically measured using a nephelometric or immunotubidimetric method. Thus, protein electrophoresis is useful for screening and identifying individuals likely to have a deficiency. A1AT is further analysed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient. Normal A1AT is termed M, as it is migrates toward the center of such an IEF gel. Other variants are less functional, and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha 1-antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above. As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although a heterozygote with one null mutant that abolishes expression of the gene will only show one band. In blood test results, the IEF results are notated as, e.g., PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that person.[citation needed]
Other detection methods include use of enzyme-linked-immuno-sorbent-assays in vitro and radial immunodiffusion. Alpha 1-antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome, whereas others have a tendency to polymerise, thereafter being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:[citation needed]
- PiMM: 100% (normal)
- PiMS: 80% of normal serum level of A1AT
- PiSS: 60% of normal serum level of A1AT
- PiMZ: 60% of normal serum level of A1AT
- PiSZ: 40% of normal serum level of A1AT
- PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)
PiZ is caused by a glutamate to lysine mutation at position 342, while PiS is caused by a glutamate to valine mutation at position 264. Other rarer forms have been described; in all there are over 80 variants.[citation needed]
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.[5]
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.[citation needed]
As α1-antitrypsin is an acute phase reactant, its transcription is markedly increased during inflammation elsewhere in response to increased interleukin-1 and 6 and TNFα production.
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
Distribution of PiZZ in Europe.
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 homozygous.
History
A1AD was discovered in 1963 by Carl-Bertil Laurell (1919–2001), at the University of Lund in Sweden.[6] Laurell, along with a medical resident, Sten Eriksson, made the discovery after noting the absence of the α1 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 Dr. Harvey Sharp et al. described A1AD in the context of liver disease.[7]
See also
- Chronic obstructive pulmonary disease (COPD)
- Emphysema
- Cirrhosis
References
- ^ a b c d e Kumar V, Abbas AK, Fausto N, ed. (2005). Robbin and Cotran Pathological Basis of Disease (7th ed.). Elsevier/Saunders. pp. 911–2. ISBN [[Special:BookSources/978-0-7216-0187-3|978-0-7216-0187-3]].
- ^ Stoller J, Aboussouan L (2005). "Alpha1-antitrypsin deficiency". Lancet 365 (9478): 2225–36. doi:10.1016/S0140-6736(05)66781-5. PMID 15978931.
- ^ Needham M, Stockley RA (2004). "α1-Antitrypsin deficiency • 3: Clinical manifestations and natural history". Thorax 59 (5): 441–5. doi:10.1136/thx.2003.006510. PMC 1746985. PMID 15115878. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1746985.
- ^ Chen B, Wen Y, Polan ML (2004). "Elastolytic activity in women with stress urinary incontinence and pelvic organ prolapse". Neurourol. Urodyn. 23 (2): 119–26. doi:10.1002/nau.20012. PMID 14983422.
- ^ a b Silverman EK, Sandhaus RA (2009). "Alpha1-Antitrypsin Deficiency". New England Journal of Medicine 360 (26): 2749–2757. doi:10.1056/NEJMcp0900449. PMID 19553648. http://content.nejm.org/cgi/content/full/360/26/2749.
- ^ Laurell CB, Eriksson S (1963). "The electrophoretic alpha 1-globulin pattern of serum in alpha 1-antitrypsin deficiency". Scand J Clin Lab Invest 15 (2): 132–140. doi:10.1080/00365516309051324.
- ^ Sharp H, Bridges R, Krivit W, Freier E (1969). "Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder". J Lab Clin Med 73 (6): 934–9. PMID 4182334.
External links
- Alpha-1 Association
- Alpha-1 Foundation
- FAQ from AlphaNet
- Alpha-1 Kids
- Alpha 1-antitrypsin deficiency on Orphanet
|
Disorders of globin and globulin proteins
|
|
| Globin |
Hemoglobinopathy: Thalassemia (alpha, beta, delta) · Sickle-cell disease/trait · HPFH
|
|
| Globulin |
|
|
| Serpin |
Serpinopathy: Alpha 1-antitrypsin deficiency · Antithrombin III deficiency · Hereditary angioedema · FENIB
|
|
|
see also globular proteins, globins, antibodies, serpins
B structural (perx, skel, cili, mito, nucl, sclr) · DNA/RNA/protein synthesis (drep, trfc, tscr, tltn) · membrane (icha, slcr, atpa, abct, othr) · transduction (iter, csrc, itra), trfk
|
|
