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Alpha-1-antitrypsin deficiency(A1ATD)

MedGen UID:
67461
Concept ID:
C0221757
Disease or Syndrome
Synonyms: A1AT deficiency; A1ATD; AAT deficiency; Alpha1-Antitrypsin Deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Alpha-1-antitrypsin deficiency (30188007); alpha-1-Proteinase inhibitor deficiency (30188007)
 
Gene (location): SERPINA1 (14q32.13)
OMIM®: 613490
Orphanet: ORPHA60

Disease characteristics

Excerpted from the GeneReview: Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin deficiency (AATD) is characterized by an increased risk for: chronic obstructive pulmonary disease (i.e., emphysema, persistent airflow obstruction, and/or chronic bronchitis) in adults; liver disease in children and adults; panniculitis; and c-ANCA positive vasculitis. Emphysema, sometimes with associated bronchiectasis, is the most common manifestation of AATD. Smoking is the major factor influencing the course of chronic obstructive pulmonary disease (COPD). The onset of respiratory disease in smokers with AATD is characteristically between ages 40 and 50 years; in non-smokers, the onset can be delayed to the sixth decade, and some non-smokers never develop COPD. Non-smokers may have a normal life span. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as obstructive jaundice and increased serum aminotransferase levels in the early days and months of life. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. The risk for hepatocellular carcinoma (HCC) is increased in individuals with AATD. [from GeneReviews]
Authors:
James K Stoller  |  Felicitas L Lacbawan  |  Loutfi S Aboussouan   view full author information

Additional descriptions

From OMIM
Alpha-1-antitrypsin deficiency is an autosomal recessive disorder. The most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age (Crystal, 1990).  http://www.omim.org/entry/613490
From GHR
Alpha-1 antitrypsin deficiency is an inherited disorder that may cause lung disease and liver disease. The signs and symptoms of the condition and the age at which they appear vary among individuals.People with alpha-1 antitrypsin deficiency usually develop the first signs and symptoms of lung disease between ages 20 and 50. The earliest symptoms are shortness of breath following mild activity, reduced ability to exercise, and wheezing. Other signs and symptoms can include unintentional weight loss, recurring respiratory infections, fatigue, and rapid heartbeat upon standing. Affected individuals often develop emphysema, which is a lung disease caused by damage to the small air sacs in the lungs (alveoli). Characteristic features of emphysema include difficulty breathing, a hacking cough, and a barrel-shaped chest. Smoking or exposure to tobacco smoke accelerates the appearance of emphysema symptoms and damage to the lungs.About 10 percent of infants with alpha-1 antitrypsin deficiency develop liver disease, which often causes yellowing of the skin and whites of the eyes (jaundice). Approximately 15 percent of adults with alpha-1 antitrypsin deficiency develop liver damage (cirrhosis) due to the formation of scar tissue in the liver. Signs of cirrhosis include a swollen abdomen, swollen feet or legs, and jaundice. Individuals with alpha-1 antitrypsin deficiency are also at risk of developing a type of liver cancer called hepatocellular carcinoma.In rare cases, people with alpha-1 antitrypsin deficiency develop a skin condition called panniculitis, which is characterized by hardened skin with painful lumps or patches. Panniculitis varies in severity and can occur at any age.  https://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency

Clinical features

Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Chronic obstructive pulmonary disease
MedGen UID:
9818
Concept ID:
C0024117
Disease or Syndrome
Chronic obstructive pulmonary disease (COPD) is a common, complex disorder associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction due to chronic bronchitis, emphysema, and/or small airways disease. Airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) (Silverman et al., 2002; Celedon et al., 2004).
Elevated hepatic transaminases
MedGen UID:
338525
Concept ID:
C1848701
Finding
Hepatocellular carcinoma
MedGen UID:
389187
Concept ID:
C2239176
Neoplastic Process
Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAlpha-1-antitrypsin deficiency
Follow this link to review classifications for Alpha-1-antitrypsin deficiency in Orphanet.

Professional guidelines

PubMed

Janciauskiene S, Ferrarotti I, Laenger F, Jonigk D, Luisetti M
Eur J Hum Genet 2011 May;19(5) Epub 2011 Jan 19 doi: 10.1038/ejhg.2010.246. PMID: 21248733Free PMC Article
Stoller JK, Snider GL, Brantly ML, Fallat RJ, Stockley RA, Turino GM, Konietzko N, Dirksen A, Eden E, Fallat RJ, Luisetti M, Stolk J, Strange C; American Thoracic Society.; European Respiratory Society.
Pneumologie 2005 Jan;59(1):36-68. doi: 10.1055/s-2004-830176. PMID: 15685488

External

Orphanet, Alpha-1 antitrypsin deficiency, 2010

Recent clinical studies

Etiology

Carleo A, Chorostowska-Wynimko J, Koeck T, Mischak H, Czajkowska-Malinowska M, Rozy A, Welte T, Janciauskiene S
Int J Chron Obstruct Pulmon Dis 2017;12:829-837. Epub 2017 Mar 8 doi: 10.2147/COPD.S125240. PMID: 28331304Free PMC Article
Sandhaus RA
Ann Am Thorac Soc 2016 Aug;13 Suppl 4:S370-3. doi: 10.1513/AnnalsATS.201510-684KV. PMID: 27564674
Stoller JK
Ann Am Thorac Soc 2016 Aug;13 Suppl 4:S317-25. doi: 10.1513/AnnalsATS.201506-349KV. PMID: 27564667
Stockley RA, Edgar RG, Pillai A, Turner AM
Int J Chron Obstruct Pulmon Dis 2016;11:1745-56. Epub 2016 Aug 1 doi: 10.2147/COPD.S111508. PMID: 27536086Free PMC Article
Topic A, Nagorni-Obradovic L, Francuski D, Ljujic M, Malic Z, Radojkovic D
Biochem Genet 2016 Oct;54(5):746-52. Epub 2016 Jun 6 doi: 10.1007/s10528-016-9748-7. PMID: 27271084

Diagnosis

Lascano JE, Campos MA
Postgrad Med 2017 Nov;129(8):889-895. Epub 2017 Oct 5 doi: 10.1080/00325481.2017.1381539. PMID: 28929906
Hazari YM, Bashir A, Habib M, Bashir S, Habib H, Qasim MA, Shah NN, Haq E, Teckman J, Fazili KM
Mutat Res 2017 Jul;773:14-25. Epub 2017 Mar 18 doi: 10.1016/j.mrrev.2017.03.001. PMID: 28927525
Carpagnano GE, Santacroce R, Palmiotti GA, Leccese A, Giuffreda E, Margaglione M, Foschino Barbaro MP, Aliberti S, Lacedonia D
Lung 2017 Oct;195(5):679-682. Epub 2017 Jul 1 doi: 10.1007/s00408-017-0033-2. PMID: 28668972
Carleo A, Chorostowska-Wynimko J, Koeck T, Mischak H, Czajkowska-Malinowska M, Rozy A, Welte T, Janciauskiene S
Int J Chron Obstruct Pulmon Dis 2017;12:829-837. Epub 2017 Mar 8 doi: 10.2147/COPD.S125240. PMID: 28331304Free PMC Article
Stoller JK
Ann Am Thorac Soc 2016 Aug;13 Suppl 4:S317-25. doi: 10.1513/AnnalsATS.201506-349KV. PMID: 27564667

Therapy

Lascano JE, Campos MA
Postgrad Med 2017 Nov;129(8):889-895. Epub 2017 Oct 5 doi: 10.1080/00325481.2017.1381539. PMID: 28929906
Habibzadeh S, Shahi JM, Ghobadi H, Maleki N
Int J Mycobacteriol 2017 Apr-Jun;6(2):187-190. doi: 10.4103/ijmy.ijmy_60_17. PMID: 28559523
Sandhaus RA
Ann Am Thorac Soc 2016 Aug;13 Suppl 4:S370-3. doi: 10.1513/AnnalsATS.201510-684KV. PMID: 27564674
Tanash HA, Ekström M, Wagner P, Piitulainen E
Int J Chron Obstruct Pulmon Dis 2016;11:1663-9. Epub 2016 Jul 26 doi: 10.2147/COPD.S109173. PMID: 27555756Free PMC Article
Stockley RA, Edgar RG, Pillai A, Turner AM
Int J Chron Obstruct Pulmon Dis 2016;11:1745-56. Epub 2016 Aug 1 doi: 10.2147/COPD.S111508. PMID: 27536086Free PMC Article

Prognosis

Habibzadeh S, Shahi JM, Ghobadi H, Maleki N
Int J Mycobacteriol 2017 Apr-Jun;6(2):187-190. doi: 10.4103/ijmy.ijmy_60_17. PMID: 28559523
Carleo A, Chorostowska-Wynimko J, Koeck T, Mischak H, Czajkowska-Malinowska M, Rozy A, Welte T, Janciauskiene S
Int J Chron Obstruct Pulmon Dis 2017;12:829-837. Epub 2017 Mar 8 doi: 10.2147/COPD.S125240. PMID: 28331304Free PMC Article
Tanash HA, Ekström M, Wagner P, Piitulainen E
Int J Chron Obstruct Pulmon Dis 2016;11:1663-9. Epub 2016 Jul 26 doi: 10.2147/COPD.S109173. PMID: 27555756Free PMC Article
Stockley RA, Edgar RG, Pillai A, Turner AM
Int J Chron Obstruct Pulmon Dis 2016;11:1745-56. Epub 2016 Aug 1 doi: 10.2147/COPD.S111508. PMID: 27536086Free PMC Article
Topic A, Nagorni-Obradovic L, Francuski D, Ljujic M, Malic Z, Radojkovic D
Biochem Genet 2016 Oct;54(5):746-52. Epub 2016 Jun 6 doi: 10.1007/s10528-016-9748-7. PMID: 27271084

Clinical prediction guides

Carleo A, Chorostowska-Wynimko J, Koeck T, Mischak H, Czajkowska-Malinowska M, Rozy A, Welte T, Janciauskiene S
Int J Chron Obstruct Pulmon Dis 2017;12:829-837. Epub 2017 Mar 8 doi: 10.2147/COPD.S125240. PMID: 28331304Free PMC Article
Al-Jameil N, Hassan AA, Buhairan A, Hassanato R, Isac SR, Al-Otaiby M, Al-Maarik B, Al-Ajeyan I
Medicine (Baltimore) 2017 Feb;96(6):e6071. doi: 10.1097/MD.0000000000006071. PMID: 28178162Free PMC Article
Stockley RA, Edgar RG, Pillai A, Turner AM
Int J Chron Obstruct Pulmon Dis 2016;11:1745-56. Epub 2016 Aug 1 doi: 10.2147/COPD.S111508. PMID: 27536086Free PMC Article
Greulich T, Nell C, Herr C, Vogelmeier C, Kotke V, Wiedmann S, Wencker M, Bals R, Koczulla AR
Orphanet J Rare Dis 2016 Jun 10;11(1):75. doi: 10.1186/s13023-016-0453-8. PMID: 27282198Free PMC Article
Topic A, Nagorni-Obradovic L, Francuski D, Ljujic M, Malic Z, Radojkovic D
Biochem Genet 2016 Oct;54(5):746-52. Epub 2016 Jun 6 doi: 10.1007/s10528-016-9748-7. PMID: 27271084

Recent systematic reviews

Ferrarotti I, Corsico AG, Stolk J, Ottaviani S, Fumagalli M, Janciauskiene S, Iadarola P
COPD 2017 Feb;14(1):56-65. Epub 2016 Nov 9 doi: 10.1080/15412555.2016.1241760. PMID: 27827549
Chorostowska-Wynimko J, Bakuła A, Kulus M, Kuca P, Niżankowska-Mogilnicka E, Sanak M, Socha P, Śliwiński P
Pneumonol Alergol Pol 2016;84(3):193-202. doi: 10.5603/PiAP.2016.0023. PMID: 27238183
North TL, Ben-Shlomo Y, Cooper C, Deary IJ, Gallacher J, Kivimaki M, Kumari M, Martin RM, Pattie A, Sayer AA, Starr JM, Wong A, Kuh D, Rodriguez S, Day IN
J Med Genet 2016 Apr;53(4):280-8. Epub 2016 Feb 1 doi: 10.1136/jmedgenet-2015-103342. PMID: 26831755Free PMC Article
Wozniak J, Wandtke T, Kopinski P, Chorostowska-Wynimko J
Hum Gene Ther 2015 Nov;26(11):709-18. Epub 2015 Sep 29 doi: 10.1089/hum.2015.044. PMID: 26413996Free PMC Article
Casas F, Blanco I, Martínez MT, Bustamante A, Miravitlles M, Cadenas S, Hernández JM, Lázaro L, Rodríguez E, Rodríguez-Frías F, Torres M, Lara B
Arch Bronconeumol 2015 Apr;51(4):185-92. Epub 2014 Jul 12 doi: 10.1016/j.arbres.2014.05.008. PMID: 25027067

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