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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
SNOMED CT: Alpha-1-antitrypsin deficiency (30188007); alpha-1-Proteinase inhibitor deficiency (30188007)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): SERPINA1 (14q32.13)
 
Monarch Initiative: MONDO:0013282
OMIM®: 613490
Orphanet: ORPHA60

Disease characteristics

Excerpted from the GeneReview: Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. Individuals with AATD are also at increased risk for panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen) and C-ANCA-positive vasculitis (granulomatosis with polyangiitis). Phenotypic expression varies within and between families. In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal life span, but can also develop lung and/or liver disease. 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 neonatal cholestasis. 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  |  Vera Hupertz  |  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 MedlinePlus Genetics
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 25 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, and fatigue. 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 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://medlineplus.gov/genetics/condition/alpha-1-antitrypsin-deficiency

Clinical features

From HPO
Gastric varix
MedGen UID:
8965
Concept ID:
C0017145
Disease or Syndrome
Extreme dilation of the submucusoal veins in the stomach.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
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).
Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.
Chronic bronchitis
MedGen UID:
3084
Concept ID:
C0008677
Disease or Syndrome
Chronic inflammation of the bronchi.
Cough
MedGen UID:
41325
Concept ID:
C0010200
Sign or Symptom
A sudden, audible expulsion of air from the lungs through a partially closed glottis, preceded by inhalation.
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing. Dyspnea is a subjective feeling only the patient can rate, e.g., on a Borg scale.
Hemoptysis
MedGen UID:
5502
Concept ID:
C0019079
Sign or Symptom
Coughing up (expectoration) of blood or blood-streaked sputum from the larynx, trachea, bronchi, or lungs.
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).
Wheezing
MedGen UID:
21917
Concept ID:
C0043144
Sign or Symptom
A high-pitched whistling sound associated with labored breathing.
Panacinar emphysema
MedGen UID:
78106
Concept ID:
C0264393
Disease or Syndrome
Panacinar emphysema involves all portions of the acinus and secondary pulmonary lobule more or less uniformly. It predominates in the lower lobes and is the form of emphysema associated with1-antitrypsin deficiency. CT scans show a generalized decrease of the lung parenchyma with a decrease in the caliber of blood vessels in the affected lung. Severe panacinar emphysema may coexist and merge with severe centrilobular emphysema. The appearance of feature less decreased attenuation may be indistinguishable from severe constrictive obliterative bronchiolitis.
Increased sputum production
MedGen UID:
1781289
Concept ID:
C5539771
Finding
An increase in the amount of airway mucus. This feature may be characterized by frequent or excessive throat clearing (exhalation through tightly constricted laryngopharyngeal tissues accompanied by vibration of the palatoglossal arch and the vocal folds serving to clear mucus from the airway).
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Reduced circulating alpha-1-antitrypsin concentration
MedGen UID:
1670949
Concept ID:
C4732808
Finding
A reduced concentration or activity of circulating alpha-1 antitrypsin, which is a 52-kDa glycoprotein mainly synthesized and secreted by hepatocytes into the bloodstream. Alpha-1 antitrypsin is a serine-proteinase inhibitor that it is crucial in maintaining protease-antiprotease homeostasis in the lungs.

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

Lurje I, Gaisa NT, Weiskirchen R, Tacke F
Mol Aspects Med 2023 Aug;92:101191. Epub 2023 May 24 doi: 10.1016/j.mam.2023.101191. PMID: 37236017
Kwo PY, Cohen SM, Lim JK
Am J Gastroenterol 2017 Jan;112(1):18-35. Epub 2016 Dec 20 doi: 10.1038/ajg.2016.517. PMID: 27995906
American Thoracic Society; European Respiratory Society
Am J Respir Crit Care Med 2003 Oct 1;168(7):818-900. doi: 10.1164/rccm.168.7.818. PMID: 14522813

Curated

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

Orphanet, Alpha-1 antitrypsin deficiency, 2010

Recent clinical studies

Etiology

Fraughen DD, Ghosh AJ, Hobbs BD, Funk GC, Meischl T, Clarenbach CF, Sievi NA, Schmid-Scherzer K, McElvaney OJ, Murphy MP, Roche AD, Clarke L, Strand M, Vafai-Tabrizi F, Kelly G, Gunaratnam C, Carroll TP, McElvaney NG
Am J Respir Crit Care Med 2023 Nov 1;208(9):964-974. doi: 10.1164/rccm.202305-0863OC. PMID: 37624745Free PMC Article
Franciosi AN, Ralph J, O'Farrell NJ, Buckley C, Gulmann C, O'Kane M, Carroll TP, McElvaney NG
J Am Acad Dermatol 2022 Oct;87(4):825-832. Epub 2021 Jan 29 doi: 10.1016/j.jaad.2021.01.074. PMID: 33516773
Janssen R, Piscaer I, Franssen FME, Wouters EFM
Expert Rev Respir Med 2019 Apr;13(4):381-397. Epub 2019 Feb 22 doi: 10.1080/17476348.2019.1580575. PMID: 30761929
Torres-Durán M, Lopez-Campos JL, Barrecheguren M, Miravitlles M, Martinez-Delgado B, Castillo S, Escribano A, Baloira A, Navarro-Garcia MM, Pellicer D, Bañuls L, Magallón M, Casas F, Dasí F
Orphanet J Rare Dis 2018 Jul 11;13(1):114. doi: 10.1186/s13023-018-0856-9. PMID: 29996870Free PMC Article
Bals R
Best Pract Res Clin Gastroenterol 2010 Oct;24(5):629-33. doi: 10.1016/j.bpg.2010.08.006. PMID: 20955965

Diagnosis

Dasí F
Med Clin (Barc) 2024 Apr 12;162(7):336-342. Epub 2023 Nov 22 doi: 10.1016/j.medcli.2023.10.014. PMID: 37993348
McElvaney OF, Fraughen DD, McElvaney OJ, Carroll TP, McElvaney NG
Expert Rev Respir Med 2023 Mar;17(3):191-202. Epub 2023 Mar 15 doi: 10.1080/17476348.2023.2174973. PMID: 36896570
Dasí F
Med Clin (Barc) 2023 Mar 10;160(5):203-205. Epub 2022 Oct 14 doi: 10.1016/j.medcli.2022.09.001. PMID: 36253208
Strnad P, McElvaney NG, Lomas DA
N Engl J Med 2020 Apr 9;382(15):1443-1455. doi: 10.1056/NEJMra1910234. PMID: 32268028
Wick MR
Semin Diagn Pathol 2017 May;34(3):261-272. Epub 2016 Dec 27 doi: 10.1053/j.semdp.2016.12.004. PMID: 28129926

Therapy

McElvaney OF, Fraughen DD, McElvaney OJ, Carroll TP, McElvaney NG
Expert Rev Respir Med 2023 Mar;17(3):191-202. Epub 2023 Mar 15 doi: 10.1080/17476348.2023.2174973. PMID: 36896570
Strnad P, McElvaney NG, Lomas DA
N Engl J Med 2020 Apr 9;382(15):1443-1455. doi: 10.1056/NEJMra1910234. PMID: 32268028
Janssen R, Piscaer I, Franssen FME, Wouters EFM
Expert Rev Respir Med 2019 Apr;13(4):381-397. Epub 2019 Feb 22 doi: 10.1080/17476348.2019.1580575. PMID: 30761929
Torres-Durán M, Lopez-Campos JL, Barrecheguren M, Miravitlles M, Martinez-Delgado B, Castillo S, Escribano A, Baloira A, Navarro-Garcia MM, Pellicer D, Bañuls L, Magallón M, Casas F, Dasí F
Orphanet J Rare Dis 2018 Jul 11;13(1):114. doi: 10.1186/s13023-018-0856-9. PMID: 29996870Free PMC Article
Greene CM, Marciniak SJ, Teckman J, Ferrarotti I, Brantly ML, Lomas DA, Stoller JK, McElvaney NG
Nat Rev Dis Primers 2016 Jul 28;2:16051. doi: 10.1038/nrdp.2016.51. PMID: 27465791

Prognosis

Dasí F
Med Clin (Barc) 2024 Apr 12;162(7):336-342. Epub 2023 Nov 22 doi: 10.1016/j.medcli.2023.10.014. PMID: 37993348
Pires Ferreira D, Gruntman AM, Flotte TR
Expert Opin Biol Ther 2023 Mar;23(3):283-291. Epub 2023 Mar 2 doi: 10.1080/14712598.2023.2183771. PMID: 36825473
Cazzola M, Stolz D, Rogliani P, Matera MG
Eur Respir Rev 2020 Mar 31;29(155) Epub 2020 Feb 12 doi: 10.1183/16000617.0073-2019. PMID: 32051168Free PMC Article
Torres-Durán M, Lopez-Campos JL, Barrecheguren M, Miravitlles M, Martinez-Delgado B, Castillo S, Escribano A, Baloira A, Navarro-Garcia MM, Pellicer D, Bañuls L, Magallón M, Casas F, Dasí F
Orphanet J Rare Dis 2018 Jul 11;13(1):114. doi: 10.1186/s13023-018-0856-9. PMID: 29996870Free PMC Article
Kelly E, Greene CM, Carroll TP, McElvaney NG, O'Neill SJ
Respir Med 2010 Jun;104(6):763-72. Epub 2010 Mar 20 doi: 10.1016/j.rmed.2010.01.016. PMID: 20303723

Clinical prediction guides

Dasí F
Med Clin (Barc) 2024 Apr 12;162(7):336-342. Epub 2023 Nov 22 doi: 10.1016/j.medcli.2023.10.014. PMID: 37993348
Fraughen DD, Ghosh AJ, Hobbs BD, Funk GC, Meischl T, Clarenbach CF, Sievi NA, Schmid-Scherzer K, McElvaney OJ, Murphy MP, Roche AD, Clarke L, Strand M, Vafai-Tabrizi F, Kelly G, Gunaratnam C, Carroll TP, McElvaney NG
Am J Respir Crit Care Med 2023 Nov 1;208(9):964-974. doi: 10.1164/rccm.202305-0863OC. PMID: 37624745Free PMC Article
Strnad P, Mandorfer M, Choudhury G, Griffiths W, Trautwein C, Loomba R, Schluep T, Chang T, Yi M, Given BD, Hamilton JC, San Martin J, Teckman JH
N Engl J Med 2022 Aug 11;387(6):514-524. Epub 2022 Jun 25 doi: 10.1056/NEJMoa2205416. PMID: 35748699
Merkle T, Merz S, Reautschnig P, Blaha A, Li Q, Vogel P, Wettengel J, Li JB, Stafforst T
Nat Biotechnol 2019 Feb;37(2):133-138. Epub 2019 Jan 28 doi: 10.1038/s41587-019-0013-6. PMID: 30692694
Torres-Durán M, Lopez-Campos JL, Barrecheguren M, Miravitlles M, Martinez-Delgado B, Castillo S, Escribano A, Baloira A, Navarro-Garcia MM, Pellicer D, Bañuls L, Magallón M, Casas F, Dasí F
Orphanet J Rare Dis 2018 Jul 11;13(1):114. doi: 10.1186/s13023-018-0856-9. PMID: 29996870Free PMC Article

Recent systematic reviews

Ferrarotti I, Wencker M, Chorostowska-Wynimko J
Orphanet J Rare Dis 2024 Feb 22;19(1):82. doi: 10.1186/s13023-024-03069-1. PMID: 38388492Free PMC Article
Huang DQ, Chan KE, Tan C, Zeng RW, Koh B, Ong EYH, Ong CCH, Ong CEY, Tan DJH, Lim WH, Cho E, Tan EXX, Teng MLP, Ng CH, Nah B, Lim MC, Muthiah M, Clark VC, Loomba R
Aliment Pharmacol Ther 2023 Jul;58(2):152-158. Epub 2023 Apr 23 doi: 10.1111/apt.17516. PMID: 37089038Free PMC Article
Miravitlles M, Herepath M, Priyendu A, Sharma S, Vilchez T, Vit O, Haensel M, Lepage V, Gens H, Greulich T
Eur Respir Rev 2022 Mar 31;31(163) Epub 2022 Mar 23 doi: 10.1183/16000617.0262-2021. PMID: 35321931Free PMC Article
Edgar RG, Patel M, Bayliss S, Crossley D, Sapey E, Turner AM
Int J Chron Obstruct Pulmon Dis 2017;12:1295-1308. Epub 2017 May 2 doi: 10.2147/COPD.S130440. PMID: 28496314Free PMC Article
Gøtzsche PC, Johansen HK
Dan Med Bull 2010 Sep;57(9):A4175. PMID: 20816015

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