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HandWiki. Alpha 1-Antitrypsin Deficiency. Encyclopedia. Available online: (accessed on 24 June 2024).
HandWiki. Alpha 1-Antitrypsin Deficiency. Encyclopedia. Available at: Accessed June 24, 2024.
HandWiki. "Alpha 1-Antitrypsin Deficiency" Encyclopedia, (accessed June 24, 2024).
HandWiki. (2022, November 10). Alpha 1-Antitrypsin Deficiency. In Encyclopedia.
HandWiki. "Alpha 1-Antitrypsin Deficiency." Encyclopedia. Web. 10 November, 2022.
Alpha 1-Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (A1AD or AATD) is a genetic disorder that may result in lung disease or liver disease. Onset of lung problems is typically between 20 and 50 years old. This may result in shortness of breath, wheezing, or an increased risk of lung infections. Complications may include COPD, cirrhosis, neonatal jaundice, or panniculitis. A1AD is due to a mutation in the SERPINA1 gene that results in not enough alpha-1 antitrypsin (A1AT). Risk factors for lung disease include cigarette smoking and environmental dust. The underlying mechanism involves unblocked neutrophil elastase and build up of abnormal A1AT in the liver. It is autosomal co-dominant, meaning that one defective allele tends to result in milder disease than two defective alleles. The diagnosis is suspected based on symptoms and confirmed by blood tests or genetic tests. Treatment of lung disease may include bronchodilators, inhaled steroids, and when infections occur antibiotics. Intravenous infusions of the A1AT protein or in severe disease lung transplantation may also be recommended. In those with severe liver disease liver transplantation may be an option. Avoiding smoking is recommended. Vaccination for influenza, pneumococcus, and hepatitis is also recommended. Life expectancy among those who smoke is 50 years old while among those who do not smoke it is almost normal. The condition affects about 1 in 2,500 people of Europeans descent. Severe deficiency occurs in about 1 in 5,000. In Asians it is uncommon. About 3% of people with COPD are believed to have the condition. Alpha-1 antitrypsin deficiency was first described in the 1960s.

neutrophil elastase liver transplantation lung transplantation

1. 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 causes impaired liver function in some patients and may lead to cirrhosis and liver failure (15%). In newborns, alpha-1 antitrypsin deficiency has indicators that include early onset jaundice followed by prolonged jaundice. It is a leading indication for liver transplantation in newborns.

1.1. 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.

α1-antitrypsin deficiency has been associated with a number of diseases:

  • Cirrhosis
  • COPD
  • Pneumothorax
  • Asthma
  • Granulomatosis with polyangiitis
  • Pancreatitis
  • Gallstones
  • Bronchiectasis
  • Pelvic organ prolapse[2]
  • Primary sclerosing cholangitis
  • Autoimmune hepatitis
  • Emphysema, predominantly involving the lower lobes and causing bullae
  • Secondary membranoproliferative glomerulonephritis
  • Cancer
    • Hepatocellular carcinoma (liver)
    • Bladder carcinoma
    • Gallbladder cancer
    • Lymphoma
    • Lung cancer

2. Genetics

Serpin peptidase inhibitor, clade A, member 1 (SERPINA1) is the gene that encodes the protein alpha-1 antitrypsin. SERPINA1 has been localized to chromosome 14q32. Over 75 mutations of the SERPINA1 gene have been identified, many with clinically significant effects.[3] The most common cause of severe deficiency is a single base-pair substitution leading to a glutamate to lysine mutation at position 342 (dbSNP: rs28929474), while PiS is caused by a glutamate to valine mutation at position 264 (dbSNP: rs17580). Other rarer forms have been described (see OMIM).

3. 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.

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 may vary with analytical method but are typically around 1.0-2.7 g/l.[4] In individuals with PiSS, PiMZ and PiSZ genotypes, 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 genotype, A1AT levels are less than 15% of normal, and they are likely to develop panacinar emphysema at a young age. Between 10 to 15% of these people will develop liver fibrosis or liver cirrhosis, because the A1AT is not secreted properly and therefore accumulates in the liver.[5] A liver biopsy in such cases will reveal PAS-positive, diastase-resistant granules. Unlike glycogen and other mucins which are diastase sensitive (i.e., diastase treatment disables PAS staining), A1AT deficient hepatocytes will stain with PAS even after diastase treatment - a state thus referred to as diastase resistant.

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.

4. 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 labeled as having COPD without an underlying cause. It is estimated that about 1% of all COPD patients actually have an A1AT deficiency. Thus, testing should be performed for all patients with COPD, asthma with irreversible airflow 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.[6] The Alpha-1 Foundation offers free, confidential testing.

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 immunoturbidimetric method. Thus, protein electrophoresis is useful for screening and identifying individuals likely to have a deficiency. A1AT is further analyzed 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 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.

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 polymerize, thereafter being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:

  • 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)

5. Treatment

Treatment of lung disease may include bronchodilators, inhaled steroids, and when infections occur antibiotics.[7] Intravenous infusions of the A1AT protein or in severe disease lung transplantation may also be recommended.[7] In those with severe liver disease liver transplantation may be an option.[7] Avoiding smoking and getting vaccinated for influenza, pneumococcus, and hepatitis is also recommended.[7]

5.1. A1AT Protein

People with lung disease due to A1AD 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.[8] It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.[6]

As of 2015 there are four IV augmentation therapy manufacturers in the United States, Canada, and several European countries. Intravenous (IV) therapies are the standard mode of augmentation therapy delivery. Researchers are exploring inhaled therapies. IV augmentation therapies are manufactured by the following companies and have been shown to be clinically identical to one another in terms of dosage and efficacy.

Augmentation therapy is not appropriate for people with liver disease; treatment of A1AD-related liver damage focuses on alleviating the symptoms of the disease. In severe cases, liver transplantation may be necessary.

6. Epidemiology

Distribution of PiZZ in Europe.

People of Northern European and Iberian ancestry are at the highest risk for A1AD. Four percent carry the PiZ allele; between 1 in 625 and 1 in 2000 are homozygous.

Another study detected a frequency of 1 in 1550 individuals and a gene frequency of 0.026. The highest prevalence of the PiZZ variant was recorded in the northern and western European countries with mean gene frequency of 0.0140.[9]

7. History

A1AD was discovered in 1963 by Carl-Bertil Laurell (1919–2001), at the University of Lund in Sweden.[10] 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 Harvey Sharp et al. described A1AD in the context of liver disease.[11]

8. Research

Recombinant and inhaled forms of A1AT are being studied. Other experimental therapies are aimed at the prevention of polymer formation in the liver.[12]


  1. Robbins and Cotran Pathological Basis of Disease (7th ed.). Elsevier/Saunders. 2005. pp. 911–2. ISBN 978-0-7216-0187-8. 
  2. "Elastolytic activity in women with stress urinary incontinence and pelvic organ prolapse". Neurourol. Urodyn. 23 (2): 119–26. 2004. doi:10.1002/nau.20012. PMID 14983422.
  3. Silverman, Edwin K.; Sandhaus, Robert A. (2009-06-25). "Alpha1-Antitrypsin Deficiency". New England Journal of Medicine 360 (26): 2749–2757. doi:10.1056/NEJMcp0900449. ISSN 0028-4793. PMID 19553648.
  4. Donato, Leslie et al. (2012). "Reference and Interpretive Ranges for α1-Antitrypsin Quantitation by Phenotype in Adult and Pediatric Populations". American Journal of Clinical Pathology 138 (3): 398–405. doi:10.1309/AJCPMEEJK32ACYFP. PMID 22912357. Retrieved 17 January 2014. 
  5. Townsend, S.A; Edgar, R.G; Ellis, P.R; Kantas, D; Newsome, P.N; Turner, A.M (2018). "Systematic review: the natural history of alpha-1 antitrypsin deficiency, and associated liver disease". Alimentary Pharmacology & Therapeutics 47 (7): 877–885. doi:10.1111/apt.14537. PMID 29446109.
  6. "Alpha1-Antitrypsin Deficiency". New England Journal of Medicine 360 (26): 2749–2757. 2009. doi:10.1056/NEJMcp0900449. PMID 19553648. 
  7. "Alpha-1 antitrypsin deficiency" (in en). 2016. Retrieved 12 December 2017. 
  8. Gøtzsche, Peter C.; Johansen, Helle Krogh (2016-09-20). "Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease". The Cochrane Database of Systematic Reviews 9: CD007851. doi:10.1002/14651858.CD007851.pub3. ISSN 1469-493X. PMID 27644166.
  9. Luisetti, M; Seersholm, N (February 2004). "Alpha1-antitrypsin deficiency. 1: epidemiology of alpha1-antitrypsin deficiency". Thorax 59 (2): 164–9. doi:10.1136/thorax.2003.006494. PMID 14760160.
  10. "The electrophoretic alpha 1-globulin pattern of serum in alpha 1-antitrypsin deficiency". Scand J Clin Lab Invest 15 (2): 132–140. 1963. doi:10.1080/00365516309051324.
  11. "Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder". J Lab Clin Med 73 (6): 934–9. 1969. PMID 4182334.
  12. "A review of augmentation therapy for alpha-1 antitrypsin deficiency". Expert Opin Biol Ther 12 (6): 685–700. June 2012. doi:10.1517/14712598.2012.676638. PMID 22500781.
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