Alpha-1 Antitrypsin Deficiency (AATD)

Alpha-1 antitrypsin deficiency (AATD) is an under-appreciated genetic disease.1 While it is not considered a disease per se, in fact, it predisposes to many other diseases, chiefly emphysema and other chronic lung diseases having different clinical features and frequent overlaps with each other, in addition to various manifestations in the liver (including cirrhosis and hepatocellular carcinoma) seen in children and adults.2

The human serum contains alpha-1 antitrypsin (AAT) as the most frequent protease inhibitor.1 Its formation is in high quantities and secretion is predominantly by hepatocytes.3 AAT is not only a significant lung anti-protease, but it also has important anti-inflammatory actions on many types of cells. It is also a modulator of inflammation generated by the host and microbial factors. Hence, it has a major role in modulating the main immune properties of cells and preventing the lungs from damage produced in response to proteases and inflammation.2

In advanced cases, the respiratory, hepatic, and musculocutaneous systems are affected which leads to various complications. 

Respiratory Complications

Emphysema and COPD

It was Laurell and Eriksson who discovered the association between AATD deficiency and emphysema in the early 1960s.4 Emphysema is a form of chronic progressive lung disease defined by abnormal permanent enlargement of airspaces due to the destruction of alveolar walls.5 Many of the patients have emphysema as a result of smoking, however, in 1% to 2% of cases, emphysema develops due to genetic deficiency of the plasma proteinase inhibitor α1-antitrypsin.6 


Bronchiectasis is usually associated with severe AATD due to the loss of anti-protease activity in the lung and airways.7 Though bronchiectasis is seen in many AATD patients, it is usually noted in cases that have underlying emphysema. This suggests that there is a shared pathophysiological process underway. Bronchiectasis can also occur as a part of Pulmonary Langerhans cell histiocytosis (PLCH). PLCH is strongly associated with cigarette smoking, presents in young adults, and shows polycystic lung lesions. Patients with AATD may be at a higher risk of developing PLCH, with observation of cystic pulmonary lesions.8

There is confirmed evidence of a direct impact of neutrophil elastase on bronchiectasis disease progression through effects on the ciliated epithelium, mucus production, emphysema development and immune response inactivation. However, whether bronchiectasis comes from a primary mechanism of the disease or is the result of recurrent respiratory infection is still under debate.2

Bronchial Asthma 

The association between asthma and AATD is not yet clear, although it is considered that patients who are diagnosed with AATD at an early age are more probably specified as asthmatics. Often, symptoms of asthma with fixed or reversible obstruction in lung function are the reason for recommending AATD testing in a whole spectrum of respiratory patients.

Cases of allergic asthma are more frequent in younger patients, and serum levels of AAT are found to be reduced in asthmatic carriers of a Z allele. Although, the presence of a deficient allele (S or Z) has no impact on the risk of wheezing in childhood and subsequent development of asthma in adolescence, and there is no association between AATD genotypes or severity of lung function and allergic asthma. Thus, further research is needed as there is insufficient literature to confirm an association between AATD and asthma.8

Liver Complications

The most common presentation of AATD-associated liver disease is neonatal cholestasis causing hyperbilirubinemia, jaundice, and raised serum aminotransferase levels in an early age. The overall risk to develop severe liver disease in childhood is low (~2%) in the PI*ZZ genotype. However, the risk becomes higher among siblings of a child with the PI*ZZ genotype and liver disease.9 The PI*MZ and PI*SZ genotypes do not show an association of a higher risk for childhood liver disease.9

In the adult population, liver disease presenting as fibrosis and cirrhosis can occur without a previous history of neonatal or childhood liver disease. Liver disease is found to be more frequent in men than women. The propensity to develop the liver disease at age 20 to age 40 is around 2% and at age 41 to age 50 is around 4%.

The risk for hepatocellular carcinoma in AATD with the PI*ZZ genotype is more and shows an association with liver cirrhosis. The higher risk is due to failure of apoptosis of injured cells with retained Z protein, sending a chronic regeneration signal to hepatocytes with a lesser load of retained Z protein.9,10

Other Complications

Rare complications, such as necrotizing panniculitis and vasculitis with positive c-ANCA, have also been noted in association with AATD. Few other reported associations of AATD from previous literature among cases and small cohort studies include rheumatoid arthritis, fibromyalgia, inflammatory bowel disease, glomerulonephritis, vascular abnormalities (fibromuscular dysplasia of the arteries, abdominal and brain aneurysms, and arterial dissection), chronic urticaria, psoriasis, multiple sclerosis, and pancreatitis.

These associations, though rare, are possible, because the properties of AAT are immunomodulatory and anti-inflammatory and therefore, its deficiency can increase the risk of inflammatory and autoimmune disorders. It has also been speculated that AAT could be beneficial in preventing these disorders, but it is not yet established.


  1. Blanco I, de Serres FJ, Fernández-Bustillo E, et al. Estimated numbers and prevalence of PI*S and PI*Z alleles of α1-antitrypsin deficiency in european countries. Eur Respir J 2006; 27: 77–84. doi:10.1183/09031936.06.00062305
  2. Cazzola M, Stolz D, Rogliani P, Matera MG. α1-Antitrypsin deficiency and chronic respiratory disorders. Eur Respir Rev. 2020;29(155):190073. Published 2020 Feb 12. doi:10.1183/16000617.0073-2019
  3. Bergin DA, Hurley K, McElvaney NG, et al. Alpha-1 antitrypsin: a potent anti-inflammatory and potential novel therapeutic agent. Arch Immunol Ther Exp 2012; 60: 81–97. doi:10.1007/s00005-012-0162-5
  4. Laurell CB, Eriksson S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. 1963. COPD. 2013;10 Suppl 1:3-8. doi:10.3109/15412555.2013.771956
  5. Abboud RT, Ford GT, Chapman KR. Emphysema in alpha1-antitrypsin deficiency: does replacement therapy affect outcome?. Treat Respir Med. 2005;4(1):1-8. doi:10.2165/00151829-200504010-00001
  6. Mahadeva R, Lomas DA. Alpha1-antitrypsin deficiency, cirrhosis and emphysema Thorax 1998;53:501-505.
  7. Eden E, Choate R, Barker A, et al. The clinical features of bronchiectasis associated with alpha-1 antitrypsin deficiency, Common variable immunodeficiency and primary ciliary dyskinesia–results from the US bronchiectasis research registry. Chronic Obstr Pulm Dis. 2019;6(2):145-153. doi:10.15326/jcopdf.6.2.2018.0156
  8. Santos G, Turner AM. Alpha-1 antitrypsin deficiency: an update on clinical aspects of diagnosis and management. Fac Rev. 2020;9:1. Published 2020 Oct 28. doi:10.12703/b/9-1
  9. Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 antitrypsin deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; October 27, 2006. Accessed July 10, 2021.
  10. Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res. 2006;60(2):233-238. doi:10.1203/01.pdr.0000228350.61496.90

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.