The comorbidities commonly associated with alpha-1 antitrypsin deficiency (AATD) predominantly affect the respiratory, hepatic, dermatological, and circulatory systems.
Carl-Bertil Laurell first described AATD and it was Sten Eriksson who observed that patients who had emphysema were lacking the alpha-1 antitrypsin protein, which he noted via electrophoresis.1 Emphysema is defined as an obstructive lung disease characterized by damage to the alveoli in the lungs. These tiny, weakened air sacs rupture, creating large air spaces instead of many smaller air spaces, which reduces the surface area of the lungs for gas exchange to occur. Eventually, the old, stale air becomes trapped in these swollen air spaces preventing oxygenated air from entering, which in turn causes dyspnea.2 Pulmonary emphysema has an earlier onset than chronic obstructive pulmonary disease (COPD) in patients with AATD and is more prevalent with patients who are smokers.3
Chronic Obstructive Pulmonary Disease (COPD)
COPD is a progressive, chronic, inflammatory lung disease that obstructs flow of air from the lungs. It is most often caused by long-term exposure to cigarette smoke, irritating gases, or particles in the air. Emphysema and chronic bronchitis are two of the most common conditions contributing to COPD.4 Patients with the Pi*ZZ genotype of AATD who smoked <20 pack-years had a greater risk of developing COPD. Smoking also increased the risk of COPD in patients with the Pi*MZ AATD genotype; whereas non-smoking Pi*MZ and smoking Pi*MM individuals did not demonstrate an increased risk of COPD.3
Chronic bronchitis results from long term inflammation of the lining of the bronchial tubes presenting with daily cough and sputum production.4 Patients with chronic bronchitis and AATD are typically younger with less tobacco usage and better lung function.5
Lung disease in AATD may be misdiagnosed as asthma patients with AATD present with asthma-like symptoms at a younger age than most COPD patients.3 To add to the difficulty of making an accurate diagnosis, it is possible that AATD and asthma coincide.6 Those with both AATD and asthma are at risk for accelerated progression of lung disease due to the presence of uncontrolled inflammation. It is surmised that AATD itself might incline patients to develop asthma by contributing to airway hyperresponsiveness.6 The increased, unregulated presence of neutrophil elastase in individuals with AATD may also promote an inflammatory, contractile effect on airway smooth muscle tissues which is associated with asthma.7 The Alpha-1 Foundation Registry provided information that nearly 46% of 500 individuals with severe AATD had also been diagnosed with either asthma or allergic disease.8
Bronchiectasis has been associated with AATD given the similarity of each condition having ineffective control of neutrophil elastase activity.3 To diagnose bronchiectasis clinically, criteria include a chronic cough with sputum production in addition to dilation of at least four bronchial segments.3 Two recent studies, one conducted in Germany, and one in the US, calculated that AATD and bronchiectasis coincided in 9.82% and 9.4% of the patient populations, respectively.9,10
Researchers studied common comorbidities in 344,528 Medicare patients with COPD in the US. They compared the comorbidities of those with the combined diagnosis of COPD and AATD to those with COPD alone. Hypertension, cardiac arrhythmias, and fluid and electrolyte disorders were the most common comorbidities in those with COPD alone. The individuals with COPD and AATD presented with statistically significant higher rates of liver disease including, viral hepatitis, chronic liver disease, cirrhosis, liver abscess with sequelae of chronic liver disease, and liver transplantation.11 The risk for hepatocellular carcinoma (HCC) is increased in people with AATD.12
Panniculitis is a rare comorbidity associated with AATD. Individuals with AATD are at increased risk for developing this skin disorder in which migratory, inflammatory nodules grow in the subcutaneous tissue under the skin. The nodules cause a hardening of the skin and sometimes ulceration of the skin in the legs and lower abdomen.12
Individuals with AATD are at increased risk for developing C-ANCA-positive vasculitis, or granulomatosis with polyangiitis.12 Granulomatosis with polyangiitis is a rare inflammatory disorder that affects the flow of blood to various body regions and organs including the nose, sinuses, throat, kidneys, and lungs.13
The Medicare study which showed that individuals with COPD and AATD had statistically higher rates of liver disease compared with people who had COPD alone additionally indicated that individuals with COPD and AATD had higher probabilities of pulmonary circulatory disease.11
- Laurell, CB, Eriksson, S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. Scandinavian Journal of Clinical and Laboratory Investigation. 1963; 15(2):132-140. Republished in: COPD: Journal of Chronic Obstructive Pulmonary Disease. 2013;10(S1):3-8.
- Emphysema: overview. Mayo Clinic. Accessed on June 3, 2021.
- Cazzola M, Stolz D, Rogliani P, Matera MG. α1-antitrypsin deficiency and chronic respiratory disorders. European Respiratory Review. 2020; 29(155). doi:10.1183/16000617.0073-2019
- COPD: Overview. Mayo Clinic. Accessed on June 3, 2021.
- Piras B, Ferrarotti I, Lara B, et al. Clinical phenotypes of italian and spanish patients with α1-antitrypsin deficiency. Eur Respir J. 2013;42(1):54-64. doi:10.1183/09031936.00104712
- Eden E. Asthma and COPD in alpha-1 antitrypsin deficiency. evidence for the dutch hypothesis. COPD: Journal of Chronic Obstructive Pulmonary Disease. 2010;7(5):366-374. doi:10.3109/15412555.2010.510159
- Lockett AD, Wu Y, Gunst SJ. Elastase alters contractility and promotes an inflammatory synthetic phenotype in airway smooth muscle tissues. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2017;314(4):L626-L634. doi:10.1152/ajplung.00334.2017
- Kelbel T, Morris D, Walker D, Henao MP, Craig T. The allergist’s role in detection of severe alpha-1 antitrypsin deficiency. The Journal of Allergy and Clinical Immunology: In Practice. 2017;5(5):1302-1306. doi:10.1016/j.jaip.2017.01.008
- Greulich T, Nell C, Herr C, et al. Results from a large targeted screening program for alpha-1-antitrypsin deficiency: 2003 – 2015. Orphanet J Rare Dis. 2016;11(1):75. doi:10.1186/s13023-016-0453-8
- 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; 6:145–153. doi:10.15326/jcopdf.6.6.2018.0156
- Sandhaus R, Strange C, Stone G, et al. Comorbidity associations with AATD among commercially insured and medicare beneficiaries with COPD in the us. Int J Chron Obstruct Pulmon Dis. 2020;15:2389-2397. doi:10.2147/copd.S263297
- 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.
- Granulomatosis with polyangiitis: Overview. Mayo Clinic. Accessed on June 3, 2021.
Article reviewed by Harshi Dhingra, MD, on July 1, 2021.