Alpha-1 antitrypsin deficiency is congenital lack of a primary lung antiprotease, alpha-1 antitrypsin, which leads to increased protease-mediated tissue destruction and emphysema in adults. Hepatic accumulation of abnormal alpha-1 antitrypsin can cause liver disease in both children and adults. Serum alpha-1 antitrypsin level < 11 mmol/L (< 80 mg/dL) supports the diagnosis. Diagnosis should be confirmed with testing of specific genotypes or phenotypes. Treatment is smoking cessation, bronchodilators, early treatment of infection, and, in selected cases, alpha-1 antitrypsin replacement. Severe liver disease may require transplantation. Prognosis is related mainly to degree of lung impairment.
Alpha-1 antitrypsin deficiency is an inherited disorder caused by alpha-1 antitrypsin allele variants, leading to reduced levels or dysfunctional alpha-1 antitrypsin protein, which can result in lung disease (eg, emphysema) and liver disease (1).
General reference
1. Strnad P, McElvaney NG, Lomas DA. Alpha1-Antitrypsin Deficiency. N Engl J Med. 2020;382(15):1443-1455. doi:10.1056/NEJMra1910234
Pathophysiology of Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin is a neutrophil elastase inhibitor (an antiprotease), the major function of which is to protect the lungs from protease-mediated tissue destruction (1, 2). Most alpha-1 antitrypsin is synthesized by hepatocytes and monocytes and passively diffuses through the circulation into the lungs; some is secondarily produced by alveolar macrophages and epithelial cells. The protein conformation (and hence functionality) and quantity of circulating alpha-1 antitrypsin are determined by codominant expression of parental alleles; > 140 different alleles have been identified and described by protease inhibitor (PI*) phenotype (3) (see table ).
Liver
Inheritance of some variant alleles causes a change in conformation of the alpha-1 antitrypsin molecule, leading to polymerization and retention within hepatocytes. The hepatic accumulation of aberrant alpha-1 antitrypsin molecules causes neonatal cholestatic jaundice in 10 to 15% of patients; the remaining patients are probably able to degrade the abnormal protein, although the exact protective mechanism is unclear (4). Approximately 20% of cases of neonatal hepatic involvement result in development of cirrhosis in childhood. Approximately 10% of patients without childhood liver disease develop clinical cirrhosis as adults. Autopsy series find that cirrhosis may be found in approximately one third of affected adults (5). Liver involvement increases the risk of liver cancer.
This light micrograph of hematoxylin- and eosin-stained tissue shows alpha-1 antitrypsin deficiency liver disease. The histologic hallmark of the disease in the liver is the presence of globules (light pink circles) within liver cells.
ZIAD M. EL-ZAATARI/SCIENCE PHOTO LIBRARY
Lungs
In the lungs, alpha-1 antitrypsin deficiency increases neutrophil elastase activity, which facilitates tissue destruction, leading to emphysema (especially in patients who smoke, because cigarette smoke also increases protease activity). Alpha-1 antitrypsin deficiency accounts for approximately 1 to 2% of all cases of chronic obstructive pulmonary disease (COPD) (6). Alpha-1 antitrypsin deficiency most commonly causes early emphysema; symptoms and signs of lung involvement occur earlier in people who smoke than in those who do not, but lung involvement is rare in patients younger than age 25 years. Some patients with alpha-1 antitrypsin deficiency may also develop bronchiectasis.
Other tissues
Other disorders possibly associated with alpha-1 antitrypsin allele variants include panniculitis (an inflammatory disorder of the subcutaneous tissue), life-threatening hemorrhage (through a mutation that converts alpha-1 antitrypsin from a neutrophil elastase to a coagulation factor inhibitor), aneurysms, ulcerative colitis, antineutrophilic cytoplasmic antibody (ANCA)-positive vasculitis, and glomerular disease.
Pathophysiology references
1. Feitosa PHR, Castellano MVCO, Costa CHD, et al. Recommendations for the diagnosis and treatment of alpha-1 antitrypsin deficiency. J Bras Pneumol. 2024;50(5):e20240235. doi:10.36416/1806-3756/e20240235
2. Strnad P, McElvaney NG, Lomas DA. Alpha1-Antitrypsin Deficiency. N Engl J Med. 2020;382(15):1443-1455. doi:10.1056/NEJMra1910234
3. Mróz J, Pelc M, Mitusińska K, Chorostowska-Wynimko J, Jezela-Stanek A. Computational Tools to Assist in Analyzing Effects of the SERPINA1 Gene Variation on Alpha-1 Antitrypsin (AAT). Genes (Basel). 2024;15(3):340. doi:10.3390/genes15030340
4. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. doi:10.1164/rccm.168.7.818
5. Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol. 2008;103(8):2136-2142. doi:10.1111/j.1572-0241.2008.01955.x
6. McGrady T, Mannino DM, Malanga E, et al. Characteristics of Chronic Obstructive Pulmonary Disease (COPD) Patients Reporting Alpha-1 Antitrypsin Deficiency in the WebMD Lung Health Check Database. Chronic Obstr Pulm Dis. 2015;2(2):141-151. doi:10.15326/jcopdf.2.2.2015.0160
Classification of Alpha-1 Antitrypsin Deficiency
The normal PI phenotype is PI*MM. More than 95% of people with severe alpha-1 antitrypsin deficiency and emphysema are homozygous for the Z allele (PI*ZZ). Prevalence in the general population is 1/2000 to 1/10,000 (1). Most patients are people of Northern European descent; the Z allele is rare in people of Asian descent and in those of African descent.
Although emphysema is common among patients who are homozygous for the Z allele, many patients who do not smoke and are homozygous for PI*ZZ do not develop emphysema; patients who do typically have a family history of COPD. People who smoke and are homozygous for PI*ZZ have a lower life expectancy than people who do not smoke and are homozygous for PI*ZZ. People who are PI*ZZ homozygotes who do not smoke have a lower life expectancy than people who are PI*MM regardless of whether they smoke. If they smoke, people who are PI*MZ heterozygous are more likely to experience more rapid decreases in forced expiratory volume in 1 second (FEV1) over time than do people in the general population.
Other rare phenotypes include PI*SZ and 2 types of alpha-1 antitrypsin deficiency with nonexpressing alleles, PI*Z-null and PI*null-null (see table ). The null phenotype leads to undetectable serum levels of alpha-1 antitrypsin. Normal serum levels of malfunctioning alpha-1 antitrypsin may occur in patients with rare mutations.
Expression of Phenotype in Alpha-1 Antitrypsin Deficiency
Phenotype | Alpha-1 Antitrypsin Serum Level* | Risk of Emphysema |
|---|---|---|
PI*ZZ | 20–45 mg/dL (2.5–7 micromol/L) | High |
PI*MZ | 90–210 mg/dL (17–33 micromol/L) | Minimally increased |
PI*SZ | 75–120 mg/dL (8–16 micromol/L) | Slightly increased |
PI*SS | 100–200 mg/dL (15–33 micromol/L) | Minimally increased |
PI*MM | 150–350 mg/dL (20–48 micromol/L) | Normal |
* Serum levels given are measured using a typical commercial standard (mg/dL) and the purified standard (micromol/L) used in the U.S. Registry. | ||
Data from American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. doi:10.1164/rccm.168.7.818 | ||
Classification reference
1. Ali-Munive A, Leidy P, Proanos NJ, et al. Prevalence of genetic mutations in alpha-1 antitrypsin deficiency (aatd) in patients with chronic obstructive pulmonary disease in Colombia. BMC Pulm Med. 2023;23(1):156. doi:10.1186/s12890-023-02453-0
Symptoms and Signs of Alpha-1 Antitrypsin Deficiency
Neonates with hepatic involvement present with cholestatic jaundice and hepatomegaly during the first week of life; jaundice usually resolves by 2 to 4 months of age. Cirrhosis and hepatocellular carcinoma may develop in childhood or adulthood.
Adults with emphysema typically present with symptoms and signs of COPD, including progressive dyspnea, productive cough, wheezing, and prolonged expiration.
The severity of pulmonary disease varies greatly depending on phenotype, smoking status, and other factors. Pulmonary function is well preserved in some patients who smoke and are homozygous for PI*ZZ. Pulmonary function can be severely impaired in some patients who are homozygous for PI*ZZ but do not smoke. People who are homozygous for PI*ZZ identified in population surveys (ie, those without symptoms or pulmonary disease) tend to have better pulmonary function, whether they smoke or not, than do patients identified because they have pulmonary disease. Airflow obstruction occurs more frequently in males and in patients with asthma, recurrent respiratory infections, occupational dust exposure, and a family history of pulmonary disease.
Panniculitis, an inflammatory disorder of subcutaneous soft tissue, manifests as indurated, tender, discolored plaques or nodules, typically on the lower abdomen, buttocks, and thighs.
Diagnosis of Alpha-1 Antitrypsin Deficiency
Serum alpha-1 antitrypsin level
Genotyping
Alpha-1 antitrypsin deficiency is suspected in the following:
People who smoke who develop emphysema before age 50 years
People who do not smoke and have no occupational exposures who develop emphysema at any age
Patients whose chest radiograph shows predominately lower lung emphysema
Patients with a family history of emphysema or unexplained cirrhosis
People with a family history of alpha-1-antitrypsin deficiency
Patients with panniculitis
Neonates with jaundice or liver enzyme elevations
Patients with unexplained bronchiectasis or liver disease
Screening is usually done with genotyping. Diagnosis is confirmed by identifying serum alpha-1 antitrypsin levels < 80 mg/dL (< 15 micromol/L) if measured by the radial immunodiffusion method or levels < 50 mg/dL (< 9 micromol/L) if measured by nephelometry (1, 2).
Diagnosis references
1. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. doi:10.1164/rccm.168.7.818
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD): Diagnosis and assessment. Global Strategy for the Prevention, Diagnosis, and Management of COPD: 2026 report.
Treatment of Alpha-1 Antitrypsin Deficiency
Supportive care
For pulmonary disease, often alpha-1 antitrypsin replacement
Treatment of pulmonary disease is with purified human alpha-1 antitrypsin, which can maintain the serum alpha-1 antitrypsin level above a target protective level of 80 mg/dL (35% of normal) when measured by radial immunodiffusion.
Because emphysema causes permanent structural change, therapy cannot repair damaged lung structure or improve lung function but is given to halt progression. Treatment is reserved for patients who do not smoke and who have 2 abnormal alleles, mild to moderately abnormal pulmonary function, and confirmation of diagnosis by low serum alpha-1 antitrypsin levels. It is not indicated for patients who have severe disease or for patients in whom one or both alleles are normal. Patients who are homozygous for PI*ZZ with normal lung function should be monitored with annual spirometry to identify those with rapid decline in lung function. The typical threshold for initiating replacement therapy is an FEV1 less than 65% predicted and greater than 35% predicted.
Smoking cessation, use of bronchodilators, and early treatment of respiratory infections are particularly important for patients with alpha-1 antitrypsin deficiency and emphysema.
For severely impaired people < 60 years, lung transplantation should be considered.
Lung volume reduction surgery for treating the emphysema of alpha-1 antitrypsin deficiency is controversial; outcomes are inferior to those in patients without alpha-1 antitrypsin deficiency.
Treatment of liver disease is supportive. Enzyme replacement does not help because the disease is caused by abnormal processing rather than by enzyme deficiency. Liver transplantation may be used for patients with liver failure.
Treatment of panniculitis is not well defined. Dapsone, glucocorticoids, and tetracyclines have been used (1).
Treatment reference
1. Franciosi AN, Ralph J, O'Farrell NJ, et al. Alpha-1 antitrypsin deficiency-associated panniculitis. J Am Acad Dermatol. 2022;87(4):825-832. doi:10.1016/j.jaad.2021.01.074
Prognosis for Alpha-1 Antitrypsin Deficiency
As a group, people with severe alpha-1 antitrypsin deficiency who have never smoked have a normal life expectancy and only moderate impairment of pulmonary function (1).
The most common cause of death in alpha-1 antitrypsin deficiency is emphysema, followed by cirrhosis, often with hepatocellular carcinoma.
Prognosis reference
1. Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. 2006 Oct 27 [Updated 2023 Jun 1]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1519/
Key Points
Alpha-1 antitrypsin deficiency should be suspected in patients with unexplained emphysema, liver disease (particularly in neonates), panniculitis, or bronchiectasis.
Preliminary diagnosis based on genotyping and confirmed using serum alpha-1 antitrypsin levels < 80 mg/dL (< 15 micromol/L).
Treatment of selected patients (patients who do not smoke in whom both alleles are abnormal and who have mild to moderately abnormal pulmonary function and low serum alpha-1 antitrypsin levels) is with purified human alpha-1 antitrypsin.
Liver transplantation should be considered if liver failure develops.
More Information
The following English-language resources may be useful. Please note that The Manual is not responsible for the content of these resources.
Centers for Disease Control and Prevention (CDC). Public Health Genomics and Precision Health Knowledge Base (v10.0). Alpha-1 Antitrypsin Deficiency. February 29, 2026. Accessed April 17, 2026.
Drug Information for the Topic
