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.
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. 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 (1) (see table Expression of Phenotype in Alpha-1 Antitrypsin Deficiency).
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 (2). 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 (3). Liver involvement increases the risk of liver cancer.
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 1 to 2% of all cases of chronic obstructive pulmonary disease (COPD). 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 bronchiectasis have alpha-1 antitrypsin deficiency.
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. 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
2. 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 168(7):818–900, 2003. doi:10.1164/rccm.168.7.818
3. 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
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 Expression of Phenotype in Alpha-1 Antitrypsin Deficiency). 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.
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 may develop in childhood or adulthood (symptoms and signs of cirrhosis and hepatocellular carcinoma are discussed elsewhere in THE MANUAL).
Adults with emphysema have symptoms and signs of COPD, including dyspnea, cough, wheezing, and prolonged expiration.
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 45 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).
Diagnosis reference
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 168(7):818–900, 2003. doi:10.1164/rccm.168.7.818
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 expensive and 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.
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.
1).
Treatment reference
1. Franciosi AN, Ralph J, O'Farrell NJ, et al: Alpha-1 antitrypsin deficiency-associated panniculitis. J Am Acad Dermatol 87(4):825–832, 2022. 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.
The most common cause of death in alpha-1 antitrypsin deficiency is emphysema, followed by cirrhosis, often with hepatocellular carcinoma.
Key Points
Suspect alpha-1 antitrypsin deficiency if patients have unexplained emphysema, liver disease (particularly in neonates), panniculitis, or bronchiectasis.
Diagnose using genotyping and confirm using serum alpha-1 antitrypsin levels < 80 mg/dL (< 15 micromol/L).
Treat 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) with purified human alpha-1 antitrypsin.
Consider liver transplantation if liver failure develops.
