All iLive content is medically reviewed or fact checked to ensure as much factual accuracy as possible.
We have strict sourcing guidelines and only link to reputable media sites, academic research institutions and, whenever possible, medically peer reviewed studies. Note that the numbers in parentheses ([1], [2], etc.) are clickable links to these studies.
If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please select it and press Ctrl + Enter.
Alpha1-antitrypsin deficiency.
Medical expert of the article
Last reviewed: 04.07.2025
Alpha-1 antitrypsin deficiency is a congenital deficiency of the predominantly pulmonary antiprotease alpha-1 antitrypsin, leading to increased protease tissue destruction and emphysema in adults. Accumulation of abnormal alpha-1 antitrypsin in the liver can cause liver disease in both children and adults. A serum antitrypsin level of less than 11 mmol/L (80 mg/dL) confirms the diagnosis. Treatment of alpha-1 antitrypsin deficiency involves smoking cessation, bronchodilators, early treatment of infection, and, in some cases, alpha-1 antitrypsin replacement therapy. Severe liver disease may require transplantation.
Epidemiology of alpha1-antitrypsin deficiency
More than 95% of people with severe alpha-1 antitrypsin deficiency and emphysema are homozygous for the Z allele (PI*ZZ) and have alpha-1 antitrypsin levels of approximately 30–40 mg/dL (5–6 μmol/L). The prevalence in the general population is 1 in 1,500–5,000. Northern European Caucasians are most affected; the Z allele is rare in Asians and blacks. Although emphysema is common in PI*ZZ patients, many homozygous nonsmokers do not develop emphysema; those who do usually have a family history of COPD. PI*ZZ smokers have a shorter life expectancy than PI*ZZ nonsmokers, and both have a shorter life expectancy than nonsmokers and PI*MM smokers. Non-smoking PI*MM heterozygotes may have an increased risk of developing a more rapid decline in FEV over time than normal individuals.
Other rare phenotypes include PI*SZ and 2 types with unexpressed alleles, PI*Z-null and Pl*null-null. The null phenotype results in undetectable serum alpha1-antitrypsin levels. Normal serum levels of low-function alpha1-antitrypsin can be detected with rare mutations.
What causes alpha1 antitrypsin deficiency?
Alpha1-antitrypsin is a neutrophil elastase inhibitor (antiprotease) whose primary function is to protect the lungs from protease-mediated tissue destruction. Most alpha1-antitrypsin is synthesized by liver cells and monocytes and passively distributed through the bloodstream to the lungs; some is secondarily produced by alveolar macrophages and epithelial cells. The protein structure (and hence functionality) and the amount of circulating alpha1-antitrypsin are determined by the codominant expression of the parental alleles; more than 90 different alleles have been identified and characterized by the protease inhibitor (PI*) phenotype.
Inheritance of certain allele variants causes changes in the structure of the alpha1-antitrypsin molecule, leading to its polymerization and retention in hepatocytes. Hepatic accumulation of aberrant alpha1-antitrypsin molecules causes neonatal cholestatic jaundice in 10–20% of patients; in the remainder, the abnormal protein is probably destroyed, although the precise protective mechanism is not fully understood. Approximately 20% of neonatal liver lesions progress to cirrhosis in childhood. Approximately 10% of patients without liver disease in childhood develop cirrhosis in adulthood. Liver involvement increases the risk of liver cancer.
In the lung, alpha1-antitrypsin deficiency increases neutrophil elastase activity, which contributes to the destruction of lung tissue leading to emphysema (especially in smokers, as cigarette smoke also increases protease activity). Alpha1-antitrypsin deficiency is thought to be responsible for 1-2% of all cases of COPD.
Other disorders possibly associated with alpha1-antitrypsin variants include panniculitis, life-threatening bleeding (due to a mutation that redirects the inhibitory effect of alpha1-antitrypsin from neutrophil elastase to a coagulation factor), aneurysms, ulcerative colitis, and glomerulonephritis.
Symptoms of Alpha-1 Antitrypsin Deficiency
Infants with liver disease have cholestatic jaundice and hepatomegaly during the first week of life; the jaundice usually resolves by two to four months of age. Liver cirrhosis may develop in childhood or adulthood.
Alpha-1 antitrypsin deficiency usually causes early emphysema; symptoms of alpha-1 antitrypsin deficiency are the same as those of COPD. Pulmonary involvement occurs earlier in smokers than in nonsmokers, but in both cases it rarely develops before age 25 years. The severity of lung involvement is highly variable; lung function is well preserved in some PI*ZZ smokers and may be severely impaired in some PI*ZZ nonsmokers. PI*ZZ people identified in population studies (ie, those with no symptoms or lung disease) have better lung function, whether they smoke or not, than identified patients (who are identified because they have lung disease). People in the unidentified group with severe antitrypsin deficiency who have never smoked have a normal life expectancy and only a small decline in lung function. Airflow obstruction is more common in men and in people with asthma, recurrent respiratory infections, occupational exposure to dust, and a family history of lung disease. The most common cause of death in alpha-1 antitrypsin deficiency is emphysema, followed by cirrhosis, often with liver cancer.
Panniculitis, an inflammatory disease of the soft tissues beneath the skin, appears as indurated, tender, discolored patches or nodules, usually on the lower abdominal wall, buttocks, and thighs.
[ 7 ]
What's bothering you?
Diagnosis of alpha1-antitrypsin deficiency
Alpha-1 antitrypsin deficiency is suspected in smokers who develop emphysema before age 45; in non-occupational non-smokers who develop emphysema at any age; in patients with predominantly lower lobe emphysema (based on chest radiography); in patients with a family history of emphysema or unexplained cirrhosis; in patients with panniculitis; in neonates with jaundice or elevated liver enzymes; and in any patient with unexplained liver disease. The diagnosis is confirmed by measuring serum alpha-1 antitrypsin levels (< 80 mg/dL or < 11 μmol/L).
What do need to examine?
How to examine?
What tests are needed?
Who to contact?
Treatment of alpha1-antitrypsin deficiency
Treatment of the pulmonary form of the disease is with purified human alpha1-antitrypsin (60 mg/kg intravenously over 45-60 min given once a week or 250 mg/kg over 4-6 h given once a month), which can maintain serum alpha1-antitrypsin levels above the protective target level of 80 mg/dL (35% of normal). Because emphysema results in permanent structural changes, therapy cannot improve damaged lung structure or function but is used to halt progression. Treatment of alpha1-antitrypsin deficiency is extremely expensive and is therefore reserved for patients who are nonsmokers, have mild to moderate lung function abnormalities, and have serum alpha1-antitrypsin levels < 80 mg/dL (< 11 μmol/L). Treatment of alpha1-antitrypsin deficiency is not indicated for patients with severe disease or with a normal or heterozygous phenotype.
Smoking cessation, use of bronchodilators, and early treatment of respiratory tract infections are especially important for alpha1-antitrypsin-deficient patients with emphysema. Experimental drugs such as phenylbutyric acid, which can reverse the metabolism of abnormal antitrypsin proteins in hepatocytes, thereby stimulating the release of proteins, are under study. For people with severe deficiency under age 60, lung transplantation should be considered. Lung volume reduction to treat emphysema in antitrypsin deficiency is controversial. Gene therapy is under study.
Treatment of liver disease is effective. Enzyme replacement therapy is ineffective because alpha1-antitrypsin deficiency is caused by abnormal metabolism, not enzyme deficiency. Liver transplantation may be performed in patients with liver failure.
Treatment of panniculitis is not well developed. Glucocorticoids, antimalarial drugs and tetracyclines are used.
What is the prognosis for alpha1 antitrypsin deficiency?
Alpha-1 antitrypsin deficiency has a variable prognosis, mainly related to the degree of lung damage.