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Alpha-1 Antitrypsin Deficiency
α1-Antitrypsin deficiency is congenital lack of a primary lung antiprotease, α1-antitrypsin, which leads to increased protease-mediated tissue destruction and emphysema in adults. Hepatic accumulation of abnormal α1-antitrypsin can cause liver disease in both children and adults. Serum α1-antitrypsin level < 11 μmol/L (< 80 mg/dL) confirms the diagnosis. Treatment is smoking cessation, bronchodilators, early treatment of infection, and, in selected cases, α1-antitrypsin replacement. Severe liver disease may require transplantation. Prognosis is related mainly to degree of lung impairment.
α1-Antitrypsin is a neutrophil elastase inhibitor (an antiprotease), the major function of which is to protect the lungs from protease-mediated tissue destruction. Most α1-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 α1-antitrypsin are determined by codominant expression of parental alleles; > 90 different alleles have been identified and described by protease inhibitor (PI*) phenotype.
Inheritance of some variant alleles causes a change in conformation of the α1-antitrypsin molecule, leading to polymerization and retention within hepatocytes. The hepatic accumulation of aberrant α1-antitrypsin molecules causes neonatal cholestatic jaundice in 10 to 20% of patients; the remaining patients are probably able to degrade the abnormal protein, although the exact protective mechanism is unclear. About 20% of cases of neonatal hepatic involvement result in development of cirrhosis in childhood. About 10% of patients without childhood liver disease develop cirrhosis as adults. Liver involvement increases the risk of liver cancer.
In the lungs, α1-antitrypsin deficiency increases neutrophil elastase activity, which facilitates tissue destruction leading to emphysema (especially in smokers, because cigarette smoke also increases protease activity). α1-Antitrypsin deficiency accounts for 1 to 2% of all cases of COPD. α1-Antitrypsin deficiency most commonly causes early emphysema; symptoms and signs of lung involvement occur earlier in smokers than in nonsmokers but in both cases are rare before age 25. Some patients with bronchiectasis have α1-antitrypsin deficiency.
Other disorders possibly associated with α1-antitrypsin allele variants include panniculitis (an inflammatory disorder of the subcutaneous tissue), life-threatening hemorrhage (through a mutation that converts α1-antitrypsin from a neutrophil elastase to a coagulation factor inhibitor), aneurysms, ulcerative colitis, antineutrophilic cytoplasmic antibody (ANCA)-positive vasculitis, and glomerular disease.
The normal PI phenotype is PI*MM. More than 95% of people with severe α1-antitrypsin deficiency and emphysema are homozygous for the Z allele (PI*ZZ) and have α1-antitrypsin levels of about 30 to 40 mg/dL (5 to 6 μmol/L). Prevalence in the general population is 1/1500 to 1/5000. Most are whites of Northern European descent; the Z allele is rare in people of Asian descent and blacks. Though emphysema is common among PI*ZZ patients, many nonsmoking patients who are homozygous for PI*ZZ do not develop emphysema; patients who do typically have a family history of COPD. PI*ZZ smokers have a lower life expectancy than PI*ZZ nonsmokers, who have a lower life expectancy than PI*MM nonsmokers and smokers. Nonsmoking people who are PI*MZ heterozygous are more likely to experience more rapid decreases in forced expiratory volume in 1 sec (FEV1) over time than do people in the general population.
Other rare phenotypes include PI*SZ and two types with nonexpressing alleles, PI*Z-null and PI*null-null (see Table: Expression of Phenotype in α 1 -Antitrypsin Deficiency). The null phenotype leads to undetectable serum levels of α1-antitrypsin. Normal serum levels of malfunctioning α1-antitrypsin may occur with rare mutations.
Expression of Phenotype in α 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 mo 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 (see page Chronic Obstructive Pulmonary Disease (COPD) : Symptoms and Signs), 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 PI*ZZ smokers and can be severely impaired in some PI*ZZ nonsmokers. PI*ZZ people identified in population surveys (ie, those without symptoms or pulmonary disease) tend to have better pulmonary function, whether they smoke or not, than do index people (those identified because they have pulmonary disease). Airflow obstruction occurs more frequently in men and in people 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 (see page Panniculitis).
α1-Antitrypsin deficiency is suspected in the following:
Smokers who develop emphysema before age 45
Nonsmokers without occupational exposures who develop emphysema at any age
Patients whose chest x-ray shows predominately lower lung emphysema
Patients with a family history of emphysema or unexplained cirrhosis
Patients with panniculitis
Neonates with jaundice or liver enzyme elevations
Patients with unexplained bronchiectasis or liver disease
Diagnosis is made by identifying serum α1-antitrypsin levels < 80 mg/dL (< 15 μmol/L) if measured by the radial immunodiffusion method or levels < 50 mg/dL (< 9 μmol/L) if measured by nephelometry. Patients with low levels should have confirmation by genotyping.
Treatment of pulmonary disease is with purified human α1-antitrypsin (60 mg/kg IV over 45 to 60 min given once/wk or 250 mg/kg over 4 to 6 h given once/mo [pooled only]), which can maintain the serum α1-antitrypsin level above a target protective level of 80 mg/dL (35% of normal). 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 therefore reserved for nonsmoking patients who have two abnormal alleles, mild to moderately abnormal pulmonary function, and confirmation of diagnosis by low serum α1-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 α1-antitrypsin–deficient patients with emphysema. Experimental treatments, such as phenyl butyric acid that can reverse the misfolding of the abnormal α1-antitrypsin proteins in the hepatocytes, thereby stimulating protein release, are being investigated. For severely impaired people < 60 yr, lung transplantation should be considered. Lung volume reduction in treating the emphysema of α1-antitrypsin deficiency is controversial. Gene therapy is under study.
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. Corticosteroids, antimalarials, and tetracyclines have been used.
Suspect α1-antitrypsin deficiency if patients have unexplained emphysema, liver disease (particularly in neonates), panniculitis, or bronchiectasis.
Diagnose using serum α1-antitrypsin levels < 80 mg/dL (< 15 μmol/L) and confirm by genotyping.
Treat selected patients (nonsmoking patients in whom both alleles are abnormal and who have mild to moderately abnormal pulmonary function and low serum α1-antitrypsin levels) with purified human α1-antitrypsin.
Consider liver transplantation if liver failure develops.
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