- Author: Dora E Izaguirre, MD; Chief Editor: Ryland P Byrd, Jr, MD more...
Alpha1-antitrypsin deficiency (AATD) was first described by Laurell and Eriksson in 1963.[1, 2] Laurell noted the absence of the band of alpha1- protein in 5 of 1500 serum protein electrophoreses (SPEP) submitted to his laboratory in Sweden. Laurell and Eriksson found that 3 out of the 5 patients had emphysema at young age, and that one had a family history of emphysema. Hence, the cardinal clinical features of AATD were established: absence of a protein in the alpha1 region of the SPEP, emphysema with early onset, and a genetic predisposition.
AATD is a relatively common genetic condition, often undiagnosed. People with AATD are predisposed to obstructive pulmonary disease and liver disease (eg, cirrhosis and hepatocellular carcinoma in children and adults).[2, 1, 3] AATD is one of the most common inherited disorders among white persons. Its primary manifestation is early-onset panacinar emphysema. About 1-5% of patients with diagnosed chronic obstructive pulmonary disease (COPD) are estimated to have alpha1-antitrypsin deficiency. Although extremely rare, emphysema in children with AATD has been reported. The incidence of liver disease increases with age.
Slowly progressive dyspnea is the primary symptom, though many patients initially have symptoms of cough, sputum production, or wheezing. Treatment involves smoking cessation, preventive vaccinations, bronchodilators, supplemental oxygen when indicated, and physical rehabilitation in a program similar to that designed for patients with smoking-related COPD. In addition, intravenous (IV) augmentation therapy with alpha1-antitrypsin benefits some patients.
AATD is a genetic inherited autosomal-codominant condition with more than 120 alleles identified.[1, 2] Alpha1-antitrypsin is the prototype member of the serine protease inhibitor (serpin) superfamily of proteins. AATD is caused by mutations in the SERPINA1 gene located in the long arm of chromosome 14.[1, 2] This genetic defect alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. As a result, serum levels of alpha1-antitrypsin are decreased, leading to low alveolar concentrations, where the alpha1-antitrypsin molecule normally would serve as protection against proteases such neutrophil elastase. The resulting protease excess in alveoli destroys alveolar walls and causes emphysema. The accumulation of excess alpha1-antitrypsin in hepatocytes can also lead to destruction of these cells and ultimately, clinical liver disease.
AATD is 1 of the 3 most common lethal genetic diseases among adult white persons, affecting 1 per 3000-5000 individuals. Severe AATD affects an estimated 70,000-100,000 individuals, and approximately 25 million people carry of at least 1 deficient gene. However, less than 10% of severely deficient individuals are currently identified.[5, 1, 2, 6]
AATD has been identified in all populations, but it is most common in individuals of Northern European (1 in 1600) and Iberian descent. Similar rates are found among white persons worldwide, with an estimated 117 million carriers and 3.4 million affected individuals.
Specific morbidity and mortality rates are unknown. Not all patients with homozygous deficiency develop symptomatic emphysema or cirrhosis; however, among those who develop symptomatic disease, the history of having symptoms for several years and being evaluated by multiple physicians before the diagnosis was made is common. At present, the median time between the observation of symptoms and diagnosis is approximately 8 years. The mortality rate is high in symptomatic patients.
White persons constitute an estimated 117 million carriers and 3.4 million affected individuals. Racial groups other than whites are affected less frequently.
Women and men are affected in equal numbers.
The enzyme deficiency is congenital and has a bimodal distribution with respect to symptoms. It can be seen in neonates as a cause of neonatal jaundice and hepatitis. It can present in infants as cholestatic jaundice and in children as hepatic cirrhosis or liver failure. AATD is also the leading underlying condition requiring liver transplantation in children.
In adults, AATD leads to chronic liver disease in the fifth decade of life. As a cause of emphysema, it is seen in nonsmokers in the fifth decade of life and during the fourth decade of life in smokers.
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