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Alpha1-Antitrypsin Deficiency

  • Author: Dora E Izaguirre, MD; Chief Editor: Ryland P Byrd, Jr, MD  more...
 
Updated: Sep 24, 2014
 

Background

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.[1] 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.[1]

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.[4] Although extremely rare, emphysema in children with AATD has been reported.[3] The incidence of liver disease increases with age.[3]

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.

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Pathophysiology

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.

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Epidemiology

Frequency

United States

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]

International

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.

Mortality/Morbidity

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.[6] The mortality rate is high in symptomatic patients.

Race

White persons constitute an estimated 117 million carriers and 3.4 million affected individuals. Racial groups other than whites are affected less frequently.

Sex

Women and men are affected in equal numbers.

Age

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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Contributor Information and Disclosures
Author

Dora E Izaguirre, MD Primary Care Physician; Researcher, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Dora E Izaguirre, MD is a member of the following medical societies: American Heart Association, American Medical Association, American Public Health Association, Colegio Medico de Honduras

Disclosure: Nothing to disclose.

Coauthor(s)

Klaus-Dieter Lessnau, MD, FCCP Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Jesus Lanza, MD Fellow in Pulmonary and Critical Care Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Ryland P Byrd, Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Ryland P Byrd, Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Acknowledgements

Paul Fairman, MD Director, Pulmonary Hypertension Service, Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University

Paul Fairman, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Sarah Catherine Lyman Hellewell, MD Consulting Staff, Lynchburg Pulmonary Associates

Sarah Catherine Lyman Hellewell is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, and American Thoracic Society

Disclosure: Nothing to disclose.

Rajiv Malhotra, DO Assistant Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Section of Interventional Pulmonary Medicine, Virginia Commonwealth University Health System

Rajiv Malhotra, DO is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Osteopathic Association

Disclosure: Nothing to disclose.

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Close-up chest radiograph of the right lower zone of a 39-year-old woman with alpha1-antitrypsin deficiency (AATD). Normal lung markings are absent in the costophrenic angle. Some lung markings are present in the pericardiac region, but even these are diminished.
CT scan of the right middle and right lower lobes in a 38-year-old patient with alpha1-antitrypsin deficiency (AATD). Entire middle lobe and much of the lower lobe are emphysematous; normal lung structures have been replaced by abnormal airspaces. Only the posterior portions of the right lower lobe maintain a normal architecture.
Graph outlines alpha1-antitrypsin levels and risk of lung disease for the 5 most common phenotypes of alpha1-antitrypsin deficiency (AATD). Dashed line at 11 mmol/L (80 mg/mL) represents the threshold level below which emphysema is common.
Breath sound assessment. Video courtesy of Therese Canares, MD, and Jonathan Valente, MD, Rhode Island Hospital, Brown University.
 
 
 
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