Alpha1-Antitrypsin Deficiency 

  • Author: Paul Fairman, MD; Chief Editor: Zab Mosenifar, MD   more...
 
Updated: Mar 16, 2011
 

Background

Alpha1-antitrypsin (AAT) deficiency, first described in 1963, is one of the most common inherited disorders among white persons. Its primary manifestation is early-onset panacinar emphysema. About 1-3% of patients with diagnosed chronic obstructive pulmonary disease (COPD) are predicted to have alpha1-antitrypsin deficiency. Slowly progressive dyspnea is the primary symptom, though many patients initially have symptoms of cough, sputum production, or wheezing.

Treatment involves smoking cessation, bronchodilation, 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. Alpha1-antitrypsin deficiency is also an unusual cause of hepatic cirrhosis in children and adults.

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Pathophysiology

The genetic defect in alpha1-antitrypsin (AAT) deficiency 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 antiproteases. 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

Alpha1-antitrypsin (AAT) deficiency is 1 of the 3 most common lethal genetic diseases among adult white persons, affecting 1 per 3000-5000 individuals. Severe alpha1-antitrypsin deficiency affects an estimated 100,000 individuals, and approximately 25 million people carry of at least 1 deficient gene. However, less than 6% of severely deficient individuals are currently identified.

International

Alpha1-antitrypsin deficiency has been identified in all populations, but it is most common in individuals of Northern European 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 mortality rate is high.

Race

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. Alpha1-antitrypsin deficiency is also the leading cause of liver transplantation in children.

In adults, alpha1-antitrypsin deficiency leads to chronic liver disease in the fifth decade. 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

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: Gilead Honoraria Speaking and teaching; United Therapeutics Corp Honoraria None

Coauthor(s)

Rajiv Malhotra, DO  Assistant Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care 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.

Specialty Editor Board

Ryland P Byrd Jr, MD  Professor, Department of Internal Medicine, Division of Pulmonary Medicine and Critical Care Medicine, Program Director of Pulmonary Diseases and Critical Care Medicine Fellowship, James H Quillen College of Medicine, East Tennessee State University; Medical Director of Respiratory Therapy, James H Quillen Veterans Affairs Medical Center

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

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H  Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California Keck School of Medicine

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Osler Society, American Thoracic Society, New York Academy of Medicine, and Royal Society of Medicine

Disclosure: Nothing to disclose.

Timothy D Rice, MD  Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University School of Medicine

Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians

Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD  Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

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 (AAT) deficiency. 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 (AAT) deficiency. 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 (AAT) levels and risk of lung disease for the 5 most common phenotypes of AAT deficiency. Dashed line at 11 mmol/L (80 mg/mL) represents the threshold level below which emphysema is common.
 
 
 
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