eMedicine Specialties > Pulmonology > Obstructive Airways Diseases

Alpha1-Antitrypsin Deficiency

Author: Paul Fairman, MD, Director, Pulmonary Hypertension Service, Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University
Coauthor(s): Rajiv Malhotra, DO, Fellow, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University Health System
Contributor Information and Disclosures

Updated: Apr 16, 2009

Introduction

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.

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.

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.

Clinical

History

Symptoms of alpha1-antitrypsin (AAT) deficiency emphysema are limited to the respiratory system.

• The initial symptoms of alpha1-antitrypsin deficiency include cough, sputum production, and wheezing. Symptoms are initially intermittent, and, if wheezing is the predominant symptom, patients often are told they have asthma. If recurrent episodes of cough are most prominent, patients may be treated with multiple courses of antibiotics and evaluated for sinusitis, postnasal drip, or gastroesophageal reflux.
  • Dyspnea is the symptom that eventually dominates alpha1-antitrypsin deficiency.
  • Similar to other forms of emphysema, the dyspnea of alpha1-antitrypsin deficiency is initially evident only with strenuous exertion. Over several years, it eventually limits even mild activities.
  • Patients with alpha1-antitrypsin deficiency frequently develop dyspnea 20-30 years earlier (at age 30-45 y) than do smokers with emphysema and normal alpha1-antitrypsin levels.
• Cigarette smoking accelerates the progression of emphysema in patients with alpha1-antitrypsin deficiency. Symptoms develop about 10 years earlier in alpha1-antitrypsin–deficient individuals who smoke regularly.
• By the time dyspnea becomes the dominant manifestation and a diagnosis is established, most patients will have seen several physicians over several years. Efforts to improve the interval between the onset of symptoms and the diagnosis of alpha1-antitrypsin deficiency have been disappointing. Between 1968 and 2003 a significant improvement has not been noted in the average interval (approximately 8 y), although improvement has been shown in the alpha1-antitrypsin deficiency detection in older individuals.¹

Physical

No single physical sign confirms a diagnosis of alpha1-antitrypsin deficiency emphysema. Signs characteristic of increased respiratory work, airflow obstruction, and hyperinflation eventually develop but are dependent on the severity of emphysema at the time of diagnosis.

• Increased respiratory work is evident as tachypnea, scalene and intercostal muscle retraction, and tripod position.
• Airflow obstruction manifests as pursed-lip breathing, wheezing, and pulsus paradox.
• Hyperinflation results in barrel chest, increased percussion note, decreased breath sound intensity, and distant heart sounds.
• Patients with mild emphysema generally have no abnormal findings on physical examination.
  • Even moderate disease may be evident only when a complicating acute infection occurs.
  • Most of the signs generally considered a part of emphysema (from any cause) are signs of moderate-to-severe disease.
  • Mild-to-moderate disease is easily missed if the physician relies solely on physical findings.

Causes

Alpha1-antitrypsin deficiency is an uncommon but not rare disease. It is under diagnosed. The responsible genetic defect affects 1 in 3000-5000 individuals, making it 1 of the 3 most common lethal genetic diseases among whites. (The other 2 common fatal genetic defects are cystic fibrosis and Down syndrome.) Fortunately, not every individual with alpha1-antitrypsin deficiency develops clinically significant disease.

• The major biochemical activity of the alpha1-antitrypsin molecule is inhibition of several neutrophil-derived proteases (eg, trypsin, elastase, proteinase 3, cathepsin G). Therefore, the protein is more accurately termed alpha1-antiprotease. However, most physicians, and virtually all patients, refer to the disease as alpha1-antitrypsin deficiency, and doctors and patients often refer to those who are affected as "alphas."
• Hepatocytes synthesize alpha1-antiprotease.
  • After its release from the liver, alpha1-antiprotease circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principle function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particulates in the alveolus.
  • Alpha1-antiprotease constitutes about 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction. In patients with the Z allele, the alpha1-antitrypsin produced has a lysine substituted for glutamate. This results in spontaneous polymerization within the endoplasmic reticulum of the hepatocyte, which leads to decreased serum levels of alpha1-antitrypsin and thus a deficiency of peripheral alpha1-antitrypsin.
  •  Additionally, the accumulation of intrahepatic alpha1-antitrypsin is thought to result in apoptosis of hepatocytes. This initially can manifest as laboratory abnormalities, but also can progress to hepatitis, followed by fibrosis and cirrhosis.²
• In healthy persons, alpha1-antiprotease serves as a protective screen that prevents alveolar wall destruction. The lungs have a large surface area and are continuously exposed to a high burden of airborne pathogens, which results in a cellular immune response. This is characterized by local release of oxidants and proteases. The presence of alpha1-antiprotease serves to keep these proteases in check and protect the lungs from unregulated protease activity. Individuals with the alpha1-antitrypsin genetic defect do not release alpha1-antiprotease from the liver, and serum and alveolar levels of the protein are low. Consequently, alveoli lack antiprotease protection. The imbalance of proteases-antiproteases in the alveolus leads to unimpeded neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema.
• Alveolar cell apoptosis may also play an important role in emphysema pathogenesis. Recent evidence suggests that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation.³
• Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years by increasing the number of neutrophils (and neutrophil elastase) in the alveolus and inactivating the remaining small amounts of antiprotease. Other factors that can accelerate the onset or worsen symptoms of disease include infections and exposures to dust and fumes, which can also cause the recruitment of neutrophils to the alveoli.
• The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. The SERPINA1 (formerly known as Pi) gene responsible for encoding alpha1-antitrypsin is located on chromosome 14 and is highly pleomorphic, with more than 100 allelic variants. The variants are classified based on serum levels of alpha1-antitrypsin protein. M alleles are the most common and normal variants. Most patients with clinical disease are homozygous SS or ZZ or heterozygous MS, MZ, or SZ.  
  • Nearly 24 variants of the alpha1-antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1-antiprotease (serum levels of 20-53 µmol/L or 150-350 mg/dL).
  • The most common form of alpha1-antitrypsin deficiency is associated with allele Z, or homozygous PiZ (ZZ). Serum levels of alpha1-antitrypsin in these patients are about 3.4-7 µmol/L, 10-15% of normal serum levels. Serum levels greater than 11 µmol/L appear to be protective. Emphysema develops in most (but not all) individuals with serum levels less than 9 µmol/L.
• Other genotypes associated with severe alpha1-antitrypsin deficiency include PiSZ, PiZ/Null, and PiNull. The S gene is more frequent among individuals of Spanish or Portuguese descent, whereas the frequency of the Z gene is highest in patients of Northern or Western European descent.
  • Patients with the PiSZ phenotype have a 20-50% increased likelihood of developing emphysema compared with MM homozygotes. Serum levels of patients with PiSZ alpha1-antitrypsin deficiency are 75-120 mg/dL.
  • Patients with the null gene for alpha1-antitrypsin will not produce any alpha1-antitrypsin and are high risk for emphysema (100% by the age of 30 y). None with the null gene develop liver disease because of a lack of production, and thus accumulation, of alpha1-antitrypsin in the hepatocytes. The null gene is the least common of the known alleles associated with alpha1-antitrypsin deficiency.
  • Carriers or heterozygotes (MZ, MS or M/Null) have levels approximately 35% of normal levels, but they do not develop disease.

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