Alpha-1-Antitrypsin Deficiency

Taro Minami, M.D.
Joseph A. Diaz, M.D., M.P.H.

Basic Information

Definition

Alpha-1-antitrypsin deficiency is a genetic deficiency of the protease inhibitor alpha-1-antitrypsin that results in a predisposition to pulmonary emphysema and hepatic cirrhosis.

Synonyms

AATD

ICD-10CM CODES
E88.01	Alpha-1-antitrypsin deficiency

Epidemiology & Demographics

•

Underrecognized by clinicians, but accounts for approximately 2% to 5% of chronic obstructive pulmonary disease (COPD) cases in Americans
•

Prevalence is about 1 per 2000 to 5000 people in the United States
•

Inherited as an autosomal, co-dominant disorder
•

Most frequent mutation is in the SERPINA 1 gene (previously known as PI gene)
•
Most common alleles are:
1. 1.
  
  normal “M” allele (95% frequency in the U.S.)
2. 2.
  
  deficient variant “Z” allele (1% to 2%)
3. 3.
  
  deficient variant “S” allele (2% to 3%)
•

Severe deficiency is most commonly due to homozygotes ZZ
•

Risk of lung disease is uncertain with MZ genotype, but increased with SZ genotype (especially in smokers)
•

One in 10 individuals of European descent carries one of two mutations that may result in partial alpha-1-antitrypsin deficiency

Physical Findings & Clinical Presentation

•

Physical findings and clinical presentation are varied and depend on phenotype (see “Etiology”)
•

Most often affects the lungs but can also involve liver and skin
•

Classically associated with early-onset, severe, lower-lobe predominant panacinar emphysema; bronchiectasis may also be seen
•

Symptoms are similar to “typical” COPD presentation (dyspnea, cough, sputum production)
•

Liver involvement includes neonatal cholestasis, cirrhosis in children and adults, and primary carcinoma of the liver
•

Panniculitis is the major dermatologic manifestation (Rare: 1 in 1000 AATD individuals)

Etiology

•

Degree of alpha-1-antitrypsin deficiency depends on phenotype.
•

“MM” represents the normal genotype and is associated with alpha-1-antitrypsin levels in the normal range.
•

Mutation most commonly associated with emphysema is Z, with homozygote (ZZ) resulting in approximately 85% deficit in plasma alpha-1-antitrypsin concentrations.
•

Development of emphysema is believed to result from an imbalance between the proteolytic enzyme elastase, produced by neutrophils, and alpha-1-antitrypsin, which normally protects lung elastin by inhibiting elastase.
•

Deficiency of alpha-1-antitrypsin increases risk of early-onset emphysema, but not all alpha-1-antitrypsin deficient individuals will develop lung disease.
•

Smoking increases risk and accelerates onset of COPD.
•

Liver disease is caused by pathologic accumulation of alpha-1-antitrypsin in hepatocytes.
•

Similar to lung disease, skin involvement is thought to be attributable to unopposed proteolysis in skin.

Diagnosis

Differential Diagnosis

See “Chronic Obstructive Pulmonary Disease.”

See “Cirrhosis.”

Workup

•

Suspicion for alpha-1-antitrypsin deficiency usually results from emphysema developing at an early age (45 years old or younger) or emphysema without risk factors (e.g., smoking, dust exposure) and with basilar predominance of disease.

Laboratory Tests

•

Serum level of alpha-1-antitrypsin can confirm or reject suspicion of deficiency.
•

Investigate possibility of abnormal alleles with genotyping.
•

Pulmonary function testing is generally consistent with “typical” COPD.

Imaging Studies

•

Chest radiograph shows characteristic emphysematous changes at lung bases.
•

High-resolution chest CT usually confirms the basal-predominant emphysema (64%) and may also show significant bronchiectasis.

Treatment

Nonpharmacologic Therapy

•

Avoidance of smoking is of paramount importance.
•

Avoidance of other environmental and occupational exposures that may increase risk of COPD. Routine vaccinations are also recommended.

Acute General Rx

Acute exacerbations of COPD from alpha-1-antitrypsin deficiency are treated in a similar fashion to “typical” COPD exacerbations.

Chronic Rx

•

The goal of treatment in alpha-1-antitrypsin deficiency is to increase serum alpha-1-antitrypsin levels above a minimum, “protective” threshold of 50 mg/dL.
•

Although several therapeutic options are under investigation, IV administration of pooled human alpha-1-antitrypsin is currently the only approved method to raise serum alpha-1-antitrypsin levels. AAT augmentation therapy has been approved by the FDA for patients with AAT deficiency who have COPD. Augmentation therapy is expensive ($93,000 to $120,000/year) and requires lifelong treatment. However, given the cost and a lack of evidence of clinical benefit, a 2010 Cochrane Collaboration review noted that augmentation therapy with alpha-1-antitrypsin cannot be recommended.
•

Organ transplantation for patients with end-stage lung or liver disease is also an option.

Disposition

•

Prognosis of patients with alpha-1-antitrypsin deficiency will depend on phenotype and level of deficiency.
•

Among patients with severe alpha-1-antitrypsin deficiency, the most common underlying causes of death are respiratory failure (45% to 72%) and cirrhosis (10% to 13%).

Referral

•

Referral to specialists with experience in AAT deficiency is preferred
•

Pulmonary and hepatology referrals for advanced lung and liver disease, or if replacement therapy is contemplated (e.g., moderate-severe lung disease)
•

Lung and liver transplantation in suitable cases

Pearls & Considerations

•

The liver damage arising from the mutation is not from a deficiency in alpha-1-antitrypsin but from a pathologic accumulation of alpha-1-antitrypsin in hepatocytes.
•

Strong association between PI∗ZZ phenotypes and liver disease has prompted recommendations for AATD testing in individuals with unexplained liver disease.
•

Consider alpha-1-antitrypsin deficiency in patients presenting with lower-lobe predominant emphysema; in most smokers without alpha-1-antitrypsin deficiency, emphysema predominates in the upper lobes.
•

Alpha-1-antitrypsin deficiency is believed to be under-recognized.
•

The American Thoracic Society and the European Respiratory Society recommend testing for AAT deficiency in all symptomatic patients with COPD, emphysema, or asthma with irreversible obstruction, and the Global Initiative for Chronic Obstructive Lung Disease currently suggests this as well because the classic pattern with early-onset COPD (age <45 years) with lower lobe emphysema may not be always observed.

Ferri – Alpha-1-Antitrypsin Deficiency