Alpha-1 antitrypsin deficiency: An underrecognized, treatable cause of COPD
ABSTRACTAlpha-1 antitrypsin deficiency is common but underrecognized. Because delayed diagnosis is thought to be associated with adverse outcomes, clinicians are encouraged to follow available guidelines and test for the disease in all symptomatic adults with fixed airflow obstruction. The weight of available evidence supports the biochemical and clinical efficacy of intravenous augmentation therapy. Promising new therapies are being investigated.
KEY POINTS
- Only about 15% of people who have alpha-1 antitrypsin disease have received a diagnosis of it.
- The disease is genetic. People who are homozygous for the Z allele of the gene that codes for alpha-1 antitrypsin are at increased risk of lung and liver disease.
- Chronic obstructive pulmonary disease (COPD) due to alpha-1 antitrypsin deficiency is difficult to distinguish from “usual” COPD on a clinical basis, but blood tests are available.
- The basic care of a patient with COPD due to alpha-1 antitrypsin disease is the same as for any patient with COPD, ie, with bronchodilators, inhaled steroids, supplemental oxygen, preventive vaccinations, and pulmonary rehabilitation as indicated. Specific treatment consists of weekly infusions of alpha-1 antitrypsin (augmentation therapy).
DIAGNOSING ALPHA-1 ANTITRYPSIN DEFICIENCY
Available blood tests for alpha-1 antitrypsin deficiency include:
The serum alpha-1 antitrypsin level, most often done by nephelometry. Normal serum levels generally range from 100 to 220 mg/dL.
Phenotyping, usually performed by isoelectric focusing, which can identify different band patterns associated with different alleles.
Genotyping involves determining which alpha-1 antitrypsin alleles are present, most often using polymerase chain reaction testing targeting the S and Z alleles and occasionally set up to detect less common alleles such as F and I.17
Gene sequencing is occasionally necessary to achieve an accurate, definitive diagnosis.
Free, confidential testing is available
Clinical testing most often involves checking both a serum level and a phenotype or genotype. Such tests are often available in hospital laboratories and commercial laboratories, with testing also facilitated by the availability of free testing kits from several manufacturers of drugs for alpha-1 antitrypsin deficiency.
The Alpha-1 Foundation (www.alpha1.org)34 also offers a free, home-based confidential testing kit through a research protocol at the Medical University of South Carolina (alphaone@musc.edu) called the Alpha-1 Coded Testing (ACT) study. Patients can receive a kit and lancet at home, submit the dried blood-spot specimen, and receive in the mail a confidential serum level and genotype.
The availability of such home-based confidential testing allows patients to seek testing without a physician’s order and makes it easier for facilitated allied health providers, such as respiratory therapists, to recommend testing in appropriate clinical circumstances.15
TREATMENT OF ALPHA-1 ANTITRYPSIN DEFICIENCY
The treatment of patients with severe deficiency of alpha-1 antitrypsin and emphysema generally resembles that of patients with usual COPD. Specifically, smoking cessation, bronchodilators, occasionally inhaled steroids, supplemental oxygen, preventive vaccinations, and pulmonary rehabilitation are indicated as per usual clinical assessment.
Lung volume reduction surgery, which is beneficial in appropriate subsets of COPD patients, is generally less effective in those with severe alpha-1 antitrypsin deficiency,35 specifically because the magnitude of FEV1 increase and the duration of such a rise are lower than in usual COPD patients.
Augmentation therapy
Specific therapy for alpha-1 antitrypsin deficiency currently involves weekly intravenous infusions of purified, pooled human-plasma-derived alpha-1 antitrypsin, so-called augmentation therapy. Four drugs have been approved for use in the United States:
- Prolastin-C (Grifols, Barcelona, Spain)
- Aralast NP (Baxalta, Bonneckborn, IL)
- Zemaira (CSL Behring, King of Prussia, PA)
- Glassia (Baxalta, Bonneckborn, IL, and Kamada, Ness Ziona, Israel).
All of these were approved for use in the United States on the basis of biochemical efficacy. Specifically, infusion of these drugs has been shown to raise serum levels above a protective threshold value (generally considered 57 mg/dL, the value below which the risk of developing emphysema increases beyond normal).
Randomized controlled trials36,37 have addressed the efficacy of intravenous augmentation therapy, and although no single trial has been definitive, the weight of evidence shows that augmentation therapy can slow the progression of emphysema. For example, in a study by Dirksen et al,37 augmentation therapy was associated with a slower progression of emphysema as assessed by the rate of loss of lung density on computed tomography.
On the basis of the available evidence, the American Thoracic Society and European Respiratory Society14 have recommended augmentation therapy in individuals with “established airflow obstruction from alpha-1 antitrypsin deficiency.”14 Their guidelines go on to say that the evidence that augmentation therapy is beneficial “is stronger for individuals with moderate airflow obstruction (eg, FEV1 35%–60% of predicted) than for those with severe airflow obstruction. Augmentation therapy is not currently recommended for individuals without emphysema.”
The guidelines recognize that although augmentation therapy does not satisfy the usual criteria for cost-effectiveness (< $50,000 per quality-adjusted life year) due to its high cost (approximately $100,000 per year if paid for out of pocket),38 it is recommended for appropriate candidates because it is the only available specific therapy for severe deficiency of alpha-1 antitrypsin.
Novel therapies
In addition to current treatment approaches of augmentation therapy, a number of novel treatment strategies are being investigated, several of which hold much promise.
Gene therapy, using adeno-associated virus to transfect the normal human gene into individuals with severe deficiency of alpha-1 antitrypsin, has been undertaken and is currently under study. In addition, a variety of approaches to interdict production of abnormal Z protein from the liver are being examined, as well as inhaled hyaluronic acid to protect the lung.
