Alpha-1 Antitrypsin Deficiency Identification and Management: It is the Team More than the Genes

Alpha-1 antitrypsin deficiency (AATD) is an important cause of premature emphysema, infantile jaundice accompanied by hepatocellular dysfunction, and liver disease throughout adult life. Since its recognition in 1963, AATD remains the only well characterized genetic cause of COPD. Although considered a rare disease, the estimated prevalence in Caucasians of European heritage is 1:2500 to 1:3000. In the United States that leads to an estimated 80,000 to 100,000 affected individuals. That is not a trivial number. In the Alpha-1 Research Registry, University of South Carolina, there are 3290 individuals including 1590 with homozygous AATD (Dr. Charles Strange, University of South Carolina, personal communication; www.alphaoneregistry.org).

As pointed out by Fromer in this issue of the Journal of COPD (1), there are several important but frustrating issues regarding the diagnosis and management of AATD including: 1. Failure to diagnose and misdiagnosis; 2. Presence in diverse groups of patients with obstructive lung diseases such as asthma, COPD, and bronchiectasis; 3. Lack of coordinated care; 4. Therapeutic nihilism.

1. Failure to diagnose. A mail-in questionnaire study in 1994 showed that patients with AATD saw on average 3 different physicians over a mean of 7.2 years before a diagnosis was established (2). A repeat mail-in study 11 years later showed a mean of 5.6 years before a diagnosis was established, a minimal improvement raising uncertainty about attention to ongoing symptoms and findings (3). Testing is relatively straightforward and not expensive, certainly compared to some other conditions. An AAT serum level can be obtained through most hospital Clinical Pathology laboratories. Borderline or low levels require genetic testing yielding additional and confirmatory information. Whole blood can be sent to commercial laboratories. Finger-prick spotted blood samples for DNA genotypes can be performed through the Alpha-1 Research Registry or commercial “free” kits can be analyzed by reference laboratories.

2. Other obstructive lung diseases-AATD qualifies as a rare disease because its prevalence is low in general populations: PiZZ homozygotes,.02–.04% and heterozygotes, 2–4%. In pulmonary clinics including patients with COPD and asthma, the numbers are much different with PiZZ 1–3% and PiMZ 5–15% (4). Regarding asthma, from the NHLBI AATD Registry, 35% of subjects reported asthma as a diagnosis and 50% had significant reversibility after aerosol bronchodilator on spirometry (5). In a cohort of individuals with AATD, 4 times as many subjects had markers of asthma such as wheeze, elevated IgE, and atopy by skin testing as compared to those with COPD. These data suggest that even in middle-aged individuals labeled as asthma or reactive airways disease, AATD can be found (6).

3. Coordinated Care—As Fromer points out, AATD is a genetic disease modified by environmental factors (1). A comprehensive and organized care model is needed. That should certainly include AAT and genetic testing of siblings of a proband and perhaps other family members. Genetic counseling may be warranted. Extra attention regarding major cofactors including tobacco and alcohol consumption is mandatory. There is evidence that dusty workplaces may be associated with increased decline of pulmonary function (7). Following guidelines for the care of asthma and COPD is key in those individuals affected. There are now excellent printed and Web-based educational resources regarding AATD (www.alphaone.org). Linkage to one of the Clinical Resource Centers of the Alpha-1 Association (www.alpha1.org) may provide additional educational materials, consultation, consideration to participate in a research trial, and ability to communicate with other affected individuals, often a source of support and solace.

4. Therapeutic nihilism- Regarding augmentation with Alpha-1 antitrypsin intravenous purified and concentrated plasma for individuals with homozygous AATD, there are no randomized clinical trials. Nevertheless two independently accumulated large Registries of homozygous AATD individuals in the United States and Europe came to similar conclusions when examining subjects with impairment of pulmonary function. Augmentation significantly reduced the decline in FEV₁ in individuals with FEV₁ in the range 30–65% predicted (8, 9). In the U.S. NHLBI Registry, there was a mortality benefit being on augmentation replacement as compared to individuals not receiving therapy (8). A small randomized double-blind study showed a non-significant slowing of emphysema in those on intravenous Alpha-1 augmentation as compared to a group on intravenous albumin placebo as determined by quantitative chest CT density (10). A recent meta-analysis including the above trials and additional data suggested a benefit of augmentation therapy (11). Estimates available from the NHLBI Registry data suggest a randomized clinical trial could be performed over 4 years with 147 individuals in each arm (12). The expense of such a trial and a “feeling” that such therapy is effective prevention for decline in pulmonary function has retarded such a clinical trial. Augmentation with Alpha-1 intravenous infusion has been an FDA approved therapy for AATD since 1989, but is expensive at $80,000–150,000/year. It has no role in individuals with PiMZ heterozygotes (13), individuals with normal pulmonary function, or those mainly affected with the liver disease.

AATD is an important cause of obstructive lung diseases whose diagnosis requires relatively uncomplicated testing in any ambulatory setting. Management of the respiratory disease extends beyond asthma and COPD guidelines to include special attention to environmental cofactors and coordination with specialists in pulmonology and genetics.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.