Genetics Role in Common Pulmonary Disease

Alpha-1 antitrypsin deficiency is a clinically under-recognized genetic respiratory disorder that can result in lung and/or liver disease. It is inherited in an autosomal co-dominant pattern and consistently presents as emphysema, chronic bronchitis or bronchiectasis. It is estimated that 100,000 Americans are AAt deficient, but less than 10% receive a clinical diagnosis and even fewer receive proper treatment. “Recognition, testing and diagnosis allows for early treatment which can slow or arrest lung and liver degradation,” said Debashree Tosh-Mitchell, MD with Meritas Health Pulmonary Medicine.

Alpha-1 antitrypsin, an elastase inhibitor manufactured in the liver, protects the body against proteolytic degradation of elastin by neutrophil elastase in the lungs. “In patients who are AAt deficient, the elastase that naturally occurs in the body goes unchecked because there isn’t enough AAt protein to inhibit it,” explained Dr. Tosh-Mitchell The result is progressive lung degradation. Smoking, infection and environmental factors increase elastase production and can significantly accelerate lung destruction in people with AAt deficiency.

Alpha1 Radiology

HRCT findings in ZZ individuals with emphysema (tleft) and bronchiectasis (bottom).*

Early Indicators

While not every patient with AAt deficiency will demonstrate clinical manifestations, many patients do present with classic symptoms of emphysema and COPD. However, certain indicators can alert primary care physicians to possible AAt deficiency. These indicators include:

  • Unexplained dyspnea
  • Severe or early onset of emphysema or bronchiectasis in individuals <60 years of age
  • Signs of COPD in a nonsmoker or minimal smoker
  • Basilar predominant pattern of emphysema on chest imaging
  • Family history of emphysema, chronic bronchitis or bronchiectasis without evidence of long-term tobacco use
  • Unexplained elevation of liver enzymes

“If a physician has a patient who presents with any one of these indicators, I highly recommend ordering an Alpha-1 deficiency screening,” Dr. Tosh-Mitchell advised.

Pathogenesis of COPD

Pathogenesis of COPD in MZ heterozygotes. A normal protease/antiprotease balance exists in MM individuals (left panel). Non-smoking MZ individuals have intermediate levels of AAT and increased sputum IL-8 levels and neutrophil counts (middle panel). Reactive oxygen species in cigarette smoke inactivate AAT resulting in a protease/antiprotease imbalance with increased amounts of neutrophil elastase. Polymerisation of Z AAT protein and increased amounts of IL-8 increase neutrophil influx into the MZ lung. An overwhelmed anti-protease defence contributes to the development of COPD.*

Testing Protocol

Suspicion of AAt deficiency can be confirmed by testing a blood sample at the laboratory. The test, which can be ordered by either the primary care physician or a pulmonologist , measures the serum level of the AAt protein and genotypes the blood sample. A serum level below 11 micromol/L is indicative of severe AAt deficiency.

Because AAt is an acute-phase reactant, patients should be screened when they do not exhibit symptoms of an infection or other condition that may affect results. “It doesn’t matter who performs the test as long as it gets done,” Dr. Tosh-Mitchell said. “It’s about being cognizant of the disorder and having a heightened level of suspicion.” The earlier diagnosis and screening take place, the earlier treatment can begin.”

Treatment Modalities

Intravenous AAt augmentation therapy is available for people whose serum deficiency level is below the 11 micromol/L threshold. Infusions of AAt from human pooled plasma, administered weekly or biweekly, replace the AAt protein. “While it can’t restore lost lung function, augmentation therapy can slow the rate of lung destruction and significantly improve a person’s quality of life,” Dr. Tosh-Mitchell said. In addition to meeting the threshold requirement, candidates for augmentation therapy must also stop smoking. Other treatment modalities include:

  • Supportive therapies (e.g. pulmonary rehabilitation, bronchodilators, smoking cessation programs and inhalers)
  • Bullectomy
  • One-way endobronchial valves
  • Lung transplantation

For patients with Alpha-1 antitrypsin deficiency who do not present with respiratory issues and have normal spirometry results, Dr. Tosh-Mitchell recommends periodic pulmonary function testing every six months to one year.

Debashree Tosh-Mitchell, MD

Debashree Tosh-MitchellDr. Tosh-Mitchell earned her medical degree and completed her residency at the University of Missouri-Kansas City School of Medicine, where she also completed a fellowship in Pulmonary/Critical Care. Her medical interests include treating asthma, COPD and interstitial lung disease.

* Images courtesy of:

Alpha-1 Antitrypsin Deficiency — A Missed Opportunity in COPD?, COPD Clinical Perspectives, Prof. Ralph Panos (Ed.), InTech, DOI: 10.5772/58602. Available from: Intech