Rare Disease Report

Should Emphysemia Patients be Screened for Alpha-1-antitrypsin Deficiency?

JUNE 12, 2016
Ruth J Hickman, MD
Results of a recent study published in Orphanet Journal of Rare Diseases suggest that targeted screening programs can successfully increase the rates of diagnosis for the genetic disease alpha-1-antitrypsin deficiency (AATD). This screening should focus primarily on patients already diagnosed with COPD, emphysema, or bronchiectasis. The study’s first author, Dr Timm Greulich, worked with a team of researchers out of the Philipp University of Marburg, in Marburg, Germany.


AATD is caused by different kinds of mutations in the gene that codes for the protein alpha-1-antitrypsin (AAT). AAT normally works to inactivate another protein released from white blood cells to fight infection. When not tightly controlled by AAT, this protein can damage normal tissues, especially those in the lungs. That is why AATD predisposes people to lung disease, especially chronic obstructive pulmonary disease (COPD). The risk is even higher in people who smoke. AATD also causes liver disease in about 10% of patients. More rarely it causes other lung problems like bronchiectasis and other medical conditions like panniculitis and vasculitis.
There is no cure for AATD, but doctors can treat the lung disease and other problems.

Patients can also receive infusions of AAT protein, which may help some people with severe lung disease. But once severe damage to the lungs occurs, it cannot be corrected. 

Underdiagnosis and its consequences

In people of European descent, AATD is one of the most common genetic disorders. Yet the condition is underdiagnosed, especially among primary care physicians, who provide care to most COPD patients. In the US, it is estimated that only 10% of people with severe AATD lung disease have received a correct diagnosis. On average, these patients are not diagnosed until 6 years after symptoms begin.
The European Respiratory Society and the American Thoracic Society both recommend testing for all adults with persistent airway obstruction from COPD, emphysema, or asthma, as well as for individuals with unexplained liver disease, necrotizing panniculitis, or multisystemic vasculitis. But many primary care physicians do not follow these recommendations in practice.
This is problematic, because early treatment makes a big difference. Patients may continue to smoke, further worsening their disease. The disease may also affect whole clusters of individuals within families, all of whom could benefit from diagnosis.
Screening programs have been shown to improve diagnosis rates, particularly in those who already have lung disease. Dr Greulich and colleagues analyzed the results of such a screening program in Germany.

Study results

From August 2003 to September 2015, the researchers supplied greater than 50,000 free test kits that had been requested by patient advocacy groups and physicians. Their final analysis included a total of 18,683 kits with blood samples and information about patient symptoms and diagnoses. Of these, 1048 were obtained by patient advocacy groups during general screenings. Doctors returned the remaining kits based on patient symptoms or family history.
On genetic testing, 6919 (37%) of the samples in the entire group carried at least one disease mutation. In 1835 (10%), these were mutations that result in severe AATD. These percentages are consistent with rates previously found in previous screenings for AATD. The number of disease mutations found was dramatically lower in the subset of samples obtained through general screenings. History of COPD, emphysema, and bronchiectasis were significant predictors of the AATD mutations. History of asthma, symptoms of cough, and symptoms of phlegm were not.
Figure. Clinical characteristics predictive for the genotype

Thus the study supports targeted screening in patients with COPD, emphysema, or bronchiectasis, but not in those with other lung diseases such as asthma. Also, the study confirms prior work about the inefficiency of screening the population at large. The authors acknowledge that such a screening approach may miss some people with severe mutations who do not have symptoms. They suggest, however, that this is the most cost-effective and realistic approach.


Greulich T, Nell C, Herr C, et al. Results from a large targeted screening program for alpha-1-antitrypsin deficiency: 2003 – 2015. Orphanet J Rare Dis. 201611:75 DOI: 10.1186/s13023-016-0453-8

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