I have a deep interest in alpha-1 antitrypsin deficiency (AATD), a condition that is highly under-recognized. Every individual with dyspnea should have pulmonary function tests, and every individual with fixed airflow obstruction on pulmonary function tests should be tested for alpha-1 antitrypsin deficiency with a serum alpha-1 antitrypsin level and a genotype, as guidelines suggest.
Alpha-1 antitrypsin deficiency is a genetic, autosomal-codominant condition that predisposes to the development of emphysema and liver disease. The role of alpha-1 antitrypsin is to provide protection against neutrophil elastase, which when unopposed in the lung causes proteolytic damage to the alveolar walls that causes emphysema. Individuals with severe deficiency of alpha-1 antitrypsin (AAT) have very low levels of AAT in their blood and in their lungs. If they have lung inflammation, as in individuals who smoke, individuals with dusty occupational exposures, or even non-smokers sometimes have, they can develop accelerated emphysema, sometimes at an early age.
The best prevalence estimates are that there are probably 100,000 Americans with severe deficiency of alpha-1 antitrypsin, what we call PI*ZZ type, in the United States. And yet fewer than 15,000 of those individuals are recognized clinically. Now, some of those 100,000 PI*ZZ individuals have very severe symptoms, very severe emphysema and/or chronic bronchitis, and are recognized to have emphysema or bronchitis but not recognized to have it on the basis of AATD because they have not been tested for AATD. Other individuals with alpha-1 antitrypsin deficiency are unaffected, particularly if they are never smokers. Because it is an autosomal-codominant condition, alpha-1 antitrypsin deficiency can affect first-degree relatives—children, parents, and siblings—of an index case, all of whom are at risk of having similar deficiency.
There are many patients with alpha-1 antitrypsin deficiency who have shortness of breath and may go many years with dyspnea before being detected as having AATD. This delay between first symptom and first diagnosis can be called the “diagnostic delay interval.” In 2023, this diagnostic delay interval remains between five and eight years, largely unchanged from estimates from 1995 when first studied.
If a patient presents with shortness of breath and has pulmonary function tests that are normal, that directs the doctor to consider other reasons, including cardiac disease or anemia. There's a long differential diagnosis of dyspnea, including cardiac causes, anemia, metabolic causes, neurologic causes, deconditioning, etc. But if the patient with dyspnea is found to have airflow obstruction on pulmonary function tests, and the obstruction doesn't reverse with a bronchodilator, that patient is considered to have some element of fixed airflow obstruction. According to guidelines, every patient with fixed airflow obstruction should be tested for alpha-1 antitrypsin deficiency.
The patient history really begins with eliciting a history of dyspnea, and often it's the case that because dyspnea has many potential causes, including deconditioning, the physician may ascribe the patient's dyspnea to their being out of shape or overweight. Dyspnea can be all of those things, but dyspnea can also be on the basis of emphysema. In terms of the physical exam, not every patient with alpha-1 antitrypsin deficiency has advanced emphysema, but internists are well attuned to the signs and symptoms of emphysema. Patients who have tripod breathing, patients who have hyperinflation, are barrel-chested, or have cyanosis, certainly will be recognized as having emphysema. Prompts to test for AATD include fixed airflow obstruction on pulmonary function tests that should be ordered whenever there is a history of dyspnea. Other suggestive features include the presence of liver disease that is otherwise unexplained by other causes (e.g., alcohol, viral hepatitis, hemochromatosis, etc.), panniculitis, and/or a family history of emphysema and/or liver disease in a first-degree relative (i.e., parent, child, or sibling). The liver disease associated with AATD is the result of intra-hepatic accumulation of unsecreted AAT molecules (so-called “toxic gain of function”), which occurs in the most common genotype that is associated with clinical disease, so-called PI*ZZ.
There are other, less common clinical associations with AATD, such as panniculitis, which is an inflammatory condition of the skin characterized by painful inflammatory nodules that may migrate and weep fluid, perhaps especially in areas of trauma (e.g., the trunk, arms, etc.). Individuals with panniculitis should also be tested for AATD, with a serum AAT level and genotype.
I know that the well-trained internist would both suspect emphysema or airflow obstruction as a cause of dyspnea and therefore order pulmonary function tests. Alternatively, of course, they might refer such a patient for further assessment to a pulmonologist.