AATD Testing
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In medical school, would-be doctors are taught the mantra that, in medicine, “common things are common.” This is meant to orient students’ minds to think of a list of common differentials before moving on to rarer diseases. 

Within a few years, medical students are expected to become familiar with common diseases across all medical disciplines and get acquainted with rarer ones as well. They may then become too conscious of extremely rare diseases and make the mistake of assuming the worst when the patient has a minor illness. Or, at the other end of the spectrum, rare diseases never even make it on their list of differential diagnoses. 

Alpha-1 antitrypsin deficiency (AATD) is often just such a disease. AATD “is usually underdiagnosed owing to its variable penetrance and clinical heterogeneity,” wrote the authors of a recent study published in Faculty Reviews.

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Those researchers reviewed the scientific literature from the last 5 to 10 years on the clinical aspects of AATD. This article will focus on those clinical features, as well as the known genetic mutations that cause AATD. 

A Number of Genetic Mutations 

AATD is an autosomal codominant disease caused by a number of genetic mutations. The AAT protein protects the lungs by inactivating neutrophil elastase when the lung experiences injury, such as in the case of smoking. The absence of AAT in AATD disables this function and thus leads to the progressive destruction of the lung, resulting in diseases such as chronic obstructive pulmonary disease (COPD). In the liver, alcohol stimulates excessive AAT production, which can lead to diseases such as cirrhosis. 

What are the known genotypes of AATD? They are a few. The PiZZ genotype is established to be linked to worse outcomes by causing the development of emphysema and early-onset COPD. Aside from the PiZZ genotype, other genotypes have also been identified, although they tend to cause milder forms of the disease. 

Read more about AATD etiology

For example, compared to the PiZZ genotype, research suggests that the survival rate in patients with the PiSZ genotype is better. The PiSZ genotype carries the major risk of developing COPD. However, AATD is often missed when patients develop emphysema because it has an apical dominance, while physicians typically screen for AATD mainly in basal emphysema. Behavioral studies show that PiSZ patients are more likely to exhibit unhealthy behaviors compared to PiZZ patients, such as leading a sedentary lifestyle, smoking, or being overweight. They are also more likely to have frequent exacerbations and hospital visits. 

The PiMZ and the PiMS genotypes are among the most common in AATD patients. Not much is known about the PiMS genotype because the AAT levels in PiMS patients are usually close to normal; the PiMZ genotype, however, is known to be especially relevant in smokers because the risk of developing COPD is about the same as that of PiSZ. In general, PiMZ patients are more likely to exhibit unhealthy behaviors than PiZZ, especially prior to the development of lung disease. Behavioral studies also indicate that they are less likely to engage in smoking cessation programs compared to PiZZ or PiSZ patients. This is significant because “smoking cessation is the most important protective effect in AATD,” wrote the authors of the study. 

The PiSS genotype is rarer than other genotypes and is rarely diagnosed in clinical practice, meaning we still do not know much about its clinical phenotype. For example, its relationship with lung disease is unknown, but studies indicate that it carries a minor risk factor for liver cirrhosis in patients who are known alcohol abusers. 

Pulmonary and Liver Involvement

The most common clinical features of AATD relate to pulmonary involvement, leading to calls for AATD tests to be conducted in a wide spectrum of respiratory diseases. Emphysema and COPD are most commonly observed in AATD patients; however, the severity of those diseases varies depending on genotype and behavioral choices, complicating efforts to identify and diagnose the disease. When lung disease occurs, the reversibility of airflow obstruction is a major prognostic indicator. 

Bronchiectasis is commonly found in AATD patients, especially those with emphysema, since both diseases share a common pathophysiology. Bronchiectasis in AATD seems to increase the risk of nontuberculous mycobacterial infection in comparison to primary ciliary dyskinesia and common variable immunodeficiency. The proposed reason for this is that AAT enhances macrophage immunity against mycobacterial infections, so the lack of it makes patients more vulnerable. 

Read more about AATD prognosis

Little is known about the relationship between asthma and AATD, although allergic asthma is more commonly observed in younger AATD patients. 

Extrapulmonary involvement in AATD patients mainly consists of liver disease, such as cirrhosis. Diseases such as necrotizing panniculitis and systemic vasculitis with positive c-ANCA are also associated with AATD. Other inflammatory and autoimmune diseases have also been linked with AATD, such as inflammatory bowel disease, fibromyalgia, pancreatitis, psoriasis, and multiple sclerosis. This link is tenuous but plausible because AATD itself is an anti-inflammatory and immunomodulatory disease. 

An Increased Understanding

This study indicates that our understanding of AATD has improved over the past decade, but much more research needs to be done for our knowledge of it to be on par with more common diseases.

“Monitoring and managing AATD patients remains an area of active research,” the authors of this study wrote. At present, behavioral changes, such as smoking cessation and limiting alcohol consumption, should be emphasized.

With more investment into rare disease research, we can expect our grasp of AATD to continue to improve in the decades to come. 


Santos G, Turner AM. Alpha-1 antitrypsin deficiency: an update on clinical aspects of diagnosis and management. Fac Rev. Published online October 28, 2020. doi:10.12703/b/9-1

Stockley RA, Turner AM. α-1-antitrypsin deficiency: clinical variability, assessment, and treatment. Trends Mol Med. 2014;20(2):105-15. doi:10.1016/j.molmed.2013.11.006.