A Diagnosis Hiding in Plain Sight: The Alpha-1 Story

November is Alpha-1 Antitrypsin Deficiency (AATD) Awareness Month. AATD is an inherited disorder that can cause serious lung and liver disease at any age and varies widely in severity, even within families. Despite affecting thousands, it remains largely underdiagnosed—over 90% of Americans with severe AATD are unaware they have it, leading to years of misdiagnosis and preventable damage. Let’s explore a hypothetical clinical story to show how clinicians can improve awareness.

A 68-year-old woman, non-smoker, with moderate exposure to second-hand smoke, is evaluated for chronic cough, shortness of breath, and fatigue. She reports the family history of a brother who passed away at age 8 months due to infantile hepatitis and another, a smoker and alcoholic, who passed away at age 34 due to chronic obstructive pulmonary disease (COPD) and cirrhosis of the liver, possibly from some type of inherited condition but she was unaware of any specifics. The patient is initially diagnosed with allergies and asthma. Over the next year her symptoms worsen, and she is diagnosed with pneumonia. Another year passes and her diagnosis is changed to emphysema. Even though she has never smoked in her life, she is treated accordingly but continues to get sicker. She returns to her primary care physician with tightness in her chest, wheezing, and severe shortness of breath. A consultation with a pulmonologist, who also took a full family history and conducted some specialized tests, results in a diagnosis of Alpha-1 antitrypsin deficiency, genotype PI* ZZ, 3 years after her initial symptoms. She is started on weekly intravenous infusions of alpha-1 proteinase inhibitor replacement therapy, which she will have to take for the rest of her life. Her symptoms have improved dramatically, and she is back to leading a normal life.  With appropriate treatment her life expectancy is predicted to be close to the general population, which would not be the case in untreated individuals.  The patient’s workup and testing lead to evaluating additional at-risk family members.  A retrospective diagnosis of AATD is suggested for her infant brother who passed, and a review of medical records the patient was able to produce confirms her 34-year-old brother had been diagnosed with AATD before his death.

While AATD is considered a rare genetic disorder, it is not as uncommon as often believed. AATD has an estimated prevalence of ~1 in 3,000-5,000 individuals, making it one of the most common lethal genetic diseases among children and adults of European descent, rivaling that of cystic fibrosis.

The most common barrier to diagnosing AATD is that its primary symptoms are nearly identical to those of more common respiratory conditions like asthma and chronic obstructive pulmonary disease (COPD). A patient with AATD will present with a chronic cough, wheezing, and shortness of breath—all classic signs of asthma or COPD.

The patient’s brother who passed at age 34 exemplifies how, in many cases, an AATD diagnosis is confounded by a history of smoking and/or alcoholism. While smoking is the leading cause of COPD, it is also a powerful accelerant for lung damage in people with AATD.

Similarly, while alcoholism is the leading cause of cirrhosis of the liver, it too can quicken the liver damage seen in people with AATD.  A clinician trained to think "smoker equals COPD" or “alcoholism equals liver cirrhosis” can fail to consider the less common genetic deficiency.

However, AATD can cause emphysema or cirrhosis of the liver even in young, lifelong nonsmokers and nondrinkers — a red flag that is frequently missed. 

Both the American Thoracic Society and the European Respiratory Society recommend testing all patients with COPD or unexplained liver disease for AATD, but awareness and compliance with these guidelines has been reported to be low. Without adherence to guidelines, the patient is likely experiencing irreversible lung and/or liver damage during this time of being undiagnosed.

Testing for AATD can be done with a simple blood test and is offered through many testing laboratories, including Quest Diagnostics. If the blood test suggests a low level of a specific protein, follow-up confirmatory studies, like genetic testing, are also widely available, often at the same testing laboratory.  Confirming the right diagnosis in one family member is also key to identifying others who may be at risk.

The patient’s brother who passed at 8 months exemplifies how, unlike some other genetic diseases, AATD is not universally screened for at birth in the United States, nor are there systematic screening programs later in life. Diagnosis is typically initiated based on a doctor's suspicion, and for all the reasons above, that suspicion is often lacking. 

Studies have shown that many physicians believe that no specific treatment exists for AATD, which incorrectly diminishes the urgency of screening.  Beyond patient-driven behavioral changes, treatments primarily focus on minimizing damage to the lungs or increasing alpha-1 antitrypsin protein (AAT) levels.  A greater sensitivity to prescribing antibiotics to treat lung infections, as well as prescribing inhaled bronchodilators or corticosteroids can help manage lung inflammation and improve breathing.  The primary treatment for AATD is weekly lifelong infusions of AAT protein, called augmentation therapy, which boosts the AAT levels in the lungs and blood and can slow further lung damage.

A delayed diagnosis of AATD carries a heavy price. It deprives patients of the opportunity for early intervention with augmentation therapy, which can help slow the progression of lung disease. It also prevents patients from making crucial lifestyle changes, such as quitting smoking or steering away from professions with respiratory toxins, and avoiding alcohol consumption, that could dramatically alter their disease course. Finally, it leaves family members in the dark about their own risk for a condition that can have life-altering consequences.

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1. Brantly M, Campos M, Davis AM, et al. Detection of alpha-1 antitrypsin deficiency: the past, present and future. Orphanet J Rare Dis. 2020;15(1):96. doi: 10.1186/s13023-020-01352-5.
2. Greulich T, Vogelmeier CF. Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis. Ther Adv Respir Dis. 2016;10(1):72-84. doi: 10.1177/1753465815602162.
3. Schumacher RC, Chiu CY, Lubarda J, Aboulsaoud P, Bomberger J, Wells JM. A Novel Provider Education Module to Enhance Detection of Alpha-1 Antitrypsin Deficiency. ATS Sch. 2023;4(4):490-501. doi: 10.34197/ats-scholar.2023-0028OC.
4. Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Published October 27, 2006.Updated June 1, 2023. Accessed October 1, 2025.: University of Washington, Seattle; 1993-2025. https://www.ncbi.nlm.nih.gov/books/NBK1519/