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Why is Alpha-1 antitrypsin deficiency (AATD) underdiagnosed?

AND WHEN SHOULD YOU TEST FOR IT?

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Clinical presentation offers few clues to diagnosis of AATD.

Average 7 yrs icon depicting the length between onset of symptoms and diagnosis of Alpha-1.
~7 years

between onset of symptoms and diagnosis1

Three healthcare providers (HCPs) icon depicting that 3 HCPs are typically seen before patients receive a correct Alpha-1 diagnosis.
3 physicians

are typically seen before correct diagnosis2*

Three persons icon with 1 person circled, depicting that 1 out of 3 Alpha-1 patients report receiving correct diagnosis by first physician.
1 out of 3

patients report correct diagnosis by first physician2*

*Based on a study of 1020 individuals.

As many as 100,000 people in the US have AATD and more than 90% of them are potentially undiagnosed.2 AATD-related lung disease can be difficult to diagnose because it presents with common respiratory symptoms3:

  • History of suspected allergies
  • Chronic asthma or emphysema
  • Frequent lower respiratory tract infections
  • Decreased exercise tolerance
  • Dyspnea (84%)4
  • Wheezing (76%)4*†
  • Cough (42%)4*
  • Excess sputum production (50%)4*

*Based on a prospective, longitudinal natural history study (N=1129).

†With upper respiratory tract infection.

When should you test for AATD?

AATD can be difficult to diagnose because symptoms often mimic other lung conditions. Learn what symptoms may alert you to testing for AATD.

See AATD Testing Guidelines

When should you perform an Alpha-1 antitrypsin test on your patients?

The average age of patients who are diagnosed with AATD is 45 years.2 Delayed diagnosis or underdiagnosis is common, but testing may help physicians uncover this disease earlier in patients at higher risk. The 2024 GOLD Report and ATS/ERS Standards recommend Alpha-1 antitrypsin testing for all adults with symptomatic emphysema or COPD.5,6

Line chart icon.

Testing is recommended for:

  • Adults with symptomatic emphysema or COPD6
  • Symptomatic adults with asthma with airflow obstruction that is incompletely reversible after aggressive treatment with bronchodilators6
  • Individuals with unexplained liver disease6
  • Siblings of an individual with AATD6
  • Adults with necrotizing panniculitis6
  • Asymptomatic individuals with persistent obstruction on pulmonary function tests with identifiable risk factors (eg, cigarette smoking, occupational exposure)6
Bar chart icon.

Testing should be discussed for*:

  • Adults with bronchiectasis without evident etiology6
  • Asymptomatic individuals with persistent airflow obstruction and no risk factors6
  • Adults with C-ANCA-positive (anti-proteinase 3-positive) vasculitis6
  • Individuals with a family history of COPD or liver disease not known to be attributable to AATD6
  • Relatives of an individual who is homozygous or heterozygous for AATD6

*Genetic testing should be discussed and could be reasonably accepted or declined.

The role of the Alpha-1 antitrypsin protein in AATD

Understanding AATD begins with an overview of the Alpha-1 antitrypsin protein. Alpha-1 antitrypsin (AAT) plays a role in maintenance of normal elastase activity in lung tissue.7

  • Alpha-1 antitrypsin is a 52 kDa protein produced in hepatocytes and released into the bloodstream8
  • Normal range of Alpha-1 antitrypsin level is ~90-200 mg/dL or 20-53 µM9,10

When AAT is deficient, imbalance between elastase and AAT in the lungs can cause emphysema.

  • AAT is a proteinase inhibitor (PI) synthesized mainly by the liver11
  • AAT is thought to be a participant in the immune response and is an acute-phase reactant7
  • AAT protects lung alveoli from the proteolytic effects of neutrophil elastase by maintaining a balance between anti-inflammatory and pro-inflammatory proteins in the lower respiratory tract7

The elastase/anti-elastase imbalance hypothesis was the first viable hypothesis to explain emphysema.11 AAT keeps elastase “in check” and prevents lung tissue (alveoli) breakdown.

Alpha-1 antitrypsin deficiency emphysema is a component of COPD.

  • Chronic bronchitis – inflammation and small airway narrowing lead to decreased lung function11,12
  • Emphysema – reduction in lung elasticity leading to parenchymal destruction and decreased gas transfer5,11,12

The relative contributions of airway narrowing and emphysema to symptoms in patients with chronic obstructive pulmonary disease (COPD) vary from patient to patient.5 AATD remains markedly undiagnosed as a cause of COPD.13

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References

  1. Stoller JK, et al. Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem. Chest. 2005;128(4):1989-1994.
  2. Campos MA, et al. Chest. 2005;128(3):1179-1186.
  3. Alpha-1 Foundation. Accessed September 18, 2023. https://www.alpha1.org/Newly-Diagnosed/Learning-about-Alpha-1/Lung-Disease/
  4. McElvaney NG, et al. Chest. 1997;111(2):394-403.
  5. Agustí A, Celli BR, Criner GJ, et al. Global Initiative for Chronic Obstructive Lung Disease 2024 Report. Accessed April 12, 2024. https://goldcopd.org/2024-gold-report/
  6. American Thoracic Society; European Respiratory Society. Am J Respir Crit Care Med. 2003;168(7):818-900.
  7. Siri D, et al. Ann Allergy Asthma Immunol. 2013;111(6):458-464.
  8. Fregonese L, Stolk J. Orphanet J Rare Dis. 2008;3:16.
  9. Stoller JK, Aboussouan LS. Lancet. 2005;365(9478):2225-2236.
  10. Greulich T, Vogelmeier CF. Ther Adv Respir Dis. 2016;10(1):72-84.
  11. Janciauskiene SM, et al. Respir Med. 2011;105(8):1129-1139.
  12. Barnes PJ, et al. Nat Rev Dis Primers. 2015;1:1-21.
  13. Soriano JB, et al. Eur Respir J. 2018;52(1):1800360.