How bad is the underdiagnosis of alpha-1 antitrypsin deficiency?
The underdiagnosis is substantial, even in severe cases. A multicenter study of liver transplant candidates whose explanted livers showed signs of AATD found that 45% were never diagnosed before or after transplant, and only 40% were diagnosed before the transplant [1]. This means nearly half of people with a severe, life-threatening form of the condition were missed entirely by the medical system.
In a broader clinical population, the problem is also clear. A study of over 1,400 pulmonary outpatients found that 30.5% carried AATD-related gene variants, yet many of these patients had not been previously diagnosed [2]. The same study estimated that the PI*Z allele, the most common disease-causing variant, occurs in about 2.1% of the general population, suggesting a large pool of undiagnosed individuals [2].
Why does underdiagnosis happen?
A major reason is low awareness among healthcare providers. In a survey of liver transplant specialists in France, 78% rated their knowledge of AATD as very low to moderate, and consistent pre-transplant screening occurred in only 59.3% of cases [1]. A European survey of 166 professionals found that 25% reported no specific testing guidelines in their country, and 36% said there was no standardized testing protocol [5].
Provider education can make a real difference. A study of over 11,000 healthcare providers found that a targeted education module improved confidence in identifying high-risk patients (the share who felt 'not confident' dropped from 19.4% to 7.7%) and more than doubled the actual screening rate in a pulmonary clinic, from 9.7% to 20.4% [6]. Among those screened, 27.2% had results consistent with AATD, showing that many cases are waiting to be found [6].
What are the consequences of missing the diagnosis?
Missing AATD means missing opportunities to prevent or manage serious lung and liver disease. Severe AATD (the Pi*ZZ genotype) is a well-known risk factor for early-onset emphysema and liver fibrosis. A longitudinal study of PiZZ individuals found they had a dramatically higher risk of liver cancer (hazard ratio 23.4) and a modestly higher risk of non-liver cancers (hazard ratio 1.3) compared to the general population [3].
There is also emerging evidence that treatment may help the liver as well as the lungs. A study of 760 adults with severe AATD found that those receiving augmentation therapy (which raises blood levels of the protective protein) had lower liver enzyme levels and less liver fibrosis on non-invasive tests compared to those not treated [4]. This suggests that earlier diagnosis could open the door to treatments that slow liver damage, not just lung damage.
About These Sources
This answer is built on 6 peer-reviewed studies — published from 2022 to 2025, 1 from 2024 or later, 4 in Q1 journals, collectively cited 62 times — selected as the most relevant from 6 studies that passed quality screening, drawn from 31 papers retrieved from a database of over 500 million.
Sources used in this answer
Underdiagnosis of Alpha‐1 Antitrypsin Deficiency in Cirrhotic Liver Transplant Candidates: Findings From a Multicenter Retrospective Study
In a multicenter retrospective study of 58 liver transplant candidates with confirmed AATD, 45% were never diagnosed before or after transplant, and only 40% were diagnosed pre-transplant. A survey of French liver specialists found 78% rated their AATD knowledge as very low to moderate.
Frequency of alleles and genotypes associated with alpha-1 antitrypsin deficiency in clinical and general populations: Revelations about underdiagnosis
In a study of 1,493 pulmonary outpatients, 30.5% carried AATD-related gene variants. The estimated frequency of the PI*Z allele in the general population was 2.1%, and the PI*ZZ genotype prevalence was 1 in 2,162 in La Palma, Spain.
Cancer risk in severe alpha-1-antitrypsin deficiency
A longitudinal study of 1,595 PiZZ individuals (severe AATD) found a 23.4-fold higher risk of liver cancer and a 1.3-fold higher risk of non-liver cancer compared to 5,999 population controls over a median 17-year follow-up.
Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ)
In a multinational cohort of 760 PiZZ adults, those receiving augmentation therapy had lower liver enzyme levels (AST 71% vs 75% of upper limit of normal) and lower liver stiffness (6.5 vs 7.2 kPa) compared to untreated individuals, suggesting a potential liver benefit.
Diagnosing Alpha 1 Antitrypsin Deficiency in Europe – insights from a European survey
A European survey of 166 professionals from 18 countries found that 25% reported no specific testing guidelines for AATD in their country, and 36% reported no standardized testing protocol, with significant variation in testing methods between countries.
A Novel Provider Education Module to Enhance Detection of Alpha-1 Antitrypsin Deficiency
A provider education module delivered to 11,385 healthcare providers improved confidence in AATD screening (those 'not confident' dropped from 19.4% to 7.7%) and more than doubled screening rates in a pulmonary clinic (from 9.7% to 20.4%). Among those screened, 27.2% had results consistent with AATD.