This site is intended for health professionals only

How not to miss – alpha 1 antitrypsin deficiency

Worst outcomes if missed

Respiratory failure and death 

Alpha-1-antitrypsin deficiency (A1ATD) is the most common genetic cause of emphysema. As a result, COPD develops in many patients and may progress to respiratory failure and premature death.1,2 In a Swedish A1ATD registry, the standardised mortality ratio for patients with respiratory symptoms was 4.7, with the most common causes of death being respiratory failure, pneumonia and pneumothorax.

Liver failure and death

Accumulation of the alpha-1-antitrypsin protein in the liver may cause liver disease in infants or during late adulthood. Around 15% of infants with A1ATD develop some evidence of liver disease, and in a small number this is severe enough to require transplantation. Deaths related to liver disease are typically due to complications of cirrhosis, including liver failure or hepatocellular carcinoma.3 


A1ATD is a genetic disorder where a mutation exists in the gene on chromosome 14 that codes for the protein. The most common phenotype of the non-functioning protein is known as PiZZ, although many other – over 100 – less common mutations exist. In the UK, around one in 2,000-5,000 individuals have A1ATD, yet most of these individuals will be undiagnosed or have a delayed diagnosis. 

Symptoms and signs

Alpha-1-antitrypsin is produced in the liver and protects the lung against proteolytic enzymes. Mutations in the alpha-1-antitrypsin gene lead to an abnormal protein, which forms polymers in hepatocytes that cannot then be released into the circulation. The principle manifestations of disease are related to the accumulation of protein in the liver and low levels of circulating alpha-1-antitrypsin, which renders the lung susceptible to serine proteases such as neutrophil elastase, destroying elastin and leading to premature panacinar emphysema. Patients with A1ATD typically present with early onset COPD, and symptoms include dyspnoea, cough, increased sputum and poor exercise tolerance. Patients diagnosed with COPD who have never smoked or who smoke but present at a younger age, around 30 to 40 years old, should prompt GPs to consider if A1ATD is present. 

Although the abnormal protein accumulates in hepatocytes, manifestations of liver disease are heterogeneous even within the same genotype, and many individuals will remain asymptomatic. In infants, cholestasis leading to jaundice is the most common sign of disease and usually improves, and progression to cirrhosis is uncommon. In adults, many individuals will be asymptomatic but demonstrate abnormal LFTs. Less frequently, patients present with cirrhosis and the complications involved, including hepatocellular carcinoma. Treatment of liver disease is largely supportive, although when indicated, liver transplantation is curative. 

Differential diagnosis

In patients presenting with pulmonary symptoms, the differential diagnosis includes other causes of COPD, asthma, bronchiectasis and heart failure. Many patients with A1ATD may be misdiagnosed with asthma, as they may be younger than typical patients with COPD and demonstrate some airway reversibility. A1ATD and asthma can also co-exist and may delay the final diagnosis. Typically, patients are diagnosed with A1ATD around eight years after pulmonary symptoms first develop and following consultations with several clinicians. In part, the delay in diagnosis is because many clinicians believe that the typical A1ATD patient is young with emphysema and a trivial smoking history, while the average age at diagnosis is 55 years, with a pack-year smoking history of more than 20. 

Key questions

  • How old were you when your symptoms began?
  • How many cigarettes do you/have you smoked?
  • Have you had liver problems?
  • Do you have a family history of COPD?


In patients with respiratory symptoms suggestive of COPD, spirometry should be performed to confirm a diagnosis. A post-bronchodilator FEV1/FVC <0.7 confirms the presence of persistent airflow obstruction and therefore the presence of COPD. Levels of 5 alpha-1-antitrypsin can be measured in blood, and if they are low patients can be further characterised by genetic testing. The American Thoracic Society and European Respiratory Society joint task force recommends testing for A1ATD in the following groups:

  • All symptomatic patients with emphysema or COPD regardless of smoking history.
  • Symptomatic patients with asthma where airflow obstruction is incompletely reversed by bronchodilators.
  • Asymptomatic individuals with persistent airflow obstruction and identifiable risk factors such as smoking and unexplained liver disease.4 
  • Testing should also be offered to siblings of individuals with A1ATD.

The 2010 NICE COPD guidelines recommend a much higher threshold for testing, and suggest specialist referral concerning testing for A1ATD in patients with an onset of symptoms before the age of 40, or minimal smoking history, or a family history of A1ATD. This approach will undoubtedly miss many cases, but is likely to be a more realistic and widely adopted strategy for primary care. 

Patients identified with A1ATD should be referred to a specialist with an interest in COPD. Smoking cessation and family screening for other affected individuals are particularly important in this patient group, as is vigilance for liver disease.

Five red herrings

1 Patient is older than 50 years with symptoms of COPD (although A1ATD is thought of as a disease of young adults, the average age at diagnosis is 55 years)

2 Significant smoking history (common in patients with A1ATD)

3 Presence of wheeze or previous diagnosis of asthma (a degree of airway reversibility may occur in A1ATD)

4 No family history of A1ATD (does not exclude the diagnosis)

5 Normal chest radiograph (may be normal in earlier stages of pulmonary disease

Dr Matt P Wise is a consultant in adult critical care at the University Hospital of Wales

Dr Stephen Chapman is a consultant in respiratory medicine at Oxford University Hospitals and Oxford Biomedical Research Centre


1 Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med 2012; 185:246-59.

2 Brode SK, Ling SC, Chapman KR. Alpha-1 antitrypsin deficiency: a commonly overlooked cause of lung disease.  CMAJ 2012; 184:1365-71.  

3 Nelson DR, Teckman J, Di Bisceglie AM, Brenner DA. Diagnosis and management of patients with α1-antitrypsin (A1AT) deficiency. Clin Gastroenterol Hepatol 2012; 10:575-80.  

4 American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003; 168:818-900.

Global Initiative for Chronic Obstructive Lung Disease. Pocket guide to COPD diagnosis, management and prevention, updated 2015.