This information is an aid to the diagnosis and management of patients and their relatives with alpha-1 antitrypsin deficiency.
Testing for Alpha 1 Antitrypsin Deficiency (AATD): Information for GPs
What is AATD?
Alpha-1 antitrypsin deficiency is a common autosomal recessive inherited disease affecting the lungs and liver. To have the condition, an individual must inherit two faulty copies of the AAT gene, one from each parent.
Alpha-1 antitrypsin (AAT) is an inhibitor of proteinase enzymes. It is produced in the liver and protects the lung from enzymes which are secreted by neutrophils in response to infection and irritants.
Affected individuals have a predisposition to
- Lung disease (COPD). 1-2% of COPD is due to AATD
- Liver disease (cirrhosis)
AATD affects 1 in 3000 in the UK. It is under diagnosed, especially in adults, however it is relatively easy to detect by testing. Early diagnosis leads to prolonged life expectancy, therefore ‘cascade’ screening of close relatives of affected individuals is recommended.
How Does AATD Occur?
There are many different genetic variants of AAT.
M is the normal variant. The two most important abnormal variants are called S and Z. S produces moderately low levels of AAT whilst Z produces very little AAT.
There are varying degrees of severity depending on the combination of genes:
- 90% of North Europeans are MM and have normal AAT levels.
- MZ or MS (carriers) and SS have lower, but sufficient levels of AAT. They do not have a significant increased risk of lung or liver disease, but should be advised that is sensible not to smoke, and to take alcohol in moderation.
- SZ individuals have AATD. They have a 60% risk of developing early onset COPD, and an increased risk of liver disease.
- ZZ individuals have AATD. All will develop early onset COPD, and have increased risk of liver disease.
How does AATD present and progress?
AATD most commonly presents as an adult-onset respiratory condition.
The lack of sufficient levels of AAT leads to lung damage by the proteinase enzymes, especially if combined with the patient smoking, or being exposed to cigarette smoke passively.
Patients present with breathlessness and wheeze which can be misdiagnosed as asthma. Smokers will develop COPD between age 30-45 yr, 10-15 years later in non-smokers.
In those patients who raise your suspicions of possible AATD, whom are breathless and yet have a relatively well preserved FEV1 (>80%), referral to the respiratory team for consideration of carbon monoxide diffusion tests should be considered, since those with AATD can have significant emphysematous changes despite having a satisfactory FEV1.
AATD is the most common inherited cause of liver disease in children. Liver disease is rare in childhood, so the possibility of AATD should spring to mind.
It can present with a ‘neonatal hepatitis syndrome’, with jaundice, pale stools, hepatomegaly or bleeding. Most will improve, but a small few can progress to cirrhosis and liver failure. ZZ and SZ children should have their LFTs monitored and be referred to a paediatric gastroenterologist if they are persistently abnormal.
Liver disease due to AATD can be overlooked in adults as there are many more common causes of liver disease, such as alcohol induced or hereditary haemochromatosis. It can take many years for the symptoms to develop, but can eventually present with jaundice, hepatomegaly, bleeding and increased risk of hepatoma and hepatocellular carcinoma. The risk of cirrhosis is greatest for men over 50 yr of age.
Testing for Alpha 1 Antitrypsin Deficiency (AATD): Information for GPsReferral process for First degree relative of patient who has a diagnosis of AATD / Patient with suspected AATD
- AATD results in increased lung tissue damage by neutrophil proteases in response to infection, inflammation and smoking. Affected individuals have a significantly increased risk of COPD.
- COPD risk is highest in smokers. COPD risk is lower in non-smokers and shows delayed age at presentation.
- People with the most common form of AATD (PiZ, see Interpretation of results) produce abnormal AAT protein which aggregates in liver cells. There is an increased risk of liver cirrhosis.
- A small subset of babies with PiZ AATD has neonatal liver disease (prolonged jaundice).
- AATD is inherited in an autosomal recessive pattern. The population carrier frequency is estimated at around 1 in 25.
- More information can be found at: www.newcastle-hospitals.org.uk/services/ng_npcg_common_aatd.aspx
- Diagnosis of a genetic condition may impact of life/critical illness/income protection insurance and may result in increased premiums or exclusions.
Who to test
- People with clinical features suggestive of AATD (please give clinical details on sample referral form)
- First degree adult relatives (parents, siblings and children) of an affected person. Testing of more distant healthy relatives is not generally recommended
- AATD is an adult onset condition therefore carrier testing is not recommend in healthy children. To clarify the risk to children partners of an affected or carrier person may be tested
- If testing is declined by patient: Give lifestyle advice regarding smoking and alcohol.
How to test
- 2 to 5ml blood in EDTA (anticoagulant) tube sent with DNA request card to Northern Molecular Genetic Service via your local hospital pathology department.
- Include reasons for testing or name of affected relative on sample referral form where applicable.
- Sample referral forms can be downloaded at https://www.newcastlelaboratories.com/lab_service/clinical-services/
- By completing the form, this indicates that patients have consented to testing, and DNA being stored by the testing laboratory.
- Results are usually available within 4 weeks and will be returned to refer given on the request (placing others details in this section will result in a delay to the patient)
Interpretation of results and management:
|Normal AAT level||Person does not have AATD. It is still possible that they are a carrier though this chance is also reduced.||Reassure patient that s/he will not develop symptoms due to AATD. Small chance s/he is a carrier but we would not expect this to affect their health.|
|Reduced AAT level||The patient may be affected with AATD (if levels are very low) or be a carrier.||Laboratory will usually proceed to protein phenotyping (results explained below). If levels are borderline the lab may seek confirmation that phenotyping is needed.|
|Test result||Meaning||Interpretation and Management|
|PiM||No abnormal protein detected||Normal. No further AATD management required.|
|PiMZ||Z isoform and normal protein detected||Carrier (partial AATD) Unlikely to impact on health. Smoking and alcohol advice as per general population. If a couple of childbearing ages are both PiMZ carriers, referral to genetics can be considered.|
|PiMS||S isoform and normal protein detected||Carrier (partial AATD) Unlikely to impact on health. Smoking and alcohol advice as per general population.|
|PiS||Only S isoform detected||Partial deficiency Unlikely to impact on health. Smoking and alcohol advice as per general population.|
|PiZ||Only Z isoform detected||Affected Significantly increased risk of COPD and increased risk of liver disease Encourage reporting symptoms which may suggest COPD and/or chest infection early as prompt treatment reduces lung tissue damageSmoking cessation and alcohol moderation adviceAnnual LFT Avoidance of environmental exacerbating factors e.g. industrial dustReferral on to appropriate specialties (respiratory or liver teams) in symptomatic individualsCOPD is managed as per COPD in the general population|
|PiSZ||S and Z isoforms detected||Affected Increased risk of COPD (but lower than in PiZ individuals) Risk of liver disease is not thought to be increased Management advice as per PiZ for COPD risk|
|Other results (rare)||Rare isoform detected||See advice from laboratory|
Information/support for patients:Alpha 1 Patient info – Alpha 1 antitrypsin deficiency leaflet BLF – support for you alpha 1 antitrypsin deficiency Genetic Alliance
This leaflet is based, with permission, on a leaflet produced by the Yorkshire Regional Genetics Service.