Alpha 1 Antitrypsin Deficiency (AATD) DRAFT

Overview

Alpha 1 Antitrypsin Deficiency (AATD) is an autosomal recessive disorder affecting about 1:2500 people. In AATD there is an increased risk of development of emphysema at an earlier age than usual, for example, in the third to fourth decades of life. Less frequently, liver disease may arise and cause cirrhosis and liver failure in children or adults. Environmental factors, particularly cigarette smoking, increase the risk of emphysema at an earlier age and high alcohol use increases risk of liver damage.

Most carriers for AATD are unaffected, but their risk of emphysema is also exacerbated by smoking.

Most individuals with AATD can be managed in primary care with lifestyle advice, but referral to a specialist service (Respiratory, Hepatology or Paediatrics) may be required if there are significant symptoms.

The SERPINA1 gene produces Alpha-1 Antitrypsin (AAT), a protein that protects airways from proteolytic damage. The different copies (forms) of a gene are called alleles. Every individual has two SERPINA1 alleles and inherits one from each parent. The three main alleles to be aware of in AAT are M, S and Z. M is the most common and associated with normal AAT levels. Z and S are alleles associated with lower AAT levels. S causes moderately reduced but sufficient AAT levels, whereas Z causes very low AAT levels which are associated with deficiency. Individuals with one M allele and another abnormal allele (S or Z) are called ‘carriers’. Other rarer alleles also exist. 

Testing and who to refer

Who to test for AATD in primary care:

• As part of non- invasive liver screen of patients with persistently deranged liver function tests - see Liver disease page.
• Consider testing in early-onset emphysema or emphysema in the absence of any risk factors (e.g. smoking and occupational dust exposure).
• Consider testing if there is a strong family history of lung or liver disease.
• Consider testing first degree relatives or partners of those who are affected or confirmed carriers of AATD.
• Test and consider referral to clinical genetics:
  • Members of a couple of reproductive age who have abnormal alleles (e.g. MZ, MS, ZS, ZZ or other rare alleles), as they may be at risk of having a child with alpha-1-antitrypsin deficiency.
  • Parents of reproductive age who have a child who has been diagnosed with alpha-1-antitrypsin deficiency.

Practicalities about testing

Also see regional pathway document.

Patients with symptoms -  request alpha-1 antitrypsin (AAT) serum levels only (UHBW ICE: search Alpha-1. NBT ICE search A-1).

Relatives/partners of those who are affected or confirmed carriers of AATD -  test both serum alpha-1 antitrypsin (AAT) levels and AATD phenotype (UHBW ICE*: Alpha-1-AT phenotype. NBT ICE: A-1AT Phenotype). Measurement of serum AAT level alone is not reliable for determining carrier status. This is because the range of serum AAT levels among most carriers may overlap with the normal serum range and/or may be elevated in certain situations eg during periods of acute inflammation and in pregnancy.

More detailed genomic testing (DNA analysis) is rarely indicated, but in certain situations, genetic testing may be recommended following the initial AAT testing (above) to clarify a patient’s status. This can be organised in primary care.

*UHBW ICE request for AATD:

• Alpha 1 antitrypsin phenotype | North Bristol NHS Trust (nbt.nhs.uk)
• Enter 'alpha’ into the search bar on the left hand side
• Select ‘alpha-1-antitrypsin’ option on the right to order alpha-1-antitrypsin’ serum levels
• Also select ‘alpha -1-AT phenotype'.
• This will open a window asking if the patient is known to clinical genetics. Select 'no' or ‘yes’ as appropriate.
• You will then be prompted to enter the relative and phenotype details of the patient. Do this, then click 'OK‘. If relevant relative not specified, just pick any.
• Then click ‘Continue with request…’

Patient Information Leaflet

Management

* Relevant specialist = Respiratory, Hepatology or Paediatrics.

** If a patient has low levels of AAT and may have other rare alleles, genetic testing of the SERPIN1A gene can be considered based on criteria in the National Genomic Test Directory test R191 (rare- and-inherited-disease-eligibility-criteria-v2.pdf (england.nhs.uk)

Referral

Genetics Referral

Refer if indicated (see advice above) via eRS to the Clinical Genetics Service (RAS). The Clinical Genetics Department is based at St Michaels Hospital offers genetic assessment, investigations, diagnosis and counselling.

***May 2024 - Note on referral restrictions - Patients are usually seen by genetic counsellors so referral restrictions should not apply.***

Specialty Advice and Referral

Refer if indicated (see advice above). Consider advice and guidance services or refer to Respiratory, Hepatology or Paediatrics (general) via eRS as appropriate.

Resources

Further sources of information on Alpha-1-Antitrypsin deficiency can be found at:

• GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1519/)
• British Lung Foundation patient information (https://www.blf.org.uk/support-for-you/alpha- 1-antitrypsin-deficiency)
• Patient UK patient.co.uk
• Health Education England https://www.genomicseducation.hee.nhs.uk/genotes/knowledge- hub/alpha-1-antitrypsin-deficiency/

Questions regarding this pathway can be directed to the Bristol Clinical Genetics Service ubh- tr.ClinicalgeneticsUHB@nhs.net

Efforts are made to ensure the accuracy and agreement of these guidelines, including any content uploaded, referred to or linked to from the system. However, BNSSG ICB cannot guarantee this. This guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, in accordance with the mental capacity act, and informed by the summary of product characteristics of any drugs they are considering. Practitioners are required to perform their duties in accordance with the law and their regulators and nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.

Information provided through Remedy is continually updated so please be aware any printed copies may quickly become out of date.