Presentation: Patient with alpha-1-antitrypsin deficiency

A 45-year-old man with chronic obstructive pulmonary disease is referred to the gastroenterology clinic with abnormal liver function on routine blood testing, including alanine transaminase (ALT) of 60IU/L, aspartate aminotransferase (AST) of 72IU/L and a fibrosis-4 score of 2.79. He has a normal BMI, type 2 diabetes mellitus and consumes 10 units of alcohol weekly. Fibroscan reveals a liver stiffness of 7.5kPa, corresponding to F2 fibrosis. His non-invasive liver screen reveals a borderline low alpha-1-antitrypsin (A1AT) plasma level and an inconclusive A1AT genotyping test.

• Phenotype testing is sufficient to establish the diagnosis of alpha-1-antitrypsin (A1AT) deficiency in the majority of cases.
• Genomic testing should be targeted at those where a genomic diagnosis will guide management for the proband or family.
• When diagnostic confirmation is required, the National Genomic Test Directory eligibility criteria for genomic testing are:
  • plasma concentration of A1AT below normal range; and
    • prolonged neonatal jaundice with an inconclusive A1AT phenotyping result; or
    • where variant analysis will inform reproductive choice; or
    • an adult with cirrhosis or emphysema where a genetic diagnosis would influence management following an inconclusive A1AT phenotyping result.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For investigation of A1AT deficiency, the appropriate panel to choose is:
  • R191 Alpha-1-antitrypsin deficiency: This is targeted variant testing that screens for common pathogenic variants in the SERPINA1 gene. These tests are performed on a singleton basis.
• For tests that do not include whole genome sequencing, such as R191, you can use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• Most tests, including R191, are DNA based and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory

References:

• Fromme M, Schneider CV, Trautwein C and others. ‘Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder‘. Journal of Hepatology 2021: volume 76, issue 4, pages 946–958. DOI: 10.1016/j.jhep.2021.11.022
• Strnad P, McElvaney NG and Lomas DA. ‘Alpha₁-Antitrypsin Deficiency‘. New England Journal of Medicine 2020: volume 382, issue 15, pages 1,443–1,455. DOI: 10.1056/NEJMra1910234

For patients

• Alpha-1 UK support group
• Asthma and Lung UK: Alpha-1-antitrypsin deficiency (AATD)
• British Liver Trust: Alpha 1 antitrypsin deficiency (AATD)
• Children’s Liver Disease Foundation: Alpha-1 Antitrypsin Deficiency