Presentation: Patient with unexplained iron overload

A 36-year-old man, otherwise well, was noted to have a serum ferritin level of 3000mcg/l (normal range 5–204mcg/l) with transferrin saturation of 20% (normal range 16%–55%), excluding secondary causes and HFE-related haemochromatosis as the likely cause. An abdominal MRI scan showed iron deposition in the liver and spleen. Subsequent genomic testing confirmed a pathogenic variant in SLC40A1, which encodes ferroportin. A diagnosis of ferroportin disease was thus confirmed.

• HFE genotyping should be performed in the context of a raised ferritin level and transferrin saturation.
• Extended genomic testing for iron overload can be considered if iron overload remains unexplained or in the context of significant hyperferritinaemia with normal transferrin saturation (where typical causes such as metabolic dysfunction-associated steatotic liver disease have been excluded).

• 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 containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For the investigation of unexplained iron overload, the appropriate test directory panels are:
  • R95 Iron overload – hereditary haemochromatosis testing: This will test common HFE variants with targeted variant testing. Select this for unexplained iron overload (with raised transferrin saturation and/or serum ferritin) suggestive of hereditary haemochromatosis.
  • R96 Iron metabolism disorders – not common HFE variants: This is a gene panel test covering a small number of genes that are known to be associated with other disorders of iron metabolism. Select this where iron overload (with raised transferrin saturation and/or serum ferritin) or features of other disorders of iron metabolism associated with common HFE variants have been excluded or are unlikely.
• For tests such as R95 and R96, which do not include whole genome sequencing, you can use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• The majority of tests are DNA-based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube).
• 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

References:

• Bacon B, Adams P, Kowdley K and others. ‘Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases‘. Hepatology 2011: volume 54, issue 1, pages 328–343. DOI: 10.1002/hep.24330
• Fitzsimons EJ, Cullis JO, Thomas DW and others. ‘Diagnosis and therapy of genetic haemochromatosis (review and 2017 update)‘. British Journal of Haematology 2018: volume 181, issue 3, pages 293–303. DOI: 10.1111/bjh.15164
• Zoller H, Schaefer B, Vanclooster A and others. ‘European Association for the Study of the Liver (EASL) Clinical Practice Guidelines on haemochromatosis‘. Journal of Hepatology 2022: volume 77, issue 2, pages 479–502. DOI: 10.1016/j.jhep.2022.03.033

For patients

• British Heart Foundation: Haemochromatosis
• British Liver Trust: Haemochromatosis
• Diabetes UK: Haemochromatosis and diabetes
• Haemochromatosis UK
• NHS A to Z: Haemochromatosis