Haemochromatosis is iron overload of the liver, pancreas, heart, joints and other organs, impairing their structure and function.
Hereditary Haemochromatosis is a common inherited disorder characterised by the genetic predisposition to absorb excess dietary iron. In Northern Europe, 95% of patients with HHC will have mutations in the HFE gene.
Secondary iron overload is seen in a variety of conditions including alcoholic liver disease, cirrhosis from any cause, haemolytic anaemia, and transfusional/parenteral iron overload.
Genetics
In Northern Europe, 10% of people are carriers of one of the two significant mutations: C282Y and H63D, with 1 in 200 being homozygous (having two copies) for the C282Y mutation.
Clinical signs of iron overload can be seen in C282Y homozygosity, or when there is one copy of each of the mutations C282Y and H63D (so called compound heterozygotes). C282Y heterozygosity and H63D homozygosity do not lead to clinically significant iron overload.
Not everyone who inherits two mutations will develop iron overload, and even fewer will develop the clinical syndrome.
Testing
Transferrin Saturation (TS) and Ferritin
If these biochemical results suggest possible haemochromatosis then genetic testing is appropriate.
How to test
- 2 to 4ml 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.
By completing the form, this indicates that patients have consented to testing, and DNA being stored by the testing laboratory.
Who to test
- People with biochemical features suggestive of haemochromatosis. Please give clinical details on sample referral form.
- First degree adult relatives (parents, siblings and children) of an affected person or C282Y carrier. Testing of more distant healthy relatives is not generally recommended.
- Haemochromatosis 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
Results
Results are usually available within 4 weeks and will be returned to referrer given on the request.
Interpretation of results and management
| Result | Interpretation and Management |
|---|---|
| C282Y Homozygous | Interpretation: Patient has 2 copies of the C282Y variant. At risk of iron overload. Management: In men: SF>300µg/l, TS >50%, in women: >200µg/l, TS >40%. Refer to secondary care (gastroenterology) for management and treatment. If asymptomatic SF and TS checked annually. Patient could consider blood donation. Dietary advice to limit iron intake may offer some benefit. |
| C282Y Carrier (also known as C282Y heterozygote) | Interpretation: Patient carries a single copy of C282Y variant. Carriers do not usually iron load. Management: No further follow up required. If symptomatic, consider other causes of Haemochromatosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment/consideration of other rarer genetic causes. |
| C282Y/H63D Compound Heterozygous | Interpretation: Patient carries a single C282Y variant, and a single H63D variant. Management: Most patients with this genotype do not have iron overload. However, 3 yearly checks of TS and ferritin are recommended. If symptomatic consider other causes of Hemochromatosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment/consideration of other rarer genetic causes |
| H63D Homozygous | Interpretation: Patient has 2 copies of the milder H63D variant. Most people with this genotype never develop symptoms of iron overload. Management: No further follow up or monitoring required. If symptomatic consider other causes of Haemochromatosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment. Secondary care may also consider other rarer genetic causes. Relatives: Both biological parents and any children will all be obligate carriers of the milder H63D variant. H63D is a milder variant and very rarely causes patients to iron overload even when they have 2 copies of the variant (homozygous). Therefore, no testing is recommended for any relatives in the absence of any symptoms. |
| H63D Carrier | Interpretation: Patient has a single copy of the H63D variant. Carriers of H63D are at a very low risk of iron overload. Management: No further follow up or monitoring required. If symptomatic consider other causes of Haemochromatosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment. Secondary care may also consider other rarer genetic causes. Relatives: At least one biological parent will be a carrier of the milder variant H63D. Siblings and children are at 50% risk of also being a carrier of the H63D variant. As this is a mild variant, in the absence of symptoms no testing is recommended. |
| Not a carrier (C282Y not present) | Interpretation: Patient does not carry either of the most common variants for Haemochromatosis. Management: No further follow up or monitoring required If symptomatic consider other causes of Haemochromatosis e.g. obesity and alcohol intake. Refer to secondary care for management/treatment/consideration of other rarer genetic causes |
gastroenterology.
