Haemochromatosis: genetic iron overload disease

Haemochromatosis: genetic iron overload disease

Summary for patients

C282Y homozygotes

You have two copies of the HFE C282Y genetic variant.

Based on your genotype, you have higher risk of haemochromatosis than the general population.

* Estimates are from our community sample of UK Biobank European descent individuals [1]. People tested because of a health problem or with high iron levels may have different risk. See below Technical Details section for more information, and the Risk Modifiers page. Page updated 12th February 2024.

Males

Males are known to have higher risk of iron overload disease compared to females.

Haemochromatosis – We estimated that 56.4% of UK Biobank males with two copies of HFE C282Y would be diagnosed with haemochromatosis by age 80, compared to 0.2% of individuals with no faulty HFE genes.

56.4 in 100 diagnoses of haemochromatosis by age 80 in C282Y homozygous males vs. 0.2 in 100 in the general population [1].

Mortality – We estimated that 33.1% of UK Biobank males with two copies of HFE C282Y would die by age 80, compared to 25.4% of individuals with no faulty HFE genes.

33.1 in 100 deaths by age 80 in C282Y homozygous males vs. 25.4 in 100 in the general population [1].

Liver cancer – Male C282Y homozygotes were more likely to be diagnosed with liver cancer by age 80 than men without faulty HFE variants (5.5% vs. 0.8%).

Liver disease – 20.3% of male C282Y homozygotes were diagnosed with liver disease (non-cancer related) by age 80, compared to only 8.3% of men without either HFE variants.

Females

Haemochromatosis – We estimated that 40.5% of UK Biobank females with two copies of HFE C282Y would be diagnosed with haemochromatosis by age 80, compared to 0.1% of individuals with no faulty HFE genes

40.5 in 100 diagnoses of haemochromatosis by age 80 in C282Y homozygous females vs. 0.1 in 100 in the general population [1].

Liver disease – 8.9% of female C282Y homozygotes were diagnosed with liver disease (non-cancer related) by age 80, compared to only 6.8% of women without either HFE variants.

Risk of disease/mortality – In our study of mortality and disease risk to age 80 in UK Biobank, females with two copies of the HFE  C282Y gene variant did not have increased risk of death or liver cancer.

What should I do?

The UK NHS website for haemochromatosis (link) says to speak to your GP about getting a test if:

  • you have persistent symptoms of haemochromatosis – these symptoms can have a number of causes, and the GP may want to rule out some of these before arranging a blood test
  • a parent or sibling has been diagnosed with haemochromatosis – even if you do not have any symptoms, you may be at risk of developing the condition

Because you have two copies of HFE C282Y you are at higher risk of haemochromatosis than the general population, and should therefore consider talking to your GP even if you do not currently have symptoms.

Technical details

1. See below effect estimates for disease and mortality for male and female C282Y homozygotes:

  • Male C282Y homozygotes
    • All-cause mortality: Hazard ratio (HR)1.29 (95% CI 1.12-1.48) p=4.70*10-04
    • Liver cancer: HR 7.90 (95% CI 5.46-11.43) p=5.50*10-28
    • Liver disease (any): HR 2.56 (95% CI 2.10-3.12) p=8.70*10-21
  • Female C282Y homozygotes
    • All-cause mortality: HR 1.10 (95% CI 0.92-1.31) p=0.28
    • Liver cancer: HR 1.17 (95% CI 0.37-3.66) p=0.79
    • Liver disease (any): HR 1.62 (95% CI 1.27-2.05) p=7.80*10-05

2. Genetic differences among different populations can influence the risk of disease prevalence and rates of mortality. Therefore, the generalisability of our study findings may be limited to individuals of European descent.

3. Early follow-up years are liable to be impacted by healthy volunteer bias in the UK Biobank. However, the present study’s findings reported incident outcomes with sufficient follow-up time (median of 13.3 years), thus, limiting the influence of a healthy volunteer bias.

4. The current study does not take into account other genotypes that are known to influence iron metabolism. Therefore, the potential implication of such modifiable effects on iron could have affected any associated risks of disease or mortality. However, further research is required to determine the extent of such effects.

5. We determined C282Y genotype status through whole exome sequencing.

6. Although our study had an adequate duration of follow-up, the incidences of our studied health outcomes were limited, thus, affecting the statistical power of our reporting capabilities. For example, we observed <5 liver cancer diagnoses among female individuals with the C282Y homozygous genotype.

Images showing predicted diagnoses of outcomes from age 40 to 80 years:

Males

Over time, until the age of 80, there will be more deaths in male C282Y homozygotes compared to the general population [1]
Over time, until the age of 80, there will be more cases of liver cancer in male C282Y homozygotes compared to the general population [1]
Over time, until the age of 80, there will be more cases of liver disease in male C282Y homozygotes compared to the general population [1]

Females

Over time, until the age of 80, there will be more case of liver disease in female C282Y homozygotes compared to the general population [1]

References

[1] Mitchell R Lucas, Janice L Atkins, Luke C Pilling, Jeremy D Shearman, David Melzer. HFE genotypes, haemochromatosis diagnosis and clinical outcomes at age 80: a prospective cohort study in the UK Biobank. BMJ Open. 2024; doi:10.1136/bmjopen-2023-081926

[2] UK NHS Haemochromatosis overview – https://www.nhs.uk/conditions/haemochromatosis/