Genomics in general practice


Hereditary haemochromatosis
☰ Table of contents


Practice point


Hereditary haemochromatosis (HHC) is a common condition that affects an estimated one in 250 individuals of northern European backgrounds. Genetic testing for HHC should be performed in patients with proven iron overload. Cascade screening of relatives is also important when specific gene variants causing HHC are confirmed in the family.1

Screening for HHC in the general population is currently not recommended given its variable expressivity and incomplete penetrance.2,3



What do I need to know?


HHC is a condition with an autosomal recessive inheritance pattern where excessive iron absorption leads to increased blood iron stores. HHC is underdiagnosed as the symptoms are usually non-specific; however, early diagnosis and treatment reduces serious complications and possible early death.

The most common genetic cause of HHC (up to 90%) is homozygosity of the C282Y gene variant in the HFE gene (HFE-haemochromatosis). About one in 10 people are carriers of a C282Y variant, while one in every 200 carriers is homozygous for the C282Y variant. Another common variant in the HFE gene is H63D. Not all individuals with a genetic predisposition to HHC will develop iron overload (incomplete penetrance).2

The risk of iron overload varies according to genotype (Table 1).3–5

 

Table 1. Varying genotypes and risk of iron overload

Genotype

Risk of iron overload with genotype

Frequency of genotype*

Heterozygous C282Y

No increased risk

1 in 10

Homozygous C282Y

Greatly increased risk – 40–60% for females and 75–100% for males

1 in 200

Heterozygous H63D

No increased risk

1 in 4

Homozygous H63D

No increased risk

1 in 50

Compound heterozygous C282Y/H63D

Small increase in risk – 1%

1 in 50

*Frequency data are approximate for those of northern European ancestry and ethnicity.

 


Genetic testing


Genetic testing for the risk of HHC is recommended in individuals with suspected iron overload (ie elevated serum ferritin concentration >200 µg/L [(females)] or >300 µg/L [(males)], and a transferrin saturation >45% will identify almost all patients with HFE-haemochromatosis).2,6–8

Cascade screening is warranted for all first-degree relatives of patients with HHC who are C282Y homozygous or C282Y/H63D compound heterozygous.
A Medicare Benefits Schedule (MBS) rebate for the HFE gene test applies where the patient has an elevated transferrin saturation or elevated serum ferritin on repeat testing or a first-degree relative with haemochromatosis or is homozygous for the C282Y gene variant or a compound heterozygote.9
 

Other considerations


Asymptomatic individuals (identified through cascade screening) who are C282Y homozygous or C282Y/H63D compound heterozygous should have their serum ferritin regularly monitored.2,6

Patients with HFE-haemochromatosis should be encouraged to:8

  • inform all first-degree relatives of increased risk
  • direct family to information about haemochromatosis (eg Haemochromatosis Australia)
  • advise family members to discuss their risk with their general practitioner (GP).


Resource for general practitioners


Seckington R, Powell L. HFE-associated hereditary haemochromatosis. GeneReviews. Seattle, WA: University of Washington, 2000


Resources for patients


Information

Centre for Genetics Education, Fact sheet 47: Hereditary haemochromatosis

National Library of Medicine (US), Hereditary hemochromatosis

Support

Haemochromatosis Australia

 


Genomics in general practice




 

 

  1. The Royal Australian College of General Practitioners. Guidelines for preventive activities in general practice. 9th edn. Melbourne: RACGP, 2016.  [Accessed 20 December 2017].
  2. European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010;53(1):3–22.
  3. US Preventive Services Task Force. Screening for hemochromatosis: Recommendation statement. Ann Intern Med 2006;145(3):204–08.
  4. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload–related disease in HFE hereditary hemochromatosis. N Engl J Med 2008;358(3):221–30.
  5. Goot K1, Hazeldine S, Bentley P, Olynyk J, Crawford D. Elevated serum ferritin: What should GPs know? Aust Fam Physician 2012;41(12):945–49.
  6.  Allen K. Hereditary haemochromatosis: Diagnosis and management. Aust Fam Physician 2010;39(12):938.
  7. St John AT, Stuart KA, Crawford DHG. Testing for HFE-related haemochromatosis. Aust Prescr 2011;34(3):73–76.  [Accessed 20 December 2017].
  8. Gastroenterological Society of Australia. Haemochromatosis. 3rd edn. Sydney: Digestive Health Foundation, 2007.
  9. Department of Health. Medicare Benefits Schedule (MBS) Online. Canberra: DoH, 2017. [Accessed 20 December 2017].

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