Hereditary Hemochromatosis (HH) can be caused by mutations in different genes. Mutations in the HFE gene are the most common cause of adult onset iron overload^1,2. This GECKO Messenger deals EXCLUSIVELY with HFE-associated HH.

Mutations in the HFE gene alter the regulation of iron absorption through the mucosal lining of the gastrointestinal tract. In some predisposed individuals, excessive iron absorption and subsequent storage in various organs (Table 1) eventually lead to cellular injury. If untreated, over time this can cause irreversible damage and shorten life expectancy. With early identification of at-risk individuals, proper surveillance of iron indices, and treatment when necessary, all complications can be avoided.

Table 1. Organs at risk of damage due to excessive iron storage³.

While any of these health concerns can be caused by HH, the presence of two or more should greatly increase suspicion that the condition is present.

What do I need to know about the genetics of HH?

Inherited HH is most commonly caused by mutations in the HFE gene on chromosome 6. Standard testing by North American molecular genetics laboratories is targeted mutation analysis to look specifically for the two most common HFE mutations, C282Y and H63D. These mutations account for over 90% of HH³. Some, but not all, laboratories also test for a rare HFE gene mutation, S65C, which predisposes to iron overload when combined with C282Y similarly to H63D⁴.

Pattern of inheritance

Autosomal recessive

• An individual who has inherited two mutations in the HFE gene, one from each parent, has the predisposition to develop iron overload.
• A person with a single mutation is called a ‘carrier’ and is not at risk of iron overload.

How common is HFE-HH?

About 1 in 3 individuals of northern European ancestry are carriers (heterozygotes) of the C282Y or H63D HFE gene mutations³. About 1 in 260 individuals have two copies of (are homozygous for) the C282Y HFE gene mutation (genotype C282Y/C282Y)². The prevalence of HFE-HH in other ethnicities is lower.

Genetic Testing should be offered^1,2,3:

To adults with biochemical evidence of iron overload (>45% transferrin saturation (TS) and >300µg/L serum ferritin (SF) in men and post-menopausal women or >200µg/L SF in pre-menopausal women)
If your adult patient has a first-degree relative (sibling, parent or child) with one of the following genetic test results:

• C282Y/C282Y (homozygote)
• C282Y/H63D (compound heterozygote)
• C282Y/S65C (compound heterozygote)
• C282Y heterozygote (carrier)

If your patient has unexplained chronic liver disease and increased transferrin saturation (TS)

Individuals with HFE-HH occasionally demonstrate a normal TS and an elevated ferritin. If clinical suspicion is high and/or the patient has a family history of HFE-HH, genetic testing is still warranted

Who should not be offered genetic testing?

Children do not require genetic testing for HFE-HH. [Please refer to the Canadian Pediatric Society and the Canadian College of Medical Geneticists published guidelines relating to the question of genetic testing of healthy children. For conditions that will not present until adulthood (susceptibility or predictive testing) and where there is no benefit to the child, testing should be deferred until the child is competent to understand the purpose of the test and make an autonomous decision.]

General population screening for HFE-HH is not recommended as the disease penetrance is low^1,2.

Who should be offered Biochemical testing for iron overload?

If your patient has suggestive symptoms, physical findings or a family history of HH, transferrin saturation and serum ferritin are ideally ordered together to determine the likelihood of iron overload.

Transferrin saturation (TS)

TS is a reliable screen for iron overload and does not vary with age or the presence of clinical findings. A fasting TS of greater than 45% is considered a sensitive but not specific threshold for identifying individuals who may have iron overload. TS should be performed on a fasting sample as the result can be falsely elevated if a patient has not been fasting.

Serum ferritin (SF)

Normal ranges for SF vary with gender and age and vary slightly from lab to lab. In combination with persistent elevation of fasting TS, ferritin levels of greater than 300mg/ml in men or post-menopausal women and greater than 200mg/mL in pre-menopausal women are suspicious for iron overload.

Remember that SF is an acute phase reactant that can be elevated by other inflammatory processes. Therefore an elevated SF does not necessarily imply iron overload and is not a reliable first or only screen.

The actual risk to develop iron overload is dependent on how many and which gene mutations have been inherited, in addition to other genetic and non-genetic factors.

Click to see what your patient’s genetic test result means:

Patient has two HFE gene mutations

Patient has one HFE gene mutation

Patient has no HFE gene mutation

Other considerations:

Women are less likely to develop iron overload as a result of menstruation and pregnancy^1,2,3
Iron overload due to HFE mutations does not occur in childhood^1,2,3
Typically, symptoms of HH present in men aged 40 to 60 and in post-menopausal women; however, onset is variable and can occur much earlier or much later³
Early symptoms are nonspecific and include weakness, lethargy, joint pain and/or stiffness, and abdominal pain with or without hepatomegaly³
Before the onset of symptoms, biochemical evidence of iron overload will be present: >45% transferrin saturation (TS) and >300mµ/L serum ferritin (SF) in men and post-menopausal women, or >200mµ/L SF in pre-menopausal women ^1,2,3
Alcohol consumption can exacerbate iron overload and HH- related liver disease³

Genetic testing is performed on a blood sample. Click here to find your closest molecular genetics laboratory and the requisition to order testing. These laboratories prefer that you attach their requisition to the Ministry of Health requisition but you can use the MOH requisition alone if necessary.

It is important to include the following information on any requisition for the best test interpretation:

Indication for testing e.g. ‘symptoms of indicated disease’ or ‘abnormal iron indices’ or ‘positive family history’
Ethnicity e.g. Northern European
Relevant family history e.g. parent/sibling with HH (include genetic test results of affected individual if known)
Relevant medical history/investigations; e.g. biochemical iron overload

Click here to find your local genetics clinic.

You might refer to genetics if your patient has had a positive genetic test result and would like genetic counselling to discuss the implications for self and family.

Note that genetics clinics vary with regard to the referrals they choose to accept. You may want to contact your local centre for more information.

Include all relevant information on your referral (e.g. family history, genetic test results, and investigations like iron indices) to prevent unnecessary delays due to further clarification needed before an appointment can be booked.

If mutations are identified

• Appropriate Surveillance and Management of the risk of iron overload can be initiated

If no mutations are identified

• If your patient was tested because of a known family mutation, he/she no longer needs frequent monitoring of iron indices and is not at increased risk to develop iron overload. The test has ruled out HH.
• If your patient was tested because of a reported positive family history, more information is needed before ruling out HH in this individual. Your patient should be encouraged to obtain confirmation of the familial mutations and/or diagnosis.
• If your patient was tested because of persistently high iron indices, additional investigations should be considered

Limitation: Targeted mutation analysis

• Not every HFE gene mutation is looked for, however, the most common mutations account for more than 90% of all mutations, thus fewer than 10% will be missed using current testing strategies.

Potential harm: Insurance discrimination

• Genetic testing in an asymptomatic individual may challenge his/her ability to obtain life, disability, critical illness, long-term care and/or extended health insurance. However, while this is true of all genetic diseases, HH is a treatable condition and some insurance companies will not deny coverage to a treated individual.

Care map for surveillance and management of your patient identified to have two HFE gene mutations. (Adapted from [2])

Treatment is usually initiated and monitored by a specialist (e.g. haematologist or gastroenterologist). Therapeutic phlebotomy, which is safe and effective, is the mainstay of treatment for iron overload. Treatment is usually indicated in the presence of biochemical evidence of iron overload, symptoms (Table 1 in What is HH?), end-organ damage, and/or a SF of 1000 mµ/L or greater.^1,2,3

Iron, cast-iron cooking utensils and vitamin C supplements should not be used by those at risk for, and those with, iron overload. Raw and undercooked shellfish should be avoided because they may carry bacteria that thrive on iron. Dietary iron modification does not significantly alter SF levels and is not a substitute treatment for individuals with iron overload.^1,2,3

Individuals with two HFE gene mutations should consider the hepatitis A&B vaccines³.

[1] Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases. 2011. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 54:328–43

[2] European Association for the Study of the Liver. 2010. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 53:3–22

[3] GeneReviews. HFE-Associated Hemochromatosis. http://www.ncbi.nlm.nih.gov/books/NBK1440/ Updated April 19^th, 2012 [Accessed February 2013]
Expert-authored, peer-reviewed, current disease descriptions that apply genetic testing to the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions.

[4] Wallace DF, Walker AP, Pietrangelo A, Clare M, Bomford AB, Dixon JL, Powell LW, Subramaniam VN, Dooley JS. 2002. Frequency of the S65C mutation of HFE and iron overload in 309 subjects heterozygous for C282Y. J Hepatol. 36(4):474-9.

Gene Messenger. November 2010. HFE-related Hereditary Hemochromatosis http://www.cfp.ca/content/suppl/2009/01/13/55.1.53.DC1/Hemochromatosis_ud.pdf Collection of short reviews on genetics topics designed by a team family physicians, genetic counsellors and geneticists.

Moore AM, Richer J, Canadian Paediatric Society Bioethics Committee. Genetic testing and screening in children. Paediatr Child Health. 2022 Jul 18;27(4):243-253. PMID: 35859682; https://cps.ca/en/documents/position/genetic-testing

Canadian Hemochromatosis Society. Established to create awareness about the disorder. Additionally provides information and support. www.cdnhemochromatosis.ca [Accessed October 2012].