HFE-Associated Hereditary Hemochromatosis Investigations and Management

BC Guidelines Logo

Effective Date: April 15, 2013

Recommendations and Topics


This guideline provides recommendations for the biochemical investigation, genetic testing and management of HFE* associated hereditary hemochromatosis (HFE-HH) in adults aged > 19 years. The objectives are the early identification and management of individuals at risk for iron overload caused by HFE-HH.

*The HFE gene encodes the hereditary hemochromatosis protein. HFE-HH refers to HFE-associated hereditary hemochromatosis. For this guideline the condition will be referred to as hemochromatosis.


Key Recommendations and Updates

  • Screening the general population is not recommended.
  • Testing non-Caucasians for HFE-HH is not recommended.
  • Ferritin, rather than transferrin saturation, is measured as the initial marker of hemochromatosis and to determine if further testing is warranted.1
  • Revision of criteria for genetic testing of first-degree family members of individuals with HFE-HH.
  • Discontinuation of testing for the H63D variant in HFE.



Differential Diagnosis
Iron overload occurs when iron absorption exceeds physiological requirements or when iron derived from repeated blood transfusions or excessive ingestion overflows normal body iron stores. Excess iron is deposited in the organs, leading to parenchymal damage and organ dysfunction. Iron overload may result from either inherited or acquired disorders.

The common form of hereditary hemochromatosis is due to a (C282Y) mutation in a gene called HFE - a mutation which occurs predominantly in Caucasians, and leads to excessive absorption of dietary iron. HFE-associated hereditary hemochromatosis (HFE-HH) is an autosomal recessive disorder and therefore, both alleles of HFE must be abnormal for risk to occur (1 in 230 in Caucasians is homozygous for the C282Y mutation).23 Notably, however, fewer than 10% of C282Y homozygotes develop clinical manifestations.1

There are other rare genetic conditions leading to iron overload for which genetic testing is not available. For example, Asians with elevated ferritin are very unlikely to have HFE-HH4 and a number of mutations in other iron related genes have been identified in this population.5 These rare disorders are outside the scope of this guideline; suspected cases should be referred to a specialist.

Acquired (Outside the scope of this guideline)

  • transfusion dependent anemias
  • anemia from ineffective erythropoiesis
  • various liver diseases
  • excessive ingestion of medicinal iron


Signs and Symptoms

Because hemochromatosis can lead to gradual damage in a number of organs over many years, its symptoms can be confused with those of much more common diseases, such as alcoholic liver disease, diabetes, and osteoarthritis. If untreated, hemochromatosis can cause serious disease and premature death. Pre-symptomatic detection and treatment can completely prevent clinical sequelae and, in symptomatic patients, phlebotomy effectively reduces morbidity and mortality.23

Table 1: Consequences of Iron Storage by Organ

Iron Storage



Enlargement, progressing to cirrhosis and predisposing to hepatocellular carcinoma


Congestive heart failure and/or arrhythmia due to cardiomyopathy


Diabetes - difficult to control type 2


Increased skin pigmentation; association with porphyria cutanea tarda


Hair loss


Arthritis, classically involvement of MCP and proximal IP joints of thumb, index and middle fingers; chondrocalcinosis


Hypogonadism and hypothyroidism



Most patients with hemochromatosis develop only one or a few of the above problems, with liver involvement and enlargement being the most common, occurring in most affected patients. Patients are often not diagnosed until aged > 40 years in males and even later in females. However, nonspecific symptoms such as arthralgias, fatigue, and abdominal pain may be noted years before organ dysfunction becomes apparent.

Significant end-organ damage is rare with a ferritin value < 600 µg/L. The routine complete blood count (CBC) is normal in hereditary hemochromatosis.



HFE-HH is diagnosed upon demonstration of increased iron stores (with or without clinical symptoms) and C282Y homozygosity.

Whom to Test

  1. Individuals of Caucasian ethnicity with signs and symptoms that might be caused by iron overload. These include:
    • enlarged liver, unexplained persistent elevation of liver enzymes, cirrhosis
    • arthritis (including premature osteoarthritis and classic arthropathy of thumb, index and middle fingers)
    • unexplained congestive heart failure or cardiomyopathy
    • adult-onset, brittle diabetes
    • hypogonadism
    • increased skin pigmentation

Test to Order: Ferritin (hemochromatosis)
Serum ferritin reflects total body iron stores, and a serum ferritin ≥ 600 µg/L provides a sensitive indicator of patients at risk for clinical manifestations of hemochromatosis1 warranting follow-up genetic testing. Ferritin levels that are elevated but < 600 µg/L are less specific due to ferritin fluctuation as an acute-phase reactant.† In these cases genetic testing will proceed only when the transferrin saturation is also elevated. Transferrin saturation alone lacks both sensitivity and specificity as an indicator of hemochromatosis.8

  1. Individuals of Caucasian ethnicity with persistently elevated serum ferritin discovered incidentally and notsecondary to underlying systemic disease (e.g., chronic alcohol abuse, infection, autoimmunity, malignancy).

Test to Order: Ferritin (hemochromatosis)
For example, an elevated ferritin may be noted as part of an investigation for possible iron deficiency. Such elevations in ferritin should be followed up as patients with hemochromatosis may initially present with non-specific symptoms and upon confirmation of diagnosis would be eligible for therapy.

  1. Parents, siblings, and adult children of individuals with confirmed genetic diagnosis of HFE-HH (i.e., C282Y/C282Y homozygotes).
    • Parents: the results of the serum iron tests(s) determine the need for the HFE genetic testing (see Appendix A - Figure 2: Laboratory Testing Algorithm [PDF, 206KB]).
    • Siblings and adult children (≥ 19 years): testing for HFE C282Y mutation will proceed in all cases; if C282Y/C282Y homozygote, measure serum ferritin; treat and/or follow as indicated, based on ferritin results.

Test to Order: Ferritin (hemochromatosis). Provide family history on requisition and genetic testing may proceed according to protocol.
Individuals that have previously been treated for hemochromatosis should be offered genetic testing if not already performed. When ordering, indicate that the patient has previously been treated for hemochromatosis.

† Ferritin is both a maker of intracellular iron stores and an acute phase reactant. Aside from HFE-HH, some common causes of elevated ferritin include inflammation, liver disease, dysmetabolic hyperferritemia9, transfusional iron overload, and non-HFE related genetic iron overload. Serum ferritin values may vary between laboratories and with patient age and gender. Refer to the normal reference interval provided by your local laboratory.

Whom Not to Test
Screening the general population is not recommended. Testing non-Caucasians for HFE-HH is not recommended as the mutation is rare to non-existent in the non-Caucasian population. Non-Caucasian patients with evidence of iron overload should be referred to a specialist

Genetic Testing
Genetic testing is currently only offered through the Molecular Genetics Laboratory (MGL) at the Children's and Women Health Centre of BC.

Genetic testing should not be offered to:

  • children ≤ 19 years of age**
  • non-Caucasians
  • first-degree relatives†† of individuals identified to be heterozygous (carriers) for C282Y
  • first-degree relatives of individuals previously identified to be compound heterozygotes for C282Y/H63D or to have only the H63D variant

Genetic testing of samples to confirm HFE-HH can be done in one of two ways:

  1. The provincial standard laboratory requisition form (found on the physician secure section of the Doctors of BC website, at www.doctorsofbc.ca/)
    1. Select HFE hemochromatosis testing within the Hematology section (see Appendix A [PDF, 206KB] for the testing algorithm followed by laboratories.)
  2. The laboratory requisition from the Molecular Genetics Laboratory (www.genebc.ca)
    1. Provide reason for testing (check boxes, mid-left side of page) as in Figure 1.

**As HFE-HH is an adult-onset disorder, genetic testing is not generally indicated in children < 19 years of age. Genetic testing for adult-onset disorders should only be requested when an individual can, themselves, provide informed consent.
††First-degree relatives: parents, siblings and children.

Figure 1: Hemochromatosis Test Ordering with MGL Requisition

Note: Requests for ferritin and/or transferrin saturation do NOT constitute requests for HFE-HH testing.

Patients in whom iron overload is confirmed in the absence of C282Y/C282Y homozygosity should be referred to a specialist.



Management and Surveillance of Hemochromatosis
Therapeutic phlebotomy is the treatment of choice for hemochromatosis and for other primary iron overload disorders. Possible exceptions include those who are already anemic, or have limited life expectancy due to other diseases or those with congestive heart failure with hemodynamic instability.

Prior to initiating a phlebotomy program, the patient should be thoroughly assessed for possible end organ damage (e.g., arthritis, liver dysfunction, diabetes, heart disease). Patients with ferritin > 1000 µg/L should have liver function tests because of the increased risk of cirrhosis and hepatoma.1011

Phlebotomy technique is important for maintaining venous access. Refer to Appendix B - Therapeutic Phlebotomy Using an 18 Gauge Cannula (PDF, 206KB).

Volume and frequency of phlebotomy need to be individualized according to the patient's age and clinical and biochemical presentation. For severely iron overloaded patients, weekly phlebotomy of 500 ml of whole blood should be continued until serum ferritin is < 50 µg/L. Patients with massive iron overload may require in excess of 100 phlebotomies.

Serum ferritin and hemoglobin should be monitored regularly (e.g., every 4th phlebotomy) to assess response to therapy. It is unusual for iron overloaded patients to develop anemia early in the course of phlebotomy therapy. If this occurs, the frequency of phlebotomy needs to be reduced.

Once patients have been successfully depleted of excess iron stores (ferritin < 50 µg/L), a program of monitoring and maintenance should be established. The need for maintenance phlebotomy is quite variable; some patients require phlebotomy every 2-4 months to maintain a low-normal ferritin, and some may not re-accumulate for many years.

At minimum, the CBC and ferritin should be checked every 12 months, and phlebotomy should be re-initiated if the ferritin is rising toward the upper limit of normal.

End organ damage should be reassessed periodically. If liver enzymes have been abnormal, they often improve once iron stores have been depleted. There may also be improvement in iron-induced cardiac dysfunction. Diabetic patients often note improvement in blood sugars with less dependency on insulin or oral hypoglycemic agents. Conditions that often do not improve with phlebotomy include arthropathy, cirrhosis and testicular atrophy.


  • Phlebotomy results in formation of new red cells; therefore HbA1c may underestimate glycemia for up to three months after phlebotomy.
  • Although iron can be pharmacologically removed using chelating agents such as deferasirox and desferrioxamine, these are reserved for patients who are unable to tolerate phlebotomy (i.e., patients with chronic anemia due to thalassemia major, myelodysplastic syndromes, etc.). Phlebotomy is safe and cost-effective and thus the preferred modality of iron removal for patients able to tolerate it.
  • Strict avoidance of dietary iron is not necessary but iron and vitamin C12 supplements may need to be avoided. Patients with liver damage should limit or not drink alcohol.13
  • Patients on maintenance therapy may be eligible to donate to the Canadian Blood Services.




  1. Waalen J, Felitti VJ, Gelbart T, et al. Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood 2008;111:3373-3376.
  2. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352:1769-1778.
  3. Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:328-343.
  4. Yenson PR, Yoshida EM, Li CH, et al. Hyperferritinemia in the Chinese and Asian community: A retrospective review of the University of British Columbia experience. Can J Gastroenterol. 2008;22:37-40.
  5. Lok CY, Merryweather-Clarke AT, Viprakasit V, et al. Iron overload in the Asian community. Blood 2009;114:20-5.
  6. Cook L. Therapeutic phlebotomy - A review of diagnoses and treatment considerations. J Infus Nurs. 2010;33:81-88.
  7. Adams PC, Barton JC. How I treat hemochromatosis. Blood 2010;116:317-325.
  8. Adams PC, Reboussin DM, Press RD, et al. Biological variability of transferrin saturation and unsaturated iron-binding capacity. Am J Med. 2007;120:999.e1-7.
  9. Chen LY, Chang SD, Sreenivasan GM, et al. Dysmetabolic hyperferritinemia is associated with normal transferrin saturation, mild hepatic iron overload, and elevated hepcidin. Ann Hematol. 2011;90:139-43.
  10. Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous Hemochromatosis. Gastroenterology 1998;115:929-936.
  11. Barton JC, Barton JC, Acton RT, et al. Increased risk of death from iron overload among 422 treated probands with HFEhemochromatosis and serum levels of ferritin greater than 1000 µg/L at diagnosis. Clin Gastroenterol Hepatol. 2012;10:412-6.
  12. Herbert V. Hemochromatosis and vitamin C. Ann Intern Med. 1999;131:475-476.
  13. Fletcher LM, Dixon JL, Purdie DM, et al. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology 2002;122:281-289.

Diagnostic Codes
257.0 Disorders of iron metabolism
275.01 Hereditary hemochromatosis
275.02 Hemochromatosis due to repeated red blood cell transfusions
275.03 Other hemochromatosis
275.09 Other disorders of iron metabolism


  • Molecular Genetics Laboratory BC www.genebc.ca
  • Canadian Hemochromatosis Society: www.toomuchiron.ca/, Toll-Free (Canada): 1 877 BAD-IRON (1 877 223-4766)
  • HealthLink BC Dietician Services: www.healthlinkbc.ca, Dial 811 or TTY (deaf and hearing-impaired) call 711


Appendix A - HFE-Associated Hemochromatosis Laboratory Testing Algorithm (PDF, 206KB)

Appendix B - Therapeutic Phlebotomy Using an 18 Gauge Cannula (PDF, 206KB)

Associated Documents

The following document accompanies this guideline:

This guideline is based on scientific evidence current as of the Effective Date.

This guideline was developed by the Guidelines and Protocols Advisory Committee, approved by the British Columbia Medical Association, and adopted by the Medical Services Commission.


The principles of the Guidelines and Protocols Advisory Committee are to:

  • encourage appropriate responses to common medical situations
  • recommend actions that are sufficient and efficient, neither excessive nor deficient
  • permit exceptions when justified by clinical circumstances.
Contact Information
Guidelines and Protocols Advisory Committee
Victoria BC V8W 9P1
E-mail: hlth.guidelines@gov.bc.ca
Web site:
Clinical Practice Guidelines


Disclaimer The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problems.  We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.