Hemochromatosis

Hemochromatosis is a disorder of iron regulation in which the body absorbs substantially more dietary iron than it needs, and the excess is progressively deposited in the liver, heart, pancreas, joints, skin, and anterior pituitary gland rather than being safely stored or excreted.^[1] The great majority of cases are hereditary hemochromatosis, caused by mutations in the HFE gene on chromosome 6 — almost always homozygosity for the C282Y variant — which impairs the liver's ability to produce hepcidin, the hormone that normally restrains intestinal iron absorption and iron release from storage cells. With hepcidin deficient, the iron-export channel ferroportin stays abnormally active on both gut enterocytes and iron-recycling macrophages, so more iron is absorbed from every meal and more is released back into circulation than the body actually needs, year after year.^[1]

A separate, distinct etiology worth naming clearly from the outset is secondary (acquired) iron overload — iron accumulation from repeated red blood cell transfusions (as in transfusion-dependent thalassemia, sickle cell disease, or myelodysplastic syndrome), from excessive parenteral or oral iron administration, or occasionally from a chronic liver disease that itself dysregulates iron handling. This is a genuinely different clinical problem: the iron loading is driven by an external source rather than a genetic absorption defect, and — as covered in Choose Initial Treatment — it changes which first-line therapy actually makes sense.^[1]

Hereditary hemochromatosis is genuinely common, and genuinely relevant to Canadian practice. It is one of the most common inherited disorders in people of Northern European ancestry, and Liver Canada (formerly the Canadian Liver Foundation) estimates it affects roughly 1 in 327 Canadians.^[2] Population studies more broadly put the C282Y-homozygous genotype at roughly 1 in 200 to 1 in 400 people of Northern European descent, with some populations — Ireland in particular — estimated even higher.^[3]

The single most important nuance in this chapter, easy to miss and important not to: carrying the C282Y-homozygous genotype is not the same as having clinical disease. Longitudinal cohort data show that only about 38-50% of C282Y homozygotes ever develop an elevated serum ferritin, and only about 10-33% go on to develop clinical hemochromatosis with organ involvement — the remaining 75-90% with biochemical evidence of iron loading stay asymptomatic. Penetrance is also strongly sex-skewed: roughly 28% of male C282Y homozygotes develop clinical disease compared with roughly 1% of female homozygotes, largely because regular menstrual blood loss provides women a natural, ongoing iron-reduction mechanism until menopause.^[1] This is why genetic confirmation alone does not automatically mean a treatment decision — see Assessment & Diagnosis and Treatment Targets.

Because iron accumulates gradually over decades, hereditary hemochromatosis is classically diagnosed in a patient's 40s to 50s, with women typically presenting later than men for the menstrual-blood-loss reason noted above.^[4] Earlier detection through opportunistic iron-panel screening means the florid late-stage picture below is now genuinely uncommon — most patients today are identified while still in the nonspecific or single-organ stage.^[4]

• C282Y homozygosity (two copies of the C282Y HFE variant) — accounts for roughly 80-100% of clinically recognized hereditary hemochromatosis in people of Northern European ancestry, and is the genotype the diagnostic and treatment pathways in this chapter are built around.^[3]
• C282Y/H63D compound heterozygosity — a substantially milder genotype; fewer than about 11% of compound heterozygotes ever develop clinical iron overload, and disease when it occurs is typically driven by an additional cofactor (alcohol use, metabolic dysfunction-associated steatotic liver disease, viral hepatitis) rather than the genotype alone.^[3]
• H63D homozygosity — generally does not cause clinically significant iron overload on its own in people of Northern European ancestry.^[3]
• Rare non-HFE hereditary forms — juvenile hemochromatosis (HJV or HAMP mutations, causing severe iron overload and organ failure typically in the 20s-30s), and mutations in TFR2 or the ferroportin gene (SLC40A1). These are uncommon and generally need genetics/hepatology referral for confirmation once HFE testing is negative despite confirmed iron overload (see Assessment & Diagnosis).^[1]
• Male sex — roughly 28% clinical penetrance in C282Y-homozygous men versus roughly 1% in C282Y-homozygous women, and men are typically diagnosed at a younger age since they lack the menstrual-blood-loss protection women have until menopause.^[1]
• A first-degree relative with confirmed hereditary hemochromatosis — the single strongest reason to test even an asymptomatic person (see Non-Pharmacologic Treatment).^[4]
• Northern European ancestry, particularly Irish, Scottish, English, or Scandinavian.^[3][2]
• Cofactors that increase the likelihood or severity of clinical disease in a genetically susceptible person: significant alcohol use, viral hepatitis, and metabolic dysfunction-associated steatotic liver disease.
• Secondary (acquired) iron overload — a distinct, non-genetic risk pathway: repeated red blood cell transfusions (transfusion-dependent thalassemia, sickle cell disease, myelodysplastic syndrome), excessive medicinal iron intake, or certain chronic liver diseases. This population is managed differently — see Choose Initial Treatment and Special Populations.^[1]

Complications of inadequately treated iron overload

Left undetected or untreated, progressive iron deposition can cause hepatic fibrosis, cirrhosis, and a meaningfully increased risk of hepatocellular carcinoma; dilated or restrictive cardiomyopathy and arrhythmia (particularly atrial fibrillation); diabetes mellitus from pancreatic iron deposition; hypogonadotropic hypogonadism from pituitary iron deposition; a distinctive arthropathy; and an increased susceptibility to certain iron-loving ("siderophilic") bacterial infections — most notably Vibrio vulnificus, but also Yersinia enterocolitica and Listeria monocytogenes — because these organisms grow markedly faster in iron-rich serum (see Non-Pharmacologic Treatment for the specific food-safety counseling this drives).

Step 1 — transferrin saturation and ferritin

Fasting transferrin saturation (TS) is the most sensitive initial screening test and should be checked first; a TS of 45% or higher is the threshold that should prompt further workup.^[5][4] Serum ferritin is checked alongside it — a level above roughly 300 ng/mL in men or 200 ng/mL in women is the commonly used threshold suggesting iron overload — but ferritin is also an acute-phase reactant, so an elevated level in isolation, especially without an elevated TS, should prompt consideration of inflammation, infection, malignancy, or metabolic dysfunction-associated steatotic liver disease as the actual cause before assuming iron overload.^[4]

Step 2 — HFE genetic testing

An elevated TS and/or ferritin should be followed by HFE genetic testing for the C282Y and H63D variants. Population-wide genetic screening of asymptomatic people without an abnormal iron panel or a family history is not recommended.^[4]

^[3][1]

Step 3 — assessing severity: MRI versus liver biopsy

For most patients, MRI-based hepatic iron quantification (R2*/T2*) has replaced liver biopsy as the preferred way to confirm and quantify hepatic iron loading noninvasively.^[5] Liver biopsy is now reserved for a smaller group: patients with a ferritin over roughly 1000 ng/mL, persistently abnormal liver enzymes, or genuine diagnostic uncertainty, where directly assessing the degree of fibrosis or confirming cirrhosis changes management (see Red Flags & Refer and Monitoring & Follow-Up for the hepatocellular carcinoma surveillance this triggers).^[5]

Differential diagnosis

Before attributing an elevated ferritin to hereditary hemochromatosis, consider: secondary iron overload (transfusion history, excess medicinal iron); ferritin elevation from inflammation, infection, or malignancy as an acute-phase reactant, independent of true iron overload; metabolic dysfunction-associated steatotic liver disease, which commonly causes a mildly elevated ferritin without true iron overload; alcohol-related liver disease; and porphyria cutanea tarda, which is associated with HFE mutations and iron overload in its own right. A normal or only mildly elevated TS with a markedly elevated ferritin should raise suspicion for one of these alternative causes rather than hereditary hemochromatosis.

Other investigations to complete the picture

Liver enzymes (baseline and to help decide on biopsy); fasting glucose or HbA1c to screen for pancreatic involvement; an ECG, with echocardiography if there are cardiac symptoms or signs; and, if hypogonadism is suspected clinically, testosterone with LH/FSH.

• Reduce total body iron burden to normal levels — the specific ferritin targets for the induction and maintenance phases of phlebotomy are detailed in Choose Initial Treatment.
• Prevent, or halt further progression of, iron-related organ damage (hepatic, cardiac, endocrine, articular).
• Achieve a normal life expectancy — genuinely achievable for a patient who begins treatment before significant organ damage, particularly before cirrhosis or diabetes develops; this is worth stating explicitly to a newly diagnosed patient, since the diagnosis can otherwise sound far more frightening than the realistic prognosis with timely treatment.^[5]
• Manage any organ complications already present (diabetes, cardiomyopathy, arthropathy, hypogonadism) in parallel with iron reduction — iron already deposited does not reverse quickly, and some of these complications need their own dedicated management regardless of how well iron levels are subsequently controlled.
• For a patient in whom cirrhosis is already established: maintain lifelong hepatocellular carcinoma surveillance, since that risk persists even after iron stores are successfully normalized.^[5]
• Complete first-degree relative cascade testing.
• Counsel on the specific dietary and food-safety measures that meaningfully reduce risk in this condition (see Non-Pharmacologic Treatment).

Induction phase

Remove approximately 450-500 mL of whole blood weekly (twice weekly is sometimes used if well tolerated), adjusting frequency and volume based on tolerance. Check hemoglobin/hematocrit before each session — reduce the frequency or volume if it is dropping too quickly or the patient is symptomatic — and check serum ferritin monthly. Continue until ferritin reaches approximately 50 ng/mL; do not intentionally drive it lower, since that risks iatrogenic iron-deficiency anemia rather than any additional benefit.^[4][5] Full induction commonly takes many months — occasionally over a year — of weekly treatment to reach target, and setting that expectation with the patient up front meaningfully helps adherence.^[6]

Maintenance phase

Once the induction target is reached, reduce frequency to roughly every 2-4 months (about three to four sessions a year), with ferritin rechecked approximately every 6 months, keeping ferritin generally within the 50-100 ng/mL range. Maintenance phlebotomy is lifelong — iron reaccumulates if it stops, so this is not a course of treatment with a defined end date.^[4][5]

Phlebotomy adverse effects

Minor adverse effects — vasovagal reactions, local site bruising/hematoma, or transient fatigue — occur in a meaningful minority of patients and are usually manageable by adjusting volume or session frequency rather than stopping treatment.^[4]

Dietary counseling

• Avoid iron supplements and multivitamins that contain iron — an obvious but easily overlooked source, especially in an over-the-counter multivitamin taken out of habit.^[2]
• Limit vitamin C supplementation — vitamin C significantly enhances nonheme iron absorption and, in high doses, can mobilize tissue iron in a way that carries theoretical cardiotoxic risk in an iron-overloaded patient; a reasonable practical ceiling is under 500 mg per day, and vitamin C-containing supplements are best avoided outright rather than merely reduced.^[4]
• Moderate, rather than eliminate, red meat and other heme-iron-rich foods — heme iron is absorbed considerably more efficiently than the nonheme iron in plant foods, so moderating intake meaningfully helps, even though dietary iron restriction alone is never sufficient treatment on its own.^[4]
• Avoid or substantially limit alcohol — alcohol and iron overload act synergistically on the liver, and alcohol use significantly increases the risk of cirrhosis in a patient with hemochromatosis; this matters even more once any degree of fibrosis is already present.^[4]

Patient education

Hemochromatosis is a manageable, lifelong condition, not a life-limiting one, when treatment starts before significant organ damage — this reassurance is worth giving explicitly at diagnosis. Set the expectation up front that induction-phase phlebotomy is frequent (typically weekly) and can take many months to over a year to reach target, and that maintenance-phase phlebotomy continues indefinitely afterward — an easy point for a patient to misunderstand as a finite course of treatment.^[4] Where the patient meets standard donor-eligibility criteria, mention that maintenance-phase phlebotomy can often be completed as a regular Canadian Blood Services donation rather than a hospital procedure (see Choose Initial Treatment).^[6]

Family cascade screening

Hereditary hemochromatosis is inherited in an autosomal recessive pattern. Every first-degree relative of a confirmed C282Y-homozygous patient should be offered HFE genetic testing — if both parents of an index patient's sibling are carriers, each sibling has a 25% chance of being homozygous, a 50% chance of being a heterozygous carrier, and a 25% chance of inheriting neither variant. Testing does not need to start before adulthood (roughly age 18).^[4][1] Counsel that a relative who tests homozygous still benefits meaningfully from knowing early, given the low but real penetrance and the fact that early detection — well before any symptoms develop — is exactly the scenario in which treatment achieves the best outcome (see Red Flags & Refer).

Pregnancy

Phlebotomy is generally avoided during pregnancy — normal pregnancy already increases iron demand and causes a degree of physiologic anemia, and standard iron-panel interpretation is altered by pregnancy itself. Iron-reduction treatment is typically deferred until postpartum in a patient without severe iron overload, with the treating specialist individualizing management for anyone with more significant disease.

Breastfeeding

No hemochromatosis-specific restriction applies to breastfeeding itself. Chelating agents have limited breastfeeding safety data and should be avoided unless a treating specialist judges the benefit clearly outweighs the uncertainty — phlebotomy, where otherwise appropriate, avoids this question entirely.

Pediatrics

Because iron accumulates gradually over decades, clinical HFE-related hereditary hemochromatosis essentially never presents in childhood. Juvenile hemochromatosis (caused by HJV or HAMP mutations) is a distinct, rare, more aggressive entity that typically causes severe cardiac and endocrine complications in the 20s-30s rather than in childhood itself, and needs pediatric/adult genetics and hepatology referral for confirmation and management rather than the HFE-based pathway in this chapter.^[1]

Older adults

Continue phlebotomy as tolerated; older adults and those with cardiac comorbidity may tolerate large-volume removal less well, so individualize volume and frequency and watch more closely for vasovagal reactions and anemia during induction.

Renal and hepatic impairment

Adjust chelator dosing per the product monograph in renal impairment, particularly for deferasirox, which itself can raise serum creatinine and therefore needs closer renal monitoring in this population. Once cirrhosis is established, hepatocellular carcinoma surveillance is required indefinitely — see Monitoring & Follow-Up — regardless of how effectively iron levels are subsequently controlled.^[5]

Secondary/transfusion-dependent iron overload

This population is managed differently from HFE-related hereditary hemochromatosis from the start: ongoing transfusion dependence for an underlying hematologic condition (transfusion-dependent thalassemia, sickle cell disease, myelodysplastic syndrome) means phlebotomy would worsen the anemia the transfusions are correcting, so chelation therapy is first-line here rather than a fallback reserved for phlebotomy-ineligible patients (see Choose Initial Treatment). Management is typically directed by the treating hematology team managing the underlying transfusion-dependent condition.^[1]

• Induction phase: hemoglobin/hematocrit before each phlebotomy session; serum ferritin monthly, to track progress toward the approximately 50 ng/mL induction target.^[4]
• Maintenance phase: serum ferritin approximately every 6 months, adjusting phlebotomy frequency to keep it generally within the 50-100 ng/mL range; this continues for life.^[4][5]
• Liver enzymes periodically, particularly for any patient who had an elevated ferritin or abnormal LFTs at diagnosis.
• Once cirrhosis is confirmed, hepatocellular carcinoma surveillance (ultrasound, with or without alpha-fetoprotein) approximately every 6 months, indefinitely — this risk does not go away once iron levels normalize, and losing track of ongoing surveillance once a patient feels well on maintenance phlebotomy is a genuine, avoidable error (see Common Errors to Avoid).^[5]
• Periodic fasting glucose/HbA1c screening for pancreatic involvement, and cardiac follow-up (repeat ECG, echocardiography as indicated) for anyone with baseline cardiac involvement or symptoms.
• For a patient on chelation therapy: agent-specific monitoring — for deferiprone, weekly absolute neutrophil count for at least the first 6 months, then a reduced but ongoing frequency; for deferasirox, regular renal function/urinalysis, LFTs, and CBC; for deferoxamine, periodic audiometry and ophthalmologic examination.
• Confirm first-degree relative cascade testing has actually been completed, not just discussed once and left open.

1. Ferritin not declining as expected during induction phlebotomy: first confirm the patient is actually attending sessions as scheduled, then reconsider whether an alternative or additional cause of the elevated ferritin is present — occult inflammation, undiagnosed metabolic dysfunction-associated steatotic liver disease, ongoing significant alcohol use, or an unrecognized secondary iron source — rather than assuming phlebotomy itself has failed.
2. Anemia or intolerance limiting phlebotomy frequency: reduce the volume or frequency of sessions before concluding the patient cannot tolerate phlebotomy at all; refer for chelation therapy only if a genuinely sustainable phlebotomy schedule cannot be found.
3. New or worsening cardiac, endocrine, or hepatic complications despite adequate iron reduction: co-manage with the relevant specialist — cardiology, endocrinology, or hepatology — since organ damage already present does not necessarily reverse quickly, or at all, even once iron burden is well controlled going forward.
4. Cirrhosis or hepatocellular carcinoma surveillance findings: refer hepatology promptly; iron control alone does not eliminate the ongoing hepatocellular carcinoma risk once cirrhosis is established.^[5]
5. Non-adherence to lifelong maintenance-phase phlebotomy once a patient feels well and the initial target has been reached: reinforce explicitly that stopping maintenance treatment allows iron to reaccumulate over time — this is not a course of treatment with a natural endpoint, and framing it that way to the patient at diagnosis (see Non-Pharmacologic Treatment) helps prevent this specific failure mode.
6. HFE genotype-negative despite confirmed, significant iron overload: reconsider a non-HFE hereditary cause or a secondary/acquired source rather than concluding the patient does not have an iron-overload disorder at all; refer genetics/hepatology (see Assessment & Diagnosis).

• Diagnosing iron overload from an isolated elevated ferritin without also checking transferrin saturation — ferritin alone is an acute-phase reactant and can be elevated for reasons that have nothing to do with iron overload.^[4]
• Assuming a confirmed C282Y-homozygous genotype automatically means the patient has, or will develop, clinical disease — most homozygotes never do, and genotype alone is not itself a treatment decision (see Clinical Snapshot).^[1]
• Starting iron chelation therapy as a first-line choice in a patient who is actually phlebotomy-eligible, rather than reserving it for genuine phlebotomy ineligibility or secondary/transfusion-dependent iron overload.
• Driving induction-phase ferritin below the roughly 50 ng/mL target, causing iatrogenic iron-deficiency anemia rather than any additional benefit.^[4]
• Stopping phlebotomy once the induction target is reached instead of transitioning to lifelong maintenance-phase treatment.
• Not offering HFE genetic testing to first-degree relatives of a confirmed patient.^[4]
• Treating secondary (transfusion- or medication-related) iron overload with phlebotomy rather than recognizing it as a distinct etiology generally requiring chelation instead.
• Losing track of hepatocellular carcinoma surveillance once cirrhosis has been identified, particularly once a patient is doing well on maintenance phlebotomy and iron levels look normal.^[5]
• Not specifically counseling against raw or undercooked shellfish — a distinct, genuinely important point beyond the more obvious "avoid iron supplements" advice.
• Continuing a vitamin C supplement, or an iron-containing multivitamin taken out of habit, without anyone specifically asking about it at a medication review.

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Therapeutic Phlebotomy — First-Line

Not a drug — the standard, preferred first-line intervention for essentially every phlebotomy-eligible patient. Simple, highly effective, and markedly less costly than any chelation alternative.

Iron Chelation Therapy

Reserved for patients who cannot use phlebotomy (significant anemia, cardiac instability, poor venous access) or who have secondary/transfusion-dependent iron overload, where chelation is first-line rather than a fallback. Requires specialist consultation and initiation. Doses are adult doses and require patient-specific, product-monograph-confirmed titration.

What to Avoid

Confirm neither of these is being taken, including inadvertently through a routine multivitamin, at every medication review.