Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder in Northern European populations. It is caused by mutations in the HFE gene (chromosome 6p21.3), which normally upregulates hepcidin production in response to iron stores. Loss of this signaling leads to constitutively low hepcidin, unregulated intestinal iron absorption, and progressive iron deposition in parenchymal organs — liver, pancreas, heart, pituitary, joints, and skin.

The hepcidin–ferroportin axis, with each hemochromatosis subtype mapped to its molecular node

HFE Gene Mutations

Mutation	Clinical Relevance
C282Y homozygosity	~80–85% of clinical HH in Northern European populations; highest penetrance for iron overload and end-organ disease
H63D homozygosity	Mild or no iron overload; rarely causes clinical disease alone
C282Y/H63D compound heterozygosity	Mild iron overload in some patients; rarely causes end-organ disease

Penetrance

Only ~28% of male C282Y homozygotes develop clinically significant end-organ damage; penetrance in women is substantially lower (<1–5%), making sex an important modifier in counselling (EASL 2022, PMID 35662478). The majority are identified incidentally via biochemical screening or family cascade testing. Alcohol use, and hepatic steatosis also reduce penetrance further or modify disease expression — menstrual blood loss provides a natural form of iron removal that partially offsets iron accumulation in premenopausal women.

Non-HFE Hemochromatosis

Rare subtypes caused by mutations in other iron-regulatory genes:

Type 2A (Juvenile)

Hemojuvelin (HJV)

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Type 2B (Juvenile)

Hepcidin (HAMP)

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Type 3

Transferrin Receptor 2 (TFR2)

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Type 4 (Autosomal Dominant)

Ferroportin (SLC40A1)

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Quick recall

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A 45-year-old with C282Y homozygous HH and ferritin 820 μg/L starts weekly phlebotomy. What are the target end-points, and when is phlebotomy frequency reduced to maintenance?

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Transferrin Saturation

Transferrin saturation (TS) ≥45% is the recommended screening threshold. TS is the most sensitive early marker of iron overload and is elevated before ferritin rises significantly.

TS Formula

TS = (Serum Iron ÷ TIBC) × 100
A TS >45% with ferritin elevation should prompt HFE genotyping. TS rises early in HH — before ferritin is substantially elevated — making it the first-line biochemical screen.

Serum Ferritin

Ferritin as Acute-Phase Reactant

Ferritin is elevated in inflammation, active alcohol use, metabolic dysfunction-associated steatotic liver disease (MASLD), and acute infection — independent of iron stores. An elevated ferritin alone does not establish hemochromatosis and must be interpreted in context of the transferrin saturation, clinical setting, and genotype. In C282Y homozygotes, ferritin >1000 µg/L strongly predicts advanced fibrosis (F3–F4) and cirrhosis. Ferritin is used to set treatment targets and assess iron depletion progress — not as a stand-alone diagnostic marker.

HFE Genotyping

First-line confirmatory test after biochemical suspicion (elevated TS + ferritin). C282Y homozygosity establishes the diagnosis without the need for liver biopsy in most cases, provided ferritin and liver enzymes do not suggest advanced disease requiring staging.

Non-Biopsy Diagnosis Rule

In a patient with TS ≥45%, elevated ferritin, and confirmed C282Y homozygosity — and who has ferritin <1000 µg/L and normal transaminases — liver biopsy is not required for diagnosis. Genotyping has largely replaced empirical biopsy for diagnosis in this setting.

Hepatic Iron Quantification

Liver biopsy was historically the reference standard for both hepatic iron quantification and fibrosis staging. Per the ACG 2019 guideline, MRI-based iron quantification has now largely displaced biopsy for measuring liver iron (see below); biopsy is reserved mainly for fibrosis staging in patients at risk of advanced disease (ferritin >1000 µg/L or abnormal transaminases). The classic biopsy thresholds remain useful to recognise:

Hepatic iron concentration (HIC) >36 µmol/g dry weight (>2,000 µg/g dry weight) confirms iron overload
Hepatic Iron Index (HII) = HIC (µmol/g) ÷ age — HII ≥1.9 historically supported HH diagnosis; less commonly used now that genotyping is routine
Biopsy now reserved for: ferritin >1000 µg/L or elevated transaminases (to stage fibrosis); genotype-indeterminate cases with high clinical suspicion

MRI R2* (FerriScan) — Non-Invasive Iron Quantification

MRI-based hepatic iron concentration measurement using R2* relaxometry. FDA-cleared for HIC measurement. Preferred non-invasive alternative to biopsy for quantifying liver iron — useful for monitoring treatment response and in patients who decline or cannot safely undergo biopsy.

Therapeutic Phlebotomy — First-Line Treatment

Phlebotomy is safe, effective, and inexpensive. Each 450–500 mL unit of whole blood removes approximately 250 mg of iron.

Phase	Protocol and Target
Induction (Depletion Phase)	450–500 mL whole blood removed weekly until iron depletion is achieved
Depletion Goal	Ferritin 50–100 µg/L (some guidelines target 50–75 µg/L) with transferrin saturation <50%
Maintenance Phase	Phlebotomy every 2–4 months to maintain ferritin 50–100 µg/L; individualize interval by ferritin trend
CBC Monitoring	Check CBC before each session; hold if hemoglobin <11 g/dL (relative threshold — individualize)

Phlebotomy Session Protocol

Confirm all safety criteria before each session:

CBC checked — hemoglobin ≥11 g/dL

Hold phlebotomy if Hgb <11 g/dL

Required before session

450–500 mL whole blood removed

Each session removes ~250 mg of iron

Standard dose

Ferritin trend documented

Target ferritin 50–100 µg/L and TS <50%

Track progress

Patient counseled: avoid Vit C supplements, iron-fortified supplements, raw shellfish, limit alcohol

Vibrio vulnificus risk is serious in iron overload + cirrhosis

Critical

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Contraindications

Severe symptomatic anemia; hemoglobin persistently <10 g/dL; hemodynamically significant or unstabilized cardiac dysfunction (acute cardiomyopathy may worsen acutely with volume shifts from phlebotomy). In these patients, iron chelation should be considered as an alternative.

What Phlebotomy Can and Cannot Do

Phlebotomy prevents progression of liver disease and may improve cardiac function and diabetes control when initiated before end-organ damage is established. It does not reliably reverse established arthropathy, hypogonadism, or cirrhosis. HCC risk remains elevated in cirrhosis even after successful iron depletion.

Iron Chelation — Alternative When Phlebotomy Is Not Feasible

Chelation is reserved for patients who cannot tolerate phlebotomy. It is less efficient than phlebotomy for iron removal (phlebotomy removes ~250 mg/session vs. chelation removing ~10–20 mg/day) and is rarely needed in uncomplicated HH.

First-Line Treatment

Therapeutic Phlebotomy

450–500 mL whole blood per session → removes ~250 mg iron
Induction: Weekly until ferritin 50–100 µg/L and TS <50%
Maintenance: Every 2–4 months to sustain targets
Check CBC before each session; hold if Hgb <11 g/dL (relative)
Safe, effective, inexpensive — standard of care for HH

Oral Chelator

Deferasirox (Exjade / Jadenu)

14–28 mg/kg/day (Exjade) or 7–21 mg/kg/day (Jadenu film-coated)
First-choice oral chelator for phlebotomy-ineligible patients
Monitor: renal function, hepatic enzymes, auditory/ocular function
GI side effects common; avoid in significant renal impairment
Less efficient than phlebotomy — reserve for phlebotomy-ineligible

Parenteral Chelator

Deferoxamine (Desferal)

20–60 mg/kg/day SC infusion over 8–24 hours
Older agent; reserved for severe cases or oral chelation contraindication
Risk of Yersinia infection — iron provides bacterial growth substrate
Less convenient than oral route; parenteral administration required

Hereditary Hemochromatosis

HFE Gene Mutations

Non-HFE Hemochromatosis

Organ Involvement

Transferrin Saturation

Serum Ferritin

HFE Genotyping

Hepatic Iron Quantification

Interactive Risk Predictor Checklist

Therapeutic Phlebotomy — First-Line Treatment

Phlebotomy Session Protocol

Iron Chelation — Alternative When Phlebotomy Is Not Feasible

Dietary and Lifestyle Considerations

Family Screening

HCC Surveillance

Clinical Case Vignette

References