hereditary hemochromatosis
Contents
Autosomal recessive iron-overload disorder, overwhelmingly due to C282Y homozygosity in the HFE gene. Screen with transferrin saturation (Tsat) — if ≥45%, check HFE genotyping. Clinical penetrance is incomplete (~28% of male and ~1% of female C282Y homozygotes develop clinical disease). Phlebotomy is curative when started before cirrhosis. Liver biopsy is no longer routine — reserve for staging when ferritin >1000 µg/L or ALT is elevated. HCC surveillance is lifelong once cirrhosis is established, even after iron depletion.
diagnostic algorithm
flowchart TD
A["elevated ferritin or<br>clinical suspicion"] --> B["fasting Tsat"]
B -->|"< 45%"| C["hemochromatosis<br>excluded"]
B -->|"≥ 45%"| D["HFE genotyping"]
D -->|"C282Y/C282Y"| E["hereditary<br>hemochromatosis confirmed"]
D -->|"C282Y/H63D"| F["low risk of iron<br>overload — investigate<br>other causes"]
D -->|"H63D/H63D or<br>wild type"| G["not HFE-related —<br>consider secondary<br>causes or rare types"]
E --> H{"ferritin"}
H -->|"< 1000 µg/L<br>+ normal ALT"| I["phlebotomy<br>no biopsy needed"]
H -->|"≥ 1000 µg/L<br>or elevated ALT"| J["liver biopsy or<br>LSM → assess<br>for cirrhosis"]Ferritin is an acute-phase reactant elevated by inflammation, infection, MASLD, alcohol, and malignancy. Transferrin saturation is the screening test. Tsat <45% has ~97% NPV for excluding iron overload (see approach to elevated liver enzymes).
HFE genotypes and penetrance
| genotype | iron-overload risk | notes |
|---|---|---|
| C282Y/C282Y | highest — ~28% M, ~1% F develop clinical disease | the classic hemochromatosis genotype |
| C282Y/H63D | low (~1–2% develop mild overload) | most compound heterozygotes never develop significant disease; look for a cofactor (alcohol, MASLD) if ferritin is high |
| H63D/H63D | negligible | does not cause clinically significant iron overload on its own |
Penetrance is modified by sex (premenopausal women protected by menstrual losses), alcohol, hepatic steatosis, and other genetic modifiers.
organ involvement
Iron accumulates preferentially in parenchymal cells. Clinical manifestations typically appear after age 40 in men, post-menopause in women.
| organ | manifestation |
|---|---|
| liver | elevated ALT → fibrosis → cirrhosis → HCC (risk persists after iron depletion if cirrhosis established) |
| pancreas | ”bronze diabetes” — T2DM from beta-cell iron deposition; may not reverse with phlebotomy |
| heart | dilated or restrictive cardiomyopathy, arrhythmias (particularly in juvenile hemochromatosis) |
| joints | 2nd/3rd MCP arthropathy (chondrocalcinosis), may worsen despite iron depletion |
| pituitary | hypogonadotropic hypogonadism — check testosterone/LH/FSH |
| skin | bronze hyperpigmentation |
Joint symptoms are the most treatment-resistant manifestation and may even progress after iron normalisation. Early treatment prevents other organ damage but does not reliably prevent or reverse arthropathy.
treatment
phlebotomy
The mainstay — effective, safe, and curative if started before irreversible organ damage.
Induction phase:
- 500 mL whole blood (≈250 mg iron) every 1–2 weeks
- target: ferritin <50 µg/L (some guidelines use <100 µg/L)
- monitor ferritin every 4–6 phlebotomy sessions; check Hb before each session (hold if Hb <110 g/L)
Maintenance phase:
- phlebotomy every 2–4 months to keep ferritin 50–100 µg/L
- lifelong
when phlebotomy is not possible
- Chelation therapy (deferasirox) — reserved for patients with anaemia, poor venous access, or intolerance to phlebotomy. More side effects and cost than phlebotomy.
- Erythrocytapheresis — removes more iron per session; consider if poor tolerance to volume removal
dietary advice
- avoid iron supplements and vitamin C supplements (enhances iron absorption)
- avoid excess alcohol (synergistic hepatotoxicity)
- raw shellfish avoidance — Vibrio vulnificus sepsis risk with iron overload (rare but classically tested)
- no need for a low-iron diet; the above restrictions suffice
HCC surveillance
- All patients with cirrhosis — abdominal US ± AFP q6 months, lifelong
- HCC risk persists after iron depletion if cirrhosis was present at diagnosis
- Non-cirrhotic hemochromatosis patients do not require HCC surveillance (unlike HBV, where surveillance can apply without cirrhosis)
family screening
- First-degree relatives of a confirmed C282Y homozygote should be offered HFE genotyping + fasting Tsat + ferritin
- If partner is tested and is not a C282Y carrier → children are obligate heterozygotes and do not need further testing
- Screening is most impactful in siblings (25% chance of homozygosity)
common traps
- Ordering HFE genotyping before Tsat — genotyping is only indicated when Tsat ≥45%. Most elevated ferritins are not hemochromatosis.
- Diagnosing iron overload from H63D homozygosity — this genotype does not cause clinically significant disease. Look for the real cause (alcohol, MASLD, inflammation).
- Stopping HCC surveillance after iron depletion — if cirrhosis is established, cancer risk is lifelong regardless of iron status.
- Ignoring cofactors in compound heterozygotes — C282Y/H63D with elevated ferritin usually has a second driver (alcohol, obesity). Treat the cofactor.
- Assuming normal ferritin excludes early disease — young C282Y homozygotes may have normal ferritin but elevated Tsat. Tsat is the earlier marker.
related: approach to elevated liver enzymes · cirrhosis · MASLD · autoimmune and metabolic liver diseases