What is hereditary haemochromatosis?

Hereditary haemochromatosis (HH) is a genetic disorder of iron metabolism — HFE gene mutations (most commonly C282Y homozygosity) reduce hepcidin, causing progressive iron overload over decades: liver (cirrhosis → cancer); pancreas (type 3c diabetes); heart (cardiomyopathy); pituitary (hypogonadism); joints (2nd/3rd MCP arthropathy; chondrocalcinosis); skin (bronzing). Most common in Northern European populations (approximately 1 in 200 C282Y homozygous). Most now diagnosed incidentally from elevated ferritin or family screening.

Fasting transferrin saturation (TS): earliest marker (>45% men, >40% women). Serum ferritin (>200 μg/L women, >300 μg/L men) with elevated TS: suggests HH. HFE genotyping: confirms C282Y homozygosity. Liver MRI (FerriScan/T2*): non-invasive iron quantification. Liver biopsy: if ferritin >1,000 μg/L or abnormal LFTs — stage fibrosis. Differentiate from elevated ferritin due to alcohol, obesity, NAFLD, inflammation (all elevate ferritin without proportionally elevated TS or HFE mutations).

What are the signs of haemochromatosis?

Early: fatigue (non-specific, often attributed to other causes); elevated transferrin saturation + ferritin (incidental). Intermediate: joint pain (2nd and 3rd MCP joints — pathognomonic); elevated liver enzymes; reduced libido (pituitary iron). Late ("bronze diabetes" triad): liver cirrhosis; type 3c diabetes (insulin-deficient); skin bronzing. Skin bronzing: grey-brown, particularly in sun-exposed areas and genitals. Cardiac: cardiomyopathy, arrhythmia (late, now rare with earlier detection).

How does GMJ News cover haemochromatosis?

GMJ News covers HFE C282Y epidemiology, hepcidin regulation, transferrin saturation (first elevated marker), HFE genotyping, venesection protocol, 2nd/3rd MCP arthropathy, bronze diabetes triad, chondrocalcinosis, reversible vs irreversible complications, liver MRI staging, cascade family screening, and deferoxamine for secondary overload. Relevant to PHIG's hepatology, genetics and primary care programmes.

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Hereditary Haemochromatosis

Q: How is HH treated?

Venesection (phlebotomy): remove 450-500mL blood every 1-2 weeks until ferritin <50 μg/L (depletion phase: typically 1-3 years). Maintenance: 3-4 phlebotomies per year to keep ferritin <50. Fully prevents all complications if started before organ damage. Reverses: fatigue (dramatic improvement within weeks); pre-cirrhotic liver fibrosis; skin bronzing; early cardiomyopathy. Does NOT reverse: established cirrhosis; type 3c diabetes; joint damage.

GMJ News knowledge hub · last reviewed August 2026 · Georgian Medical Journal

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Hereditary haemochromatosis (HH) — caused predominantly by homozygous HFE C282Y mutations (present in approximately 0.5% of Northern European white populations), which disrupt hepcidin regulation and cause progressive iron overload — is among the most common autosomal recessive conditions in Northern European populations and, if untreated, leads to iron deposition in the liver (cirrhosis), pancreas (“bronze diabetes”), heart (cardiomyopathy), joints (arthropathy — most commonly affecting the 2nd and 3rd metacarpophalangeal joints — the pathognomonic joint pattern), pituitary (hypogonadism) and skin (bronzing) (WHO). The treatment is both elegantly simple and profoundly effective: venesection (phlebotomy) of 450-500mL blood every 1-2 weeks until ferritin normalises to <50 μg/L, then maintenance 3-4 times/year — one of medicine’s most satisfying therapeutic relationships (iron removed by the pint, organs preserved), with all complications preventable if iron overload is identified before irreversible organ damage occurs.

Key messages

HFE C282Y homozygosity — common Northern European genetic condition

Hereditary haemochromatosis (HH) is caused predominantly by HFE C282Y homozygosity — present in approximately 0.5% of Northern European white populations. The HFE mutation disrupts hepcidin regulation → unchecked intestinal iron absorption → progressive iron accumulation. Penetrance is incomplete: approximately 70-80% of C282Y homozygous males and 20-30% of females develop elevated ferritin; only approximately 10-20% develop clinical disease.

Transferrin saturation >45% — the earliest diagnostic marker

Transferrin saturation (TS = serum iron / TIBC × 100%): elevated before ferritin rises — the most sensitive early screening test for HH. TS >45% (men) / >40% (women) on a fasting sample → HFE genotyping. Serum ferritin correlates with iron stores but is an acute phase reactant (elevated in infection, obesity, alcohol, NAFLD — causing false positives). Ferritin >1,000 μg/L with elevated TS → liver biopsy/MRI to assess fibrosis.

2nd/3rd MCP arthropathy — the pathognomonic joint pattern

Iron arthropathy in haemochromatosis predominantly affects the 2nd and 3rd metacarpophalangeal (MCP) joints — a distribution unlike any other arthritis and pathognomonic of HH. CPPD crystals (calcium pyrophosphate) deposit in joints — chondrocalcinosis visible on X-ray (knee menisci, wrist triangular fibrocartilage). This joint pattern in a middle-aged adult should immediately trigger ferritin + transferrin saturation testing.

Venesection — the most satisfying simple treatment in medicine

Treatment: venesection (phlebotomy) 450-500mL blood every 1-2 weeks (each removes approximately 200-250mg iron) until ferritin <50 μg/L. Then maintenance 3-4 times/year to keep ferritin <50. Prevents ALL complications if started before organ damage. Reverses: fatigue; early liver fibrosis; skin bronzing; early cardiac dysfunction. Does NOT reverse: established cirrhosis; type 3c diabetes; arthropathy. Hence the critical importance of early diagnosis.

"Bronze diabetes" — the preventable late triad

The classical late-stage HH triad: hepatic cirrhosis (iron-induced hepatocyte damage → fibrosis → cirrhosis → 200× elevated liver cancer risk); type 3c diabetes ("bronze diabetes" from beta-cell iron deposition → insulin deficiency); skin bronzing (melanin + iron pigment → grey-bronze discolouration). This triad is now largely preventable with early detection and venesection — but neither cirrhosis, diabetes nor arthropathy reverse with treatment.

Cascade screening — first-degree relatives

Screen all first-degree relatives of confirmed C282Y homozygotes: HFE genotyping + fasting TS + ferritin. If homozygous: annual TS + ferritin monitoring. Start venesection when ferritin rises above normal or TS persistently >45%. Population screening not recommended (low penetrance, non-Northern European populations rarely affected) — targeted family cascade screening is the cost-effective strategy.

Key statistics

~0.5%

of Northern European white populations are HFE C282Y homozygous

EASL 2022

TS >45%

transferrin saturation — first elevated marker; trigger for HFE genotyping

EASL/NICE

~200mg

iron removed per 500mL venesection; target ferritin <50 μg/L

EASL

2nd/3rd MCP

arthropathy — the pathognomonic joint pattern of haemochromatosis

EASL/Rheumatology

200×

increased liver cancer risk after HH-related cirrhosis

EASL/NEJM

10-20%

of C282Y homozygotes develop clinical disease (incomplete penetrance)

EASL/Genetics

Haemochromatosis — organ involvement and reversibility with venesection

Source: EASL 2022. Early-stage manifestations are fully reversible; established cirrhosis, diabetes and arthropathy are not.

Glossary of key terms

Hepcidin — the master iron regulator
HaematologyHepcidin: liver-produced peptide hormone that binds and degrades ferroportin (the only cellular iron exporter) on intestinal enterocytes, macrophages and hepatocytes → reduces iron export → maintains homeostasis. HFE (mutated in C282Y) normally upregulates hepcidin in response to iron loading. HFE mutation → inappropriately low hepcidin → unchecked ferroportin activity → excess iron absorption → progressive iron overload.

HFE genotypes
GeneticsC282Y (p.Cys282Tyr): most common HH mutation; Northern European. C282Y homozygous: high clinical risk. H63D: very common (15% Europeans); H63D homozygous rarely causes significant overload alone. C282Y/H63D compound heterozygous: mild iron loading; rarely clinically significant. HFE genotyping: indications — elevated TS; family cascade screening of C282Y homozygotes.

Liver MRI for iron quantification
RadiologyNon-invasive iron quantification — T2* or R2* mapping (FerriScan) — accurately estimates hepatic iron concentration against biopsy as reference standard. Replaces liver biopsy for iron quantification in most cases. Liver biopsy still required if: ferritin >1,000 μg/L (stage fibrosis); abnormal LFTs; clinical concern about significant liver disease. Histology: Perls' Prussian blue stain shows periportal iron deposits in hepatocytes (HH pattern vs transfusional iron in Kupffer cells).

Chondrocalcinosis and CPPD in HH
RheumatologyCalcium pyrophosphate dihydrate (CPPD) crystals deposit in joint cartilage in HH — visible as chondrocalcinosis on X-ray (knee menisci; wrist TFCC; symphysis pubis). Pseudogout attacks (acute crystal-shedding arthritis) occur. Young chondrocalcinosis (<55 years) → consider metabolic causes: HH; hyperparathyroidism; hypomagnesaemia; hypothyroidism; acromegaly.

Deferoxamine vs venesection
HaematologyVenesection is for hereditary haemochromatosis (normal haematopoiesis tolerates regular blood removal). Iron chelation (deferoxamine, deferasirox, deferiprone) is for secondary transfusional iron overload (thalassaemia, sickle cell, MDS) — where anaemia prevents venesection. Chelators are not used for HH unless venesection is contraindicated (cardiac failure, severe anaemia).

Cascade family screening protocol
EASL/GeneticsFirst-degree relatives of confirmed C282Y homozygotes: offer HFE genotyping + fasting TS + ferritin. If also C282Y homozygous: annual monitoring (TS, ferritin, LFTs). Start venesection when ferritin rises above normal or TS >45% persistently. Children of homozygous parents: if C282Y/C282Y — begin monitoring from age 18 (or earlier if symptomatic). Partner of C282Y homozygote: check C282Y carrier status (if partner also C282Y heterozygous, children have 25% risk of homozygosity).