Haemochromatosis & Disorders of Iron Metabolism: GP Guide

Haemochromatosis is a systemic disorder of excessive iron absorption from the gut → progressive iron overload → iron deposition in organs (liver, heart, pancreas, joints, skin) → risk of irreversible damage if untreated.

Among the most common genetic disorders in people of Northern European ancestry.
Primary care relevance: Often asymptomatic early; picked up via ↑ ferritin or LFTs, or family screening.

Type	Cause	Key Features
Primary (Hereditary)	HFE gene mutations (esp. C282Y homozygosity)	Autosomal recessive; ↑ intestinal iron absorption
Secondary	Chronic transfusions, haemolytic anaemia, liver disease, iron-loading anaemias (e.g. thalassaemia major)	Acquired iron overload from exogenous or pathological sources
Other iron disorders (DDx)	Iron deficiency anaemia, anaemia of chronic disease, sideroblastic anaemia	Varying iron studies; distinguish via transferrin saturation & ferritin pattern

Clinical Presentation of Haemochromatosis

Onset: usually adulthood, often asymptomatic for years
Early symptoms: nonspecific & insidious → delayed diagnosis
Higher penetrance in men; women often present post-menopause (due to loss of menstrual iron)

🧩 Common Symptoms (early/nonspecific)

Fatigue, weakness (most common, ~70%)
Joint pain/arthritis (esp. MCP joints, ankles, knees; ~80%)
Abdominal pain (liver discomfort)
Mood & cognition: depression, brain fog, memory issues (~40–60%)
Skin changes: hyperpigmentation/bronze or grey tone (“bronze diabetes”, ~70%)
Sexual dysfunction: ↓ libido, impotence, hypogonadism (~57%)
Weight loss, lethargy

Advanced / Organ-Specific Manifestations

Liver: hepatomegaly, abnormal LFTs, cirrhosis, liver failure, ↑ risk HCC
Pancreas: diabetes mellitus
Heart: arrhythmias, cardiomyopathy, heart failure
Endocrine: hypothyroidism, hypogonadism, amenorrhoea
Joints: arthropathy, CPPD (calcium pyrophosphate deposition disease)
Skin: bronze/grey hyperpigmentation.

Clinical Clues to Suspect

Unexplained ↑ liver enzymes
Family history of haemochromatosis
Northern European ancestry (↑ prevalence)
Transfusion-dependent anaemias (secondary iron overload)
Presentation typically >40y men, post-menopause women

Diagnosis

Test	Relevance
Serum ferritin (SF)	Screening; ↑ in iron overload but also in inflammation, alcohol, NAFLD, metabolic syndrome
Transferrin saturation (TSAT)	Most sensitive early marker; >45% suspicious
Genetic testing (HFE mutations)	Confirms diagnosis; C282Y homozygous most common
LFTs (ALT/AST)	May be ↑; assess hepatic involvement
FBC	To rule out anaemia (esp. in secondary causes)

Initial Diagnostic Approach

Check SF + TSAT
- SF >300 µg/L (♂, post-menopausal ♀) OR >200 µg/L (pre-menopausal ♀)
- TSAT >50% (♂, post-menopausal ♀) OR >45% (pre-menopausal ♀)
Normal SF + TSAT → iron overload unlikely
If SF ↑ but TSAT normal → consider inflammation, alcohol, NAFLD, metabolic syndrome

Genetic Testing (HFE mutations: C282Y, H63D)
- Indications: ↑ TSAT (>45%), ↑ ferritin, or FHx of HH
- TSAT >45% = key discriminator for iron overload.
- Interpretation:
  - C282Y/C282Y = confirms primary HH
  - C282Y/H63D = moderate risk (clinical disease uncommon without cofactors)
  - H63D/H63D or single heterozygotes = usually not clinically significant
  - Negative HFE but persistent iron overload → refer (consider rare non-HFE HH)
General Blood Tests
- FBC → rule out anaemia/polycythaemia
- LFTs → may be mildly ↑ (ALT, AST, γGT)
- HbA1c / fasting glucose → check for diabetes
- CRP/ESR → if ferritin ↑ with normal TSAT, consider inflammation/malignancy
- TFTs → hypothyroidism can raise ferritin
- Consider ECG/echo if cardiac symptoms

Genotype	Meaning	Clinical Significance
C282Y homozygous	Two copies of the C282Y mutation	✅ Confirms primary HH; highest risk of iron overload
C282Y/H63D compound heterozygous	One copy of C282Y + one copy of H63D	⚠️ Usually mild/moderate risk; lower penetrance
H63D homozygous	Two copies of H63D	Rarely causes HH; usually no significant iron overload
Non-C282Y variants	Less common mutations (e.g., S65C)	🧾 Rare cause; consider referral to hepatology/genetics

UK Epidemiology & Screening

Genetic prevalence:
~1 in 150–200 in the UK are C282Y homozygous (highest in Northern European / Celtic ancestry).
Carrier frequency:
~10% of people in Northern Europe carry C282Y or H63D mutations.
Penetrance:
Many risk genotypes do not develop clinical disease → incomplete penetrance.
Sex & age differences:
- Men: higher risk, earlier onset.
- Women: present later (iron loss from menstruation/pregnancy delays onset).
Screening policy (UK):
- ❌ No general population screening recommended (UK NSC 2021).
- ✅ Targeted testing: family members (cascade screening), symptomatic patients, abnormal LFTs.

Family Screening

Test first-degree relatives >16y of C282Y homozygous / C282Y-H63D compound heterozygotes
Siblings: 25% risk; if one parent affected, 50% risk
Test partner genotype → assess child risk
Genetic counselling recommended (Haemochromatosis UK offers free service)
No routine testing for H63D carriers without symptoms

Imaging & Specialist Tests

MRI (liver iron quantification)
- ↓ liver signal = primary haemochromatosis
- ↓ liver + spleen signal = secondary iron overload.

Potential complictions

System	Potential Complications
Liver	Cirrhosis (↑ risk if ferritin >1000 µg/L or alcohol), HCC (20–100× risk if cirrhosis), fibrosis, portal HTN
Cardiac	Cardiomyopathy (dilated/restrictive), arrhythmias (AF, conduction defects), heart failure
Endocrine	Type 2 diabetes (20–50% symptomatic cases), hypogonadism (impotence, amenorrhoea), hypothyroidism, adrenal insufficiency (rare)
Joints & Bone	Arthropathy (MCP, wrists, ankles), resembles OA, may not improve with venesection; osteoporosis
Skin	Hyperpigmentation (“bronze diabetes”), grey-brown skin tone
Infections	↑ risk with iron-loving bacteria: Vibrio vulnificus, Yersinia enterocolitica, Listeria (esp. raw shellfish)
Other	Fatigue, cognitive impairment (“brain fog”), depression

Management of Haemochromatosis

Primary Haemochromatosis

Iron removal (first-line)

Phlebotomy (venesection):
- Induction: Weekly/biweekly until serum ferritin (SF) ↓ to <50 µg/L
- Maintenance: Every 2–4 months to keep SF 50–100 µg/L
- Improves symptoms, prevents organ damage if started early

Chelation therapy (second-line):

Deferoxamine, deferasirox, deferiprone
Use if: anaemia, poor venous access, or cardiac involvement

Lifestyle & diet:

🚫 Alcohol (esp. with liver disease)
🚫 Iron & vitamin C supplements
🚫 Raw shellfish (infection risk with Vibrio vulnificus)
Moderate red meat; maintain healthy weight/BMI

Referral:

Gastroenterology/haematology for initiation & monitoring
Urgent if SF >1000 µg/L (↑ risk cirrhosis/HCC)

Monitoring & Follow-up

Routine bloods: SF, TSAT, Hb for phlebotomy titration
Fibrosis assessment: FIB-4 / elastography (<6.4 kPa rules out advanced fibrosis)
Liver biopsy: if SF >1000 µg/L or unexplained ↑ LFTs
HCC surveillance: Ultrasound ± AFP q6m if cirrhosis/advanced fibrosis
Bone health: DEXA scan (risk of osteoporosis/osteopenia)
GPs may monitor stable patients after specialist input
Encourage blood donation if suitable

Secondary Haemochromatosis

Iron overload not due to HFE gene mutations, but secondary to chronic transfusions, liver disease, or ineffective erythropoiesis.

Cause	Examples	Mechanism
Transfusion-related	Thalassaemia major, sickle cell disease, myelodysplastic syndrome, aplastic anaemia	Each transfused unit ≈ 250 mg iron → cumulative overload
Chronic liver disease	Alcoholic liver disease, hepatitis C, NAFLD, cirrhosis	Impaired metabolism & secondary iron deposition
Ineffective erythropoiesis	Rare congenital anaemias, sideroblastic anaemia	↑ Gut iron absorption on top of anaemia

Treat underlying cause (e.g., transfusion burden, liver disease)
Phlebotomy if not anaemic
Chelation therapy if anaemia present or venesection unsuitable
Monitoring similar to primary, but prognosis depends on cause

Key Points for Primary Care

Do not misinterpret raised ferritin in transfusion-dependent patients as idiopathic HH
Management = iron chelation (deferoxamine, deferasirox, deferiprone) or sometimes phlebotomy (if not anaemic)
Always refer to the appropriate specialty:
- Haematology → transfusional overload
- Hepatology → liver disease–related overload.

References

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