Hereditary Haemochromatosis

Overview

• Inherited autosomal recessive disorder due to mutations in the HFE gene (located on chromosome 6).
• Results in inappropriately increased intestinal iron absorption, progressive iron overload, and eventual parenchymal iron deposition in multiple organs.
• complications
  • Clinically significant HH is rare, despite common genetic mutations.
  • Only ~10% of individuals homozygous for C282Y develop overt disease.
  • Cirrhosis occurs in only 1–2% of C282Y homozygotes.
• Disease manifestations are more common and severe in males (likely due to iron loss in menstruating females).

Differential Diagnosis of Raised Ferritin / Secondary Iron Overload

• Not all elevated ferritin reflects genetic haemochromatosis. Consider:
  • Parenteral iron therapy (e.g. iron dextran)
  • Inflammatory conditions (acute or chronic)
  • Chronic anaemia (e.g. thalassaemia major)
  • Chronic liver disease:
    • Viral hepatitis
    • Alcohol-related liver disease
    • Non-alcoholic fatty liver disease (NAFLD/NASH)
  • Malignancy
  • Iron supplementation (usually not a cause unless parenteral)
  • Multiple blood transfusions

Genetics

• Inheritance: Autosomal recessive disorder caused by HFE gene mutations on chromosome 6.
• HFE protein modulates hepcidin (an iron-regulatory hormone).
• ↓ Hepcidin → ↑ Intestinal iron absorption → Progressive iron overload tissue iron deposition, with potential for multi-organ damage.

Genetic Basis and Mutations

Mutation	Protein Effect	Inheritance Pattern	Prevalence (Caucasians)
C282Y (Cys→Tyr)	Disrupts HFE–β2-microglobulin binding	Autosomal Recessive	~90% of clinically significant cases
H63D (His→Asp)	Less functional impact on HFE protein	Autosomal Recessive	~10–15% carrier rate
S65C	Uncommon; often clinically insignificant alone	Autosomal Recessive	Rare (~1%)

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Etiologies

🔹 1. C282Y/C282Y (Homozygous) – Classic HH Genotype

Feature	Details
Genetic change	Homozygous missense mutation at position 282: Cysteine → Tyrosine (C282Y)
Prevalence	~0.5–0.6% in Northern Europeans (1 in 250–300)
Penetrance	Low – only 10–15% develop clinical disease
Biochemical abnormalities	~50% will have elevated transferrin saturation or ferritin
Iron overload risk	High, particularly in men
Organ damage risk	Cardiomyopathy, cirrhosis, diabetes, arthritis

Pathophysiology:

• Mutation disrupts HFE–β2 microglobulin interaction, impairing hepcidin upregulation.
• Hepcidin levels remain inappropriately low despite rising iron stores.
• Leads to:
  • ↑ Duodenal iron absorption (via ferroportin)
  • ↑ Iron release from macrophages
  • Gradual parenchymal iron accumulation in liver, pancreas, heart, joints

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🔹 2. C282Y/H63D (Compound Heterozygote)

Feature	Details
Genetic change	One C282Y mutation + one H63D mutation
Prevalence	~1.5–2% of white populations
Penetrance	Very low – <1% develop significant disease
Biochemical abnormalities	Often normal; some may have mild ↑ ferritin or TSAT
Iron overload risk	Low to moderate, usually only with additional hepatic stressors (e.g. alcohol, hepatitis C)
Organ damage risk	Uncommon, usually not severe unless cofactors present

Pathophysiology:

• Partial hepcidin dysregulation due to combination of milder (H63D) and stronger (C282Y) mutations.
• Hepcidin suppression is less severe than in C282Y/C282Y.
• Mild increase in iron absorption, usually not sufficient to cause tissue damage without other risk factors.

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🔹 3. H63D/H63D (Homozygous for H63D)

Feature	Details
Genetic change	Homozygous H63D mutation (Histidine → Aspartate at position 63)
Prevalence	~1% of the population
Penetrance	Very low
Biochemical abnormalities	Usually normal
Iron overload risk	Minimal
Organ damage risk	Very rare, usually absent

Pathophysiology:

• H63D mutation has a much weaker effect on HFE protein function.
• Minimal impairment in hepcidin regulation.
• Iron metabolism remains near-normal.
• If ferritin or TSAT is elevated, consider alternate causes (e.g. NAFLD, inflammation).

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🔹 4. C282Y Heterozygote (Carrier only)

Feature	Details
Genetic change	One C282Y mutation, one normal allele
Prevalence	~10% of people of Northern European descent
Penetrance	None (carrier state only)
Biochemical abnormalities	Rarely mild ↑ TSAT, usually normal ferritin
Iron overload risk	None significant in isolation

Pathophysiology:

• One functional HFE allele is sufficient for normal hepcidin regulation.
• Occasional mild TSAT elevation may occur but clinically insignificant.
• No need for monitoring unless ferritin/TSAT is persistently elevated or other risk factors exist.

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🔹 5. H63D Heterozygote (Carrier only)

Feature	Details
Genetic change	One H63D mutation, one normal allele
Prevalence	~15–20% of general population
Penetrance	None
Biochemical abnormalities	None expected
Iron overload risk	None significant in isolation

Pathophysiology:

• Minimal impact on HFE function when heterozygous.
• No impact on hepcidin regulation or iron metabolism.
• No role in disease unless co-inherited with C282Y or underlying liver disease.

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Genotype vs Clinical Significance

Genotype	Biochemical Abnormalities	Risk of Iron Overload	Clinical Relevance
C282Y/C282Y	Frequent ↑TSAT/ferritin	High	Classic HH; monitor and treat if needed
C282Y/H63D Compound heterozygotes	Occasionally mild ↑	Low–moderate	Rare overload; risk if comorbid liver disease
H63D/H63D	Rare	Minimal	Rarely clinically relevant
C282Y heterozygote	Very rare mild ↑	None	Carrier only
H63D heterozygote	None	None	Carrier only
S65C or other variants	Rare	Unclear/Low	May contribute with other mutations

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Pathophysiology of Hereditary Hemochromatosis (HH)

• Core defect: Inappropriate suppression of hepcidin due to HFE mutation → unregulated intestinal iron absorption.
• Result: Gradual accumulation of iron in parenchymal tissues (e.g. liver, pancreas, heart, joints).

• Absorption (in the duodenum/jejunum)
  • Fe³⁺ (Ferric) from food is reduced to Fe²⁺ (Ferrous) for absorption
  • Fe²⁺ is absorbed by enterocytes in the gut.
  • Some is stored intracellularly as ferritin, and the rest is exported into circulation.
• Transport
  • Transferrin binds Fe³⁺ in plasma and transports it to tissues
  • Plasma iron level is about 3 mg.
• Utilization
  • Iron is delivered primarily to:
    • Bone marrow for incorporation into haemoglobin in erythrocytes.
    • Muscle tissue for myoglobin.
• Storage
  • Excess iron is stored as ferritin in the liver, macrophages, and spleen.
  • Approximate iron storage is ~1000 mg.
  • Erythrocytes hold the largest iron pool (~2500 mg).
• When iron is needed (e.g. for making haemoglobin), it is released from ferritin.
  • Hepcidin (a liver hormone) controls how much iron is absorbed and released — it blocks iron absorption and release when iron stores are high.
  • In hereditary haemochromatosis, hepcidin levels are too low → too much iron is absorbed and stored.

• Daily excess absorption: Only 1–3 mg/day above normal, but cumulative over decades.
• Normal total body iron: ~3–4 g.
• Iron overload timeline:
  • >4 g by age 10 (in homozygotes).
  • >20–25 g → tissue injury (typically age 30–40).
  • >30–40 g → risk of cirrhosis and complications (age 40+ if untreated).

Factors Influencing Disease Expression

Factor	Mechanism/Effect
Male sex	No menstrual iron loss → earlier and more severe iron overload
Hepatitis C infection	Accelerates hepatic fibrosis
Alcohol abuse	Synergistic hepatotoxicity and iron loading
Alcohol threshold	>60 g/day (~4+ standard drinks) → 9-fold increase in cirrhosis risk

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Clinical Manifestations of HH

🧱 Classic Triad (Late-stage)

• Bronze skin pigmentation
• Diabetes mellitus (“bronze diabetes”)
• Cirrhosis

🧩 Common Early Symptoms

Typically emerge between 30 and 60 years of age:

System	Symptoms
General	Fatigue, lassitude, weakness
Musculoskeletal	Arthralgia (especially MCP joints), early osteoarthritis
Endocrine	Erectile dysfunction, amenorrhoea
Hepatic	Mild LFT derangement, hepatomegaly
Dermatological	Hyperpigmentation (bronze/grey skin)
Abdominal	Discomfort or vague pain
Other	Weight loss, loss of libido

Physical Examination Findings

Finding	Explanation
Hepatomegaly	Early liver involvement
Skin hyperpigmentation	Iron + melanin deposition
Loss of body hair, testicular atrophy	Secondary hypogonadism
Synovitis of 2nd/3rd MCP joints	Classic HH-associated arthropathy
Peripheral edema, ascites	Suggest advanced liver disease (cirrhosis)
Peripheral neuropathy	Less common, possible iron-mediated nerve injury

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Complications of Untreated HH

🔹 Hepatic

• Cirrhosis (most common serious complication)
• Hepatocellular carcinoma (HCC):
  • Lifetime risk ↑ 20-fold if cirrhotic
  • Annual incidence ~4% once cirrhosis develops
• Portal hypertension: Variceal bleeding, splenomegaly
• Spontaneous bacterial peritonitis (SBP)
• Hepatic encephalopathy, hepatorenal and hepatopulmonary syndromes

🔹 Pancreatic

• Type 2 diabetes mellitus (iron-mediated β-cell dysfunction)

🔹 Cardiac

• Restrictive or dilated cardiomyopathy (can be reversible if treated early)
• Diastolic dysfunction
• Conduction abnormalities: AV block, arrhythmias

🔹 Endocrine

• Hypogonadotropic hypogonadism
• Hypothyroidism (less common)

🔹 Rheumatological

• Arthritis (especially 2nd and 3rd MCP joints)
• Chondrocalcinosis, pseudogout

🔹 Dermatological

• Bronze skin pigmentation

🔹 Infectious

Increased risk of infection with siderophilic organisms, especially in:

• Raw seafood exposure, iron-overload states
• Includes:
  • Vibrio vulnificus
  • Listeria monocytogenes
  • Yersinia enterocolitica
  • Pasteurella pseudotuberculosis

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Genetic Screening & Family Risk

Who to Screen

• All first-degree relatives of individuals with C282Y homozygosity or clinical HH.
• Genetic testing is preferred to confirm carrier or affected status.

Risk by Family Relationship

Relationship	Estimated Risk of HH Genotype
Sibling of affected patient	25% chance of C282Y homozygosity
Child of affected parent	5% chance (assuming the other parent is unaffected)
Offspring of two carriers	25% chance of homozygosity

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Investigations

🔹 Initial Testing

Patients with suspected iron overload should undergo the following first-line tests:

Test	Purpose
Serum Ferritin	Marker of iron stores and hepatic inflammation
Transferrin Saturation (TSAT)	Marker of iron overload due to increased absorption

Note: Fasting is not strictly necessary, but measuring TSAT in the morning after fasting can reduce diurnal variability.

Serum Ferritin

Interpretation	Thresholds
Elevated ferritin suggestive of iron overload	>300 µg/L in men >200 µg/L in women
Ferritin <1000 µg/L	Cirrhosis is unlikely
Ferritin >1000 µg/L	Suggests high iron burden → consider further evaluation for liver fibrosis or other causes of hyperferritinaemia

📌 Important: Ferritin is an acute phase reactant and may be elevated in non-HH conditions.

❗ Differential Diagnosis of Elevated Ferritin

Category	Examples
Chronic inflammation	Rheumatoid arthritis systemic infections
Alcohol+++ (associated liver injury)	High ferritin + normal TSAT → think alcohol, metabolic dysfunction, inflammation. High ferritin + high TSAT (>45 %) → think HH or combined pathology. Typical in chronic drinkers due to direct marrow toxicity and folate deficiency. – Marked macrocytosis (MCV > 100 fL) with normal TSAT
Liver disease	NAFLD/MAFLD, viral hepatitis
Malignancy or bone marrow disorders	Myelodysplasia, leukemia, lymphoma
Hemolytic or ineffective erythropoiesis	Thalassemia, sickle cell disease, sideroblastic anemia
Iron overload from external sources	Repeated transfusions, iron supplementation for anemia
Metabolic syndrome/obesity	Often associated with mild-moderate ferritin elevation (<1000 µg/L)

Transferrin Saturation (TSAT)

• Calculated as:
  TSAT (%) = (Serum Iron ÷ Total Iron Binding Capacity) × 100

Threshold	Interpretation
>45%	Suggestive of early iron overload
>60% in men >50% in women	Strongly suggestive of HFE-related HH, even if ferritin is normal

Transferrin saturation typically increases before ferritin, making it a sensitive early marker of iron overload in HH.

Role of Transferrin

• Transferrin is the major circulating iron-binding protein.
• In HH, transferrin saturation increases due to:
  • Normal or reduced transferrin levels
  • Elevated serum iron levels
• TSAT >45% is often the earliest biochemical abnormality in HFE-HH.
• Although fasting is not strictly necessary, fasted morning samples improve reproducibility.

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Further Evaluation if Ferritin >1000 µg/L or Secondary Iron Overload Suspected

Consider these investigations to rule out non-HFE iron overload:

Investigation	Purpose
Peripheral blood film	Identify hemolysis or marrow disorders
FBC with indices	Detect microcytosis, hemolysis, ineffective erythropoiesis
Hemoglobinopathy screen	Rule out thalassemia, sickle cell disease
Genetic testing	Confirm HFE mutations (C282Y, H63D)
MRI liver iron quantification	Non-invasive method to assess hepatic iron burden
Liver function tests (LFTs)	Detect hepatic injury, screen for chronic liver disease

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Next Steps After Abnormal Results

Finding	Recommended Action
TSAT >45% AND ferritin elevated	Proceed to HFE genotyping (C282Y, H63D)
Ferritin >1000 µg/L	Evaluate for liver fibrosis (FibroScan, MRI, or biopsy)
TSAT normal, ferritin elevated	Consider alternate causes of hyperferritinaemia

🔹 HFE Genetic Testing

• HFE genotyping should be performed in all patients with:
  • Elevated serum ferritin, and
  • Increased transferrin saturation (TSAT >45%).
• C282Y homozygosity alone does not confirm a diagnosis of hereditary haemochromatosis (HH).
  Diagnosis requires biochemical evidence of iron overload and/or evidence of increased hepatic iron stores.
• Individuals who are C282Y homozygotes with normal iron indices should undergo regular monitoring of ferritin and TSAT.
• In patients with compound heterozygosity (C282Y/H63D) or H63D homozygosity, elevated ferritin levels should prompt evaluation for alternative causes, particularly:
  • Alcohol-related liver disease
  • Metabolic (dysfunction)-associated fatty liver disease (MAFLD/NAFLD)

🔹 Liver Biopsy

• A liver biopsy should be considered in:
  • C282Y homozygotes with serum ferritin >1000 µg/L, due to the increased risk of advanced fibrosis or cirrhosis.
• Histological features suggestive of HH:
  • Hepatic iron index (HII) > 1.9 (calculated as μmol iron per gram dry weight liver ÷ age in years)
  • Predominant iron deposition in hepatocytes (as opposed to Kupffer cells)
  • Perl’s stain shows excessive haemosiderin in hepatocytes
• Iron distribution pattern helps differentiate: CauseIron Predominantly Deposited InHereditary haemochromatosisHepatocytesSecondary iron overload (e.g. transfusions, hemolysis)Kupffer cells / RES macrophages

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Management of Hereditary Haemochromatosis

Screening

• Test all first-degree relatives of patients with confirmed HFE-haemochromatosis (C282Y homozygotes or compound heterozygotes), regardless of clinical status.

Therapeutic Venesection

Venesection is the first-line treatment for patients with iron overload due to hereditary haemochromatosis.

Eligibility Criteria for Venesection

Venesection should be offered to patients who meet all of the following:

• Confirmed HFE-haemochromatosis:
  • C282Y homozygosity, or
  • C282Y/H63D compound heterozygosity with evidence of iron overload (not indicated for heterozygotes with normal TSAT).
• Biochemical or imaging evidence of iron overload, e.g.:
  • Serum ferritin >300 μg/L (men) or >200 μg/L (women)
  • Confirmed by Ferriscan® MRI or liver biopsy
• Stable haemoglobin >120 g/L
• Serum ferritin >25 μg/L (usually >50 μg/L)
• Stable cardiovascular status:
  • Systolic BP: 110–160 mmHg
  • Diastolic BP: 60–95 mmHg
  • Pulse: 50–100 bpm

Other indications for venesection include:

• Polycythaemia vera
• Porphyria cutanea tarda

Iron Unloading Phase

🎯 Goal: Lower serum ferritin to ~50 μg/L

• Frequency: Weekly venesection (~7 mL/kg; max 550 mL)
• Pre-venesection checks:
  • Haemoglobin:
    • If Hb <120 g/L → delay for 1 week
  • Ferritin:
    • Monitor every 4–6 venesections, or more often as ferritin approaches 100 μg/L
• Duration: May take months to years, depending on iron burden

💊 Supportive Measures

• Oral vitamin supplementation to support erythropoiesis:
  • Vitamin B12 5 μg/day
  • Folic acid 500 μg/day

Lifelong Maintenance Phase

🎯 Goal: Maintain serum ferritin ~50–100 μg/L

• Venesection frequency: Tailored to the individual; typically 2–6 sessions per year
• Pre-venesection Hb: Check before each procedure
• Serum ferritin monitoring:
  • At least annually
  • Often required every 2–6 months

Key principle: Ferritin monitoring is essential to avoid both under- and over-treatment.

Potential Complications of Venesection

Complication	Management
Haematoma	Local compression, apply cold pack
Hypovolaemia	Monitor BP, ensure adequate hydration
Vasovagal syncope	Lay patient flat, monitor vitals
Venous scarring	Rotate venesection sites
Phlebitis	Warm compresses, analgesia if needed
Adverse reaction to lignocaine (if used)	Observe and manage anaphylaxis if required
Acute distress (e.g. tachycardia, hypotension, diaphoresis)	Stop venesection and review immediately

Expected Outcomes of Phlebotomy

System	Effect
Iron stores	Gradual depletion and normalization
Fatigue	Often improves or resolves
Skin pigmentation	Gradual fading of bronzing
Cardiac	Improved function; cardiomyopathy may reverse if early
Liver	Reduced hepatomegaly and improved LFTs 30% regression of fibrosis
Diabetes	May not improve significantly with iron removal

Dietary Advice

• Avoid high-dose supplements — vitamin C enhances iron absorption and may exacerbate iron overload.
• Alcohol: Strongly advised to avoid due to hepatotoxicity.
• Iron-rich foods: No need for a low-iron diet, as venesection is highly effective, but:
• Patients may choose to moderate red meat intake (e.g. ~90–120 g/day) to reduce venesection frequency.
• Vitamin C supplements: Avoid high-dose supplements — vitamin C enhances iron absorption and may exacerbate iron overload.

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what if Low Haemoglobin + Raised Ferritin in a Known/ Suspected HFE-Haemochromatosis Patient

Step	Key question	Management	Rationale
1️⃣ Stabilise	Is the anaemia acute and symptomatic?	– Resuscitate – Transfuse packed RBCs if Hb < 70 g/L (or < 80 g/L with CV disease / symptoms)	Blood transfusion is life-saving and unavoidable iron comes with it.
2️⃣ Clarify cause	Is the low Hb due to blood loss or true iron deficiency?	Investigate & control bleeding (endoscopy, imaging, etc.).	In HFE patients ↓Hb is almost always blood loss (or marrow disease), not insufficient body iron.
3️⃣ Check iron indices once stable	After bleed is controlled and inflammation settled (≈ 4 weeks): – Ferritin – TSAT	• Typical finding: ferritin still high, TSAT > 45 % → iron overload persists → NO iron supplementation. • Uncommon scenario: ferritin < 30 µg/L and TSAT < 20 % → genuine iron deficiency → consider short oral iron course only then.	Ferritin is an acute-phase reactant; re-test when CRP normal. True iron deficiency is rare in HH but can occur after prolonged venesection + chronic bleeding.
4️⃣ Resume venesection	Has Hb recovered to ≥ 120 g/L and bleeding stopped?	Restart unloading / maintenance venesection schedule.	Prevents re-accumulation of toxic iron.

Practical rules of thumb

1. Do not give IV or oral iron up-front to an HH patient with anaemia.
2. Treat or transfuse first, investigate second, supplement iron only if objective deficiency is proven.
3. A high ferritin with low Hb ≠ iron deficiency in HH — it almost always reflects blood loss + inflammation.
4. Resume venesection only when Hb is safe; pausing briefly does not harm, but iron supplementation can.

Bottom line:
In hereditary haemochromatosis, anaemia almost never needs iron replacement; focus on controlling bleeding, transfuse if necessary, and verify true deficiency before you prescribe iron.