Hereditary Haemochromatosis

Overview & Definition

Haemochromatosis is a syndrome of excessive systemic iron accumulation that, untreated, deposits in and ultimately destroys parenchymal organs. The term spans two broad categories:^[3][7]

• Hereditary (genetic) haemochromatosis (HH) — inherited defects that decrease hepcidin production or activity, removing the brake on intestinal iron absorption and macrophage iron release. Most cases are autosomal recessive; Type 4 (ferroportin) is autosomal dominant.
• Secondary iron overload — iron enters from outside (transfusions, dietary, parenteral) or accumulates from ineffective erythropoiesis (thalassaemia, sideroblastic anaemia, MDS). Macrophage iron is the dominant pool here, and the molecular defect is not in the hepcidin–ferroportin axis (although secondary hepcidin suppression occurs). ^[1]

In day-to-day practice and in NEET-PG/INICET, "haemochromatosis" almost always means HFE Type 1 hereditary haemochromatosis. The clinical skill is recognising iron overload early (when fatigue and arthralgia are the only symptoms) and treating with venesection before cirrhosis develops, because once cirrhosis is established the risk of hepatocellular carcinoma persists even after complete iron depletion.^[1]

The disease is highly penetrant biochemically but weakly penetrant clinically: most C282Y homozygotes develop raised transferrin saturation and ferritin, but only a minority develop the full bronze-diabetes-cirrhosis picture. This explains why screening of first-degree relatives is so rewarding.^[5][6]

Classification

Hereditary haemochromatosis is classified by the mutated gene, the inheritance, the age of onset, and the distribution of iron deposition (parenchymal versus reticuloendothelial/macrophage):^[2][3]

^[1]

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Non-HFE genetic iron overload (rarer, but examinable):^[2]

• Aceruloplasminemia (CP gene, AR) — the triad of diabetes, retinal degeneration and basal-ganglia neurological disease (parkinsonism, ataxia) with low serum iron and absent caeruloplasmin; iron trapped in brain and pancreas.
• Atransferrinemia (TF gene) — severe iron-loading anaemia with low transferrin.
• DMT1 (SLC11A2) mutation — microcytic anaemia with hepatic iron loading. ^[1]

Secondary iron overload (must be distinguished from HH before venesection): transfusional iron overload (thalassaemia major, sickle-cell, MDS), chronic ineffective erythropoiesis (sideroblastic anaemia), chronic haemolysis, dietary iron overload (African/Bantu siderosis), excess parenteral iron, and iron overload of chronic liver disease (alcohol, hepatitis C, NAFLD/NASH, porphyria cutanea tarda).^[3]

Epidemiology & Risk Factors

• HFE C282Y homozygosity is the commonest monogenic disorder in people of Northern European (Celtic, Nordic) descent — gene frequency about 1 in 200 to 1 in 250, with a carrier rate of about 1 in 8 to 1 in 10 in this population.^[5]
• Clinical penetrance is low: only about 1 to 2 percent of C282Y homozygotes develop the full bronze-diabetes-cirrhosis picture; biochemical penetrance (raised iron indices) is about 50 to 75 percent in men and lower in women.^[6]
• Sex: clinical disease is 5 to 10 times more common in men. Women lose iron through menstruation and pregnancy, which delays onset until post-menopause (or after hysterectomy); men present at 40 to 60 years.^[3]
• Ethnicity: rare in African, Asian, Hispanic and Polynesian populations (HFE C282Y essentially absent; African iron overload is a separate, non-HFE entity).
• Alcohol: a major co-factor — alcohol increases iron absorption and adds direct hepatotoxicity, accelerating cirrhosis.
• Co-factors that accelerate expression: hepatitis B or C, NAFLD, porphyria cutanea tarda (50 to 70 percent of PCT patients carry HFE mutations), and exogenous iron or vitamin C supplementation.^[3]

Pathophysiology

The hepcidin–ferroportin axis is the master regulator of systemic iron. Understanding it explains every clinical feature of HH.^[2][7]

Normal iron physiology: ^[9][10]

• Humans have no regulated iron excretion — iron losses are comparatively very small, so total body iron content is determined by intestinal absorption and its regulation by hepcidin and ferroportin.^[9]
• Hepcidin, a liver-derived peptide hormone, inhibits iron entry into plasma by binding to and inactivating the iron exporter ferroportin in target cells such as duodenal enterocytes and tissue macrophages — iron is trapped inside cells.^[10]
• Hepcidin is induced in response to increased body iron stores (via the BMP/SMAD signalling pathway) to switch off further absorption, is negatively regulated by the activity of erythrocyte precursors, and its synthesis is induced by inflammatory signals such as interleukin-6.^[10][9]

What goes wrong in HFE haemochromatosis: ^[3]

1. Inappropriately low production of hepcidin is the final common metabolic pathway of the genetic forms — in HFE disease the C282Y/C282Y liver under-produces hepcidin relative to its iron load.^[3]
2. Hepcidin deficiency allows inappropriately increased iron absorption and efflux into the bloodstream — with too little hepcidin, ferroportin is not inactivated and keeps pumping iron into plasma.^[10]
3. Plasma iron concentration rises, with gradual buildup of unshielded non-transferrin-bound iron (NTBI), and iron accumulates in parenchymal cells — particularly hepatocytes, pancreatic cells and cardiomyocytes.^[10][7]
4. Over years this causes excessive parenchymal iron deposition with eventual tissue damage and organ failure — cirrhosis, diabetes, cardiomyopathy, arthropathy, hypogonadism.^[3]

At the molecular level, C282Y is a cysteine-to-tyrosine substitution at position 282 of the HFE protein. HFE is structurally MHC class I-like; to function it must fold correctly, bind beta-2-microglobulin, and travel to the basolateral hepatocyte membrane where it interacts with transferrin receptor 1. The C282Y mutation abolishes the critical disulphide bond, so the misfolded protein is retained in the endoplasmic reticulum and never reaches the cell surface — the liver literally cannot "see" its own iron stores and under-produces hepcidin. The milder H63D mutation (aspartate-to-histidine at position 63) distorts the ligand-binding pocket but still allows surface trafficking, which is why H63D homozygotes and C282Y/H63D compound heterozygotes load iron far less often and rarely develop end-organ disease.^[2][7]

Organ-specific consequences of parenchymal iron:^[3][7]

• Liver — hepatocyte necrosis activates Kupffer cells, which release TGF-beta and activate hepatic stellate cells, driving fibrosis → cirrhosis. Cirrhosis carries a 200-fold increased risk of hepatocellular carcinoma (the leading cause of death in treated adult HH).
• Pancreas — beta-cell iron deposition impairs insulin secretion, producing diabetes mellitus (often insulin-requiring).
• Heart — myocyte iron causes dilated cardiomyopathy and conduction disease/arrhythmia (atrial fibrillation, ventricular tachycardia). Cardiac failure is the leading cause of death in juvenile (Type 2) disease.
• Skin — increased melanin plus dermal iron produces the characteristic bronze/slate-grey pigmentation (so the disease is "bronze" rather than purely "iron-grey").
• Pituitary and gonads — iron in gonadotrophs causes hypogonadotropic hypogonadism: impotence and loss of libido in men, amenorrhoea and infertility in women, testicular atrophy, gynaecomastia.
• Joints — iron in synoviocytes promotes calcium pyrophosphate deposition (chondrocalcinosis, pseudogout) and a characteristic osteoarthritis of the 2nd and 3rd metacarpophalangeal joints with hook-like osteophytes.
• Infection susceptibility — iron is an essential growth factor for Vibrio vulnificus (raw shellfish, fatal septicaemia), Listeria monocytogenes, Yersinia enterocolitica and some Candida; iron overload impairs neutrophil and macrophage function. ^[1]

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^{[7] [10] [3]}

Clinical Presentation

The classic tetrad (only seen in late, untreated disease) is cirrhosis, diabetes mellitus, skin pigmentation and hypogonadism — historically called bronze diabetes.^[3] Most modern patients present earlier and more subtly, and many are detected by screening iron studies before any symptom.

^{[8] [6] [12]}

Early / non-specific presentation (the commonest modern picture): ^[1]

• Fatigue, lethargy, weakness (80 percent of symptomatic cases) — vague and often misattributed.
• Arthralgia (40 to 60 percent) — often the first specific symptom, typically 2nd and 3rd MCP ("handshake pain"), wrists, knees, ankles; may precede organ damage by years.
• Right-upper-quadrant discomfort, abdominal pain.
• Loss of libido, erectile dysfunction, amenorrhoea. ^[1]

Established / late presentation — by organ: ^[1]

• Skin — bronze or slate-grey pigmentation, most marked in sun-exposed areas, flexural creases, scars and oral mucosa; due to increased melanin plus dermal iron.
• Liver — hepatomegaly early; later, stigmata of chronic liver disease (palmar erythema, spider naevi, jaundice, ascites, encephalopathy, splenomegaly from portal hypertension).
• Pancreas — diabetes mellitus; frequently insulin-requiring; ketoacidosis uncommon.
• Heart — dilated cardiomyopathy (exertional dyspnoea, oedema, raised JVP, S3 gallop), arrhythmias (atrial fibrillation, ventricular ectopy, sudden death), conduction blocks.
• Endocrine — hypogonadotropic hypogonadism (impotence, testicular atrophy, gynaecomastia, amenorrhoea, loss of axillary/pubic hair); hypothyroidism and adrenal insufficiency less common.
• Joints — chronic arthropathy (2nd and 3rd MCP with hook-like osteophytes, wrists, knees, ankles), chondrocalcinosis (knee menisci, pubic symphysis), pseudogout attacks; spine involvement rare. ^[1]

Atypical presentations to recognise (a recurring examiner theme): ^[1]

• Women — disease delayed to post-menopause by menstrual and pregnancy iron losses; may present after hysterectomy or with early menopause.
• Asymptomatic — abnormal iron indices on routine bloods or during evaluation of fatigue, arthritis, raised ALT, or incidentally found hepatomegaly.
• Elderly — may present with arthropathy alone (mistaken for osteoarthritis), new atrial fibrillation, or heart failure with preserved ejection fraction.
• Juvenile (Type 2, HJV/HAMP) — severe cardiomyopathy and hypogonadism before age 30, often with milder liver disease than HFE; cardiac death if untreated.
• Porphyria cutanea tarda — photosensitive bullous lesions on sun-exposed skin, fragile skin, hypertrichosis; often co-inherited with HFE mutations.
• Acute severe presentation — acute liver failure (rare), or severe sepsis with raw-shellfish exposure (Vibrio vulnificus) or Yersinia bacteraemia in unrecognised iron overload. ^[1]

Differential Diagnosis

A complete differential, with distinguishing features, follows:^[2][3]

The key discriminator across the iron-overload syndromes is the transferrin-saturation pattern with the iron distribution: in HFE haemochromatosis hyperferritinaemia associates with high transferrin saturation, iron-spared macrophages and progressive parenchymal-cell iron load, whereas in ferroportin disease iron is trapped in tissue macrophages (hepatic Kupffer cells) with inappropriately low transferrin saturation.^[11]

• Ferroportin disease (Type 4) — autosomal dominant; macrophage/Kupffer-cell iron; inappropriately low transferrin saturation; one of the commonest causes of genetic hyperferritinaemia regardless of ethnicity.^[11]
• Aceruloplasminemia and atransferrinaemia — further inherited disorders of iron overload caused by deficiency of ceruloplasmin (the plasma ferroxidase) or transferrin (the plasma iron carrier) respectively.^[10]
• Other non-HFE genetic forms — TFR2, HJV and HAMP disease are rarer but share the parenchymal-loading phenotype; FPN1 polymorphisms are the gene variants most commonly responsible for hyperferritinaemia in Africans.^[10][11]
• Alcohol — less a mimic than a modulator: alcohol consumption is an environmental factor that modulates phenotypic expression in C282Y homozygotes.^[3]
• Secondary iron overload — transfusional, dietary or parenteral iron entering from outside, or accumulation from ineffective erythropoiesis (see Classification); assessment of plasma iron parameters, imaging and genetic testing settles the diagnosis non-invasively.^[7]

Clinical & Bedside Assessment

A focused bedside examination looks for organ-specific iron damage:^[1]

• Skin — bronze/slate-grey pigmentation, especially sun-exposed areas, scars, palmar creases, oral mucosa, external genitalia; look for stigmata of chronic liver disease.
• Hands — 2nd and 3rd MCP bony swelling, "handshake sign" (pain on dorsiflexion of the index/MCP joints), hook-like osteophytes; chondrocalcinosis of wrist/knee.
• Abdomen — hepatomegaly (early), later splenomegaly, ascites, caput medusae of portal hypertension; test for hepatic encephalopathy (asterixis).
• Cardiovascular — signs of dilated cardiomyopathy (raised JVP, displaced apex, S3 gallop, basal crackles), irregularly irregular pulse of atrial fibrillation.
• Endocrine / genital — testicular atrophy, gynaecomastia, loss of body hair in men; signs of hypothyroidism; clinical diabetes (random glucose).
• Neurological — peripheral neuropathy, and (in aceruloplasminemia) cerebellar/extrapyramidal signs. ^[1]

Named signs: "Handshake sign" (pain on dorsiflexion of the second and third MCP joints) is characteristic; bronze diabetes is the classic eponymous phenotype; Kayser–Fleischer rings are not present in haemochromatosis (they belong to Wilson disease). ^[1]

Investigations

A two-step strategy: screening iron indices, then confirmatory HFE genotyping, then staging of organ damage.^[1][4]

Step 1 — Screening iron studies

• Fasting transferrin saturation (TSAT) = serum iron divided by total iron-binding capacity (TIBC) multiplied by 100. The earliest and most sensitive abnormality. Thresholds: over 45 percent (some guidelines say over 50 percent in men, over 45 percent in women) warrants HFE testing. A TSAT over 60 percent in men or over 50 percent in women is highly suggestive.^[1]
• Serum ferritin — proportional to body iron stores but is an acute-phase reactant (rises with inflammation, infection, liver disease, alcohol). Investigate if over 300 micrograms per litre (men) or over 200 micrograms per litre (women); over 1000 micrograms per litre strongly suggests significant iron loading and is the trigger for liver fibrosis assessment.
• Repeat abnormal iron indices fasting, on two separate occasions, when the patient is well before pursuing the diagnosis (false positives from recent alcohol, hepatitis, inflammation).

Step 2 — Confirmatory genetic testing

• HFE genotyping for C282Y and H63D (and S65C). C282Y homozygosity with raised iron indices confirms Type 1 HH and obviates the need for liver biopsy purely to confirm the diagnosis.^[1]
• C282Y/H63D compound heterozygotes and H63D homozygotes have low penetrance; treat only if iron loading is confirmed biochemically.
• Non-C282Y cases with confirmed iron loading — request HJV, HAMP, TFR2, SLC40A1 sequencing (juvenile, ferroportin).

Step 3 — Quantify and stage

• Liver biopsy with Perls' Prussian blue stain — historically the gold standard. Quantifies hepatic iron concentration (HIC); hepatic iron index (HII) = HIC divided by age; over 1.9 micromoles per gram dry weight per year supports HH (vs secondary overload). Biopsy is now reserved for staging fibrosis when ferritin over 1000 micrograms per litre, age over 40, elevated AST/ALT, or non-C282Y homozygotes.^[1][4]
• Non-invasive fibrosis — FibroScan (transient elastography), FIB-4, APRI; MRI-based methods.
• MRI T2-star — non-invasive quantification of hepatic and cardiac iron; FerriScan (R2 MRI) is FDA-cleared for liver iron concentration. T2-star under 20 ms indicates significant cardiac iron loading.
• Organ function tests — LFTs, glucose/HbA1c, fasting lipid, FSH/LH/testosterone (or oestradiol), TSH, morning cortisol, alpha-fetoprotein (AFP).
• Cardiac assessment — 12-lead ECG (arrhythmia, conduction), echocardiogram (systolic/diastolic function), cardiac MRI T2-star.
• Liver ultrasound plus AFP every 6 months — hepatocellular carcinoma surveillance in cirrhotics.
• Exclusion of co-factors — hepatitis B and C serology, alcohol history, lipids, glucose; screen for porphyria cutanea tarda (urinary porphyrins) if skin lesions.

Family screening — all first-degree relatives (siblings and children) should have HFE genotyping plus fasting transferrin saturation and ferritin. C282Y homozygous relatives are followed even if biochemically normal.^[1][5]

Management — Resuscitation

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^{[8] [7]}

HH is a chronic disease and rarely presents acutely, but two scenarios need urgent management:^[3]

• Decompensated cirrhosis — treat as for any acute-on-chronic liver failure and refer to a hepatology/transplant centre; remember that cirrhotic patients have shortened life expectancy and a high risk of liver cancer even when complete iron depletion has been achieved.^[12]
• Cardiac decompensation — standard heart-failure and rhythm management; phlebotomy remains the mainstay of iron removal, although iron chelation can be used in some patients when phlebotomy is not tolerated.^[7]

Management — Definitive & Stepwise

The cornerstone of treatment is iron removal.^[1][4]

^{[8] [11]}

First-line: therapeutic venesection (phlebotomy)

• Rationale — phlebotomy is the mainstay therapy for haemochromatosis, and early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications.^[7][8]
• Induction phase — regular venesection with the treatment target of serum ferritin under 50 micrograms per litre (EASL 2022).^[8]
• Maintenance phase — once at target, continue with less-intensive phlebotomy to keep serum ferritin under 100 micrograms per litre during the maintenance phase (EASL 2022).^[8]
• Ferroportin disease (Type 4) — use a non-aggressive phlebotomy regimen with careful monitoring of transferrin saturation and haemoglobin because of the risk of anaemia.^[11]

Second-line: iron chelation (when venesection contraindicated)

Indications: anaemia (thalassaemia, MDS, sideroblastic), severe cardiac failure/cardiomyopathy where venesection not tolerated, Type 4 ferroportin disease with early anaemia.^[3]

• Iron chelation — can be used in some patients in whom phlebotomy is not tolerated or is contraindicated; choice of agent and dosing follow specialist iron-overload protocols.^[7]

Erythrocytapheresis

Removes more iron per session than simple phlebotomy (plasma returned, only red cells removed) — useful where available for rapid depletion or anaemia-prone patients. ^[1]

Lifestyle measures

• Avoid iron supplements (including multivitamins with iron) and high-dose vitamin C (vitamin C enhances iron absorption and, in massive overload, has caused fatal arrhythmia).
• Avoid alcohol (accelerates cirrhosis); counsel abstinence or strict limits.
• Avoid raw shellfish and undercooked seafood (Vibrio vulnificus risk).
• Avoid uncooked marine fish if severely iron loaded; the risk falls to normal once iron depleted. ^[1]

Management of complications

• Hepatocellular carcinoma surveillance — liver ultrasound plus alpha-fetoprotein every 6 months in all cirrhotic HH patients (HCC risk persists after iron depletion).
• Diabetes — standard therapy; insulin frequently required; metformin if appropriate.
• Hypogonadism — testosterone replacement (men), hormone replacement (women, until usual menopause age); fertility needs gonadotrophin therapy.
• Arthropathy — simple analgesia (paracetamol first-line, NSAIDs with caution in cirrhosis/renal impairment), physiotherapy; joint replacement for end-stage disease.
• Cirrhosis — variceal screening (OGD at diagnosis and every 1 to 3 years), hepatocellular carcinoma surveillance, vaccinations (hepatitis A and B, influenza, pneumococcal).
• Liver transplantation — for decompensated cirrhosis or hepatocellular carcinoma meeting criteria; outcomes are worse than for other indications because of cardiac iron involvement and infectious risk, so optimise iron pre-transplant. ^[1]

Family screening and genetic counselling

• Test all first-degree relatives of confirmed cases with HFE genotyping and iron studies.
• Asymptomatic C282Y homozygous relatives: lifelong clinical and biochemical surveillance from early adulthood; venesection if iron loading develops.
• Reproductive counselling for juvenile and ferroportin forms (AR vs AD inheritance changes the recurrence risk). ^[1]

Specific Subtypes & Scenarios

• Juvenile haemochromatosis (Type 2, HJV/HAMP) — more severe and rarer than HFE disease; in a systematic review of HJV-HH, hepatic iron deposition and hypogonadism were the most frequently reported complications, with early-onset disease in the large majority of biallelic cases.^[13][10]
• Ferroportin disease (Type 4, SLC40A1) — autosomal dominant; iron is trapped preferentially in tissue macrophages (the hallmark is marked iron accumulation in hepatic Kupffer cells), transferrin saturation is inappropriately low, and there is a tendency to anaemia after bloodletting — use a non-aggressive phlebotomy regimen with careful monitoring of transferrin saturation and haemoglobin.^[11]
• African iron overload — ferroportin (FPN1) polymorphisms are the gene variants most commonly responsible for hyperferritinaemia in Africans.^[11]
• Women — HFE haemochromatosis typically manifests later in women than in men (diagnosed at 52.6 vs 47.4 years in one prospective series), and pregnancy does not appear to be a protective factor against progressive iron accumulation.^[14]
• Iron overload in a chronic-anaemia patient (thalassaemia, MDS) — phlebotomy is usually not feasible; iron chelation can be used in some patients.^[7]

Complications & Pitfalls

Complications:^[3]

• Cirrhosis — present in about 10 to 15 percent of untreated C282Y homozygotes at diagnosis.
• Hepatocellular carcinoma — 200-fold increased risk, only in cirrhotics; the leading cause of death in treated adult HH; risk persists after iron depletion.
• Cardiomyopathy and arrhythmia — dilated cardiomyopathy, atrial fibrillation, sudden cardiac death; dominant in juvenile disease.
• Diabetes mellitus — usually irreversible.
• Hypogonadism, impotence, infertility — often irreversible.
• Arthropathy — usually irreversible despite iron depletion; major quality-of-life burden.
• Osteoporosis — from hypogonadism.
• Infection — Vibrio vulnificus (raw oysters, septicaemia, haemorrhagic bullae), Yersinia enterocolitica (mesenteric adenitis, septicaemia — iron-dependent), Listeria, Candida; iron withdrawal (venesection) reduces risk. ^[1]

Pitfalls: ^[1]

• Misdiagnosing elevated ferritin as iron overload — ferritin rises in inflammation, infection, alcohol, NAFLD, hepatitis and malignancy; transferrin saturation distinguishes true iron overload (high) from inflammation (low/normal).
• Forgetting to screen the family — a single diagnosis should trigger testing of all first-degree relatives; pre-symptomatic treatment prevents disease.
• Over-venesecting to very low ferritin — causes iron-deficiency anaemia, fatigue and restless legs; aim for 50 to 100 micrograms per litre, not zero.
• Missing HCC surveillance — cirrhotic HH needs 6-monthly ultrasound plus AFP for life, even after iron normalisation.
• Using aggressive venesection in Type 4 ferroportin disease or anaemia — causes dangerous anaemia; switch to small-volume phlebotomy or chelation.
• Failing to vaccinate cirrhotic patients (hepatitis A and B, influenza, pneumococcal). ^[1]

Prognosis & Disposition

• Treated before cirrhosis — normal life expectancy. Iron depletion reverses fatigue, skin pigmentation and hepatic inflammation and may partly improve diabetes and cardiac function.^[1]
• Once cirrhosis develops — survival reduced; HCC risk persists even after complete iron depletion; lifelong HCC surveillance required.
• Arthropathy, hypogonadism and (often) diabetes are irreversible despite iron depletion; manage symptomatically.
• Cardiac iron overload — potentially reversible with chelation and venesection; the dominant reversible cause of death in juvenile disease.
• Disposition — most patients managed as outpatients; admit for decompensated cirrhosis, severe cardiac failure/arrhythmia, severe sepsis or for intensive chelation. Coordinate care between hepatology, cardiology, endocrinology and haematology; consider specialist iron-overload clinic.

Special Populations

• Women — HFE haemochromatosis typically manifests later in women than in men (52.6 vs 47.4 years at diagnosis in one prospective series); pregnancy does not appear to be a protective factor against iron accumulation.^[14]
• Children and young adults — juvenile (Type 2, HJV/HAMP) disease presents early: in a systematic review most biallelic HJV cases had early-onset haemochromatosis, with hepatic iron deposition and hypogonadism the most frequent complications — urgent specialist management.^[13]
• Patients who cannot tolerate phlebotomy — iron chelation can be used in some patients; in ferroportin disease a non-aggressive phlebotomy regimen with careful transferrin-saturation and haemoglobin monitoring is recommended.^[7][11]

Evidence, Guidelines & Regional Differences

Key guidelines:^[1][4]

• AASLD 2011 practice guideline (Bacon et al.) — fasting transferrin saturation over 45 percent triggers HFE testing in symptomatic patients or those with family history; HFE genotyping confirms Type 1; venesection first-line to ferritin 50 to 100 micrograms per litre; liver biopsy to stage fibrosis when ferritin over 1000 micrograms per litre, age over 40, or elevated ALT/AST.
• EASL 2010 guideline — broadly concordant; emphasises non-invasive fibrosis assessment and 6-monthly HCC surveillance in cirrhosis.
• BSH (British Society for Haematology) / UK guideline (Dooley & Worwood) — recommends screening of first-degree relatives and the same iron-study thresholds; UK uses ferriScan and MRI T2-star increasingly. ^[1]

Landmark evidence:^[5][6]

^{[5] [6]}

Controversies: ^[1]

• Population screening for HFE — favoured in Northern-European-origin populations on cost-effectiveness grounds but contested because of low clinical penetrance and the ethical burden of identifying a gene most carriers never express.
• Chelation versus venesection in HFE disease with mild anaemia — venesection remains first-line; chelation is rarely needed in pure HFE Type 1. ^[1]

^{[1] [1] [1]}

Exam Pearls

^{[8] [12] [6] [5]}

• Commonest cause of HH in Northern Europeans = C282Y/C282Y homozygosity of HFE on chromosome 6p21.3 (autosomal recessive). H63D is common but weakly penetrant.^[2]
• Bronze diabetes = cirrhosis plus diabetes plus skin pigmentation (plus hypogonadism for the full tetrad).
• Screen with fasting transferrin saturation (over 45 percent) and ferritin; confirm with HFE genotyping (no biopsy needed for diagnosis in C282Y homozygotes).
• Pathophysiology in one sentence: mutant HFE fails to up-regulate hepcidin; ferroportin unchecked; unregulated iron absorption; Fenton-chemistry oxidative injury to parenchymal cells.
• Treatment = venesection first-line (one unit/week, target ferritin 50 to 100 micrograms per litre); chelation (deferasirox, deferiprone, deferoxamine) if venesection contraindicated.
• Mnemonic "ABCDEF" for organs: Arthropathy, Bronze skin, Cardiomyopathy, Diabetes, Endocrine (hypogonadism), Fibrosis (liver).
• Iron deposits in parenchymal cells (hepatocytes) — distinguishes HFE disease from secondary overload (macrophage-predominant).
• Avoid alcohol, iron supplements, vitamin C, raw shellfish (Vibrio vulnificus).
• HCC only in cirrhosis; surveillance 6-monthly ultrasound plus AFP for life.
• Cardiac death is the leading cause in juvenile (Type 2) HH (HJV or HAMP).
• Handshake sign — pain on dorsiflexion of 2nd/3rd MCP.
• Screen all first-degree relatives (siblings and children) with HFE plus iron studies.
• Porphyria cutanea tarda co-inherits HFE mutations — venesection treats both.
• Treated before cirrhosis — normal life expectancy.

Exam application bank (NEET-PG / INICET)

One-line answer

Hereditary haemochromatosis (HH) is an autosomal recessive disorder of iron homeostasis causing inappropriate, unregulated intestinal iron absorption that progressively deposits in parenchymal organs — liver (cirrhosis, hepatocellular carcinoma), pancreas (diabetes), heart (cardiomyopathy, arrhythmia), skin (bronzing), joints (arthropathy), pituitary and gonads (hypogonadism). The commonest cause is homozygous C282Y mutation in the HFE gene on chromosome 6p (Type 1). Screen with transferrin saturation over 45 percent and serum ferritin; confirm with HFE genetic testing. Cornerstone treatment is therapeutic venesection (phlebotomy) to target ferritin 50 to 100 micrograms per litre, with iron chelation reserved for those who cannot be venesected. Treated before cirrhosis, life expectancy is normal.

Worked stems (answer without another resource)

Stem 1 — Classic presentation. Map symptoms to mechanism; name the first investigation and first treatment step with dose/route if drug therapy is standard. ^[1]

Stem 2 — Unstable / complicated. List red flags that force immediate resuscitation, theatre, ICU, antidote, or reperfusion — and what you do in the first 15 minutes. ^[1]

Stem 3 — Atypical group. Elderly, pregnancy, child, or immunocompromised: how presentation and thresholds change. ^[1]

Stem 4 — Differential trap. Name the three closest mimics and one discriminator for each. ^[1]

Stem 5 — Disposition. Who goes home with safety-netting, who is admitted, who needs HDU/ICU/theatre, and what follow-up is mandatory. ^[1]

Rapid viva checklist

1. Definition + classification
2. Pathophysiology chain
3. Bedside signs / criteria
4. Score with exact components (if any)
5. Emergency bundle
6. Definitive therapy with doses
7. Complications of disease and of treatment
8. Special populations
9. Guideline/trial name if classic
10. Three exam traps

Coverage self-check

If you cannot answer any stem above from this page alone, re-read the matching section — the page is intended to be self-sufficient for final-prof and NEET-PG/INICET questions on Hereditary Haemochromatosis.

References14ShowHide

1. [1]Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases Hepatology, 2011.PMID 21452290
2. [2]Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease N Engl J Med, 2004.PMID 15175440
3. [3]Powell LW, Seckington RC, Deugnier Y. Haemochromatosis Lancet, 2016.PMID 26975792
4. [4]European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis J Hepatol, 2010.PMID 20471131
5. [5]Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population N Engl J Med, 2005.PMID 15858186
6. [6]Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis N Engl J Med, 2008.PMID 18199861
7. [7]Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis Nat Rev Dis Primers, 2018.PMID 29620054
8. [8]European Association for the Study of the Liver. EASL Clinical Practice Guidelines on haemochromatosis J Hepatol, 2022.PMID 35662478
9. [9]Ganz T. Systemic iron homeostasis Physiol Rev, 2013.PMID 24137020
10. [10]Pantopoulos K. Inherited Disorders of Iron Overload Front Nutr, 2018.PMID 30420953
11. [11]Pietrangelo A. Ferroportin disease: pathogenesis, diagnosis and treatment Haematologica, 2017.PMID 29101207
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