Wilson Disease & Haemochromatosis
Medicine · GIT & Hepatology · lean revision notes
Wilson Disease & Haemochromatosis
Two classic "metal overload" disorders of the liver that are perennial NEET PG favourites. Wilson disease = copper accumulation (autosomal recessive, ATP7B); hereditary haemochromatosis = iron overload (autosomal recessive, HFE/C282Y). Both are treatable if caught early, both cause cirrhosis — and examiners love to test the diagnostic values, the eponymous signs, and the drugs of choice.
1. Wilson Disease (Hepatolenticular Degeneration)
Definition & genetics
Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutation of the ATP7B gene on chromosome 13 (13q14.3). ATP7B is a copper-transporting P-type ATPase in hepatocytes responsible for (a) incorporating copper into caeruloplasmin and (b) excreting copper into bile (the major route of copper elimination). Loss of function → copper cannot be excreted in bile → copper accumulates first in the liver, then overflows into blood and deposits in the brain (basal ganglia), cornea, kidneys and RBCs.
High-yield: The primary defect in Wilson disease is failure of biliary copper excretion, NOT impaired caeruloplasmin synthesis. Low caeruloplasmin is a consequence (copper-free apocaeruloplasmin is degraded faster).
Pathophysiology in one line
ATP7B mutation → defective biliary copper excretion + defective Cu loading onto caeruloplasmin → hepatic Cu overload → hepatocyte injury → spill-over of free (non-caeruloplasmin-bound) Cu into circulation → deposition in brain, cornea, kidney, joints, RBC.
Clinical features
Age of presentation is a strong clue:
- Hepatic presentation: typically children & young adults (5–35 yr). Spectrum: asymptomatic transaminitis → chronic hepatitis → cirrhosis → fulminant (acute) liver failure. Fulminant Wilson is classically associated with Coombs-negative (non-immune) haemolytic anaemia and a characteristically low alkaline phosphatase.
- Neurological presentation: usually later (older teens to 30s–40s). Extrapyramidal features dominate — tremor (wing-beating tremor), dystonia, dysarthria, drooling, parkinsonism, gait disturbance, "risus sardonicus" facies. Pure neurological disease almost always has Kayser-Fleischer rings.
- Psychiatric: depression, personality change, declining school performance, psychosis (common, often missed).
- Eyes: Kayser-Fleischer (KF) rings — golden-brown/greenish copper deposits in Descemet's membrane at the corneal limbus; best seen on slit-lamp examination. Sunflower cataract (lens copper).
- Others: renal — Fanconi syndrome (type 2 proximal RTA), nephrolithiasis; haemolytic anaemia; arthropathy, osteoporosis; cardiomyopathy; blue lunulae of nails.
High-yield: A young person with liver disease + neuropsychiatric symptoms + haemolysis = Wilson disease until proven otherwise. KF rings are present in almost 100% of patients with neurological Wilson but may be absent in those with isolated hepatic disease.
Investigations — the diagnostic table
| Test | Wilson disease finding | Pearl |
|---|---|---|
| Serum caeruloplasmin | Low (< 20 mg/dL; < 5 strongly suggestive) | Acute-phase reactant → can be falsely normal in inflammation/pregnancy/oestrogen |
| Serum total copper | Low (because caeruloplasmin is low) | Free (non-caeruloplasmin) copper is high |
| 24-hour urinary copper | High (> 100 µg/day); > 40 µg suggestive | Best non-invasive screen for symptomatic disease |
| Slit-lamp for KF rings | Present | Always order ophthalmology referral |
| Liver biopsy — hepatic copper | > 250 µg/g dry weight (GOLD STANDARD) | Most definitive quantitative test |
| Penicillamine challenge | Urinary Cu rises markedly | Useful in children |
| Genetic testing (ATP7B) | Confirmatory; used for family screening | > 600 mutations described |
High-yield: Hepatic copper > 250 µg/g dry weight on biopsy is the diagnostic gold standard. The best non-invasive confirmatory clue is low caeruloplasmin + high 24-hr urinary copper + KF rings.
The Leipzig (Ferenci) scoring system is the named diagnostic criteria combining KF rings, neuro symptoms, caeruloplasmin, urinary/hepatic copper, Coombs-negative haemolysis and genetics — a score ≥ 4 = diagnosis established.
MRI brain: "face of the giant panda" sign in the midbrain (classic eponymous radiological sign) and bilateral basal ganglia (putamen, globus pallidus) T2 hyperintensities.
Diagnostic flow
Suspect (young, liver ± neuro ± haemolysis) → serum caeruloplasmin + slit-lamp for KF rings → 24-hr urinary copper → if equivocal, liver biopsy for quantitative copper → ATP7B genetic testing + screen first-degree relatives.
Management / drug of choice
The principle is remove copper, then prevent re-accumulation.
| Drug | Mechanism | Notes / adverse effects |
|---|---|---|
| D-Penicillamine | Chelator → urinary copper excretion | Classic first-line. Give pyridoxine (B6) to prevent deficiency. May cause initial neurological worsening, nephrotic syndrome, marrow suppression, lupus-like reaction, elastosis perforans. |
| Trientine | Chelator (better tolerated) | Preferred if penicillamine intolerance; increasingly first-line |
| Zinc (acetate/sulphate) | Induces metallothionein in enterocytes → blocks dietary Cu absorption | Maintenance therapy & presymptomatic patients; safe in pregnancy |
| Tetrathiomolybdate | Blocks Cu absorption + binds plasma Cu | Promising for neurological Wilson (less paradoxical worsening) |
| Liver transplant | Corrects metabolic defect (curative) | For fulminant Wilson or decompensated cirrhosis not responding to chelation |
High-yield: Fulminant hepatic failure due to Wilson disease → liver transplantation (it corrects the underlying ATP7B defect). Chelators are too slow for fulminant disease. High-yield: In neurological Wilson, starting D-penicillamine can worsen neurology transiently ("initial neurological deterioration"); zinc or trientine/tetrathiomolybdate are preferred to avoid this.
Diet: avoid copper-rich foods — shellfish, liver, nuts, chocolate, mushrooms, dried fruit.
Complications
Cirrhosis & portal hypertension, hepatocellular failure, fulminant liver failure with haemolysis, irreversible neurological deficits, Fanconi syndrome/renal stones, haemolytic crises, cardiomyopathy, pancreatitis, hypoparathyroidism, infertility/recurrent abortion.
2. Hereditary Haemochromatosis (HH)
Definition & genetics
Hereditary haemochromatosis is an autosomal recessive disorder of iron metabolism leading to progressive parenchymal iron overload. Type 1 (classic, adult) HH is due to mutation in the HFE gene on chromosome 6 (6p). The commonest pathogenic mutation is C282Y (cysteine→tyrosine at codon 282; homozygosity causes most clinical disease); H63D is a second, weaker variant. It is one of the commonest autosomal recessive disorders in people of Northern European descent.
High-yield: HFE gene, chromosome 6, C282Y mutation (homozygous) is the classic exam answer for adult hereditary haemochromatosis.
Pathophysiology
HFE regulates hepcidin, the master iron-regulatory hormone. Mutated HFE → inappropriately LOW hepcidin → unrestrained ferroportin activity in enterocytes and macrophages → excessive intestinal iron absorption and release → iron deposits as haemosiderin in liver, pancreas, heart, pituitary, joints, skin, gonads → free-radical (Fenton) tissue injury and fibrosis.
High-yield: The unifying defect in HH is low hepcidin → iron hyperabsorption. Iron is deposited in parenchymal cells (vs transfusional/secondary overload where Kupffer/reticuloendothelial cells load first).
Other (non-HFE) types — quick reference
| Type | Gene/defect | Note |
|---|---|---|
| Type 1 | HFE (C282Y) | Commonest, adult onset |
| Type 2 (juvenile) | HJV (hemojuvelin) / HAMP (hepcidin) | Most severe; cardiac & hypogonadism early, < 30 yr |
| Type 3 | TfR2 (transferrin receptor 2) | |
| Type 4 | Ferroportin (SLC40A1) | Autosomal dominant |
Clinical features — the classic triad & beyond
The textbook triad of advanced disease ("bronze diabetes"):
- Skin hyperpigmentation (slate-grey/bronze — due to melanin + haemosiderin)
- Diabetes mellitus (pancreatic islet iron deposition)
- Hepatomegaly / cirrhosis
Mnemonic for organ involvement — "6 C's of haemochromatosis": Cirrhosis, Cardiomyopathy, Carcinoma (HCC), Diabetes (suCrose/sugar), Chondrocalcinosis (arthropathy), and skin Colour (bronze). Add C282Y and Chromosome 6.
Other features:
- Arthropathy — characteristically 2nd & 3rd MCP joints ("iron fist"), with chondrocalcinosis/pseudogout (CPPD).
- Cardiac — restrictive then dilated cardiomyopathy, arrhythmias, conduction block (a leading cause of death).
- Endocrine — diabetes, hypogonadotrophic hypogonadism (impotence, loss of libido, amenorrhoea), hypothyroidism.
- Hepatic — cirrhosis with markedly increased risk of hepatocellular carcinoma (HCC ~ up to 200× / 20–30%).
- Increased susceptibility to infections by iron-loving organisms — Vibrio vulnificus, Listeria, Yersinia enterocolitica.
High-yield: Men present earlier and more severely than women — women are relatively protected by menstrual & pregnancy iron loss, so they present post-menopausally. Symptoms typically appear after age 40 (men) / 50 (women).
Investigations
| Test | Finding | Comment |
|---|---|---|
| Transferrin saturation (fasting) | Raised (> 45%; often > 60%) | Best initial screening test; earliest abnormality |
| Serum ferritin | Raised (> 200 women / > 300 men; often > 1000) | Marker of iron stores & prognosis; acute-phase reactant |
| Serum iron | High; TIBC low | |
| HFE genotyping (C282Y/H63D) | Confirms type 1 | After biochemical abnormality |
| Liver MRI | Quantifies hepatic iron (non-invasive) | Largely replaced biopsy |
| Liver biopsy + Perls' Prussian blue stain | Hepatic iron index; periportal/parenchymal iron | Now mainly for staging fibrosis if ferritin > 1000 / abnormal LFTs |
High-yield: Fasting transferrin saturation is the single best screening test; serum ferritin reflects total body iron load and guides therapy. A ferritin > 1000 µg/L flags higher risk of cirrhosis → consider biopsy.
Diagnostic flow
Suspect (fatigue, arthralgia, bronze skin, diabetes, abnormal LFTs, family history) → fasting transferrin saturation + ferritin → if both raised → HFE genotyping → if C282Y homozygous, confirmed → assess organ damage (LFTs, MRI iron, echo, glucose) → screen first-degree relatives.
Management / treatment of choice
High-yield: Therapeutic phlebotomy (venesection) is the treatment of choice. Remove ~500 mL blood (≈ 250 mg iron) weekly until iron-depleted, then lifelong maintenance phlebotomy.
- Target: ferritin ~ 50 µg/L and transferrin saturation < 50% during de-ironing; maintenance keeps ferritin 50–100.
- Iron chelation (deferoxamine IV/SC, or oral deferasirox/deferiprone) is reserved for those who cannot tolerate venesection (e.g. anaemia, severe cardiac disease) — and is the mainstay in secondary/transfusional iron overload (e.g. thalassaemia).
- Avoid: vitamin C supplements (enhance iron absorption & mobilisation), iron supplements, raw shellfish (Vibrio), excess alcohol.
- HCC surveillance (USG ± AFP, 6-monthly) in cirrhotics; liver transplant for decompensation/HCC.
- Phlebotomy improves skin pigmentation, cardiac function and diabetes control, and prevents cirrhosis if started before fibrosis — but does not reverse established cirrhosis, arthropathy or hypogonadism.
Complications
Cirrhosis → hepatocellular carcinoma, portal hypertension; cardiomyopathy & arrhythmias; diabetes mellitus; hypogonadism/infertility; destructive arthropathy & chondrocalcinosis; increased risk of specific infections.
3. Wilson vs Haemochromatosis — direct comparison
| Feature | Wilson disease | Hereditary haemochromatosis |
|---|---|---|
| Metal | Copper | Iron |
| Gene / chromosome | ATP7B / chr 13 | HFE (C282Y) / chr 6 |
| Inheritance | Autosomal recessive | Autosomal recessive (type 1) |
| Core defect | ↓ biliary Cu excretion | ↓ hepcidin → ↑ Fe absorption |
| Typical age | Young (5–35 yr) | > 40 yr (later in women) |
| Hallmark sign | Kayser-Fleischer ring (slit-lamp) | Bronze skin + diabetes |
| Neuropsychiatric | Prominent (basal ganglia) | Usually absent |
| Key bloods | ↓ caeruloplasmin, ↑ urine Cu | ↑ transferrin sat, ↑ ferritin |
| Biopsy gold standard | Hepatic Cu > 250 µg/g | Perls' stain + hepatic iron index |
| Eponymous imaging | "Face of giant panda" (MRI) | Hepatic iron on MRI |
| Treatment of choice | Penicillamine/trientine + zinc; transplant in fulminant | Venesection (phlebotomy); chelation if intolerant |
| Cancer risk | Low (HCC uncommon) | High HCC risk |
4. Key differentials
For Wilson disease:
- Autoimmune hepatitis, viral hepatitis, NAFLD (other causes of young-onset chronic liver disease)
- Other movement disorders: juvenile Parkinsonism, Huntington disease, dystonia, drug-induced parkinsonism
- Causes of low caeruloplasmin without Wilson: Menkes disease (also ATP-ase defect, copper deficiency), aceruloplasminaemia, severe malnutrition, nephrotic syndrome, end-stage liver disease
For haemochromatosis:
- Secondary iron overload — transfusion-dependent thalassaemia/myelodysplasia, chronic haemolysis (loads reticuloendothelial cells first)
- Alcoholic liver disease & NAFLD (can also mildly raise ferritin)
- Porphyria cutanea tarda (associated with iron overload & HCV)
- Causes of raised ferritin without true overload: inflammation/infection, Still's disease, haemophagocytic lymphohistiocytosis, malignancy
High-yield: Menkes disease = X-linked ATP7A defect → copper deficiency (kinky/steely hair, hypotonia, failure to thrive) — the "mirror image" of Wilson disease. Both are copper-ATPase disorders; examiners pair them often.
Recently asked / exam angle
- Single-best diagnostic test: Wilson → "hepatic copper > 250 µg/g dry weight (liver biopsy)"; best non-invasive screen for HH → "fasting transferrin saturation."
- Drug of choice: chelator for symptomatic Wilson = D-penicillamine (with pyridoxine); maintenance/presymptomatic = zinc; HH = venesection.
- Image-based: slit-lamp photo of Kayser-Fleischer ring; MRI "face of the giant panda" sign → Wilson. Perls' Prussian blue–stained liver → iron overload.
- Genetics one-liners: "ATP7B / chromosome 13" (Wilson) vs "HFE C282Y / chromosome 6" (HH).
- Why penicillamine + pyridoxine? — penicillamine is a pyridoxine antagonist.
- Fulminant Wilson clue: Coombs-negative haemolysis + low alkaline phosphatase + low uric acid; ALP : bilirubin ratio < 4 and AST : ALT > 2.2 suggest Wilson-related acute liver failure. Treatment = transplant.
- HH triad: "bronze diabetes" + hepatomegaly; arthropathy of 2nd/3rd MCP joints; protected in menstruating women.
- Infections in HH: Vibrio vulnificus, Listeria, Yersinia (siderophilic organisms).
- Vitamin to avoid in HH: vitamin C (increases iron absorption/toxicity).
- Caeruloplasmin caveat: it is an acute-phase reactant → can be normal despite Wilson disease.
Rapid revision
- Wilson = copper, ATP7B, chromosome 13; HH = iron, HFE C282Y, chromosome 6. Both autosomal recessive.
- Wilson's primary defect = failure of biliary copper excretion; low caeruloplasmin is secondary.
- Kayser-Fleischer rings (Descemet's membrane) on slit-lamp — near-universal in neurological Wilson.
- Wilson labs: ↓ caeruloplasmin, ↑ 24-hr urinary copper (> 100 µg); gold standard = hepatic Cu > 250 µg/g dry weight.
- Wilson MRI = "face of the giant panda"; diagnosis scored by Leipzig (Ferenci) criteria ≥ 4.
- Wilson treatment: penicillamine (+ pyridoxine)/trientine + zinc (maintenance); fulminant Wilson → liver transplant.
- Menkes (ATP7A, X-linked) = copper deficiency — the mirror image of Wilson.
- HH defect = low hepcidin → iron hyperabsorption, parenchymal deposition.
- HH best screen = fasting transferrin saturation (> 45%); ferritin reflects iron load/prognosis.
- HH classic = bronze diabetes, 2nd/3rd MCP arthropathy, cardiomyopathy, hypogonadotrophic hypogonadism, high HCC risk.
- HH treatment of choice = therapeutic venesection; chelation (deferoxamine/deferasirox) for those intolerant or for secondary overload; avoid vitamin C & raw shellfish.
- HH organism risk: Vibrio vulnificus, Listeria, Yersinia; women protected until menopause.