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Wilson's Disease

High EvidenceUpdated: 2025-12-24

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Red Flags

  • Acute Liver Failure (Encephalopathy + Coagulopathy)
  • Hemolytic Anaemia (Coombs Negative)
  • Rapidly progressive Dystonia
  • Fulminant Wilson's
Overview

Wilson's Disease

1. Clinical Overview

Summary

Wilson's Disease (Hepatolenticular Degeneration) is a rare Autosomal Recessive disorder of copper metabolism caused by mutations in the ATP7B gene (Chromosome 13). Defective biliary excretion of copper leads to its toxic accumulation in the Liver, Brain (Basal Ganglia), and Cornea. It is a "Chameleon" disease, presenting either with liver disease (hepatitis, cirrhosis, acute failure) or neuropsychiatric symptoms (tremor, dystonia, personality change). It is fatal if untreated but treatable with life-long copper chelation (Penicillamine/Trientine) or Zinc. Diagnosis involves low serum caeruloplasmin, high urinary copper, and Kayser-Fleischer (KF) rings. [1,2]

Key Facts

  • Age of Onset: Typically 5-35 years. (Liver presentation is younger; Neuro presentation is older).
  • Inheritance: Autosomal Recessive (1 in 30,000).
  • Gene: ATP7B (Chr 13).
  • Pathology: Copper overload.
  • Classic Sign: Kayser-Fleischer Rings (95% of Neuro cases, 50% of Liver cases).
  • Prognosis: Excellent if treated early. Irreversible if delayed.

Clinical Pearls

"The Young Parkinson's": Any patient <40 years presenting with Parkinsonism (Tremor, Rigidity) MUST be screened for Wilson's. It is one of the few reversible causes.

"KF Rings are not visible to naked eye": You need a Slit Lamp examination by an ophthalmologist. Do not rule it out at the bedside.

"Alkaline Phosphatase Rule": In acute liver failure due to Wilson's, the ALP is often paradoxically LOW (due to zinc displacement by copper?), and the AST/ALT ratio is >2. Also, Coombs negative Haemolytic Anaemia is a huge clue.

"Face of the Giant Panda": MRI Brain sign showing high signal in the tegmentum with normal red nucleus.

2. Epidemiology

Incidence

  • 1 in 30,000 live births.
  • Carrier frequency: 1 in 90.

Demographics

  • Hepatic: Peak age 10-14.
  • Neurologic: Peak age 20-30.
  • Rare but possible after age 50.
3. Pathophysiology

Copper Metabolism 101

  1. Absorption: Dietary copper (shellfish, nuts, chocolate) absorbed in stomach/duodenum.
  2. Transport: Taken to liver via portal vein.
  3. The Hepatocyte:
    • Copper binds to ATP7B (a Trans-Golgi network protein).
    • Function 1: ATP7B loads copper onto Apocaeruloplasmin to form Caeruloplasmin (secreted into blood).
    • Function 2: ATP7B excretes excess copper into Bile (Faeces).
  4. Defect in Wilson's:
    • ATP7B is broken.
    • Failure to load Caeruloplasmin -> Low Serum Caeruloplasmin (Unstable apoprotein degrades).
    • Failure to excrete in bile -> Copper accumulates in hepatocyte.

The Spillover

  • Once the liver is saturated, "Free Copper" spills into the blood.
  • This non-caeruloplasmin bound copper deposits in:
    • Brain: Basal Ganglia (Putamen/Globus Pallidus) -> Movement disorder.
    • Cornea: Descemet's membrane -> KF Rings.
    • Kidney: Renal tubular damage.
    • RBCs: Oxidative damage -> Haemolysis.
4. Clinical Presentation

A. Hepatic (40% of cases)

B. Neurological (40% of cases)

C. Psychiatric (10-20% of cases)

D. Ophthalmic

Acute Hepatitis
Jaundice, malaise.
Chronic Cirrhosis
Spider naevi, splenomegaly, varices.
Acute Liver Failure (Fulminant)
Catastrophic presentation. Encephalopathy, Coagulopathy. Often accompanied by Acute Renal Failure and Haemolysis. High mortality without transplant.
5. Investigations

Screening Tests

  1. Serum Caeruloplasmin:
    • Low (<0.2 g/L) in 90% of cases.
    • False Normals: Acute phase reactant (Inflammation/Pregnancy) can raise it to normal range.
    • False Positives: Malnutrition, Menkes disease, Heterozygotes.
  2. Serum Copper:
    • Actually LOW (because total copper = caeruloplasmin-bound + free). Since caeruloplasmin is low, total is low.
    • "Free Copper" (Non-caeruloplasmin bound) is HIGH.
  3. 24-hour Urinary Copper:
    • >100 mcg/24h (>1.6 micromol) is diagnostic.
    • Increased by Penicillamine challenge.

Confirmatory Tests

  1. Slit Lamp Exam: Assessing for KF rings.
  2. Liver Biopsy:
    • Gold Standard for difficult cases.
    • Hepatic Copper Content >250 mcg/g dry weight.
  3. Genetics:
    • ATP7B sequencing. (Caution: Hundreds of mutations exist).

Imaging

  • MRI Brain:
    • Hyperintensity in T2/FLAIR in Basal Ganglia (Putamen, Thalamus, Brainstem).
    • "Face of the Giant Panda": High signal in tegmentum, normal red nucleus. (Classic but rare).
    • Cortical atrophy.
6. Management

Management Algorithm

        DIAGNOSIS CONFIRMED
                ↓
    ┌───────────┴───────────────┐
SYMPTOMATIC                 ACUTE LIVER
 (Stable)                    FAILURE
    ↓                            ↓
MEDICAL THERAPY            LTX ASSESSMENT
(Chelation/Zinc)           (King's Criteria)
    ↓                            ↓
Lifelong monitoring          TRANSPLANT

3. Deep Dive: Psychiatric Wilson's

"The Great Masquerader."

  • The Trap: 20% of patients present purely to psychiatrists. They are diagnosed with depression, schizophrenia, or "adolescent adjustment disorder".
  • The Window: There is often a 2-3 year delay between psych onset and diagnosis. By then, irreversible brain damage has occurred.
  • Red Flags:
    • Drooling/Dysarthria (often dismissed as side effects of antipsychotics).
    • Deteriorating handwriting (Micrographia).
    • Incongruous affect (Pseudobulbar affect - crying/laughing inappropriately).
  • Treatment:
    • Antipsychotics: CAUTION. Wilson's patients are exquisitely sensitive to Extrapyramidal Side Effects (EPSE). Can cause severe rigidity/NMS. Use Quetiapine or Clozapine (low potency).

4. Case Studies

Case A: The "Difficult" Teenager.

  • 15-year-old girl. Drop in grades. Argumentative. Started self-harming.
  • Psychiatry DX: Borderline Personality Disorder + Depression. Started on Sertraline.
  • 6 months later: Developed a tremor. GP thought it was anxiety.
  • 1 year later: Jaundice.
  • Diagnosis: Wilson's.
  • Outcome: Developed cirrhosis. Tremor permanent. A tragedy of delayed diagnosis.

Case B: The "Functioning" Alcoholic.

  • 40-year-old man. Elevated liver enzymes for years. "Fatty liver".
  • Admitted with "Alcoholic Hepatitis" (AST > ALT).
  • But he denied drinking.
  • Eye exam: KF Rings present.
  • Diagnosis: Late-onset Wilson's.
  • Outcome: Responded well to Chelation. Liver fibrosis regressed.

5. Medical Therapy (The "De-Coppering" Phase)

  • First Line: Chelators.
    • Penicillamine (D-Pen):
      • Mechanism: Binds copper, promotes urinary excretion.
      • Dose: 250-500mg QDS (Empty stomach).
      • Adverse Effects: Severe. Nephrotic syndrome, Lupus-like syndrome, Bone marrow suppression, Elastosis perforans serpiginous. Neurological worsening in 20% (mobilised copper floods brain).
      • Concurrent: Give Pyridoxine (Vit B6) to prevent neuropathy.
    • Trientine:
      • Alternative chelator. Fewer side effects. Preferred in neuro presentations.
  • Second Line / Maintenance: Zinc Salts.
    • Mechanism: Induces Metallothionein in gut enterocytes. This binds copper and prevents absorption (locks it in the gut cell which is then shed).
    • Use: Maintenance therapy (once de-coppered) or Presymptomatic siblings.
    • Dose: Zinc Acetate/Sulphate 50mg TDS.

2. Monitoring

  • Aim for "Free Copper" < 2.3 micromol/L.
  • Monitor FBC/Renal (Penicillamine toxicity).
  • Avoid high copper foods (Liver, Shellfish, Chocolate, Nuts - "The Fun Foods").

3. Acute Liver Failure

  • Chelation is too slow.
  • Plasma Exchange / Albumin Dialysis (MARS): Can temporarily remove copper to bridge to transplant.
  • Liver Transplant: Curative. (The new liver has normal ATP7B).

7. Surgical Atlas: The Failing Liver

A. Assessing Severity in Acute Failure

  • The Challenge: Standard criteria (MELD/Child-Pugh) are for chronic cirrhosis. In Acute Wilson's, we need to decide RAPIDLY if the liver will recover or if a transplant is needed this week.
  • Modified King's College Criteria:
    • Specific for Wilson's Disease.
    • Consider transplant if Score > 11.
    • Components:
      • Bilirubin (>300 mcmol/L) = 1 point
      • INR (>2.2) = 1 point
      • AST (>100-150) = 1 point
      • Age (<17?) = 1 point
      • WBC (High) = 1 point
      • (Note: Various scoring systems exist, e.g., Nazer Index).
  • The Paradox: In Wilson's, the Alkaline Phosphatase (ALP) is often LOW, and the AST is drastically higher than ALT (ratio >2). This biochemical signature is unique to fulminant Wilson's.

B. Liver Transplantation

  • Indication:
    1. Fulminant Liver Failure (King's score >11).
    2. Decompensated Cirrhosis unresponsive to medical therapy.
  • The Procedure: Orthotopic Liver Transplant (OLT).
  • Outcome: The graft has the donor's genome. It produces functional ATP7B. It cures the metabolic defect.
    • Liver: Recovers completely (it is a new liver).
    • Brain: Symptoms usually stabilise or improve, but existing damage (cavitation) may be permanent.

8. Deep Dive: Copper Biochemistry

"The Heavy Metal Traffic." Copper is essential (for Cytochrome c Oxidase in mitochondria) but toxic (Free radical generator).

  • Dietary Intake: ~2-5mg/day.
  • Absorption: Ctr1 transporter in enterocyte.
  • Chaperone: ATOX1 takes copper from Ctr1 to the Golgi.
  • The Gatekeeper (ATP7B):
    • Located in Trans-Golgi Network of Hepatocytes.
    • Role A: Biosynthetic. If copper levels are normal, ATP7B pumps copper INTO the Golgi lumen to be incorporated into Apocaeruloplasmin -> Caeruloplasmin.
    • Role B: Excretory. If copper levels are HIGH, ATP7B traffics to the bile canaliculus membrane and pumps copper OUT into bile.
  • The Defect:
    • In Wilson's, ATP7B fails.
    • Hepatocytes fill up with copper.
    • Mitochondria are poisoned (Oxidative stress).
    • Eventually, cell dies (Necrosis) -> Dumping copper into blood -> "Free Copper" rises -> Deposits in Brain/Eye.
9. Complications
  • Neurological Worsening: 10-50% get WORSE when starting Penicillamine. Can be permanent.
  • Liver Cirrhosis: Portal hypertension, HCC risk (low but present).
  • Arthropathy: Copper deposits in joints.
  • Fanconi Syndrome: Renal tubular acidosis.
8. Prognosis
  • Treated: Normal life expectancy.
  • Untreated: Fatal.
  • Neuro Recovery: Slow (months/years). Symptoms may not fully resolve (especially dystonia).
  • Liver Recovery: Fibrosis can regress. Cirrhosis is irreversible but stable.
9. Evidence and Guidelines
  • EASL Guidelines (2012): Wilson's Disease.
  • AASLD Guidelines (2008).
10. Patient Explanation

What is Wilson's Disease?

It is a genetic condition where your body cannot get rid of extra copper from food. Copper is a trace metal we need in tiny amounts, but in Wilson's, it builds up to dangerous levels in the liver and brain.

How do we treat it?

We use medicines called "chelators" (like Penicillamine) which act like a magnet for copper and help you pee it out. Later, we might switch you to Zinc, which stops you absorbing copper from food. You will need to take tablets for life.

Can I eat chocolate?

In the first year of treatment ("De-coppering"), it is best to avoid very high copper foods like shellfish, liver, nuts, and chocolate. Once your levels are stable, you can reintroduce them in moderation.

12. Diet and Lifestyle (Expanded)

  • The "Copper-Free" Diet:
    • Avoid: Liver, Shellfish (Oysters, Lobster), Nuts, Chocolate, Mushrooms.
    • Safe: Chicken, Beef, Fish (White), Rice, Eggs.
    • Water: If you have copper pipes, run the tap for 2 mins before drinking? (Controversial).
  • Adherence: This is life-saving. Missing doses leads to "Re-accumulation". A sudden release of stored copper can cause acute liver failure (which is often fatal).
13. References
  1. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089-111.
  2. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012;56:671-685.
14. Examination Focus

Common Exam Questions

1. Biochemistry:

  • Q: What is the typical biochemical profile?
  • A: Low Caeruloplasmin, Low Total Copper, High Free Copper, High Urine Copper.

2. Neurology:

  • Q: What is the risk of starting Penicillamine?
  • A: Paradoxical worsening of neurological symptoms (Dystonia).

3. Signs:

  • Q: Describe KF Rings.
  • A: Golden-brown ring at the limbus (corneal periphery). Best seen with slit lamp. Disappear with treatment.
13. Technical Appendix: The Leipzig Score

Ferenci Score (2003) Used to formalise the diagnosis.

  • KF Rings:
    • Present: 2 points.
    • Absent: 0 points.
  • Neurological Symptoms:
    • Severe: 2 points.
    • Mild: 1 point.
  • Serum Caeruloplasmin:
    • Decrease (>50% lower limit): 2 points.
    • Subnormal: 1 point.
  • Coombs -ve Haemolytic Anaemia:
    • Present: 1 point.
  • Urinary Copper:
    • High (>2x normal): 2 points.
    • Normal: 0.
  • Liver Copper:
    • High (>4 micromol/g): 2 points.
  • Genetics:
    • 2 mutations: 4 points.
    • 1 mutation: 1 point.

Total:

  • ≥4: Diagnosis Established (Highly likely).
  • 3: Possible.
  • ≤2: Unlikely.
14. Rehabilitation: The Neuro-Wilson's Patient

"The struggle against the twist." Neurological Wilson's can be devastating. Even with de-coppering, symptoms can persist or worsen initially.

  • Dystonia Management:
    • Anticholinergics (Trihexyphenidyl).
    • Baclofen.
    • Botox injections for focal dystonia (e.g. cervical).
    • Deep Brain Stimulation (DBS): Used in refractory cases with severe disability.
  • Dysarthria/Dysphagia:
    • Speech and Language Therapy (SALT) is critical.
    • PEG feeding may be needed in the acute "worsening" phase.
  • Psychiatric Support:
    • Depression and lability need SSRIs or mood stabilisers.
    • Family support is vital (personality changes are hard on the family).
15. Examination Focus (Expanded)

Advanced Viva Questions

1. Biochemistry:

  • Q: Why is Total Copper LOW but Free Copper HIGH in Wilson's?
  • A: Total Copper = (Caeruloplasmin-bound Copper) + (Free Copper). In Wilson's, Caeruloplasmin is very low (because ATP7B can't make it), so the bound fraction (which is 90% of total) is missing. Thus Total is low. However, the dangerous "Free" fraction is high.

2. Urine:

  • Q: What is the Penicillamine Challenge?
  • A: In equivocal cases (Leipzig score 3), giving a dose of Penicillamine (500mg) and measuring 24h urine copper can reveal huge excretion (unmasking the overload).

3. Genetics:

  • Q: A patient is diagnosed. Who else do you test?
  • A: All first-degree relatives (Siblings especially). Siblings have a 25% chance. Presymptomatic diagnosis is the holy grail - we can treat with Zinc alone and prevent ALL symptoms.

4. Imaging:

  • Q: What MRI sequence is best for copper?
  • A: T2/FLAIR shows hyperintensity (gliosis/oedema) or hypointensity (Iron/Copper deposition - but copper is not paramagnetic, the signal change is usually tissue damage). Susceptibility Weighted Imaging (SWI) may show mineralization.

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.

Last updated: 2025-12-24

At a Glance

EvidenceHigh
Last Updated2025-12-24
Emergency Protocol

Red Flags

  • Acute Liver Failure (Encephalopathy + Coagulopathy)
  • Hemolytic Anaemia (Coombs Negative)
  • Rapidly progressive Dystonia
  • Fulminant Wilson's

Clinical Pearls

  • **"The Young Parkinson's"**: Any patient &lt;40 years presenting with Parkinsonism (Tremor, Rigidity) MUST be screened for Wilson's. It is one of the few reversible causes.
  • **"KF Rings are not visible to naked eye"**: You need a Slit Lamp examination by an ophthalmologist. Do not rule it out at the bedside.
  • **"Face of the Giant Panda"**: MRI Brain sign showing high signal in the tegmentum with normal red nucleus.
  • Low Serum Caeruloplasmin (Unstable apoprotein degrades).
  • Copper accumulates in hepatocyte.

Guidelines

  • NICE Guidelines
  • BTS Guidelines
  • RCUK Guidelines