Wilson's Disease
Summary
Wilson's Disease is a rare autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. This leads to impaired biliary excretion of copper, resulting in toxic accumulation of copper in the liver, brain, cornea, and other organs. Clinical manifestations range from asymptomatic liver enzyme elevation to acute liver failure, chronic liver disease/cirrhosis, and neuropsychiatric disease (Parkinsonism, Dystonia, Tremor, Psychiatric symptoms). Kayser-Fleischer rings (copper deposits in Descemet's membrane of the cornea) are pathognomonic but not always present. Diagnosis is based on low serum Caeruloplasmin, elevated 24-hour urinary copper, liver copper content on biopsy, and genetic testing. Treatment is lifelong with copper chelation (Penicillamine, Trientine) and/or Zinc (blocks copper absorption). Liver transplantation is curative for fulminant liver failure or decompensated cirrhosis. Without treatment, Wilson's Disease is fatal; with treatment, prognosis is excellent. [1,2]
Clinical Pearls
"Think Wilson's in Any Young Person with Liver or Neuro Disease": Consider Wilson's in unexplained liver disease less than 40 years old OR any young person with movement disorder/psychiatric symptoms.
Kayser-Fleischer Rings are Pathognomonic: Brownish-green ring at limbus. Best seen on Slit Lamp examination (not always visible to naked eye). Present in ~95% with neurological Wilson's, ~50% with hepatic.
Acute Liver Failure + Coombs-Negative Haemolysis = Wilson's: This combination is highly suggestive. Copper release causes haemolysis.
Family Screening is Essential: Autosomal recessive. Screen siblings with LFTs, Caeruloplasmin, Slit Lamp. 25% chance of affected sibling.
Incidence
- Prevalence: ~1 in 30,000 (Carrier frequency ~1 in 90).
- Age of Onset: Usually 5-35 years. Hepatic presentation more common in children; Neurological in adolescents/young adults.
- Sex: Males = Females.
Genetics
- Inheritance: Autosomal Recessive.
- Gene: ATP7B (Chromosome 13). Encodes a copper-transporting ATPase in hepatocytes.
- >500 mutations identified. H1069Q is most common in European populations.
Mechanism
- ATP7B Mutation: Defective copper-transporting ATPase in hepatocytes.
- Impaired Copper Excretion: Copper normally incorporated into Caeruloplasmin and excreted into bile. In Wilson's, both are impaired.
- Hepatic Copper Accumulation: Copper accumulates in liver → Oxidative stress → Hepatocyte injury → Fatty liver, Hepatitis, Fibrosis, Cirrhosis.
- Systemic Copper Release: As liver capacity exceeded, copper released into bloodstream.
- Deposition in Other Organs:
- Brain (Basal Ganglia, esp. Putamen): Neurological symptoms.
- Cornea (Descemet's Membrane): Kayser-Fleischer Rings.
- Kidneys: Fanconi syndrome.
- RBCs: Haemolysis (especially in acute presentations).
- Heart, Bones, Endocrine: Less common.
- Low Caeruloplasmin: Caeruloplasmin (copper carrier protein) synthesis is normal, but cannot incorporate copper → Unstable, rapidly degraded → Low serum levels.
| Condition | Key Features |
|---|---|
| Wilson's Disease | Young (less than 40). Liver + Neuro. KF rings. Low Caeruloplasmin. High Urinary Copper. ATP7B mutation. |
| Autoimmune Hepatitis | Female predominant. ANA, ASMA, Anti-LKM positive. High IgG. |
| NAFLD / NASH | Metabolic syndrome. Fatty liver on imaging. No KF rings. Normal Caeruloplasmin. |
| Haemochromatosis | High Ferritin, High Transferrin Saturation. HFE gene mutation. |
| Primary Biliary Cholangitis | Middle-aged female. Cholestatic LFTs. AMA positive. |
| Parkinson's Disease | Older age. Asymmetric. No liver involvement. No KF rings. |
| Huntington's Disease | Family history (AD). Chorea. Cognitive decline. Genetic testing. |
| Drug-Induced Movement Disorder | Drug history (Antipsychotics). Acute Dystonia. |
Hepatic Manifestations (~40-50%)
| Presentation | Notes |
|---|---|
| Asymptomatic Transaminitis | Incidentally found elevated ALT/AST. |
| Chronic Hepatitis | Fatigue, Jaundice, Hepatomegaly. |
| Cirrhosis | Portal hypertension, Ascites, Varices, Splenomegaly. |
| Acute Liver Failure | Rapid onset. Often with Coombs-negative Haemolytic Anaemia. High Bilirubin, Low ALP (ALP:Bilirubin ratio less than 4). Wilson's is commonest metabolic cause of acute liver failure in young. |
Neurological Manifestations (~40%)
| Feature | Notes |
|---|---|
| Movement Disorders | Tremor (Postural, "Wing-Beating"), Dystonia, Parkinsonism (Bradykinesia, Rigidity), Chorea, Ataxia. |
| Dysarthria | Slurred, Hypophonic speech. |
| Dysphagia | Bulbar involvement. |
| Drooling | Oropharyngeal dysfunction. |
| Onset usually in 2nd-3rd decade. |
Psychiatric Manifestations (~30%)
| Feature | Notes |
|---|---|
| Personality Change | Often first noticed by family. |
| Depression, Anxiety | Common. |
| Psychosis | Can mimic Schizophrenia. |
| Cognitive Decline | Executive dysfunction. |
| Often precedes neurological signs. May be misdiagnosed as primary psychiatric illness. |
Ocular: Kayser-Fleischer Rings
Other Manifestations
| System | Features |
|---|---|
| Haematological | Coombs-Negative Haemolytic Anaemia (Acute copper release). |
| Renal | Fanconi Syndrome (Proximal RTA, Aminoaciduria). Nephrolithiasis. |
| Skeletal | Osteoporosis, Arthropathy. |
| Cardiac | Cardiomyopathy (Rare). |
Diagnostic Tests
| Test | Findings | Notes |
|---|---|---|
| Serum Caeruloplasmin | Low (less than 0.2 g/L) | Present in ~85%. Can be low in other conditions (Malnutrition, Nephrotic, Acaeruloplasminaemia). Can be normal in ~5% Wilson's. |
| 24-Hour Urinary Copper | Elevated (>100 μg/24h, often >40 μg in untreated) | >100 μg/day is highly suggestive. Repeat if borderline. |
| Slit Lamp Examination | Kayser-Fleischer Rings | Pathognomonic. Refer to ophthalmology. |
| Liver Biopsy (Copper Content) | >250 μg/g dry weight | Gold standard if diagnosis uncertain. |
| Genetic Testing (ATP7B) | Identifies mutations | Confirms diagnosis. Useful for family screening. |
| LFTs | Elevated ALT/AST. May have low ALP (in acute liver failure). | |
| Serum Copper | Often low (due to low Caeruloplasmin which carries most serum copper). "Free" (non-Caeruloplasmin-bound) copper is elevated. |
Imaging
| Imaging | Findings |
|---|---|
| MRI Brain | T2/FLAIR hyperintensity in Basal Ganglia (Putamen, Globus Pallidus, Caudate, Thalamus). "Face of the Giant Panda" sign in Midbrain (Tegmentum). |
| Liver Ultrasound | Hepatomegaly, Fatty change, Cirrhosis features. |
Leipzig Score (Diagnostic Scoring System)
- Combines clinical and lab features. Score ≥4 = High probability of Wilson's.
Management Algorithm
SUSPECTED WILSON'S DISEASE
(Young + Liver/Neuro Disease + Family History)
↓
INITIAL INVESTIGATIONS
- Serum Caeruloplasmin
- 24-Hour Urinary Copper
- LFTs (ALT, AST, Bilirubin, ALP, Albumin)
- Slit Lamp Examination (KF Rings)
↓
DIAGNOSIS CONFIRMED?
(Low Caeruloplasmin + High Urinary Cu + KF Rings
OR Liver Biopsy Cu >250 μg/g
OR Genetic Testing ATP7B)
┌────────────────┴────────────────┐
YES UNCLEAR
↓ ↓
START TREATMENT LIVER BIOPSY
+ SCREEN FAMILY (Copper Content)
+ GENETIC TESTING
↓
TREATMENT OPTIONS
┌──────────────────────────────────────────┐
│ COPPER CHELATION (Initial Treatment) │
│ - Penicillamine (D-Penicillamine) │
│ Start 250-500mg/day, increase to │
│ 1-1.5g/day in divided doses. │
│ Monitor: FBC, Urinalysis, U&E. │
│ SE: Bone marrow suppression, Lupus- │
│ like, Nephrotoxicity, Neurological│
│ worsening (10-20% initially). │
│ │
│ OR Trientine (Better tolerated) │
│ 750-1500mg/day in divided doses. │
│ Fewer side effects than Penicillamine.│
└──────────────────────────────────────────┘
↓
┌──────────────────────────────────────────┐
│ ZINC (Maintenance / Adjunct / Mild) │
│ - Zinc Acetate / Sulphate 150mg/day │
│ (50mg elemental Zn TDS). │
│ - Blocks intestinal copper absorption. │
│ - Used for maintenance after chelation, │
│ or as monotherapy in asymptomatic/ │
│ presymptomatic. │
│ SE: GI upset. │
└──────────────────────────────────────────┘
↓
┌──────────────────────────────────────────┐
│ LIVER TRANSPLANTATION │
│ - Indicated for: │
│ - Acute Liver Failure unresponsive │
│ - Decompensated Cirrhosis │
│ - (Rarely) Severe Neurological refractory│
│ - Curative (Gives functional ATP7B). │
└──────────────────────────────────────────┘
↓
MONITORING
- Regular LFTs, FBC, U&E
- 24h Urinary Copper (Target less than 500 μg/day on treatment)
- Non-Caeruloplasmin-bound Copper (Free Copper)
- Neurological Review
- Ophthalmology (KF Ring resolution)
↓
FAMILY SCREENING
- All First-Degree Relatives (Siblings, Children)
- Caeruloplasmin, LFTs, Urinary Copper
- Genetic Testing (If proband mutation known)
- Slit Lamp
Treatment Agents
| Agent | Mechanism | Dose | Notes |
|---|---|---|---|
| Penicillamine | Copper chelator (Binds and promotes urinary excretion). | 1-1.5g/day (divided). Start low. | First-line. Many side effects. Monitor FBC, Urinalysis. May cause initial neurological worsening. |
| Trientine | Copper chelator. | 750-1500mg/day (divided). | Second-line. Better tolerated. Expensive. |
| Zinc Acetate/Sulphate | Induces intestinal metallothionein → Blocks copper absorption. | 150mg/day (50mg elemental TDS). Take on empty stomach. | Maintenance therapy. Monotherapy for presymptomatic. Fewer side effects. |
| Tetrathiomolybdate | Blocks copper absorption and binds circulating copper. | Investigational. | May be useful for neurological Wilson's (less initial worsening). |
Liver Transplantation
- Curative: Liver provides normal ATP7B function.
- Indications: Acute liver failure not responding to chelation, Decompensated cirrhosis.
- Neurological symptoms may improve post-transplant (variable).
Dietary Advice
- Avoid high-copper foods in first year of treatment: Liver, Shellfish, Nuts, Chocolate, Mushrooms.
- Less important long-term if on effective therapy.
| Complication | Notes |
|---|---|
| Liver Failure / Cirrhosis | If untreated. |
| Neurological Disability | Dystonia, Parkinsonism. May be irreversible if advanced. |
| Psychiatric Disease | Depression, Psychosis. |
| Treatment Side Effects | Penicillamine: Neurological worsening, Bone marrow suppression, Lupus-like, Nephrotoxicity. |
| Death (If Untreated) | Wilson's Disease is fatal without treatment. |
- With Treatment: Excellent. Normal life expectancy.
- Without Treatment: Invariably fatal (Liver failure, Neurological decline).
- Neurological Recovery: Variable. Better if treatment started early. Some deficits may be permanent.
- Hepatic Recovery: Liver biochemistry and function typically normalise. Cirrhosis may stabilise.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| EASL Clinical Practice Guidelines: Wilson's Disease | EASL (2012) | Diagnosis, Leipzig Score, Penicillamine/Trientine/Zinc, Transplant indications. |
| AASLD Practice Guidance | AASLD | Similar. Emphasise family screening. |
What is Wilson's Disease?
Wilson's Disease is a rare inherited condition where the body cannot properly remove copper. Copper builds up in the liver and brain, causing damage.
How did I get it?
It is a genetic condition passed down from both parents (who are carriers but usually healthy). You need to inherit the faulty gene from both parents to get Wilson's.
What are the symptoms?
It can affect the liver (jaundice, fatigue, liver failure) and the brain (tremor, difficulty speaking, personality changes). Some people have brown rings around their eyes (Kayser-Fleischer rings).
How is it treated?
You will take medication to remove the excess copper from your body (chelation therapy) and to stop you absorbing more copper (Zinc). Treatment is lifelong. If the liver is severely damaged, a transplant may be needed.
Should my family be tested?
Yes. Siblings and children should be screened, as they may carry the gene or have the disease without knowing.
Primary Sources
- European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012;56(3):671-685. PMID: 22340672.
- Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111. PMID: 18506894.
Common Exam Questions
- Classic Triad: "What are Kayser-Fleischer rings and where are they found?"
- Answer: Golden-brown copper deposits in Descemet's membrane of the cornea. Best seen on Slit Lamp examination. Pathognomonic for Wilson's.
- Diagnostic Tests: "Low serum caeruloplasmin, elevated 24h urinary copper. Most likely diagnosis?"
- Answer: Wilson's Disease.
- Genetics: "What is the inheritance pattern and gene involved in Wilson's Disease?"
- Answer: Autosomal Recessive. ATP7B gene.
- Treatment: "First-line treatment for Wilson's Disease?"
- Answer: Penicillamine (Copper chelation). Alternative: Trientine.
Viva Points
- MRI Finding: "Face of the Giant Panda" sign in Midbrain.
- Acute Liver Failure Feature: Coombs-negative haemolytic anaemia + Low ALP:Bilirubin ratio.
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