Harvey's Garden

Wilson disease

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aliasesHepatolenticular degeneration

3 min read

  • Impaired copper excretion causes copper to accumulate in the body.
  • Early-stage Wilson disease is characterized by the presence of copper deposits in the liver.
  • As the disease progresses, copper accumulates in other organs as well, most importantly in the brain and cornea.

Epidemiology

Etiology

Pathophysiology

Tip

  • Apoceruloplasmin
    • Copper-free precursor synthesized in liver.
    • Unstable half-life; degrades rapidly if not loaded with copper.
  • Ceruloplasmin
    • Copper-bound form (loaded by ATP7B in Golgi).
    • Stable half-life; carries 95% of circulating copper.
    • Ferroxidase activity (links Cu metabolism to Fe metabolism).
  • Autosomal Recessive mutation of ATP7B gene on Chromosome 13.
  • Defect in hepatocyte copper-transporting ATPase (ATP7B protein).
  • Primary Defects:
    1. Inability to excrete excess copper into bile (main route of excretion).
    2. Failure to incorporate copper into apoceruloplasmin to form functional ceruloplasmin.
  • Consequences:
    • ↓ Serum ceruloplasmin (due to shorter half-life of apoceruloplasmin).
    • ↑ Free (unbound) serum copper.
    • Accumulation of toxic copper levels in tissues via Fenton reaction (oxidative damage).
  • Tissue Deposition Sequence:
    • Liver: Accumulates first → hepatocyte necrosis → micronodular cirrhosis.
    • Brain: Deposits in Basal Ganglia (specifically Putamen and Globus Pallidus) → parkinsonism, dysarthria, tremor.
    • Cornea: Deposits in Descemet membrane → Kayser-Fleischer rings.
    • Kidneys: Proximal tubule damage → Fanconi syndrome.

Tip

Don’t mess up with Hemochromatosis

Clinical features

Tip

Hepatic + neurological + psychiatric

  • Hepatic:
    • Asymptomatic transaminitis, acute hepatitis, chronic hepatitis, cirrhosis, or acute liver failure (ALF).
  • Neurological:
    • Movement disorders: Tremor (resting, postural, or “wing-beating”), ataxia, choreoathetosis, dystonia.
    • Parkinsonian features: Rigidity, bradykinesia, mask-like facies.
    • Pseudobulbar symptoms: Dysarthria (most common initial neuro sign), dysphagia, drooling.
  • Psychiatric:
    • Personality changes, depression, emotional lability, psychosis, cognitive decline/dementia.
  • Ophthalmologic:
    • Kayser-Fleischer (KF) rings: Golden-brown/greenish copper deposition in Descemet membrane of the cornea (seen via slit-lamp; present in >95% with neuro symptoms).
    • Sunflower cataracts.
  • Other:
    • Hematologic: Coombs-negative hemolytic anemia (acute intravascular hemolysis due to free copper toxicity to RBCs).
    • Renal: Fanconi syndrome (proximal tubular dysfunction), nephrolithiasis.
    • Musculoskeletal: Premature osteoarthritis, chondrocalcinosis.

Wilson disease vs hemochromatosis

  • Wilson disease has neurologic symptoms but hemochromatosis doesn’t have
  • Think about Wilson from Don’t Starve, the mad scientist

Diagnostics

  • Initial/Screening:
    • Slit-lamp examination: Specifically to identify KF rings (most cost-effective initial screening step).
    • Serum ceruloplasmin: Low (<20 mg/dL).
    • 24-hour urinary copper excretion: High (>100 mcg/24h; increased to >1000 mcg/24h after penicillamine challenge).
  • Confirmatory/Gold Standard:
    • Liver biopsy: Demonstrates elevated hepatic copper concentration (>250 mcg/g of dry weight).
    • Genetic testing (ATP7B mutation analysis) can be used for confirmation and screening of first-degree relatives.
  • Key Labs:
    • Coombs-negative hemolytic anemia (due to direct Cu-induced RBC membrane damage).
    • Elevated LFTs (AST, ALT) and signs of liver synthetic dysfunction (prolonged PT/INR, low albumin).
  • Imaging:
    • Brain MRI: T2-weighted hyperintensities in the basal ganglia (classic but non-specific “giant panda sign” in midbrain).

Treatment

General principles

  • Encourage a low-copper diet (e.g., avoidance of organ meats, shellfish, nuts, chocolate, copper-containing dietary supplements).
  • Refer patients with refractory decompensated cirrhosis or acute liver failure for liver transplantation.

Pharmacological therapy

  • First line: chelating agents, e.g., penicillamine (preferred) or trientine
    • Chelating agents facilitate renal excretion of copper by forming water-soluble compounds.
    • Adverse effect: Membranous nephropathy
  • Maintenance therapy: reduced-dose zinc salts or a chelating agent

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