= HEPATOLENTICULAR DEGENERATION

[Samuel Alexander Kinnier Wilson (1878–1937), professor of neurology at King's College Hospital, London and founding editor of the Journal of Neurology and Psychopathology]

= autosomal recessive disorder with increased intestinal resorption of copper → excessive copper retention (= copper toxicosis) with deposition and cell damage in liver + brain

Prevalence: 1÷33,000–200,000; 1÷90 persons is a heterozygous carrier

Cause: alteration of chromosome 13 resulting in inability of liver to excrete copper into bile; hypothetically due to

1. lysosomal defect in hepatocytes, or
2. deficiency of biliary copper-binding proteins, or
3. persistence of fetal mode of copper metabolism, or
4. hepatic synthesis of high-affinity copper-binding proteins

Age of onset: 7–50 years; hepatic manifestations predominate in children; neuropsychiatric manifestations predominate in adolescents + adults

• ↓levels of serum copper; ↑ urinary copper excretion
• ⇓levels of ceruloplasmin (= copper transport protein)
• ↑copper concentration in serum ceruloplasmin (BEST SCREENING TEST)
• ↓incorporation of orally administered radiolabeled copper into newly synthesized ceruloplasmin

Stages:

1. Asymptomatic copper accumulation in hepatocytic cytosol
2. Redistribution of copper into hepatic lysosomes + circulation from saturated hepatocytic cytosol
   1. gradual redistribution is asymptomatic
   2. rapid redistribution causes fulminant hepatic failure / acute intravascular hemolysis
3. Cirrhosis, neurologic, ophthalmologic, renal dysfunction: may be reversible with therapy

Rx: life-long pharmacologic therapy with chelation agents (penicillamine / trientine / zinc); liver transplantation

• CNS
  = excessive copper deposition in brain
  Location: commonly in lenticular nucleus (= lenslike configuration of putamen + globus pallidus) perhaps also in: caudate nucleus, ventrolateral aspect of thalamus, cortical and subcortical region, mesencephalon, pons, vermis, dentate nucleus
  • Kayser-Fleischer ring (= green pigmentation surrounding limbus corneae) is DIAGNOSTIC
  • dysarthria, dysphagia, dystonia
  • tremors, ataxia, Parkinsonian symptoms
  • intellectual impairment, emotional disturbance
  • diffusion restriction (in early stages)
  • cerebral white matter atrophy
  • areas of CT hypodensities + T2 prolongation
• Liver
  • jaundice / portal hypertension (with liver cirrhosis)
  
  Histo: macrovesicular fat deposition in hepatocytes, glycogen degeneration of hepatocyte nuclei, Kupffer cell hypertrophy
  in children:
  • normal hepatic attenuation (fatty infiltration + copper deposition cancel each other out)
  • normal T1 relaxation time (in spite of paramagnetic effects of copper)
  
  Cx: acute fulminant hepatitis, macronodular cirrhosis
• Skeletal manifestations (in ⅔)
  • pain, stiffness, gelling of joints (in 75%)
    Location: shoulder (frequent), knee, hip, wrist, 2^nd–4^th MCP joints
  • subarticular cysts
  • premature osteoarthritis (narrowing of joint space + osteophyte formation)
  • osteochondritis dissecans
  • chondrocalcinosis
  • premature osteoarthrosis of spine, prominent Schmorl nodes, wedging of vertebrae, irregularities of vertebral plates
  • generalized deossification may produce pathologic fractures
  
  Cx: rickets + osteomalacia (← renal tubular dysfunction) in minority of patients