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Gastrointestinal (GI) System ORGAN SYSTEMS

Wilson disease (WD)

Wilson disease (WD) or hepatolenticular degeneration is an inherited disorder of copper metabolism characterised by pathological copper accumulation in many organs, particularly the liver and brain, leading to a wide range of symptoms.

Wilson disease (WD) or hepatolenticular degeneration is an inherited disorder of copper metabolism characterised by pathological copper accumulation in many organs, particularly the liver and brain, leading to a wide range of symptoms.

  • Autosomal recessive inheritance in hepatocyte copper-transporting ATPase (ATP7B gene); chromosome 13

History

Dr Samuel Alexander Kinnier Wilson (1878–1937), U.S.-born British neurologist best known for his description of Wilson’s disease.

The disease bears the name of the British physician Samuel Alexander Kinnier Wilson (1878–1937), a neurologist who described the condition, including the pathological changes in the brain and liver, in 1912. Wilson’s work had been predated by, and drew on, reports from German neurologist Carl Westphal (in 1883), who termed it “pseudosclerosis“; by the British neurologist William Gowers (in 1888); and by Adolph Strümpell (in 1898), who noted hepatic cirrhosis. Neuropathologist John Nathaniel Cumings made the link with copper accumulation in both the liver and the brain in 1948. The occurrence of hemolysis was noted in 1967.

A timeline of key discoveries in WD Samuel Alexander Kinnier Wilson described the Wilson disease (WD) in 12 patients in 1912. However, the first cases of WD with dominant tremor symptoms were described in 1883 by Westphal, while the corneal rings pathognomonic of WD were described by Kayser and by Fleischer in 1902–1903. Then followed the discovery of disturbances in copper metabolism as the aetiology of WD and the autosomal recessive inheritance. In 1945, the first treatment for copper toxicosis in WD, British anti-Lewisite (BAL), was introduced. In 1956, d-penicillamine became the first oral drug for WD, which was followed by the availability of zinc salts in 1961 and trientine in 1982. Liver transplantation, as an ultimate treatment for WD, was performed by Starzl and coworkers in 1971. In 1993, the WD gene, ATP7B, was located to chromosome 13q and found to code a P-type ATPase involved in copper transport | Walshe, J. M. (2017). History of Wilson disease: a personal account. Handbook of Clinical Neurology, 142, 1–5. https://doi.org/10.1016/B978-0-444-63625-6.00001-X

Pathophysiology

Copper metabolism:

Outline of copper homeostasis. Copper absorbed by the proximal small intestine is taken up by the liver that plays a central role in copper homeostasis by utilizing copper for metabolic needs and excreting excess copper into bile and thereby the gut, or exporting copper as copper containing ceruloplasmin used in iron metabolism and as non ceruloplasmin bound copper that may be used by or pathologically accumulated in other tissues or excreted into urine. Treatments for Wilson disease block copper absorption by the gut and increase fecal copper excretion (zinc) or increase urinary copper excretion (chelating agents D-Penicillamine and trientine). | Thieme publication Semin Liver Dis 2011; 31(3):245–259)

Pathogenesis:

Homozygous or compound heterozygous mutations
ATP7B gene

Defective
ATP7B copper-binding protein

Mediates the excretion of copper into bile
&
Delivers copper for functional synthesis of ceruloplasmin (major copper-containing protein in the blood)

Copper overload
(in liver, brain and other organs)

The Calgary Guide | http://calgaryguide.ucalgary.ca/

Presentation

Hepatic manifestations:

The liver has the highest tissue expression of the ATP7B copper transporter and is the central organ regulating systemic copper balance. Impairment of copper biliary excretion caused by ATP7B dysfunction leads to hepatic copper accumulation. Liver injury is, therefore, the earliest and most frequent manifestation of WD.
  • First clinical manifestation (40–60%)
  • Acute hepatitis, acute-on-chronic liver failure, and cirrhosis
  • Associated with:
    • Coomb’s negative hemolytic anaemia, with transient episodes of low-grade hemolysis and jaundice (free Cu damages RBCs)

Neurological manifestations:

  • Wing beating tremor (characteristic sign, up to 55%): Can be resting, postural or kinetic and may start initially as unilateral or bilateral tremor with mainly distal upper extremities involvement and may eventually involve entire body
  • Dystonia (10-65%): Abnormal posture of various body segments commonly associated with twitching or twisting movements
    • Risus sardonicus (abnormal facial expression presenting as a fixed smile due to dystonia of the risorius muscle)
  • Parkinsonism (19–62%): Symmetric bradykinesia, rigidity, hypomimia, gait and posture disturbances as well as dysarthria, dysphagia and drooling
  • Ataxia (30%): Symptom of cerebellar dysfunction (ataxic gait and posture, impaired coordination, intentional tremor, dysarthria) usually in combination with other movement disorders
  • Chorea (rare, 6–16%): Rapid, irregular involuntary movements of face, head, trunk or extremities
  • Gait & posture disturbances (44–75%)
  • Impaired handwriting (57%): Often as an early sign of the disease
  • Dysarthria (M/C neurological symptom, 97%)
    • Clinical subtypes: 1) cerebellar; 2) extrapyramidal (dystonic, parkinsonian) and 3) mixed (unclassified due to symptoms overlapping)
  • Dysphagia (50%): Difficulties in any phase of swallowing (oral preparation, oral transit, swallowing, drooling)
    • Complications: Bronchoaspiration, pneumonia, malnutrition and weight loss.
  • Drooling (classic neurological symptom of WD, 68%): Result of dysphagia or orofacial dystonia.
Dystonia, a characteristic symptom in WD: Dystonia is present in at least a third of all patients with a neurological presentation of WD and can be generalised, segmental, multifocal, or focal (part a; focal hand dystonia)1. The most characteristic WD dystonic presentation is abnormal facial expression or risus sardonicus, which presents as a fixed smile due to dystonia of the risorius muscle (part b, severe dystonia). | Członkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., … Schilsky, M. L. (2018). Wilson disease. Nature Reviews. Disease Primers, 4(1), 21. https://doi.org/10.1038/s41572-018-0018-3

Ophthalmological manifestations:

  • Kayser-Fleischer ring (100% neurological , 40–50% of hepatic and 20–30% presymptomatic WD cases): Golden, brown or green colouration at the periphery of the cornea)
    • Due to copper deposition in Descemet’s membrane
  • Sunflower cataracts in lens (rare, 2-20%): Central disc with radiating petal-like fronds located under the lens capsule
    • Copper deposition in anterior & posterior capsule of lens, sparing epithelial and cortical cells
Kayser-Fleischer rings visualised by anterior segment optical coherent tomography: In some patients and in healthy individuals, corneal copper deposits are not seen (part a). However, on other WD patients, copper deposits can be visualised as hyperreflective points by anterior segment optical coherence tomography that are either discrete (part b), on the superior and inferior part of the cornea (part c) or form a complete Kayser-Fleischer ring (part d). | Dr Karina Broniek and Professor Jacek Szaflik from the Department of Ophthalmology, Medical University of Warsaw, Poland

Psychiatric manifestations:

Mostly secondary to the somatic and brain pathology of the disease.
  • Mood disturbances (M/C psychiatric manifestation):
    • Depression (20–60%), with a high rate of suicidal attempts (4–16%)
    • Bipolar disorder (14–18%)
    • Lesions of frontal lobe or its pathways: Emotional lability, irritability and aggression, shallow cheerfulness, euphoria, social disinhibition, hypersexuality, lack of criticism and deficits in planning and anticipating social consequences
  • Psychosis (more often in patients with neurological symptoms):
    • Schizophrenia
    • Schizoaffective disorder
    • Delusional disorder
  • Behavioural and personality disorders:
    • Most common manifestations: Irritability, aggression, and antisocial behaviour
  • Renal disease: Fanconi syndrome (generalized reabsorption defect in PCT), kidney stones

Case study:

Complications:

  • Hepatocellular carcinoma (1° liver cancer)
Copper toxicity in the pathogenesis of Wilson disease: Dietary copper (Cu) is transported via portal vein and sequestered in liver which is the central organ for systemic copper balance. Impairment of biliary copper excretion in Wilson disease caused by ATP7B dysfunction leads to gradual copper accumulation in liver. When the liver capacity to store copper is exhausted, excessive quantities of non-ceruloplasmin-bound copper enter systemic circulation and is deposited in various organs exerting extrahepatic copper toxicity. Copper accumulates in the cornea, brain, red blood cells, skeletal and cardiac muscle cells, synovial membranes of large joints, and renal parenchyma. Non-ceruloplasmin-bound plasma copper is filtrated by renal tubular epithelium and is excreted via urine. | Członkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., … Schilsky, M. L. (2018). Wilson disease. Nature Reviews. Disease Primers, 4(1), 21. https://doi.org/10.1038/s41572-018-0018-3

Diagnosis

  • ↓ Serum ceruloplasmin
  • ↑ Copper (serum & urine): 24-hour urinary copper excretion

Ophthalmic examination:

(A): Kayser–Fleischer ring on naked eye examination, (B): Kayser–Fleischer ring on slit-lamp examination. | Patil, M., Sheth, K. A., Krishnamurthy, A. C., & Devarbhavi, H. (2013). A review and current perspective on Wilson disease. Journal of Clinical and Experimental Hepatology, 3(4), 321–336. https://doi.org/10.1016/j.jceh.2013.06.002

Brain MRI:

Brain MRI changes in WD: Usual abnormalities in brain MRI in patients with WD include symmetric hyperintense changes visualised in T2-weighted images of the basal ganglia, particularly the putamen (blue arrow), caudate nuclei (orange arrow), thalami (pink arrow) and globi pallidi (green arrow)(part a). In more advanced cases, severe tissue damage can be visualised in T1-weighted images as hypointensity in the putamen (part a, blue arrow; part b, orange arrows). The most spectacular WD changes are described as the ‘face of the giant panda’ in the midbrain (part c). Another common MRI abnormality is increased T2 signal along the dentato-rubro-thalamic pathway (part d), which is a major efferent pathway from the cerebellum involved in movement disorder symptoms, including ataxia, tremor and dystonia. Particularly in severe cases of WD, diffuse brain atrophy (part e) can be seen in the midbrain (orange arrow) and cortex (blue arrow). In brain MRI scans from a 21-year old male with severe liver failure and discrete neurological signs, hyperintense changes in putamina can be visualised in T2-weighted images, which is characteristic of early stages of brain involvement (part f). Hyperintense changes in the globi palidi in T1-weighted images in the same patient are presumably due to manganese accumulation, which is characteristic of hepatic encephalopathy and hypointense changes due to neurodegeneration in the putamina (part g). Very rarely, diffuse white matter changes in both brain hemispheres are observed with preservation of the cortex, probably due to myelin destruction (part h). | MRI, magnetic resonance imaging; WD, Wilson disease. | Członkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., … Schilsky, M. L. (2018). Wilson disease. Nature Reviews. Disease Primers, 4(1), 21. https://doi.org/10.1038/s41572-018-0018-3

Liver biopsy:


Management

Chealtion therapy:

  • Cu-chelating agent: Penicillamine/trientine
  • Zn + Ammonium tetrathiomolybdate (↓ Cu-reabsorption)

Liver cirrhosis or liver failure:

  • Liver transplant

Członkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., … Schilsky, M. L. (2018). Wilson disease. Nature Reviews. Disease Primers, 4(1), 21. https://doi.org/10.1038/s41572-018-0018-3

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