Wilson's Disease: An Update

Shyamal K Das; Kunal Ray

Disclosures

Nat Clin Pract Neurol. 2006;2(9):482-493. 

In This Article

Pathogenesis and Pathology

WD is best appreciated with an understanding of copper metabolism. The body's basic daily copper requirement is about 1-2 mg, and this is met by dietary copper intake. Copper is absorbed by the intestinal cells and stored with metallothionein in a non-toxic form. The copper is later delivered into the circulation by a copper transporter protein, copper-transporting ATPase 1 (ATP7A), which is located on the membrane of enterocytes.[17] It is then transported to the liver tagged with albumin, from where it is accepted by hepatocytes. Within these cells, the ATOX1 chaperone protein[18] directs copper to its binding targets (Figure 1). Some of the copper becomes bound to metallothionein for storage, and the remainder is excreted into ATP7B-regulated biliary canaliculi. ATP7B also mediates the transfer of copper to apoceruloplasmin to form a six-copper binding protein known as ceruloplasmin, which is an α2-globulin.[19] Ceruloplasmin is released into the blood, carries 90% of the copper present in the plasma, and acts as a source of copper for peripheral organs such as the brain and kidney.

Schematic representation of copper metabolism within a liver cell. Abbreviation: ATP7B = Wilson's disease gene.

ATP7A and ATP7B are homologous copper-transporting proteins.[20] Mutation of the ATP7A gene results in the storage of copper in enterocytes, preventing entry of copper into the circulation and thereby causing a complete copper deficiency. This condition, known as Menkes disease, is an X-linked disorder characterized by severe impairment of neurological and connective tissue function. Discovery of the mutated gene in Menkes disease helped to uncover the activity of the WD-associated gene within the liver.[5] Mutations in ATP7B lead to a reduction in the conversion of apoceruloplasmin into ceruloplasmin, which, as a result, is usually present at low levels in WD patients. In addition, a failure to excrete copper into the biliary canaliculi leads to its toxic build-up within the hepatocytes.[21,22] Excess copper damages mitochondria, which produces oxidative damage to cells and allows spillage of copper into the blood, thereby overloading other organs such as the brain, kidney and red blood cells, initiating toxic damage.[21] In WD, apoptotic cell death is also accelerated by the inhibition of IAPs (inhibitor of apoptosis proteins) that is caused by toxic deposits of intracellular copper.[23] Normally, IAPs inhibit caspase-3 and caspase-7, which are responsible for apoptotic cell death.

The main areas of the brain affected in WD are the lenticular nuclei, which macroscopically appear brown in color because of copper deposition.[24] Degeneration occurs with disease progression, leading to necrosis, gliosis and cystic changes, and lesions can be seen in the brainstem, thalamus, cerebellum and cerebral cortex. In the early stages of the disease, proliferation of large protoplasmic astrocytes such as Opalski cells and Alzheimer cells occurs. With disease progression, copper deposits lead to vacuolar degeneration in proximal renal tubular cells, causing 'Fanconi syndrome' and the appearance of the golden-brown 'Kayser-Fleischer' (KF) ring in Descemet's membrane in the cornea (Figure 2). Acute release of copper into the circulation can damage red blood cells, thereby inducing hemolysis.[21]

The Kayser-Fleischer ring around the periphery of the cornea caused by deposition of copper in Descemet's membrane. This is a characteristic finding observed in most cases of neurological Wilson's disease and approximately 50% of cases of hepatic Wilson's disease. Figure courtesy of Dr Samar Basak. From Atlas on Clinical Ophthalmology.[63] Published with permission from Jaypee Brothers Medical Publishers (P) Ltd.

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