A review and current perspective on Wilson disease

Abstract

Wilson disease is a rare, inherited autosomal recessive disease of copper metabolism and may be more common where consanguinity is prevalent. Much has been known about the disease after it was first described by Kinnier Wilson as 'progressive lenticular degeneration in 1912. Over 500 mutations of the ATP7B gene has been identified with no clear genotype to phenotype correlation. Loss of ATP7B function leads various grades of reduced biliary excretion of copper and reduced incorporation of copper into ceruloplasmin; accumulation and toxicity of copper in the liver, brain and other tissues results in liver toxicity and other myriad manifestations of the disease. The clinical features may vary from asymptomatic state to chronic liver disease, acute liver failure, neuropsychiatric manifestations and hemolytic anemia. Diagnosis is based on the combination of clinical sign's, biochemical features, histologic findings and mutation analysis of ATP7B gene. Subtle geographical differences exist with a disproportionate proportion of children presenting with acute liver failure. A high index of suspicion is needed for an early diagnosis. Ratios of biochemical indices for early diagnosis need validation across geographical regions and may not be particularly applicable in children. Better biomarkers or the need for tests for early detection of ALF persists. Drugs used in the treatment of Wilson disease include copper chelating agents such as d-Penicillamine, trientine and zinc salt. Untreated Wilson disease uniformly leads to death from liver disease or severe neurological disability. Early recognition and treatment has excellent prognosis. Liver transplantation is indicated in acute liver failure and end stage liver disease. Family screening in order to detect the disorder in the first-degree relatives is warranted. This review provides an overview of different aspects of Wilson disease including geographical differences in presentations and clinical management and the limitations of currently available tests.

Keywords: ALF, acute liver failure; ATP7B; CCS1, copper chaperone for superoxide dismutase 1; CT, computerized tomography; CTR-1, copper transporter protein; MRI, magnetic resonance imaging; OLT, orthotropic liver transplantation; SOD1, superoxide dismutase; TM, tetrathiomolybdate; UNOS, United network for organ sharing; XIAP, X linked inhibitor of apoptosis; ceruloplasmin; chelators; liver failure; mutation.

Figure 1

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). (Reproduced with permission from Thieme publication Semin Liver Dis 2011; 31(3):245–259).

Figure 2

Pathways of copper metabolism in the hepatocyte. Cu = copper. CTR-1 = copper transporter 1. MT = metallothioneins. GSH = glutathione. Cp = ceruloplasmin (Reproduced with permission from Thieme publications Lancet 2007; 369:397–408).

Figure 3

Pathogenesis of copper toxicity. The main pathways of copper overload/toxicity is through both a direct oxidative stress mechanism with lipid peroxidation of membranes, mitochondria, and DNA; and also from unregulated apoptosis resulting in cell death from copper-induced changes in the anti-apoptotic protein, X-linked inhibitor of apoptosis (XIAP), and its loss of inhibitory control of caspase-3 with copper accumulation (Reproduced with permission from Thieme Publications, Semin Liver Dis 2011; 31(3):245–259).

Figure 4

(A): Kayser–Fleischer ring on naked eye examination, (B): Kayser–Fleischer ring on slit-lamp examination.

Figure 5

Liver biopsy showing mild steatosis and hepatocellular swelling. (Reproduced with permission from Thieme Medical Publishers. Semin Liver Dis. 2011;31:239–244).

Figure 6

Liver biopsy showing pericellular fibrosis in evolving cirrhosis. (Reproduced with permission from Thieme Medical Publishers. Semin Liver Dis. 2011;31:239–244).

Figure 7

Liver biopsy showing mitochondria abnormalities in Wilson disease. (Reproduced with permission from Thieme Medical Publishers. Semin Liver Dis. 2011;31:239–244).