Copper is an essential metal and a cofactor for many metabolic processes in the body. Therefore, disorders of copper metabolism result in a variety of histochemical and clinical manifestations. Wilson's disease (WD), also known as hepatolenticular degeneration, was first described by Samuel Alexander Kinnear Wilson, a British neurologist, in 1912.1–3 The initial description included the triad of cirrhosis, neurological manifestations, and Kayser-Fleischer rings.1,2
WD has a prevalence of 1 in 30,000 to 55,000 people1,3–5 with most patients presenting between age 5 and 35 years.1 Presentation before age 4 years is uncommon; the youngest patient ever reported was age 3 years.6 There is no significant difference in gender distribution in WD; however, male patients tend to have more neurologic predominant symptoms, whereas females tend to have more liver predominant symptoms with a 2:1 ratio of acute liver failure presentation in female patients.1,7
To understand the pathogenesis of WD it is important to understand normal copper metabolism. Copper, a chemical element and transitional metal, is ingested in the diet and absorbed by enterocytes in the duodenum and proximal jejunum. It is then transported into the portal circulation bound to albumin and histidine to the liver where it is absorbed.1 The liver uses some copper as a cofactor for various metabolic pathways and incorporates the remaining copper into ceruloplasmin. Ceruloplasmin is a protein synthesized in the liver and secreted by hepatocytes that carries 90% of circulating copper. Excess hepatic copper is normally excreted into bile.1
WD is caused by a genetic defect with autosomal recessive inheritance resulting in impaired copper metabolism. The responsible gene, ATP7B on chromosome 13q14.3, was not identified until 1993.1,3,5,8,9 Defects in ATP7B lead to impaired production of a metal-transporting P-type adenosine triphosphatase (ATPase) that is expressed on hepatocytes and allows for transmembrane transport of copper out of hepatocytes.1,8,9 Absent or reduced levels of the ATP7B protein leads to decreased hepatocellular excretion of copper into bile and failure of hepatocytes to incorporate copper into ceruloplasmin.1,3 The decreased copper excretion leads to copper accumulation in the liver and resultant hepatic injury. Excess copper is eventually released into the circulation where it can deposit in other organs such as the brain, kidneys, and cornea leading to other clinical manifestations of the disease.1,3
Clinical manifestations affect numerous organ systems, most notably hepatic and neurologic, and can vary widely from person to person (Table 1). Hepatic involvement is the presenting finding in about 40% of patients and is most common in the pediatric age group.3,5 Patients can present with a spectrum of liver disease that includes asymptomatic patients with incidental findings of hepatomegaly or elevated serum aminotransferases.1,3,5 Other patients have progressed to chronic liver disease with evidence of compensated or decompensated cirrhosis at the time of diagnosis including symptoms of jaundice, fatigue, malaise, anorexia, ascites, or edema. Up to 12% of patients can also present with fulminant acute liver failure in the setting of WD.3 This often manifests in the adolescent age group as a combination of the characteristic clinical findings of Coombs-negative hemolytic anemia, coagulopathy unresponsive to vitamin K administration, renal tubular injury with rapid progression to renal failure, only a modest rise in transaminases (<2,000 IU/L) compared to other etiologies of acute liver failure, and normal or abnormally low alkaline phosphatase levels (<40 IU/L).1,3
Clinical Manifestations of Wilson's Disease
Neurologic symptoms are the presenting findings in another 40% of patients.3,5 In these patients, hepatic involvement is usually more mild.5 Neurologic symptoms typically present in the third decade of life; however, they can manifest in childhood with deterioration in school work, poor hand-eye coordination, or difficulty with handwriting especially micrographia.1,5 The more typical neurologic symptoms that occur in adulthood include motor manifestations such as tremor, dysarthria, rigid dystonia, dysphagia, clumsiness, ataxia, and seizures.1,3,5
Other clinical manifestations include psychiatric, hemolytic, and ocular findings. Psychiatric symptoms can vary from subtle behavioral changes to depression, anxiety, and more rarely psychosis.1,5 A Coombs-negative hemolytic anemia can be seen in up to 15% of patients at presentation and is typically in the setting of acute decompensated liver disease.3,5 Another hallmark of WD is the ocular finding of Kayser-Fleischer rings (Figure 1), a golden-brown ring of pigment at the corneo-scleral junction, detected only by slit-lamp examination, which represents copper deposition in Descemet's membrane.3,10 Kayser-Fleischer rings are seen in up to 95% of patients with WD who have neurologic disease and in 50% to 65% with hepatic disease.1,3,5,10 Although less common, sunflower cataracts can also be detected with slit-lamp examination and are caused by copper deposition on the lens.1,3 Renal tubular dysfunction, hormone imbalances leading to amenorrhea or infertility, premature osteoporosis, and pancreatitis are other less common manifestations that have been associated with the disease.3
Kayser-Fleischer rings seen on slit-lamp examination appear as a golden-brown ring of pigment at the corneo-scleral junction. Image used with permission from the Wilson Disease Association.
The differential diagnosis for WD may depend on the predominant clinical presentation of the patient. In those patients presenting with acute liver failure, other etiologies such as viruses, toxins, alcohol, ischemia, or autoimmune hepatitis must be considered. Patients with predominantly neurologic symptoms should be evaluated for movement disorders. Bipolar disorder, depression, and schizophrenia should be ruled out in patients with psychiatric manifestations.1 WD should also be distinguished from Menke's disease, another disorder of copper transport resulting from an X-linked mutation in the ATP7A gene. Mutations in this gene lead to generalized copper deficiency. Patients present early in life with disorders of neuronal degeneration, mental retardation, abnormalities in hair (kinky or steel wool texture), bone fractures, and aortic aneurysms.11
The diagnosis of WD is based on a combination of clinical features and laboratory findings. Molecular genetics can also be useful as the identification of a genetic mutation is sufficient, however, it is not necessary for diagnosis.1,12 A scoring system to predict the likelihood of WD was developed by the 8th International Meeting on Wilson's Disease and Menke Disease in 200212 and was later validated for use in pediatrics.13 The system assigns a score based on the presence or absence of Kayser-Fleischer rings, neuropsychiatric symptoms, Coombs-negative hemolytic anemia, elevated 24-hour urinary copper concentrations, increased hepatic copper concentrations, low serum ceruloplasmin, or presence of disease-causing mutations.12
If WD is suspected, initial laboratory evaluation with liver function tests and serum ceruloplasmin should be obtained. Serum aminotransferases are often elevated with aspartate aminotransferase more significantly elevated than alanine aminotransferase (ALT), although the degree of elevation is usually only mild to moderate (<2,000 IU/L) and does not correlate with the severity of the liver disease.1,3 Alkaline phosphatase levels are usually normal or low (<40 IU/L), which can aid in distinguishing WD from other etiologies of an acute hepatitis.3 Serum ceruloplasmin levels are characteristically abnormally low in WD, although normal levels are also seen in confirmed WD cases.3 The defect in the ATP7B protein causes the liver to secrete ceruloplasmin without copper, also known as apoceruloplasmin, which has a shorter half-life than ceruloplasmin thus resulting in decreased serum ceruloplasmin levels.1,3 Normal ranges for ceruloplasmin may vary by laboratory, but a serum ceruloplasmin level of <20 mg/dL (<200 mg/L) is usually considered abnormal.1,3 It is important to note that ceruloplasmin levels can also be altered for other reasons. Low levels of ceruloplasmin can be seen with marked intestinal or renal protein loss, copper deficiency due to lack of supplementation in parenteral nutrition, Menke's disease, or aceruloplasminemia, which is a rare genetic disorder resulting in complete absence of the protein.1,3 Alternatively, ceruloplasmin can be elevated in acute inflammatory states because it is an acute phase reactant.1 For children, levels should be interpreted based on age-specific reference ranges. Initially newborns have low ceruloplasmin levels, but they increase through infancy and peak by age 2 to 3 years at a level that can be higher than the adult reference range.5
Further testing for WD includes a 24-hour urinary copper excretion that estimates the nonceruloplasmin bound copper in the circulation.1 A level >100 mcg of copper per 24-hour urine collection is considered abnormal in symptomatic patients. The collection must be done using copper-free containers, and pediatric patients may require hospital admission to ensure compliance with an accurate 24-hour collection.1,3,12 Serum copper concentrations are usually low in WD; however, in the setting of acute liver failure, the serum copper levels can be elevated due to release of hepatic copper stores from hepatic necrosis.3 Therefore, 24-hour urinary copper is a more accurate measure of copper status.
Quantitative hepatic parenchymal copper concentration from a liver biopsy specimen also provides important diagnostic information. A hepatic copper concentration of >250 mcg/g dry weight is consistent with the diagnosis of WD, although other studies have suggested that this cutoff is too high.1,3,12 Hepatic copper distribution can be heterogeneous, especially in the setting of cirrhosis; therefore, a risk of false-negative results can occur due to sampling error. This is best ameliorated by ensuring adequate biopsy specimen size.1 Hepatic copper concentration measurement is particularly useful in younger patients as the hepatic copper is mainly cytoplasmic and therefore may not be measurable by other laboratory studies.1
Routine histology of a liver biopsy specimen can vary depending on the stage of the hepatic disease-making quantitative copper concentrations more useful. Histologic findings range from mild steatosis to hepatocellular degeneration with parenchymal collapse to cirrhosis with fibrosis.3 Apoptotic hepatocytes are a common feature in the setting of acute liver failure from WD. Copper staining can also be performed on liver biopsy specimens to better elucidate hepatic copper deposits (Figure 2). Histologic features can sometimes be difficult to distinguish from autoimmune hepatitis.1
A copper stain of a liver biopsy in Wilson's disease, highlighted as red-brown granules within the hepatocytes. Original image courtesy of Dr. John Hart (Department of Pathology, The University of Chicago Medicine), reprinted with permission.
Due to the ocular manifestation of WD, slit-lamp examination by an experienced ophthalmologist to assess for Kayser-Fleischer rings is also recommended.1,12
Genetic testing by whole-gene sequencing is currently commercially available at specific laboratories. Mutation analysis can be performed to detect the over 300 mutations in the ATP7B gene that have already been identified.3 Compound heterozygotes can make the interpretation of these results more difficult.1 Once the mutation in the proband is identified, genetic testing of all first-degree relatives can be performed to identify other family members who are either affected or heterozygotes for the mutation.1,3,5
All first-degree relatives, including parents, siblings, and offspring, of patients with a confirmed diagnosis of WD should be screened for WD. Screening should include serum copper, ceruloplasmin, liver function tests, slit-lamp examination for Kayser-Fleischer rings, and a basal 24-hour urinary copper.1 If available, molecular genetic testing can be used as the primary screening method as the absence of or only one copy of the known familial mutation will exclude the diagnosis.1,3,12
WD was universally fatal prior to the use of chelation therapy with British anti-Lewisite in the 1950s.1,3,14 Now, management of WD includes lifelong pharmacologic therapy with chelating agents or oral zinc for presymptomatic/asymptomatic to mild to moderately symptomatic patients, and liver transplantation for severe cases and acute decompensation. Lifelong compliance with therapy is essential, and noncompliance is associated with progression of liver disease and need for liver transplant.1,3
Pharmacologic therapy includes chelators and oral zinc. D-penicillamine and trientine are chelators that induce urinary copper excretion or cupruria. Oral zinc blocks intestinal absorption of copper by inducing enterocyte metallothionein, which is an endogenous chelator. Metallothionein binds to copper in the intestinal tract and then is lost in the fecal matter when the enterocytes slough off. Copper excreted into saliva and gastric contents is also lost this way, thus creating a net negative copper balance.1 Ammonium tetrathiomolybdate is a newer chelator that also blocks copper absorption and can be more beneficial in treating neurologic manifestations of WD.1,3
In patients identified through family screening who are asymptomatic or presymptomatic, D-penicillamine or zinc are effective in preventing progression of the disease, and it is recommended to begin treatment at age 3 years. Therapy with zinc is recommended if treatment is initiated prior to age 3 years due to the favorable side-effect profile.1,5 If symptomatic, patients can initially be given a treatment course with chelation that lasts 2 to 6 months until there is symptomatic and/or biochemical improvement followed by maintenance dosing.1 Decompensated cirrhosis, characterized by hypoalbuminemia, ascites, jaundice, and coagulopathy, can be treated with a trial of combination chelation therapy and zinc; however, in the setting of encephalopathy, decompensated liver disease despite medical therapy, or acute decompensation, liver transplantation is the only life-saving treatment.1
Liver transplantation corrects the metabolic defect found in the livers of patients with WD allowing for the restoration of normal copper metabolism. Due to the rapid progression of liver disease, patients with acute liver failure secondary to WD are listed as status 1A, which is the highest priority for liver transplant by the United Network for Organ Sharing. Status 1A is usually reserved for the most severe cases of liver failure from acute causes; however, acute decompensation in WD, a chronic disease, is the exception.1,15 The 1-year survival rate is 79% to 87% after liver transplantation and those patients who survive through that time period tend to demonstrate long-term survival.1
Dietary modifications to avoid foods high in copper should be made especially in the first year of treatment. Foods high in copper include shellfish, chocolate, nuts, mushrooms, legumes, and liver.1,3,5 The recommended dietary intake of copper is 0.9 mg/day; however, the average adult exceeds that consuming about 2 to 5 mg/day.1 Additionally, care should be taken when consuming well water, using plumbing with copper pipes, or cooking with copper kitchenware.1
The presentation and disease progression of WD can vary greatly between patients. Pediatric patients may present with subtle findings including asymptomatic hepatomegaly, mild transaminitis, behavioral issues, or school failure. Pediatricians may be the first medical providers to recognize these symptoms and, as such, should consider WD in their differential diagnosis in patients with hepatic, neurologic, and/or psychiatric findings. There should be a low threshold for referral to a pediatric hepatologist for further investigation whenever WD is suspected.
- Roberts EA, Schilsky MLAmerican Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089–2111. doi:. doi:10.1002/hep.22261 [CrossRef]
- Kinnier Wilson SA. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain. 1912;34(4):295–507. doi:10.1093/brain/34.4.295 [CrossRef]
- Sokol R. Copper metabolism and copper storage disorders. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. 4th ed. New York, NY: Cambridge University Press; 2014:465–492. doi:10.1017/CBO9781139012102.029 [CrossRef]
- Olivarez L, Caggana M, Pass KA, Ferguson P, Brewer GJ. Estimate of the frequency of Wilson's disease in the US Caucasian population: a mutation analysis approach. Ann Hum Genet. 2001;65(Pt 5):459–463. doi:. doi:10.1046/j.1469-1809.2001.6550459.x [CrossRef]
- Weiss K. Wilson disease. In: Adam MP, Ardinger HH, Pagon RA, , eds. GeneReviews. Seattle, WA: University of Washington; 1993–2018.
- Wilson DC, Phillips MJ, Cox DW, Roberts EA. Severe hepatic Wilson's disease in preschool-aged children. J Pediatr. 2000;137(5):719–722. doi:. doi:10.1067/mpd.2000.108569 [CrossRef]
- Litwin T, Gromadzka G, Członkowska A. Gender differences in Wilson's disease. J Neurol Sci. 2012;312(1–2):31–35. doi:. doi:10.1016/j.jns.2011.08.028 [CrossRef]
- Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993;5(4):344–350. doi:. doi:10.1038/ng1293-344 [CrossRef]
- Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993;5(4):327–337. doi:10.1038/ng1293-327 [CrossRef]
- Wilson Disease Association. Kayser-Fleischer rings. http://wilsonsdisease.org/about-wilson-disease/kayser-fleischer-rings. Accessed October 31, 2018.
- Hordyjewska A, Popiołek Ł, Kocot J. The many “faces” of copper in medicine and treatment. Biometals. 2014;27(4):611–621. doi:. doi:10.1007/s10534-014-9736-5 [CrossRef]
- Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23(3):139–142. doi:10.1034/j.1600-0676.2003.00824.x [CrossRef]
- Koppikar S, Dhawan A. Evaluation of the scoring system for the diagnosis of Wilson's disease in children. Liver Int. 2005;25(3):680–681. doi:. doi:10.1111/j.1478-3231.2005.01072.x [CrossRef]
- Cumings JN. The effects of B.A.L. in hepatolenticular degeneration. Brain. 1951;74(1):10–22. doi:10.1093/brain/74.1.10 [CrossRef]
- Organ Procurement and Transplantation Network. Organ procurement and transplantation network policies. https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_09. Accessed October 31, 2018.
Clinical Manifestations of Wilson's Disease
Compensated or decompensated cirrhosis
Acute liver failure
Deterioration in school work