Wilson’s disease (WD)
What is Wilson’s disease?
It is an autosomal recessive disease characterised by hepatic copper accumulation and injury. The gene ATP7B (on chromosome 13) encodes a transmembrane transporter of copper in hepatocytes. Absent or reduced function of ATP7B protein leads to decreased hepatic excretion of copper into bile. This results in hepatic copper accumulation and injury. Eventually copper is released into the bloodstream and deposited in various other organs, notably the brain, kidneys, and cornea.
Failure to incorporate copper into ceruloplasmin is an additional consequence of the loss of functional ATP7B protein. The hepatic production and secretion of the caeruloplasmin protein without copper (apocaeruloplasmin) results in the decreased blood levels of caeruloplasmin due to the reduced half-life of the apoprotein.
Discuss the copper cycle?
The average diet provides 2-5 mg/day (almost 3 times the recommended intake).
Most dietary copper ends up being excreted. Copper is absorbed mainly in the duodenum and proximal small intestine and transported to the liver, where it is avidly removed from the circulation. The liver utilizes some copper for metabolic needs and excretes excess copper into bile. Processes that impair biliary copper excretion can lead to increases in hepatic copper content
Discuss the clinical presentation of WD?
It can present clinically as liver disease, as a progressive neurologic disorder (hepatic dysfunction being less apparent or occasionally absent), or as psychiatric illness.
The type of the liver disease can be highly variable. It can be asymptomatic with only biochemical abnormalities or present with acute or chronic hepatitis or chronic liver disease with portal hypertension or with acute liver failure.
Discuss the eye manifestations of WD?
Kayser-Fleischer (KF) rings represent deposition of copper in Descemet’s membrane of the cornea. They appear as a band of golden-brownish pigment near the limbus. A slit-lamp examination is required to identify KF rings in most patients. They may also be found in patients with chronic cholestatic diseases. KF ring is present in up to 62% of patients with hepatic disease at the time of diagnosis. KF rings are almost invariably present in patients with a neurological presentation.
Sunflower cataracts, also found by slit-lamp examination, represent deposits of copper in the lens. These typically do not obstruct vision. Both KF rings and sunflower cataracts will gradually disappear with effective medical treatment or following liver transplant.
Discuss the diagnosis of WD?
WD should be considered in any individual between the ages of 3 and 55 years with liver abnormalities of uncertain cause. Age alone should not be the basis for eliminating a diagnosis of WD. Diagnosis of WD is confirmed, if 2 of the following 3 are present:
- Serum caeruloplasmin level <20 mg/dL
- Presence of KF ring
- Hepatic copper content > or =250 µg/g dry weight. (Normal < 50 µg/g).
A basal 24-hour urinary copper of more than 40 µg (>0.6 µmoles or >600 nmoles) suggests WD.
The serum noncaeruloplasmin-bound copper concentration is elevated above 25 µg/dL in most untreated patients (normal <15 µg/dL). Total serum copper (which includes copper incorporated in caeruloplasmin) in WD is usually decreased in proportion to the decreased caeruloplasmin in the circulation.
Mutation analysis by whole-gene sequencing is possible and should be performed on individuals in whom the diagnosis is difficult to establish by clinical and biochemical testing.
When should a diagnosis of WD be considered?
- Adult patients with atypical autoimmune hepatitis or who respond poorly to standard corticosteroid therapy.
- WD should be considered in the differential diagnosis of patients presenting with nonalcoholic fatty liver or who have pathologic findings of NASH.
- WD should be suspected in any patient presenting with fulminant hepatic failure with Coombs-negative intravascular hemolysis, modest elevations in serum amino transferases, low serum alkaline phosphatase, and ratio of alkaline phosphatase to bilirubin of less than 2.
- First-degree relatives of any patient newly diagnosed with WD must be screened for WD.
Discuss the therapeutic options in WD?
D-penicillamine – is the drug of choice. It is a general chelator of metals and promotes urinary excretion of copper. Recovery from symptomatic liver disease occurs typically during the first 2-6 months of treatment. Penicillamine use is associated with numerous side effects i.e. sensitivity reactions, nephrotoxicity, lupus like syndrome, bone marrow toxicity, hepatotoxicity etc. Dose- 1000-1500 mg/day in 2-4 divided doses. Maintenance dose is usually 750-1000 mg/day.
Trientine – It is another chelator. Like penicillamine, trientine promotes copper excretion by the kidneys. Trientine is an effective treatment for WD and is indicated especially in patients who are intolerant of penicillamine. Dose- 750-1500 mg/day in 2-3 divided doses, with 750-1000 mg used for maintenance therapy. As for penicillamine, trientine should be administered one hour before or two hours after meals.
Zinc – Zinc acts by interfering with the uptake of copper from the GI tract. Zinc induces enterocyte metallothionein, which binds copper present in the enterocyte and inhibits its entry into the portal circulation. Once bound, the copper is not absorbed but is lost into the focal contents as enterocytes are shed in normal turnover. Zinc is currently reserved for maintenance treatment. Dose- 150 mg of elemental zinc per day in 2 divided doses.
How do you monitor adequacy of treatment?
Adequacy of treatment can be monitored by clinical and biochemical improvement and by measuring 24-hour urinary copper excretion while on treatment. This should run in the vicinity of 200 to 500 µg (3 to 8 µmoles) per day on treatment with chelators (less than 75 µg wit copper). Additionally, estimate of noncaeruloplasmin-bound copper may show normalization with effective treatment. Urinary excretion of zinc may be measured from time to time to check compliance
Discuss the management of WD?
- Treatment is lifelong and should not be discontinued, unless a liver transplant has been performed.
- Foods with very high concentrations of copper (shellfish, nuts, chocolate, mushrooms, and organ meats) generally should be avoided, at least in the first year of treatment.
- Antioxidants, mainly vitamin E, may have a role as adjunctive treatment.
- Treatment should be initiated with a chelating agent in both symptomatic and asymptomatic or presymptomatic patients identified through family screening. Zinc may be used as the first agent in presymptomatic patients.
- Maintenance therapy – After adequate treatment with a chelator (usually for 1-5 years), stable patients may be transitioned to treatment with zinc. They will be clinically well, with normal serum aminotransferases and hepatic synthetic function, nonceruloplasmin-bound copper concentration in normal range, and 24-hour urinary copper repeatedly in the range of 200 to 500 µg (3 to 8 µmoles) per day on treatment. The advantages of long-term treatment with zinc include that it is more selective for removing copper than penicillamine or trientine and is associated with few side effects. Adequate studies regarding the timing of this change-over in treatment are not available. No matter how well a patient appears, treatment should never be terminated indefinitely. Patients who discontinue treatment altogether risk development of intractable hepatic decompensation.
- In pregnant women, treatment must be maintained throughout the course of pregnancy for all patients with WD. Interruption of treatment during pregnancy have resulted in fulminant hepatic failure.
- Liver transplantation is indicated for all WD patients with decompensated liver disease unresponsive to medical therapy, and it is the only effective option for those who present with fulminant hepatic failure.
Discuss the prognosis?
Long-term outcome is dependent on adherence to lifelong treatment. Patients with WD who commence treatment before onset of symptomatic hepatic or neurologic disease have an excellent long-term prognosis and rarely develop symptoms. Symptomatic patients may expect to stabilize or improve on treatment. A minority of patients with neurologic disease experience worsening with initiation of therapy: some stabilize but some worsen despite treatment. The prognosis for patients with liver disease who adhere to effective treatment is excellent, even if cirrhosis was present at the time of diagnosis.
Development of hepatocellular carcinoma is a rarely reported complication of WD. Screening for hepatocellular carcinoma has not been recommended for WD patients.
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