Approach Considerations
The mainstay of therapy for Wilson disease is pharmacologic treatment with chelating agents such as D-penicillamine and trientine. [2] Other agents include sodium dimercaptosuccinate, dimercaptosuccinic acid, zinc, and tetrathiomolybdate. [13] Zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. [2]
The use of surgical decompression or transjugular intrahepatic shunting (TIPS) in the treatment of portal hypertension is reserved for individuals with recurrent or uncontrolled variceal bleeding that is unresponsive to standard conservative measures.
After the initiation of therapy with a chelating agent, the patient needs to be aware of potential adverse effects of the agents with which he or she is being treated. For instance, some of the concerning adverse effects are those commonly associated with penicillamine use. In addition, a patient must also be aware of the potential to develop worsening of some symptoms when chelation is started; in particular, patients with neurologic signs and symptoms can see worsening of these with chelation, and, in some instances, therapy needs to be reduced or stopped. Laboratory tests in patients started on penicillamine should include hematology and biochemical monitoring, as well as urinalysis.
With clinical progression, acute liver failure, or worsening hepatic function, the patient must be evaluated at a center with expertise in Wilson disease and the capability to perform liver transplantation.
Orthotopic liver transplantation is curative treatment for Wilson disease. Also see Liver Transplantation.
Diet
Patients should generally avoid eating foods with a high copper content, such as liver, chocolate, nuts, mushrooms, legumes, and shellfish (especially lobster). Drinking water from atypical sources (eg, well water) should be analyzed for copper content and replaced with purified water if the copper content is greater than 0.2 parts per million.
Pregnancy
Excessive intrauterine copper concentrations may be responsible for the high rate of spontaneous abortions in patients with Wilson disease. D-penicillamine (0.75-1.5 g/day) appears to pose no major risk to the fetus and should be continued throughout the pregnancy.
While pregnancy per se does not appear to have a deleterious effect on the course of treated patients, the risk of ascites or bleeding from gastroesophageal varices in pregnancy is increased for any individual with cirrhosis, regardless of the underlying etiology.
Pediatric
Pediatricians should consider Wilson disease in any child with hepatic abnormalities. The initial tests should be performed, and further workup by a pediatric gastroenterologist may be necessary if suspicion remains high.
Geriatric
Almost all patients have significant hepatic and neuropsychiatric symptoms before reaching the geriatric age group. Patients with Wilson disease who are untreated will most likely present with fulminant hepatic failure or with signs and symptoms of cirrhosis in the geriatric population. Consideration for liver transplantation is less likely with advancing age.
Neurologic deterioration with treatment
It is very important to recognize that some patients may develop worsening neurologic symptoms when therapy is initiated. In some of these instances, the chelating agent needs to be stopped and the patient should be run on zinc acetate alone. In patients on long-term treatment who show signs of progressive neurologic symptoms on chelating agents, medication compliance and dietary compliance require review, along with an assessment of the efficacy of laboratory testing.
Medicolegal concerns
Medicolegal issues may arise if the diagnosis is not considered in the face of appropirate clues.
Also critical is to provide the patient with information and to screen siblings of the index case for the possibility of Wilson disease, because the estimated frequency is 1 in 4 in situations in which the siblings have the same parents.
Consultations
Consider consultation with gastroenterologists with specialty training in hepatology for any patient with Wilson disease, especially when evidence of hepatic insufficiency is present. Consultation with surgeons may be sought for liver transplantation when deemed necessary.
Long-Term Monitoring
Perform a physical examination, 24-hour urinary copper excretion assay, complete blood count (CBC), urinalysis, serum free copper measurement, and renal and liver function tests on a weekly basis for the first 4-6 weeks following initiation of chelation therapy.
The best way to monitor efficacy is to measure serum nonceruloplasmin-bound copper. This is measured by the following formula: Total serum copper (mcg/dL) - 3[ceruloplasmin (mg/dL)]. The reference range is less than 15 mcg/dL.
An adjunctive way to monitor efficacy is to measure urinary copper excretion. Urinary chelator levels usually measure 200-500 mcg/day. Urinary zinc levels usually measure less than 75 mcg/day.
Bimonthly evaluations are recommended through the first year, followed by yearly examinations thereafter. In patients with Kayser-Fleischer rings, a yearly slit-lamp examination should document fading or disappearance if patients are being adequately "decoppered."
Lifelong, uninterrupted chelation therapy is necessary in all patients with Wilson disease. Frequent follow-up with patients is necessary, secondary to patient decompensation due to noncompliance. This is one of the major causes of fulminant liver failure. Patients must avoid most alcohol consumption and potential hepatotoxic drug therapy.
Molecular Adsorbents Recirculating System (MARS)
MARS is an extracorporeal liver support system using a hollow-fiber dialysis module in which the patient’s blood is dialyzed across an albumin-impregnated membrane while maintaining a constant flow of albumin-rich (20%) dialysate in the extracapillary compartment. Case reports and very small series have presented a role for this as a bridge to liver transplantation. [20]
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Computed tomography (CT) scan in a 15-year-old boy who presented with central nervous system findings consistent with Wilson disease. The CT scan reveals hypodense regions in the basal ganglia (caudate nucleus, putamen, globus pallidus). The differential diagnosis based on this image alone included leukodystrophy, vasculitis, and, less likely, infection. Ventricular enlargement and posterior fossa atrophy may also be seen on brain CT scans in a patient with Wilson disease. The extent of involvement as depicted on CT scans does not provide prognostic information.
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Approach to the diagnosis of Wilson disease (WD) in a patient with unexplained liver disease. KF = Kayser-Fleischer ring; CPN = ceruloplasmin. From the American Association for the Study of Liver Diseases Practice Guidelines.
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In this particular case, there is abundant Mallory hyaline. Another notable finding is the moderate to marked chronic inflammation which involved most portal tracts and periportal/perinodular areas.
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Prismaflex eXeed II adds citrate anticoagulation with integrated calcium management. Image courtesy of Gambro.
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Molecular adsorbents recirculating system (MARS) circuit.
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Biopsy specimen showing hepatocellular injury in an explant specimen from a patient transplanted for Wilson Disease.
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Biopsy specimen showing a more detailed image of the cellular injury in acute Wilson disease.
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Wilson disease biopsy specimen with rhodanine stain.
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Wilson disease biopsy specimen with rhodanine stain (stain specific for copper deposition).
Tables
Score |
0 |
1 |
2 |
3 |
4 |
Serum bilirubin (reference range, 3-20 mmol/L) |
< 100 |
100-150 |
151-200 |
201-300 |
>300 |
Serum aspartate transaminase (reference range, 7-40 IU/L) |
< 100 |
100-150 |
151-200 |
201-300 |
>300 |
Prothrombin time prolongation (seconds) |
< 4 |
4-8 |
9-12 |
13-20 |
>30 |
