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Wilson disease: What is still unclear in pediatric patients?

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Summary

Since Wilson disease (WD) may not be present with evident clinical symptoms of liver injury and neurological presentation is rare in children, establishing a diagnosis is often challenging, especially in childhood. Increased transaminases can be the only abnormality found in early course of WD. In clinical practice, high suspicion is crucial for early diagnosis and timely treatment to ensure better outcomes. Conventional diagnostic criteria established for adults are commonly agreed for children but may not always be appropriate in very young age. Currently, the best therapeutic approach for each specific presentation of the disease remains controversial and there are no clear indications about how to treat pediatric WD patients with a mild liver disease.

Introduction

Wilson's disease (WD) is an autosomal-recessive human copper (Cu) storage disorder caused by mutations in the ATP7B gene [1]. Clinical presentation can vary widely, but the key features of WD are liver disease and neuropsychiatric disturbances [2], [3]. Diagnosis of WD remains a challenging patchwork involving clinical, laboratory, histological and molecular tools [4]. The therapeutic success using oral copper chelating agents and zinc therapy makes WD one of the few treatable metabolic liver diseases.

Section snippets

Genetics and pathogenesis

The ATP7B gene is large and encodes copper-translocating ATPase expressed primarily in the liver. ATP7B resides in the trans-Golgi membrane compartment and mainly loads Cu on newly synthesized apoceruloplasmin [5]. The exact mechanism of copper hepatotoxicity and brain injury remains unclear. It is suggested that copper metabolism disturbance in WD is associated with significant changes in systemic antioxidant capacity parameters in a direction favoring enhanced oxidative stress [6].

To date,

Clinical features

Although the failure to excrete biliary copper is present from birth, WD symptoms generally do not develop until about three years of age, and rarely become evident before age of five. Unfortunately, symptoms at any age are frequently non-specific. Most of the pediatric WD patients present with liver disease, whereas neuropsychiatric symptoms are more common after the age of 18 years [15].

The hepatic clinical presentation ranges widely from asymptomatic hypertransaminasemia and/or fatty liver

Diagnosis

If WD is not recognized and adequately treated, the progression of hepatic and neurologic damage can be very rapid and ALF can occur. Therefore, the prompt detection of this condition is vital. Unfortunately, the diagnosis of WD is an especially challenging task [17].

In 2003, Ferenci et al [20] proposed a diagnostic score for WD, including clinical, biochemical, histologic and molecular findings. Table 1 shows scoring system clarifying for each item the diagnostic validated cutoff in pediatric

Treatment

The overall therapeutic aim for WD is the generation of a negative copper balance. Today this can be achieved either by liver transplantation, which phenotypically corrects the gene defect in the liver, or by medical therapy. Obviously liver transplantation is a treatment option for patients with severe life-threatening conditions in whom the window for medical treatment is not wide enough. It cannot be proposed as a therapeutic strategy, given the high rate of complications and the need for

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Funding source: no funding was secured for this study.

Financial disclosure: authors have no financial relationships relevant to this article to disclose.

References (24)

  • R. Bruha et al.

    Decreased serum antioxidant capacity in patients with Wilson disease is associated with neurological symptoms

    J Inherit Metab Dis

    (2012)
  • The Human Gene Mutation Database....
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