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Journal of Pediatric Gastroenterology & Nutrition:
Letters to the Editor

Wilson Disease: Diagnostic Dilemmas?

Iorio, Raffaele; Porzio, Salvatore; Mazzarella, Giuseppina; Fusco, Giuseppina; Vegnente, Angela

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Department of Pediatrics

University of Naples “Federico II”

Naples, Italy

To the editor:

We read with interest the article by Sanchez et al. (J Pediatr Gastroenterol Nutr 1999;28:186–90) regarding diagnosis of Wilson's disease (WD) in childhood. In this study, patients were considered to have WD if the following criteria were met: the alteration of two or more copper metabolism test results or the alteration of one copper metabolism test result combined with any of the following: positive rubeanic acid or orcein stain or hepatic copper concentration of more 200 μg/g dry weight, in absence of other causes that could justify an increased liver copper content. Among copper metabolism tests, the authors considered 24-hour urinary copper excretion higher than 100 μg to be abnormal (this value was present in 20 of 25 children with WD). In this study, the measurement of 24-hour urinary copper excretion after penicillamine administration was not performed, even though this test has been reported as the most accurate single diagnostic test for WD in childhood (1). In the study conducted by DaCosta et al. (1) 15 of 17 children with WD showed 24-hour urinary copper excretion after penicillamine challenge higher than 1590 μg (1). As for hepatic copper determination, considered by Brewer et al. (2) to be the gold standard for diagnosis of WD, in the study of Sanchez et al. only eight patients received measurement of liver copper levels. Furthermore, although it has been reported that copper staining is unreliable in defining the level of hepatic copper and in determining whether copper accumulation is abnormal (2), copper staining was considered of diagnostic value by Sanchez et al.

Here, we report the changes in 24-hour urinary excretion, basal and after penicillamine challenge, in 11 children (8 boys) with WD. These patients received diagnosis of WD at a median age of 6 years (range, 2.3–14.5 years). In all of them, diagnosis of WD was based on hepatic copper concentration (median value, 1029 μg/g dry weight, range, 390–1230 μg/g dry weight). The other most common causes of liver disease, including cholestatic liver diseases, were excluded in all patients. None of the patients had a symptomatic onset of WD. Ten were referred to observation for isolated hypertransaminasemia, identified at routine examination that in our country includes the evaluation of aminotransferase serum levels. One was observed because he was a sibling of a patient with WD. At clinical examination, eight patients had hepatomegaly, and one also had splenomegaly. No patient had neurologic signs. Laboratory results showed that all patients had hypertransaminasemia at diagnosis (median value of alanine aminotransferase, [ALT] 196 IU/l; range, 45–418 IU/l) with normal results in the remaining liver function tests. Normal values of serum ceruloplasmin were found in only two patients, who showed also copper serum levels in the normal range. In the remaining nine patients low levels of both ceruloplasmin and copper were documented. Five (45%) patients had a 24-hour urinary copper excretion lower than 100 μg (median value, 55 μg; range 36–91 μg). The remaining six patients had basal levels of cupriuria ranging from 116 to 198 μg/24 hours. As for urinary copper excretion after penicillamine challenge at a dosage of 500 mg twice daily, only one patient had a value higher than 1592 μg/24 hours. The remaining 10 patients had a median value of 622 μg/24 hours (range, 119–1452 μg/24 hours). No significant correlation was found between levels of cupriuria, both basal and after penicillamine challenge, and the age of patients. Probably, the low levels of cupriuria at baseline and after penicillamine challenge, observed in this study, are related to the absence of advanced disease in the studied patients, different from that reported in Sanchez et al. and DaCosta et al. (2) which included more children with severe liver disease. It should be noted that in all studied patients, liver and urine samples were carefully collected to avoid copper contamination.

Considering the discrepancy in diagnostic criteria for WD used in pediatric studies (1,2) and on the basis of our results concerning 24-hour urinary copper in children with WD, it seems clear that diagnosis of WD is a challenge for pediatricians. On the other hand, an early diagnosis of WD is essential because specific treatment can prevent further liver injury and neurologic complications. It is therefore desirable to have more definite diagnostic criteria for WD in childhood. In this context, a molecular diagnosis system, based on mutational and haplotype analyses, with all its current limitations, has to be considered very effective for making a definitive diagnosis in very young patients and also for detecting carriers (3).

Raffaele Iorio

Salvatore Porzio

Giuseppina Mazzarella

Giuseppina Fusco

Angela Vegnente

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1. DaCosta CM, Baldwin D, Portmann B, Lolin Y, Mowat PA, Mieli-Vergani G. Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson's disease. Hepatology 1992; 15:609–15.

2. Brewer GJ, MD, Yuzbasiyan-Gurkan V. Wilson disease. Medicine 1992;7:139–63.

3. Cox DW. Molecular advances in Wilson disease. Prog Liver Dis 1996; 14:245–64.

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