A comprehensive case report and review of D-penicillamine-induced pancytopenia in Wilson's disease

Wilson's disease: clinical management and therapy

Long-term Outcome for Wilson Disease: 85% Good

Wilson disease

Chapter 15 - Wilson disease – currently used anticopper therapy

Serum copper and zinc concentrations and 24 hour urinary copper and zinc excretion were determined serially from the beginning of treatment with D-penicillamine in four children with Wilson's disease. The data show a progressive decrease in both serum copper and zinc concentrations in all. Urinary copper excretion gradually levelled off to approximately 50% of initial values, but zinc excretion increased. Urinary zinc:copper ratios therefore increased with the duration of treatment. Copper elimination was considered adequate as soon as challenge with a test dose of D-penicillamine did not result in an increase in copper excretion. Urinary zinc excretion was increased further by the test dose. Zinc depletion was suspected clinically in one patient on D-penicillamine maintenance treatment. Lowering the dose alleviated the symptoms, urinary zinc loss decreased from 64 to 34 mumol/24 hours, and copper excretion remained largely unchanged. Data obtained indicate that D-penicillamine alters the metabolism of both copper and zinc. The extent of this is not only dose dependent but is also related to the efficacy of copper elimination. Both copper and zinc concentrations must by monitored to assess the benefits of treatment and the risks of inducing manifest or subclinical zinc deficiency.

This Month in Gastroenterology

We evaluate Wilson disease (WD) treatment with zinc acetate (U.S. Food and Drug Administration approved) and alternative zinc salts. Studies examining zinc therapy in WD are few, and data on alternative zinc salts are limited. We describe one of the largest recent studies of zinc therapy in WD. First, we conducted a single‐center retrospective review of 59 patients with WD (age 6‐88 years, 32 female patients) treated with zinc (50‐150 mg) for 0.8 to 52 years (median, 26 years); most were on prior chelation therapy (n = 39). Second, we developed a survey to explore patients' zinc therapy experience. Primary endpoints were alamine aminotransferase (ALT) and urine copper excretion (µg/24 hours). Urine copper was categorized as low <25 μg (possible overtreatment), target 25‐100 μg, or elevated >100 μg (possible noncompliance or treatment failure). The target range was reached in 81% of patients on zinc acetate, 73% on zinc gluconate, and 57% on alternative zinc. Low urine copper was not associated with a high ALT. ALT was normal in 77% of patients with target urine copper but only in 16% with urine copper >100 µg. ALT elevations were not significantly different between zinc salts (Kruskal‐Wallis, P = 0.26). Our survey demonstrated the mean age of starting zinc was 26.8 years (3.5‐65 years); most were treated with zinc acetate (45%) and zinc gluconate (42%). Before zinc treatment, 45% of patients were symptomatic; the majority of patients (80%) were asymptomatic on zinc. Gastrointestinal side effects were the predominant reason for changing zinc salts (38%), but most reported no side effects on current zinc therapy (67%). Conclusion: Effective treatment with zinc is possible in many patients with WD. The potential for treatment failure suggests close monitoring and consideration of alternative treatments are paramount for those without both a normal serum ALT and appropriate urine copper excretion.

We read with great interest the article by Chevalier et al 1 on copper deficiency in patients with Wilson's disease (WD) receiving anti-copper agents.Anti-copper treatment in WD is lifelong, but some patients are overtreated and develop copper deficiency. 2 However, few cases of copper deficiency in WD have been published to date, with no epidemiological data available. 2Copper deficiency may cause myeloneuropathy and aggravate the neurological symptoms of WD, such as gait disturbances, falls, and weakness. 3Such clinical worsening may prompt intensification of anti-copper treatment, which will further aggravate the neurological symptoms caused by copper deficiency. 4Similarly, anemia and neutropenia due to copper deficiency may suggest progressive liver damage or hypersplenism, leading to unnecessary treatments, including splenectomy, which can worsen these hematological complications. 1 Therefore, clinicians must be aware that copper deficiency may worsen both the neurological and hepatic symptoms of WD. 3 Copper deficiency in WD is diagnosed when urinary copper excretion is markedly reduced: < 20 g/24 h on zinc salts or <100 g/24 h on chelators, with low total serum copper and ceruloplasmin. 2 Decreased concentration of nonceruloplasmin bound copper (NCC) < 5 g/dl may also indicate copper deficiency in WD, but this method gives false negative results in nearly 20% cases. 2,5However, high concentrations of NCC (>25 g/dl) may help differentiate copper deficiency from non-compliance with chelators.In both situations, urinary copper excretion is low, but NCC is high in non-compliant patients and low in those with copper deficiency. 2 Currently, the clinical value of NCC is limited because it is calculated indirectly from serum concentrations of copper and ceruloplasmin.Measuring NCC directly seems promising, but the available methods, such as exchangeable copper, labile bound copper or dNCC need validation in practice. 5We believe that using such direct measurements of NCC will just help adjust anti-copper treatment and avoid copper deficiency in patients with WD. 5

Late-Onset Wilson’s Disease

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

Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy

Catatonia: A Rare Presenting Symptom of Wilson’s Disease

It is generally accepted that patients with Wilson's disease excrete excess copper in urine. However, there has been no study, on a large series of patients, as to whether there are differences in the rate of excretion at different stages of the disease or what changes may be expected after treatment. The present study follows from an analysis of the results of urinary copper excretion of 192 patients with Wilson's disease seen between 1955 and 2000. These patients were divided into three groups, pre-symptomatic, hepatic and neurological Wilson's disease. Patients were studied for basal pre-treatment, 24-h urinary copper excretion and for 6 h after a test dose of 500 mg penicillamine. The tests were repeated after approximately 1 and 2 years of chelation therapy with either penicillamine, or in a small minority of cases, trientine. The basal, pre-treatment copper excretion was the lowest in pre-symptomatic patients (207.93 µg/24 h) and the highest in the hepatic patients (465.75 µg/24 h). Those with neurological Wilson's disease gave an intermediate figure (305.58 µg/24 h). The response to penicillamine was the highest in the neurological patients and the lowest in the pre-symptomatic group. After 1 and 2 years of treatment all groups showed significant falls in both the basal and the after penicillamine rate of excretion of copper. The small subgroup treated with trientine, rather than penicillamine, showed similar results. The rate of copper excretion in patients with Wilson's disease shows wide variation from patient to patient, but in general patients with pre-symptomatic disease excrete less copper than those with symptomatic disease. All groups show a great increase when challenged with penicillamine. After 1 and 2 years of treatment, there is significant decrease in copper excretion in both basal and after penicillamine challenge. This presumably indicates a reduction in the body load of copper.

Wilson disease is a genetic disease involving copper metabolism disturbances that result in copper accumulations, especially in the liver and brain. Wilson disease can be treated with pharmacologic agents, such as chelators that induce urinary excretion of copper or zinc salts that inhibit copper absorption in the digestive tract. Liver transplant is the only treatment option for Wilson disease when liver failure has occurred. In some patients, that is, in those with Child-Pugh A score, neurologic disease can be seen without hepatic failure. Our recommendation is for these patients to have auxiliary partial orthotopic liver transplant. Here, we present a 36-year-old male patient with neurologic disease associated with Wilson disease who had successful related living-donor auxiliary partial orthotopic liver transplant using a left lobe. The patient, as a result of neurologic symptoms that included tremor walking and speaking problems and low serum ceruloplasmin level of 7 mg/dL, was diagnosed with Wilson disease, and a liver biopsy was performed. Chronic necroinflammatory disease activity was 4/18, and the patient received chelation treatment. His hepatic functions were normal. The donor was the patient's 57-year-old father whose liver function tests were also normal. The graft-to-recipient weight ratio was 1% using a left lobe graft. After transplant, serum ceruloplasmin levels on day 15 and month 1 were 14 and 19 mg/dL. At month 1, liver function tests were normal. Doppler ultrasonography showed normal vascular flow of the native liver and the graft. The patient's neurologic symptoms were progressively reduced. Progressive neurologic deterioration with no hepatic insufficiency is considered a suitable indication for auxiliary partial orthotopic liver transplant; this procedure is suggested before the neurologic and liver failure symptoms of Wilson disease occur.

A few patients with an affected CNS involving abnormalities in copper metabolism have been described that do not fit any known nosological entities such as Wilson's disease or Menkes' disease.Three...