Chapter 8 - Monitoring Copper in Wilson's Disease

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1. Abstract

Monitoring copper metabolism in patients with Wilson's disease is not an exact science. At present, there are no simple methods of estimating the total body load of this metal. Indirect methods must therefore be used. A survey of the current literature shows that most approaches rely on the determination of blood and urine copper concentration. Both these should decrease with treatment. In parallel with decreased copper concentration, there should be subsequent improvement in more routine laboratory tests including liver and renal function, blood count parameters, and clotting factors. Lack of compliance is revealed by a reversal of this trend. This chapter critically reviews current testing methods and describes other approaches that may be helpful.

Introduction

Wilson's disease is due to copper overload. Although principally affecting the liver and brain, it also manifests, albeit to lesser degree, in other organs such as the cornea and kidneys. There is associated failure of copper excretion from hepatocytes into the bile. This disease results from a genetic mutation on chromosome 13q14.3 that encodes for the enzyme ATPase 7b. Approximately 300 mutations for this gene have now been recognized. Monitoring copper metabolism in patients with Wilson's disease is not, however, an exact science. At present, there is no simple method for determining total body load of this metal. As such, indirect methods must therefore be used. A survey of the current literature indicates that most medical centers rely on determination of blood and urine copper concentration before and during treatment, that is, both levels should decrease if therapy is to be considered effective. In parallel, there should be an improvement in the more routine clinical laboratory indices including liver and renal function tests, blood cell counts, and clotting factors. This chapter critically reviews these tests and describes the other methods that may be of analytic value.

Despite its importance, monitoring copper metabolism in Wilson's disease has surprisingly not appeared as a specialist published study. Proceedings of the eight international conferences on Wilson's disease (up to Leipzig 2001) revealed that limited emphasis has been placed on this subject. In fact, most articles that covered treatment of Wilson's disease have referred to reduction of urinary copper excretion and decreased serum ceruloplasmin and serum copper as the main indices of successful treatment. For example, a recent review by Mak and Lam [1] recommended a 24 h excretion of free copper, that is, copper not bound to protein. This phenomenon may be particularly relevant in cases of penicillamine-induced nephrotic syndrome and other protein losing renal lesions wherein ceruloplasmin and other proteins are lost in the urine [2]. This review also referred to decreased serum ceruloplasmin concentration as a measure of therapeutic effectiveness and questioned the value of free copper measurement due to limitations inherent to the analytical techniques employed. Brewer et al.[3] indicated that serum free copper should be 3.9 μmol/L (25 μg/dL). This concentration, however, may be about twice as high as should be aimed at. Scheinberg and Sternlieb [4] advocated for estimation of serum “free copper,” that is, copper not bound to ceruloplasmin. This approach, however, required accurate determination of ceruloplasmin concentration. At this time, most laboratories used immunodiffusion, a subjective and, at best, semiquantitative technique. Poor standardization of this technique was later shown to cause erroneous results [5]. Some researchers also explored the use of radiolabeled copper (64Cu) and demonstrated that it was cleared more rapidly from the circulation following treatment [6].

The disappearance of Kayser–Fleischer rings was also considered to be of value in monitoring removal of copper from tissues [7], [8]. Estimation of hepatic copper concentration, despite its more quantitative approach, received considerably less attention due to its invasive nature and patchy distribution of copper in that organ. Although Cumings [9] first demonstrated increased hepatic copper concentration in Wilson's disease in 1948, it was not until 1964 that Scheinberg and Sternlieb [10] demonstrated in that it was possible to reduce liver copper concentration via penicillamine therapy. This observation was subsequently confirmed by Marecek et al.[11] in 1975. However, a later report by Scheinberg et al.[12] contradicted earlier findings and suggested that liver copper concentration might be increased despite histological improvement in some patients. They suggested that penicillamine had rendered the liver copper “nontoxic.” A report by Gibbs and Walshe [13] concluded that all three therapies, that is, penicillamine, trientine, and tetrathiomolybdate, appeared effective in reduction of liver copper when used regularly (Fig. 1). It should be noted, however, that such studies only became possible after the introduction of effective decoppering agents, beginning with penicillamine [14], zinc sulfate [15], and trientine [16]. These therapeutic approaches were subsequently followed by liver transplantation [17] and use of tetrathiomolybdate [18].

More recently, it has been possible to show improvement particularly in the basal ganglia and size of the ventricles by CT (computed tomography) [19] and MRI (magnetic resonance imaging) scanning [20]. However, these indices have not always mirrored clinical improvement. Regular ultrasound scanning of the liver can also provide valuable information regarding changes in organ condition. In lieu of estimated liver copper concentration, none of these techniques can do more than suggest changes in body copper load. Other approaches such as copper balance studies have proven too difficult and imprecise to be used [21]. Although many articles refer to the importance of monitoring treatment effectiveness in Wilson's disease, at present there is no technique available that can measure the total body load of this metal.

Other options include the use of routine clinical laboratory indices such as liver and renal function tests, blood cell counts, and coagulation parameters.

Section snippets

Options for Monitoring Copper Load

Because measurement of total copper load appears impractical, it is necessary to establish routine tests or sets of procedures for monitoring long-term therapeutic intervention and follow-up. Due to the paucity of published information on this subject, I have based my recommendations on actual experience in the follow-up of over 300 patients with Wilson's disease over 45 years (1955–2000). Importantly, it is essential that accurate and precise measurements be obtained prior to and during

Summary

In summary, a simple and reasoned approach to long-term control of copper status is to study the Kayser–Fleischer rings, make serial determinations of the serum “free copper,” and urinary copper when treatment has been interrupted for at least 48 h. Serial liver biopsies are not necessary. Profile whole body scans after injection of radiocopper provide valuable information as to the degree of saturated copper binding sites in the liver, and a comparison of the cupriuretic response to trientine

Acknowledgments

I thank John Wiley and Sons Inc for permission to reproduce Fig. 1 from Ref. [11]. I thank Oxford University Press, Journals Division, for permission to reproduce Fig. 2 from Ref. [20], Fig. 3 from Ref. [25], and Fig. 4 from Ref. [32], and Fig. 5 from Ref. [17].

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