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The pattern of urinary copper excretion and its response to treatment in patients with Wilson's disease

J.M. Walshe
DOI: http://dx.doi.org/10.1093/qjmed/hcr073 775-778 First published online: 27 May 2011

Abstract

Background: 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.

Design: 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.

Results: 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.

Conclusions: 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.

Introduction

It is now generally accepted that patients with Wilson's disease excrete excess copper in urine. This was first noted by Mandlebrote et al.1 in 1948 and not confirmed until Porter2 described a similar phenomenon in 1951. Cumings,3 in an extensive review of the literature, gave a figure for urinary copper in Wilson's disease as 703 µg/24 h with SD 308.0 µg. His figure for the normal was 48 µg/24 h with SD 16.3 µg. In their monographs on Wilson's disease, Scheinberg and Sternlieb4 and Hoogenraad5 scarcely mention this aspect of the disease. There appears to be no concerted study on a large series of patients to ascertain if there is any pattern to the amount of copper excreted by these patients with different presentations or at different stages of the disease.

For the present study, some 300 case notes of patients seen between the years 1955 and 2000 have been reviewed. Of these, 192 contained sufficient relevant information to be included. Patients were omitted if seen before best practice was established or were referred too late after diagnosis. Furthermore, figures for urinary copper that were sent with such cases were often found to be seriously inaccurate and this may well have been due to faulty collection techniques.6 Such patients had usually been incompletely investigated and often received suboptimal treatment. The remaining 192 patients have been divided in to three groups: 31 pre-symptomatic patients; 37 patients with hepatic presentation and illness; and 124 with predominantly neurological symptoms, though some gave a history of an earlier brief, undiagnosed episode suggesting hepatic damage. The findings are described as the basal pre-treatment, 24-h urine copper and the response from the brain following a test dose of 500 mg penicillamine collected over a 6-h period. These tests were repeated after ∼1 year on chelation treatment and again after 2 years. It must be pointed out that none of these three groups is homogeneous as there is a wide range in age of presentation and also the time, after initial symptoms, at which they were studied. Hence, the copper load will have varied greatly. Nevertheless, the standard deviations and median figures are given, though they are of doubtful significance.

Findings

Pre-symptomatic (31 patients)

The age range for this group was 3–27 years with a mean of 15.8 years and a median of 15 years. The mean basal 24-h copper excretion was 207.93 µg (SD 151.31 µg) After penicillamine, and this rose to 872.24 µg/6 h (SD 512.16 µg), median 787 µg; after 1 year of treatment the corresponding figures for basal copper was 54.12 µg (SD 31.55 µg) and, after penicillamine, 240.5 µg (SD 306.18 µg), median 326 µg. After 2 years, the basal copper excretion was slightly lower at 38.16 µg/6 h (SD 22.3 µg), median 36.0 µg, virtually in the normal range. The after penicillamine copper rose slightly to 326.79 µg/6 h (SD 214.1 µg), median 241 µg.

Hepatic (37 patients)

The age range at which these patients were first tested was from 5 to 30 years with a mean of 15.03 years and a median of 14.5 years. The basal, pre-treatment, 24-h urinary copper excretion was more than twice of that seen in pre-symptomatic patients at 465.75 µg/24 h (SD 680.14 µg), median 236 µg; after penicillamine, the figure rose to 995.52 µg/6 h (SD 732.02 µg), median 866 µg. After 1 year of treatment, the basal urinary copper was 77.83 µg/24 h (SD 89.05 µg), median 61.0 µg and rising, after penicillamine to 293.36 µg/6 h (SD 206.67 µg), median 212.5 µg. After 2 years, there was a further fall in the basal urine copper excretion to 39.79 µg/24 h (SD 20.08 µg), median 33.0 µg. After penicillamine, the figure rose to 223.45 µg/6 h (SD 123.94 µg), median 231 µg.

Neurological (124 patients)

The age range for these patients was 7–39 years and the average age at which they were first tested was 21.8 years with a median of 20 years. The basal, pre-treatment urine copper excretion was less than that seen in the hepatic patients, but higher than the pre-symptomatic group at 305.38 µg/24 h (SD 172.47 µg), median 267 µg. After penicillamine, this rose to 1232.11 µg/6 h (SD 675.99 µg), median 1058.0 µg. After 1 year of treatment, the basal figure fell to 56.25 µg/24 h (SD 35.69 µg), median50.0 µg. This rose, after penicillamine, to 356.08 µg. After 2 years of treatment, the basal urine copper showed a further slight fall to 50.23 µg/24 h (SD 33.36 µg), median 41 µg. After penicillamine, the corresponding figures were 301.53 µg/6 h (SD 175.33 µg), median 249 µg (Table 1).

View this table:
Table 1

Results for all patients studied before treatment (R) and at 1 and 2 years on treatment

Patient groupsAge at onset, yearsAge tested, yearsBefore RAt Embedded Image 1 YearAt Embedded Image 2 years
BasalPenicillamineBasalPenicillamineBasalPenicillamine
Pre-symptomatic (31 patients)
    Mean (SD)15.8207.93 (151.31)872.24 (512.16)54.12 (31.55)240.5 (306.18)38.16 (22.33)326.79 (214
    Median (range)15 (3–27)177874932636241
Hepatic (37 patients)
    Mean (SD)14.8615.03465.75 (680.14)995.52 (732.02)77.83 (89.05)293.36 (206.27)39.79 (20.08)223.45 (123.94)
    Median (range)12 (5–26)14.5 (5–30)23686661212.533231
CNS (124 patients)
    Mean (SD)18.3321.8305.38 (172.47)1232.11 (675.99)56.25 (35.69)356.05 (171.39)50.23 (33.36)301.53 (175.33)
    Median (range)17 (7–39)20 (10–42)267105850323.541249
  • The results give basal urine copper and the 6-h response to a test dose of 500 mg penicillamine.

  • c = circa; R = Treatment; CNS = Central nervous system.

A small subgroup of 15 of these patients was treated with trientine rather than penicillamine for 2 years. The basal, pre-treatment urinary copper excretion was rather lower than in the main group at 193.14 µg/24 h (SD 101.16 µg), median 236 µg. After penicillamine challenge, this rose to 1000.67 µg/6 h (SD 641.59 µg), median 947.5 µg. At 1 year, the basal copper excretion fell to 53.14 µg/24 h (SD 28.09 µg), median 45.0 µg. After penicillamine, this rose to 213.75 µg. At 2 years, the basal copper excretion fell further to 38.45 µg/24 h (SD 22.05 µg), median 36.0 µg. After penicillamine challenge, this was even lower than at 1 year at 114.01 µg/6 h (SD 42.75 µg), median 126 µg (Table 2).

View this table:
Table 2

Results, similarly expressed to those in Table 1, for 15 neurological patients treated solely with trientine for the full 2-year period

CNS (15 patients)Age, yearsBefore RTETA treated
1 Year2 Years
BasalRBasalRBasalR
Mean (SD)20.05 (6.49)193.14 (101.6)1000.67 (641.59)53.14 (28.09)213.75 (147.61)38.45 (22.05)114.01 (42.75)
Median (range)17 (10–37)253947.545174.536126
  • CNS = Central nervous system; TETA = Trientine.

Discussion

In the pre-symptomatic patients, the highest pre-treatment 24-h urine copper was 550 µg, and in the hepatic group it was 3080 µg. This particular patient was having a massive haemolytic crisis at the time, and her after penicillamine copper excretion exceeded to 9 mg/6 h. Clearly, a single figure like this will skew the statistics: while in the neurological group the corresponding highest basal figure was 782 µg. The lowest figures were: pre-symptomatic 11 µg, hepatic 61 µg and neurological patients also 61 µg. The figure of 11 µg for a 24-h urine copper in pre-sympotomatic patients requires comment. He was the identical twin of a patient with florid neurological symptoms so, by definition, he must have had the same pair of genes. Unfortunately, DNA analysis, to confirm the diagnosis, was not available at the time these patients were seen. In all groups, the response to treatment proved to be very satisfactory approaching the normal range of 30 µg/24 h,7 though this took 2 years to achieve in all groups. There was a corresponding fall in the response to a test dose of penicillamine in the hepatic and neurological patients, but in the pre-symptomatic patients the response to the penicillamine challenge, at 2 years, showed an increase although the basal excretion had fallen. The explanation for this is not clear. In the small group treated with trientine, the initial basal copper excretion (193 µg/24 h) was rather lower than in other groups, but the rest of the tests were very similar. The differences between the three groups do not achieve statistical significance because of the very large standard deviations, but these can probably be explained by the heterogeneous nature of the patients for age and duration of symptoms before study, thus leading to wide variations in the size of the copper loads available for mobilization and excretion. However, there does appear to be a valid trend: the pre-symptomatic patients with, presumably, the lowest body load of copper showing the lowest rate of excretion, while those with hepatic disease show the highest figures, probably as a result of liberation of copper from necrotic hepatocytes and it may be that this high basal rate of excretion left less copper to be mobilized by penicillamine. The very high rate of copper excretion, after penicillamine, in the neurological patients may be due to the fact that, in these patients there is a larger pool of the metal to be mobilized, not only from the liver which had not lost copper from necrotic cells, but also from the brain. To a test dose of penicillamine, though this was not apparent in the after treatment studies. It is interesting to look at the size of the increase in copper excretion in these various groups following penicillamine challenge. In the pre-symptomatic patients, before treatment this rate was 4.2 times, at 1 year 4.4, but at 2 years it was 8.3. As stated above, the reason for this is not clear. It is unlikely to be due to under-treatment as the basal copper excretion had actually fallen from 54 to 38 µg a day. In the hepatic patients, the rate of increase, before treatment was started, was only 2.1, at 1 year 3.7 and at 2 years 5.8. In the neurological patients, the corresponding figures were, before treatment, 4.0, at 1 year 7.6 and at 2 years 6.0. In the trientine-treated patients, these figures were 5.2, 4.0 and 3.0, respectively. This supports earlier observations that in long-term management trientine appears to become less able than penicillamine to mobilize copper, but in none of the groups are there wide discrepancies between these sets of figures. As has been shown elsewhere, this protocol, though somewhat time consuming, has proved valuable in monitoring copper status in patients with Wilson's disease.8

Wilson's disease patients excrete excess copper in their urine and this can be corrected with chelation treatment. It would be interesting to see similar results for patients treated with zinc or tetrathiomolybdate.

Conflict of interest: None declared.

Appendix

To convert micrograms of copper to micromoles it is necessary to divide by 63 the MW of copper. Thus, a normal 24-h urine copper excretion of 30 µg will convert to 0.48 µmols. A high urine copper excretion of say 500 µg will convert to 7.94 µmols. Micrograms have been used in this article to make the differences in the various groups and the response to treatment more obvious.

References

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