- Email: [email protected]
Treatment of Wilson's disease with zinc
LETTER TO THE EDITOR Treatment of Wilson's disease with zinc To The Editor: The Editorial 1 by Tjaard Hoogenraad that appeared in relationship to our paper 2 on long term follow-up of zinc treatment in Wilson's disease patients criticized our work in an inaccurate and inappropriate manner. Our paper was number 15 in a series on zinc treatment of Wilson's disease, with many of the articles having been published in this journal. This series of papers, over a 15-year period, laid the detailed scientific groundwork for the 1997 approval of zinc as a therapy for Wilson's disease by the US Food and Drug Administration. Paper number 15 was in many ways the most important of the series, because it provided detailed long-term follow-up in 141 patients who had received only zinc as a maintenance therapy for their Wilson's disease. It is by far the largest in terms of patient numbers, longest in terms of length of follow-up, best-controlled, and most-detailed study of any therapy for Wilson's disease that has ever been reported. Paper 15 was designed so that clinicians without a great deal of experience in Wilson's disease could use zinc therapy in an informed manner and take advantage of zinc's low toxicity as compared with other therapies. The Hoogenraad editorial 1 incorrectly claimed that much of the critical work was done in Europe and incorrectly claimed that our use of zinc was much too restrictive. The editorial also contained additional inaccurate and unfair criticisms. Hoogenraad I states that his Dutch countryman, Schouwink, "introduced zinc therapy in 1961 for the treatment of Wilson's disease." This statement is incorrect, or at least needs clarification. Shouwink did not "introduce zinc therapy" to the academic community in general because he never published any of these data. They appear only in his Dutch language thesis. 3 Further, Hoogenraad says, "Schouwink performed copper balance studies in patients with Wilson's disease and demonstrated that the copper balance became negative when zinc sulfate was given." This statement is blatantly in error. Thanks to the kindness of Dr Schouwink, I acquired a copy of his thesis. What is reported in the thesis is urine and fecal copper while two patients were on zinc therapy. Since food copper is not evaluated, it is not a "copper balance" study, and there is no way to conclude, as Hoogenraad incorrectly does, that zinc caused a negative copper balance. In fact, if copper intake of 2 to 5 mg per day had been the case, as was thought to be the average intake at that time, zinc would by Schouwink's data have seriously failed to produce a negative copper balance and would thus have been dangerous therapy for these patients (given that penicillamine was available). We were the first to report actual copper balance 322
studies in Wilson's patients on zinc therapy. 4,5 Schouwink 3 does deserve credit for thinking of zinc as a possible therapy, giving zinc to two patients, and observing an increase in fecal copper on zinc therapy. However, the failure to publish any of these data made it impossible for other scientists, such as ourselves, to take advantage of his observations. This is clearly the reason Schouwink has not received very much credit for his observations. Hoogenraad 1 goes on to claim credit for the next phase of zinc development after Schouwink. However, the two papers 6,7 he published in the interim before our first paper were both anecdotal case reports involving one patient each. In the first report, 6 a letter to the editor, the patient was given zinc intermittently with penicillamine, and it is impossible to assess zinc's effect. The second report 7 was simply a followup on one of Schouwink's two patients. Our first paper came out next, and it reported copper balance control in 5 out of 5 patients on zinc therapy. 4 Later Hoogenraad treated additional patients with zinc, 8 but we began to have serious ethical concerns about this work. It seems that patients were placed on zinc without attention to whether it was a safe alternative to an already proven effective therapy--penicillamine. Hoogenraad did not do copper balance studies, or even 64Cu absorption studies, in these patients (at least none were reported), and these are the only procedures that provide contemporaneous information that a given dose of zinc is effective in a given patient. Instead, he appears to have relied on the plasma non-ceruloplasmin copper levels, but these respond rather slowly to changing copper status. The patient could be in deep clinical trouble, if zinc were inadequately effective in that patient, prior to the detection of a significant upward change in this variable. So how could Hoogenraad be sure that these patients were not at risk of serious deterioration when he first prescribed zinc for them as the sole anticopper therapy, when penicillamine, and trientine for the penicillamine-intolerant patient, were already available? It is not enough to know that zinc was effective in Shouwink's two patients, because it might not be adequately effective in the third patient, or the fourth, etc. It seems to us that Hoogenraad's approach of putting patients on zinc and hoping the disease would be controlled raises major ethical concerns. In our own case, we made sure that each patient had copper balance control on the zinc regimen to be used for that patient before putting the patient on long-term zinc therapy.4, 5 We did not initiate our work on zinc therapy for Wilson's disease as a result of Schouwink's thesis or Hoogenraad's two case reports, although we always cite the latter. We observed copper deficiency in zinc-treated sickle cell patients,9,10 put two-and-two together, and did a clinical trial of zinc in Wil-
J Lab Clin Med Volume 134,Number 3
son's disease, being extremely careful about the ethical concerns discussed above. We have subsequently made almost all the substantive contributions to the development of zinc as a practical and valid therapy for Wilson's disease. This includes data on the negative copper balance produced by zinc4,5,11-16; the control of copper in blood, urine, and liver 11,17,18; data on the mechanism of action19,2°; effective dosages and dose responsel4jS; possible side effects that we disproved21-23; and possible interactions with other drugs. 24 We have also led the way in developing data for zinc use in pregnant and pediatric Wilson's disease patients.2 The single unique contribution of the Hoogenraad group has been to develop an oral 64copper uptake procedure to evaluate and monitor the effectiveness of zinc therapy. 6 However, contrary to the assertion of Hoogenraad in his editorial, he and his group did not discover the metallothioneinmechanism of zinc action from their 64copper work. This concept was developed by other groups working on zinc-treated animals,25,26 and we first showed that the metallothionein mechanism was applicable in the human, in zinc-treated Wilson's disease patients. 20 Throughout the editorial Hoogenraad makes errors and inappropriate assertions. For example, Hoogenraad correctly states that our first paper on this topic was in 1983, but then gives the wrong citation in his editorial. The correct citation is reference 4 of this letter. At the end of the editorial, Hoogenraad says, "It is a pity, however, that they have experience with zinc only as a maintenance treatment and that they have failed to use zinc as an initial treatment." Hoogenraad's statement is in error. In the very paper Hoogenraad reviewed, we presented data on using zinc from the beginning in presymptomatic patients, as well as data on its use in pregnant and pediatric patients. We recommended zinc for all these types of patients. Hoogenraad then states, "It would be unfortunate if their study were to give the readers of the Journal the impression that zinc is not appropriate for initial treatment, because in fact, the opposite is true. Patients should be treated with zinc from the start." Well, I hope our paper gave "the impression that zinc is not appropriate for initial treatment," at least not in all types of patients, because that is in fact what we believe. Our belief is based on three patients with neurologic presentation that we initiated on zinc, one of whom deteriorated seriously during the several-month period it took for zinc to gain control of copper toxicity. It is also based on dozens of copper balance and other studies, which give us the knowledge for an estimate of how long it takes zinc to control acute copper toxi c i t y - a b o u t 4 to 6 months. It takes about 2 weeks to fully induce intestinal metallothionein, and even then zinc provides only a very modest negative copper balance. Zinc is a slowacting drug in terms of its effect on copper. For that reason we have been developing a fast-acting drug, tetrathiomolybdate, which has ideal properties for quickly controlling copper toxicity and is extremely safe. By now we have treated over 60 neurologically presenting patients with tetra-
Letter to the Editor
323
thiomolybdate with excellent results, preventing initial deterioration and sustaining long-term recovery.27-29All of this has been documented with quantitative neurologic and speech exams carried out weekly by a neurologist and speech pathologist, respectively. Hoogenraad says of this work, "It is irrational to go on with a study of the effectiveness and safety of tetrathiomolybdate at the start of treatment," because, he says, "Patients should be treated with zinc from the start." I challenge Dr Hoogenraad to support those assertions with data. It is not enough for him to say that he started neurologically presenting Wilson's disease patients on zinc and "they did well." He must do a quantitative neurologic and speech assessment at the beginning of therapy, after 8 weeks of therapy, and after 1 year of therapy, on a meaningful number of patients, such as 20. Only after presentation of a study such as this can we fit zinc into its role as an initial therapy versus tetrathiomolybdate and other drugs. Talk is cheap, and you get what you pay for if you give too much attention to talk unsupported by data. In the last part of his editorial, Hoogenraad makes further errors. He advises increasing the zinc dose if the non-ceruloplasmin copper is too high. As we've repeatedly shown, once you have a zinc dose adequate to induce intestinal cell metallothionein, increasing the zinc dose further is meaningless--that is, there is no further dose-response beyond this point (a surrogate marker of this state is having an adequate urine zinc--over 2.0 rag/24 hours). On another point, he implies that we aim for a non-ceruloplasmin copper of 25 gg/dl, when in fact that number is our upper limit of acceptability, and we cite data in our paper indicating that controlling this value below 25 is associated with control of copper toxicity. Hoogenraad criticizes us for monitoring this variable only every 1 to 2 years. He fails to acknowledge that we monitor urine copper (which Hoogenraad doesn't bother to use as a monitoring tool), a variable that is more reliable and useful than the non-ceruloplasmin plasma copper, every 6 months in the beginning, with a mail-in system. Non-ceruloplasmin plasma copper is measured yearly in the early years of treatment, at the time of the patient's annual visit, and then later relaxed to less often in wellcornplying patients. Altogether our efficacy and safety monitoring has been excellent, because as our paper 2 shows, noncompliance is caught by urine zinc and copper before clinical deterioration begins. Thus it has been very successful. How successful has Hoogenraad been at picking up non-compliance before clinical deterioration? We don't know because he hasn't published any data on this topic. Finally, I want to turn to the choice of editorial writers by the Editors. In this case, it is obvious from this letter that Dr Hoogenraad and I don't like each other, or have much respect for each other's work. I felt this strongly enough that when I was asked to do a book review of Hoogenraad's monograph on Wilson's disease30 by a journal, I declined on the basis of conflict of interest. I felt that even if I tried to review the rnono-
324
Letter to the Editor
graph fairly, Hoogenraad would perceive a conflict of interest. It was my opinion that after putting much work into such a book, the author deserved to have it reviewed by scientists who did not have an initial bias about the work. I feel precisely the same about our paper 15. We deserved a fair editorial. I recommend as a remedy for avoiding this situation that the Editors ask the authors about the suitability of a proposed editorial writer. The authors should not have the right to choose the writer of an editorial, but they should have the right to say, "No, I would rather have my paper stand on its own merits than have an editorial about my work written by that person, who I believe has a conflict of interest."
George J. Brewer, MD Departments of Human Genetics and Internal Medicine The University of Michigan Medical School Medical Science II 4708 Ann Arbor, MI 48109-0618 REFERENCES
1. Hoogenraad TU. Zinc treatment of Wilson's disease [editorial]. J Lab Clin Med 1998;132:240-1. 2. Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JK. Treatment of Wilson's disease with zinc. XV. Longterm follow-up studies. J Lab Clin Med 1998;132:264-78. 3. Schouwink G. De hepatocecerebrale degeneratie, met een onderzoek naar de zonkstrofwisseling. MD thesis (with a summary in English, French, and German). University of Amsterdam; 1961. 4. Brewer GJ, Hill GM, Prasad AS, Cossack ZT, Rabbani R Oral zinc therapy for Wilson's disease. Ann Intern Med 1983;99:314-20. 5. Hill GM, Brewer GJ, Prasad AS, Hydrick CR, Hartmann DE. Treatment of Wilson's disease with zinc. I. Oral zinc therapy regimens. Hepatology 1987;7:522-8. 6. Hoogenraad TU, Van den Hamer CJA, Koevoet R, de Ryter Korver EGWM. Oral zinc in Wilson's disease. Lancet 1978;2:1262. 7. Hoogenraad TU, Koevoet R, de Ruyter Korver EGWM. Oral zinc sulphate as long-term treatment in Wilson's disease (hepatolenticular degeneration). Eur Neurol 1979; 18:205-11. 8. Hoogenraad TU, Van Hattum J, Van den Harner CJA. Management of Wilson's disease with zinc sulphate: experience in a series of 27 patients. J Neurol Sci 1987;77:137-46. 9. Brewer GJ, Schoomaker EB, Leichtman DA, Krnckeberg WC, Brewer LF, Meyers N. The use of pharmacological doses of zinc in the treatment of sickle cell anemia. In: Brewer GJ, Prasad AS, editors. Zinc metabolism: current aspects in health and disease. New York: Alan R. Liss; 1977. p. 241-54. 10. Prasad AS, Brewer GJ, Schoomaker EB, Rabbani R Hypocupremia induced by zinc therapy in adults. JAMA 1978;240:2166-8. 11. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson Disease. Medicine 1992;71:139-64. 12. Brewer GJ, Yuzbasiyan-Gurkan V, Lee D-Y, Appelman H. The treatment of Wilson's disease with zinc. VI. Initial treatment studies. J Lab Clin Med 1989;114:6333-8. 13. Hill GM, Brewer GJ, Juni JE, Prasad AS, Dick RD. Treatment of Wilson's disease with zinc. II. Validation of oral 64copper uptake with copper balance. Am J Med Sci 1986;12:344-9.
J Lab Clin Med September 1999
14. Brewer GJ, Yuzbasiyan-Gurkan V, Dick R. Zinc therapy of Wilson's disease. VIII. Dose response studies. Trace Elements in Experimental Medicine 1990;3:227-34. 15. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson's disease with zinc. XII. Dose regimen requirements. Am J Med Sci 1993;305: 199-202. 16. Brewer GJ, Dick RD, Yuzbasiyan-Gurkan V, Johnson V, Wang Y. Treatment of Wilson's disease with zinc. XIII. Therapy with zinc in presymptomatic patients from the time of diagnosis. J Lab Clin Med 1994;123:849-58. 17. Brewer GJ, Hill GM, Dick RD, Nostrant TT, Sams JS, Wells JJ, et al. Treatment of Wilson's disease with zinc. III. Prevention of reaccumulation of hepatic copper. J Lab Clin Med 1987; 109:526-31. 18. Brewer GJ, Hill GM, Prasad AS, Dick RD. Treatment of Wilson's disease with zinc. IV. Efficacy monitoring using urine and plasma copper. Proc Soc Exp Biol Med 1987;7:446-55. 19. Lee D-Y, Brewer GJ, Wang Y. The treatment of Wilson's disease with zinc. VII. Protection of the liver from copper toxicity by zinc induced metallothionein in a rat model. J Lab Clin Med 1989;114:639-45. 20. Yuzbasiyan-Gurkan V, Brider A, Nostrant T, Cousins RJ, Brewer GJ. The treatment of Wilson's disease with zinc. X. Intestinal metallothionein induction. J Lab Clin Med 1992;120:380-6. 21. Yuzbasiyan-Gurkan V, Brewer GJ, Abrams GD, Main B, Giacherio D. Treatment of Wilson's disease with zinc. V. Changes in serum levels of lipase, amylase, and alkaline phosphatase in Wilson's disease patients. J Lab Clin Med 1989;114:520-6. 22. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V. The treatment of Wilson's disease with zinc. IX. Response of serum lipids. J Lab Clin Med 1991;118:466-70. 23. Brewer GJ, Kaplan J, Johnson V. The treatment of Wilson's disease with zinc. XIV. Studies of the effect of zinc on lymphocyte function, J Lab Clin Med 1997;129:649-5. 24. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson's disease with zinc. XI. Interaction with other anticopper agents. J Am Coll Nutr 1993;12:26-30. 25. Richards MR Cousins RJ. Metallothionein and its relationship to the metabolism of dietary zinc in rats. J Nutr 1976;106:1591-9. 26. Hall AC, Young BW, Bremner I. Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. J Inorg Biochem 1979;11:57-66. 27. Brewer GJ, Dick RD, Yuzbasiyan-Gurkan V, Tankanow R, Young AB, Kluin KJ. Initial therapy of Wilson's disease patients with tetrathiomolybdate. Arch Neurol 1991; 48:42-7. 28. Brewer GJ, Dick RD, Johnson V, Wang Y, YuzbasiyanGurkan V, Kluin K, et al. Treatment of Wilson's disease with tetrathiomolybdate. I. Initial therapy in 17 neurologically affected patients. Arch Neurol 1994;51:545-54. 29. Brewer GJ, Johnson V, Dick RD, Kluin KJ, Fink JK, Brunberg JA. Treatment of Wilson's disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up on zinc therapy. Arch Neurol 1996;53:1017-25. 30. Hoogenraad TU. Wilson's disease. Major problems in neurology (vol 30). London: WB Saunders; 1996.
studies in Wilson's patients on zinc therapy. 4,5 Schouwink 3 does deserve credit for thinking of zinc as a possible therapy, giving zinc to two patients, and observing an increase in fecal copper on zinc therapy. However, the failure to publish any of these data made it impossible for other scientists, such as ourselves, to take advantage of his observations. This is clearly the reason Schouwink has not received very much credit for his observations. Hoogenraad 1 goes on to claim credit for the next phase of zinc development after Schouwink. However, the two papers 6,7 he published in the interim before our first paper were both anecdotal case reports involving one patient each. In the first report, 6 a letter to the editor, the patient was given zinc intermittently with penicillamine, and it is impossible to assess zinc's effect. The second report 7 was simply a followup on one of Schouwink's two patients. Our first paper came out next, and it reported copper balance control in 5 out of 5 patients on zinc therapy. 4 Later Hoogenraad treated additional patients with zinc, 8 but we began to have serious ethical concerns about this work. It seems that patients were placed on zinc without attention to whether it was a safe alternative to an already proven effective therapy--penicillamine. Hoogenraad did not do copper balance studies, or even 64Cu absorption studies, in these patients (at least none were reported), and these are the only procedures that provide contemporaneous information that a given dose of zinc is effective in a given patient. Instead, he appears to have relied on the plasma non-ceruloplasmin copper levels, but these respond rather slowly to changing copper status. The patient could be in deep clinical trouble, if zinc were inadequately effective in that patient, prior to the detection of a significant upward change in this variable. So how could Hoogenraad be sure that these patients were not at risk of serious deterioration when he first prescribed zinc for them as the sole anticopper therapy, when penicillamine, and trientine for the penicillamine-intolerant patient, were already available? It is not enough to know that zinc was effective in Shouwink's two patients, because it might not be adequately effective in the third patient, or the fourth, etc. It seems to us that Hoogenraad's approach of putting patients on zinc and hoping the disease would be controlled raises major ethical concerns. In our own case, we made sure that each patient had copper balance control on the zinc regimen to be used for that patient before putting the patient on long-term zinc therapy.4, 5 We did not initiate our work on zinc therapy for Wilson's disease as a result of Schouwink's thesis or Hoogenraad's two case reports, although we always cite the latter. We observed copper deficiency in zinc-treated sickle cell patients,9,10 put two-and-two together, and did a clinical trial of zinc in Wil-
J Lab Clin Med Volume 134,Number 3
son's disease, being extremely careful about the ethical concerns discussed above. We have subsequently made almost all the substantive contributions to the development of zinc as a practical and valid therapy for Wilson's disease. This includes data on the negative copper balance produced by zinc4,5,11-16; the control of copper in blood, urine, and liver 11,17,18; data on the mechanism of action19,2°; effective dosages and dose responsel4jS; possible side effects that we disproved21-23; and possible interactions with other drugs. 24 We have also led the way in developing data for zinc use in pregnant and pediatric Wilson's disease patients.2 The single unique contribution of the Hoogenraad group has been to develop an oral 64copper uptake procedure to evaluate and monitor the effectiveness of zinc therapy. 6 However, contrary to the assertion of Hoogenraad in his editorial, he and his group did not discover the metallothioneinmechanism of zinc action from their 64copper work. This concept was developed by other groups working on zinc-treated animals,25,26 and we first showed that the metallothionein mechanism was applicable in the human, in zinc-treated Wilson's disease patients. 20 Throughout the editorial Hoogenraad makes errors and inappropriate assertions. For example, Hoogenraad correctly states that our first paper on this topic was in 1983, but then gives the wrong citation in his editorial. The correct citation is reference 4 of this letter. At the end of the editorial, Hoogenraad says, "It is a pity, however, that they have experience with zinc only as a maintenance treatment and that they have failed to use zinc as an initial treatment." Hoogenraad's statement is in error. In the very paper Hoogenraad reviewed, we presented data on using zinc from the beginning in presymptomatic patients, as well as data on its use in pregnant and pediatric patients. We recommended zinc for all these types of patients. Hoogenraad then states, "It would be unfortunate if their study were to give the readers of the Journal the impression that zinc is not appropriate for initial treatment, because in fact, the opposite is true. Patients should be treated with zinc from the start." Well, I hope our paper gave "the impression that zinc is not appropriate for initial treatment," at least not in all types of patients, because that is in fact what we believe. Our belief is based on three patients with neurologic presentation that we initiated on zinc, one of whom deteriorated seriously during the several-month period it took for zinc to gain control of copper toxicity. It is also based on dozens of copper balance and other studies, which give us the knowledge for an estimate of how long it takes zinc to control acute copper toxi c i t y - a b o u t 4 to 6 months. It takes about 2 weeks to fully induce intestinal metallothionein, and even then zinc provides only a very modest negative copper balance. Zinc is a slowacting drug in terms of its effect on copper. For that reason we have been developing a fast-acting drug, tetrathiomolybdate, which has ideal properties for quickly controlling copper toxicity and is extremely safe. By now we have treated over 60 neurologically presenting patients with tetra-
Letter to the Editor
323
thiomolybdate with excellent results, preventing initial deterioration and sustaining long-term recovery.27-29All of this has been documented with quantitative neurologic and speech exams carried out weekly by a neurologist and speech pathologist, respectively. Hoogenraad says of this work, "It is irrational to go on with a study of the effectiveness and safety of tetrathiomolybdate at the start of treatment," because, he says, "Patients should be treated with zinc from the start." I challenge Dr Hoogenraad to support those assertions with data. It is not enough for him to say that he started neurologically presenting Wilson's disease patients on zinc and "they did well." He must do a quantitative neurologic and speech assessment at the beginning of therapy, after 8 weeks of therapy, and after 1 year of therapy, on a meaningful number of patients, such as 20. Only after presentation of a study such as this can we fit zinc into its role as an initial therapy versus tetrathiomolybdate and other drugs. Talk is cheap, and you get what you pay for if you give too much attention to talk unsupported by data. In the last part of his editorial, Hoogenraad makes further errors. He advises increasing the zinc dose if the non-ceruloplasmin copper is too high. As we've repeatedly shown, once you have a zinc dose adequate to induce intestinal cell metallothionein, increasing the zinc dose further is meaningless--that is, there is no further dose-response beyond this point (a surrogate marker of this state is having an adequate urine zinc--over 2.0 rag/24 hours). On another point, he implies that we aim for a non-ceruloplasmin copper of 25 gg/dl, when in fact that number is our upper limit of acceptability, and we cite data in our paper indicating that controlling this value below 25 is associated with control of copper toxicity. Hoogenraad criticizes us for monitoring this variable only every 1 to 2 years. He fails to acknowledge that we monitor urine copper (which Hoogenraad doesn't bother to use as a monitoring tool), a variable that is more reliable and useful than the non-ceruloplasmin plasma copper, every 6 months in the beginning, with a mail-in system. Non-ceruloplasmin plasma copper is measured yearly in the early years of treatment, at the time of the patient's annual visit, and then later relaxed to less often in wellcornplying patients. Altogether our efficacy and safety monitoring has been excellent, because as our paper 2 shows, noncompliance is caught by urine zinc and copper before clinical deterioration begins. Thus it has been very successful. How successful has Hoogenraad been at picking up non-compliance before clinical deterioration? We don't know because he hasn't published any data on this topic. Finally, I want to turn to the choice of editorial writers by the Editors. In this case, it is obvious from this letter that Dr Hoogenraad and I don't like each other, or have much respect for each other's work. I felt this strongly enough that when I was asked to do a book review of Hoogenraad's monograph on Wilson's disease30 by a journal, I declined on the basis of conflict of interest. I felt that even if I tried to review the rnono-
324
Letter to the Editor
graph fairly, Hoogenraad would perceive a conflict of interest. It was my opinion that after putting much work into such a book, the author deserved to have it reviewed by scientists who did not have an initial bias about the work. I feel precisely the same about our paper 15. We deserved a fair editorial. I recommend as a remedy for avoiding this situation that the Editors ask the authors about the suitability of a proposed editorial writer. The authors should not have the right to choose the writer of an editorial, but they should have the right to say, "No, I would rather have my paper stand on its own merits than have an editorial about my work written by that person, who I believe has a conflict of interest."
George J. Brewer, MD Departments of Human Genetics and Internal Medicine The University of Michigan Medical School Medical Science II 4708 Ann Arbor, MI 48109-0618 REFERENCES
1. Hoogenraad TU. Zinc treatment of Wilson's disease [editorial]. J Lab Clin Med 1998;132:240-1. 2. Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JK. Treatment of Wilson's disease with zinc. XV. Longterm follow-up studies. J Lab Clin Med 1998;132:264-78. 3. Schouwink G. De hepatocecerebrale degeneratie, met een onderzoek naar de zonkstrofwisseling. MD thesis (with a summary in English, French, and German). University of Amsterdam; 1961. 4. Brewer GJ, Hill GM, Prasad AS, Cossack ZT, Rabbani R Oral zinc therapy for Wilson's disease. Ann Intern Med 1983;99:314-20. 5. Hill GM, Brewer GJ, Prasad AS, Hydrick CR, Hartmann DE. Treatment of Wilson's disease with zinc. I. Oral zinc therapy regimens. Hepatology 1987;7:522-8. 6. Hoogenraad TU, Van den Hamer CJA, Koevoet R, de Ryter Korver EGWM. Oral zinc in Wilson's disease. Lancet 1978;2:1262. 7. Hoogenraad TU, Koevoet R, de Ruyter Korver EGWM. Oral zinc sulphate as long-term treatment in Wilson's disease (hepatolenticular degeneration). Eur Neurol 1979; 18:205-11. 8. Hoogenraad TU, Van Hattum J, Van den Harner CJA. Management of Wilson's disease with zinc sulphate: experience in a series of 27 patients. J Neurol Sci 1987;77:137-46. 9. Brewer GJ, Schoomaker EB, Leichtman DA, Krnckeberg WC, Brewer LF, Meyers N. The use of pharmacological doses of zinc in the treatment of sickle cell anemia. In: Brewer GJ, Prasad AS, editors. Zinc metabolism: current aspects in health and disease. New York: Alan R. Liss; 1977. p. 241-54. 10. Prasad AS, Brewer GJ, Schoomaker EB, Rabbani R Hypocupremia induced by zinc therapy in adults. JAMA 1978;240:2166-8. 11. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson Disease. Medicine 1992;71:139-64. 12. Brewer GJ, Yuzbasiyan-Gurkan V, Lee D-Y, Appelman H. The treatment of Wilson's disease with zinc. VI. Initial treatment studies. J Lab Clin Med 1989;114:6333-8. 13. Hill GM, Brewer GJ, Juni JE, Prasad AS, Dick RD. Treatment of Wilson's disease with zinc. II. Validation of oral 64copper uptake with copper balance. Am J Med Sci 1986;12:344-9.
J Lab Clin Med September 1999
14. Brewer GJ, Yuzbasiyan-Gurkan V, Dick R. Zinc therapy of Wilson's disease. VIII. Dose response studies. Trace Elements in Experimental Medicine 1990;3:227-34. 15. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson's disease with zinc. XII. Dose regimen requirements. Am J Med Sci 1993;305: 199-202. 16. Brewer GJ, Dick RD, Yuzbasiyan-Gurkan V, Johnson V, Wang Y. Treatment of Wilson's disease with zinc. XIII. Therapy with zinc in presymptomatic patients from the time of diagnosis. J Lab Clin Med 1994;123:849-58. 17. Brewer GJ, Hill GM, Dick RD, Nostrant TT, Sams JS, Wells JJ, et al. Treatment of Wilson's disease with zinc. III. Prevention of reaccumulation of hepatic copper. J Lab Clin Med 1987; 109:526-31. 18. Brewer GJ, Hill GM, Prasad AS, Dick RD. Treatment of Wilson's disease with zinc. IV. Efficacy monitoring using urine and plasma copper. Proc Soc Exp Biol Med 1987;7:446-55. 19. Lee D-Y, Brewer GJ, Wang Y. The treatment of Wilson's disease with zinc. VII. Protection of the liver from copper toxicity by zinc induced metallothionein in a rat model. J Lab Clin Med 1989;114:639-45. 20. Yuzbasiyan-Gurkan V, Brider A, Nostrant T, Cousins RJ, Brewer GJ. The treatment of Wilson's disease with zinc. X. Intestinal metallothionein induction. J Lab Clin Med 1992;120:380-6. 21. Yuzbasiyan-Gurkan V, Brewer GJ, Abrams GD, Main B, Giacherio D. Treatment of Wilson's disease with zinc. V. Changes in serum levels of lipase, amylase, and alkaline phosphatase in Wilson's disease patients. J Lab Clin Med 1989;114:520-6. 22. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V. The treatment of Wilson's disease with zinc. IX. Response of serum lipids. J Lab Clin Med 1991;118:466-70. 23. Brewer GJ, Kaplan J, Johnson V. The treatment of Wilson's disease with zinc. XIV. Studies of the effect of zinc on lymphocyte function, J Lab Clin Med 1997;129:649-5. 24. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson's disease with zinc. XI. Interaction with other anticopper agents. J Am Coll Nutr 1993;12:26-30. 25. Richards MR Cousins RJ. Metallothionein and its relationship to the metabolism of dietary zinc in rats. J Nutr 1976;106:1591-9. 26. Hall AC, Young BW, Bremner I. Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat. J Inorg Biochem 1979;11:57-66. 27. Brewer GJ, Dick RD, Yuzbasiyan-Gurkan V, Tankanow R, Young AB, Kluin KJ. Initial therapy of Wilson's disease patients with tetrathiomolybdate. Arch Neurol 1991; 48:42-7. 28. Brewer GJ, Dick RD, Johnson V, Wang Y, YuzbasiyanGurkan V, Kluin K, et al. Treatment of Wilson's disease with tetrathiomolybdate. I. Initial therapy in 17 neurologically affected patients. Arch Neurol 1994;51:545-54. 29. Brewer GJ, Johnson V, Dick RD, Kluin KJ, Fink JK, Brunberg JA. Treatment of Wilson's disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up on zinc therapy. Arch Neurol 1996;53:1017-25. 30. Hoogenraad TU. Wilson's disease. Major problems in neurology (vol 30). London: WB Saunders; 1996.