Virginia Johnson

Treatment of Wilson's disease with zinc: XV long-term follow-up studies

Wilsons disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance. The earliest approaches have used chelators, such as penicillamine or trientine, which increase the urinary excretion of copper. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation. In the present article we present data on the long-term follow-up (up to 10 years) of maintenance zinc treatment of 141 patients with Wilsons disease. The data presented document that zinc is effective as a sole therapy in the long-term maintenance treatment of Wilsons disease and that it has a low toxicity. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient from the beginning of therapy. We also present limited data on the use of zinc in the treatment of pregnant patients and children who have Wilsons disease; these data also indicate efficacy and low toxicity. The median follow-up period for the group as a whole is 4.8 years; for the presymptomatic patients it is 6.5 years; for the children it is 3.6 years.

Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc

We have treated 9 patients who presented with hepatic decompensation resulting from Wilsons disease with a combination of trientine and zinc, generally for at least 4 months, followed by transition to zinc maintenance therapy. All of these patients had hypoalbuminemia, all but 1 had hyperbilirubinemia, and 7 had ascites. All of these patients would have been candidates for liver transplantation on the basis of their initial Child-Turcotte-Pugh (CTP) scores. The minimal listing criteria for transplant candidates is a score greater than 7. Eight of the 9 patients had demonstrated a CTP score of 10 or higher. The other scoring system that has been used in Wilsons disease to determine need for transplantation is the prognostic index of Nazer, in which a score over 6 indicates that the patient is unlikely to survive without a transplant if treated with penicillamine. Two of our patients had Nazer scores higher than 6. With our medical therapy, all 9 of these patients have recovered normal liver function as reflected by normalization of their CTP scores to 5. Because of coexisting neurologic disease, 1 of our 9 patients was initiated on a neurologic protocol and by chance randomized to receive tetrathiomolybdate (TM) and zinc after 2 weeks of trientine/zinc treatment. This patients liver function recovered much more rapidly than did that of the other 8 patients, all of whom were treated with trientine/zinc, suggesting that TM therapy offers a further advantage. In summary, we were able to take 9 patients who presented with liver failure -8 of whom had CTP scores indicating a potential need for liver transplantation and 2 of whom had Nazer prognostic scores indicating that they were not likely to survive if treated only with penicillamine - and treat them medically, with recovery in all 9. We believe the trientine/zinc combination therapy should be the standard for initial treatment of liver failure in Wilsons disease because its efficacy is equal or slightly superior to that of penicillamine and because it has a much lower incidence of side effects. Moreover, TM warrants study to determine whether therapy for hepatic Wilsons disease can be further improved.

Does a vegetarian diet control Wilson's disease?

The literature indicates that copper (Cu) is less bioavailable from a vegetarian as compared to mixed diet. Further, several groups, including ours, find rather marginal average Cu intake in the typical American diet. For example, our data indicate that Wilsons disease patients on a typical American diet ingest only about 25% more Cu than is required. This suggests that a vegetarian diet, if it reduced bioavailability by about 25% or more, would be an adequate maintenance therapy for Wilsons disease. Observations in two of our patients, who were on lactovegetarian diets by choice, and who were almost totally noncompliant with anti-Cu therapy, support this view. These observations suggest that vegetarian diets may be a management tool for Wilsons disease. They also further emphasize the marginal Cu intake in American diets, and suggest that some seemingly healthy people, particularly vegetarians, may be at risk for mild Cu deficiency.

Treatment of Wilson's disease with zinc: XI. Interaction with other anticopper agents.

Zinc (Zn) is increasingly being used as a treatment for Wilsons disease. Some physicians have been prescribing Zn in conjunction with other anticopper agents, such as penicillamine or trien, although theoretically these drugs might be antagonistic in their effects. In addition, Wilsons disease patients quite often take vitamin C in high doses in conjunction with Zn therapy, and there are indications of possible interactions among vitamin C, Zn and copper (Cu). Interactions of penicillamine, trien, and vitamin C with Zn have not been previously studied in terms of the potential effects of these agents on Zn efficacy in Wilsons disease. Here we have studied these interactions in the maintenance phase of therapy, using Cu balance and absorption of orally administered 64Cu as endpoints. We find evidence for probable interactions of both penicillamine and trien with Zn; however, the end result on Cu balance is about the same with Zn alone as it is with Zn plus one of the other agents. Thus, there appear to be no advantages to concomitant administration. We find no detectable interaction of Zn and vitamin C on Cu balance, when vitamin C is taken in daily doses of 1000 mg.

Treatment of Wilson’s Disease with Zinc XII: Dose Regimen Requirements

A considerable body of data is now available indicating the efficacy and lack of toxicity of zinc treatment of Wilsons disease. Dose-response studies have shown that regimens of 50 mg of elemental zinc 3 times a day (50 mg x 3), 25 mg x 3, and 50 mg x 2 are effective, but 25 mg x 2 and 50 mg x 1 are not adequately effective. These studies indicate that 75 mg a day is close to the minimally effective dose, but do not address the question of necessary dose frequency. In the current study, the authors have used the minimally effective daily dose, 75 mg, and studied this daily dose in regimens of 25 mg x 3, 37.5 mg x 2, and 75 mg x 1 in treatment of four patients with Wilsons disease. These data have been supplemented with additional data from 11 patients treated with 25 mg 3 times a day and with data from 2 patients treated with 75 mg once a day. Efficacy was evaluated by 10-day copper balance and absorption of orally administered 64copper. The findings indicate that a daily dose of 75 mg must be divided into at least two doses to be effective, and that the 64copper procedure is more sensitive to zinc dose than copper balance.

REGRESSION OF KAYSER-FLEISCHER RINGS DURING ORAL ZINC THERAPY : CORRELATION WITH SYSTEMIC MANIFESTATIONS OF WILSON'S DISEASE

Fourteen patients presenting with neuropsychiatric manifestations of Wilsons disease were treated with oral tetrathiomolybdate (TM) for 8 weeks followed by oral zinc (Zn) maintenance therapy. The patients were evaluated prospectively at baseline and at yearly intervals for up to 5 years by slit-lamp biomicroscopy and photography, quantitative neurologic and speech pathology examinations, 24-h urine copper collection, and a quantitative scoring of magnetic resonance imaging (MRI) of the brain. Kayser-Fleischer (KF) ring size decreased significantly during the 5-year study period (p < 0.0001). Although results of neurologic examination, speech pathology examination, and 24-h urine copper level analysis in symptomatic Wilsons disease patients improved during the study period, KF ring regression did not correlate with the improvement in these clinical parameters (p > 0.05). However, there was a correlation between MRI scores and KF ring regression (p = 0.02). Anticopper therapy with TM followed by zinc maintenance therapy is a safe and effective treatment for patients with neurologically symptomatic Wilsons disease. This treatment leads to reduction in KF ring size; however, KF ring reduction is not a good predictor of clinical improvement for patients with neuropsychiatric manifestations of Wilsons disease.

Treatment of Wilson's disease with zinc: XIV studies of the effect of zinc on lymphocyte function

Although administration of zinc to human subjects has been reported to interfere with lymphocyte function, this single report has never been confirmed or refuted. We have developed zinc as a lifelong therapy for patients with Wilsons disease. Interference with lymphocyte function occurring as a side effect of zinc therapy could produce serious problems in our patients. We evaluated lymphocyte mitogenic response and natural killer cell activity in patients with Wilsons disease treated for 5 years or longer with zinc, in comparison with normal controls, and found no differences. In a second study, we evaluated these same parameters in patients with Wilsons disease before and after 1 year of zinc therapy, and again found no significant differences. We have seen no indications of immune suppression or increased susceptibility to infections in our patients, who have now been treated with zinc for up to 15 years. We conclude that any side effects from compromised lymphocyte function caused by administration of zinc are not of concern to patients with Wilsons disease.

Wilson's disease: Presymptomatic patients and Kayser-Fleischer rings

PURPOSE We evaluated patients with Wilsons disease to determine (1) whether presymptomatic patients who have Kayser-Fleischer (K F) rings demonstrate a more significant alteration of copper metabolism than those who do not have K F rings, and (2) whether presymptomatic patients have smaller K F rings than symptomatic Wilsons disease patients. METHODS Thirty-two patients with presymptomatic Wilsons disease were retrospectively analyzed. Sixteen of these had received no prior anti-copper therapy and underwent testing for baseline copper metabolism (24-hour urine copper, liver copper, and plasma ceruloplasmin). Quantitative measurements of K F rings were made for the group of untreated presymptomatic patients and a control group of symptomatic Wilsons disease patients. RESULTS We hypothesized that the 24-hour urine copper, in particular, would correlate with the presence of a K F ring. However, no significant difference was found between any of the baseline copper variables for presymptomatic patients who had K F rings compared to those who did not. K F rings of presymptomatic patients were found to be significantly smaller than K F rings of patients with symptomatic Wilsons disease (p < 0.05). CONCLUSIONS While this study does not show any relationship between urinary copper excretion and the presence of K F rings, it suggests that the larger K F ring size correlates with Wilsons disease severity.