Robert D. Dick

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.

A novel role for XIAP in copper homeostasis through regulation of MURR1

XIAP is a potent suppressor of apoptosis that directly inhibits specific members of the caspase family of cysteine proteases. Here we demonstrate a novel role for XIAP in the control of intracellular copper levels. XIAP was found to interact with MURR1, a factor recently implicated in copper homeostasis. XIAP binds to MURR1 in a manner that is distinct from that utilized by XIAP to bind caspases, and consistent with this, MURR1 did not affect the antiapoptotic properties of XIAP. However, cells and tissues derived from Xiap‐deficient mice were found to contain reduced copper levels, while suppression of MURR1 resulted in increased intracellular copper in cultured cells. Consistent with these opposing effects, XIAP was observed to negatively regulate MURR1 protein levels by the formation of K48 polyubiquitin chains on MURR1 that promote its degradation. These findings represent the first described phenotypic alteration in Xiap‐deficient mice and demonstrate that XIAP can function through MURR1 to regulate copper homeostasis.

The role of copper suppression as an antiangiogenic strategy in head and neck squamous cell carcinoma

Objective To determine whether tetrathiomolybdate (TM), a powerful chelator of copper, is capable of lowering the body stores of copper and suppressing the growth of head and neck squamous cell carcinoma in an orthotopic murine model.

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.

Treatment of Wilson's disease with zinc. II: Validation of oral 64copper with copper balance

The efficacy of zinc as a therapeutic agent to control copper balance in Wilsons disease patients has been previously documented with balance studies. In an attempt to develop a simpler and faster tool for evaluating the adequacy of zinc therapy, a technique that measures the uptake into blood of a small oral dose of 64copper was studied in conjuction with copper balance. The mean peak 64copper uptake into blood of nine Wilsons disease patients on D-penicillamine, trien, or no medication was 6.04 ± 2.74%, comparable with normal controls. Seven patients on zinc therapy had a markedly and significantly reduced mean uptake of 0.79 ± 1.05% after treatment. The data demonstrate that the prevention of copper uptake into blood in Wilsons disease patients by zinc therapy can be evaluated by 64copper uptake and that peak uptakes of less than 1% occur in patients with neutral or negative copper balance.

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.

Interactions of trace elements: Clinical significance

We examined interaction of the trace element zinc with copper and lead. In sickle cell anemia, the usual situation is one of mild to moderate zinc deficiency owing to renal loss of zinc. Zinc deficiency seems to produce a mild overburden of copper and an increased ceruloplasmin level, probably by enhancing copper absorption. With zinc therapy, this process is reversed. Pharmacological doses of zinc, when administered in a way to ensure effectiveness (without food) will usually lead to copper deficiency. We have taken advantage of the copper-depleting effect of zinc to design a new therapy for Wilsons disease. Zinc, by inducing intestinal metallothionein, inhibits absorption of copper from food, and inhibits reabsorption of endogenously secreted copper, thereby producing a negative copper balance in Wilsons disease. Once we are certain that zinc blocks accumulation of copper in the liver of Wilsons disease patients, zinc therapy will be available as one approach for treating this fatal disease. The animal literature indicates that zinc protects against lead toxicity when both elements are given orally, no doubt through the intestinal metallothionein mechanism. In preliminary experiments in rats, we have not been able to show that toxicity from lead that arrives into the body through a nonoral route is affected by oral zinc supplements.

Correction of cerebrospinal fluid copper in Menkes Kinky Hair disease

A patient with Menkes Kinky Hair disease was treated with infusions of copper-histidine which resulted in normal copper values in the cerebrospinal fluid. This tends to confirm the in vitro data that copper is transported into the central nervous system complexed with histidine or other similar ligands.