George J. Brewer

Serum thymulin in human zinc deficiency.

The activity of thymulin (a thymic hormone) is dependent on the presence of zinc in the molecule. We assayed serum thymulin activity in three models of mildly zinc-deficient (ZD) human subjects before and after zinc supplementation: (a) two human volunteers in whom a specific and mild zinc deficiency was induced by dietary means; (b) six mildly ZD adult sickle cell anemia (SCA) subjects; and (c) six mildly ZD adult non-SCA subjects. Their plasma zinc levels were normal and they showed no overt clinical manifestations of zinc deficiency. The diagnosis of mild zinc deficiency was based on the assay of zinc in lymphocytes, granulocytes, and platelets. Serum thymulin activity was decreased as a result of mild zinc deficiency and was corrected by in vivo and in vitro zinc supplementation, suggesting that this parameter was a sensitive indicator of zinc deficiency in humans. An increase in T101-, sIg-cells, decrease in T4+/T8+ ratio, and decreased IL 2 activity were observed in the experimental human model during the zinc depletion phase, all of which were corrected after repletion with zinc. Similar changes in lymphocyte subpopulation, correctable with zinc supplementation, were also observed in mildly ZD SCA subjects. Inasmuch as thymulin is known to induce intra- and extrathymic T cell differentiation, our studies provide a possible mechanism for the role of zinc on T cell functions.

Treatment of Wilson Disease With Ammonium Tetrathiomolybdate: III. Initial Therapy in a Total of 55 Neurologically Affected Patients and Follow-up With Zinc Therapy

BACKGROUND It is unclear what anticopper drug to use for patients with Wilson disease who present with neurologic manifestations because penicillamine often makes them neurologically worse and zinc is slow acting. OBJECTIVE To evaluate the frequency of neurologic worsening and drug adverse effects with ammonium tetrathiomolybdate. DESIGN Open-label study of 55 untreated patients (22 of them new) presenting with neurologic Wilson disease treated with tetrathiomolybdate varying from 120 to 410 mg/d for 8 weeks and then followed up for 3 years. Neurologic function was assessed with scored neurologic and speech tests. SETTING A university hospital referral setting. PATIENTS All untreated, newly diagnosed patients with neurologic Wilson disease. INTERVENTION Treatment with tetrathiomolybdate. MAIN OUTCOME MEASURES Neurologic function was evaluated by neurologic and speech examinations. Drug adverse effects were evaluated by complete blood cell counts and biochemical measures. RESULTS Only 2 (4%) of 55 patients treated with tetrathiomolybdate showed neurologic deterioration, compared with an estimated 50% of penicillamine-treated patients. Five of the 22 new patients exhibited bone marrow suppression and 3 had aminotransferase elevations. These numbers are higher than in the original 33 patients and appear to be due primarily to a more rapid dose escalation. CONCLUSIONS Tetrathiomolybdate shows excellent efficacy in patients with Wilson disease who present with neurologic manifestations. With rapid escalation of dose, adverse effects from bone marrow suppression or aminotransferase elevations can occur.

Oral Zinc Therapy for Wilson's Disease

Wilsons disease is an inherited disorder of copper accumulation that is fatal if untreated. Because penicillamine, the established treatment, is toxic in a substantial number of patients, we studied the efficacy of zinc treatment. We induced a negative or neutral copper balance in five out of five patients with Wilsons disease who were receiving no therapy other than zinc. Zinc acetate was given every 4 hours during the day, and the patient was not allowed to eat for 1 hour before and 1 hour after each dose. Oral zinc therapy, used according to our regimen, may now be considered in the treatment of patients with penicillamine intolerance. However, it is premature to convert patients to zinc therapy if they tolerate penicillamine well. The efficacy of zinc therapy in the initial removal of the copper burden in acutely ill patients with Wilsons disease has not yet been evaluated.

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.

Iron and Copper Toxicity in Diseases of Aging, Particularly Atherosclerosis and Alzheimer’s Disease

In this review, we point out that natural selection does not act to lessen human diseases after the reproductive and caregiving period and that normal levels of iron and copper that may be healthy during the reproductive years appear to be contributing to diseases of aging and possibly the aging process itself. It is clear that oxidant damage contributes to many of the diseases of aging, such as atherosclerosis, Alzheimer’s disease, Parkinson’s diseases, diabetes, diseases of inflammation, diseases of fibrosis, diseases of autoimmunity, and so on. It is equally clear that both iron and copper can contribute to excess production of damaging reactive oxygen species through Fenton chemistry. Here, we examine the evidence that “normal” levels of iron and copper contribute to various diseases of aging.

Recognition, Diagnosis, and Management of Wilson's Disease

Wilsons disease is a relatively rare inherited disorder of copper accumulation and toxicity, caused by a defect in an enzyme that is part of the pathway of biliary excretion of excess copper. Clinically, patients usually present as older children or young adults with hepatic, neurologic, or psychiatric manifestations, or some combination of these. Wilsons disease is unusual among genetic diseases in that it can be very effectively treated. The prevention of severe permanent damage depends upon early recognition and diagnosis by the physician, followed by appropriate anticopper treatment. Anticopper treatments have evolved considerably since the days when the only drug available was penicillamine. Zinc is now the recommended therapy for long-term management of the disease.

Zinc May Regulate Serum Leptin Concentrations in Humans

OBJECTIVE Leptin, the product of the ob gene, plays a key role in a feedback loop that maintains energy balance by signaling the state of energy stores to the brain and by influencing the regulation of appetite and energy metabolism. Zinc also plays an important role in appetite regulation. Thus, we evaluated the relationship between zinc status and the leptin system in humans. METHODS We studied nine healthy men with marginal zinc deficiency, induced by dietary means, before and after zinc supplementation. RESULTS Zinc restriction decreased leptin levels while zinc supplementation of zinc-depleted subjects increased circulating leptin levels. In addition, zinc supplementation increased IL-2 and TNF-alpha production that could be responsible for the observed increase in leptin concentrations. CONCLUSIONS Zinc may influence serum leptin levels, possibly by increasing the production of IL-2 and TNF-alpha.

Copper Control as an Antiangiogenic Anticancer Therapy: Lessons from Treating Wilson's Disease

The search for new anticopper drugs for Wilsons disease is culminating in two excellent new drugs: zinc for maintenance therapy and tetrathiomolybdate (TM) for initial therapy. Both are effective and nontoxic. TM is a very potent, fast-acting new anticopper drug and its properties may be useful well beyond Wilsons disease. Angiogenesis (new blood vessel growth) is required for tumor growth, and a sufficient level of copper appears to be required for angiogenesis. We hypothesize that there is a “window” to which the copper level can be reduced that inhibits angiogenesis in tumors, but does not interfere with vital cellular functions of copper. Using TM therapy, this approach has worked to slow or stabilize tumor growth in several animal tumor models, and preliminary results are also very encouraging in human patients with a variety of advanced and metastatic malignancies. A hypothesis is advanced that copper availability has played a fundamental role in growth regulation throughout evolution and that is the reason that so many angiogenic promoters appear to be dependent upon copper levels.

Erythrocyte Metabolism: Interaction with Oxygen Transport

Studies of the interactions between the metabolism and the function of the red cell have shown the importance of the red cells metabolism in contributing to the maintenance of adequate oxygen delivery. Some of the phosphorylated intermediates of glycolysis, especially DPG, are now known to reduce the affinity of hemoglobin for oxygen. Current evidence indicates that this phenomenon is due to the effects of the binding of DPG to the , β-chains of deoxyhemoglobin. It appears that increases in red cell concentrations of DPG commonly occur during hypoxia, and that these increases (as well as normal physiological variation) significantly enhance oxygen transport. Artificial manipulation of erythrocyte metabolism may soon prove to be of great clinical usefulness in the treatment of a great variety of disorders which limit oxygen transport.