Vilma Yuzbasiyan-Gurkan

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.

Use of zinc-copper metabolic interactions in the treatment of Wilson's disease.

Zinc acetate is becoming a well-established therapy for the treatment of Wilsons disease. It is excellent for maintenance therapy and for the treatment of the presymptomatic patient. Current evidence suggests that it will also be excellent for the treatment of the pregnant patient. Zinc acts by inducing intestinal cell metallothionein, which binds copper with high affinity, blocking its absorption, and causing its excretion in the stool. We have shown that zinc, even in doses as low as 25 mg daily, negatively affects copper balance. Zinc in doses of 50 mg three times daily, with all doses separated from food, controls the abnormal positive copper balance, blocks uptake of orally administered 64Cu, controls urine and plasma copper, prevents the reaccumulation of hepatic copper, and prevents the development or progression of symptoms of copper toxicosis in Wilsons disease patients. Zinc acetate will probably be licensed in the near future for the treatment of Wilsons disease. We recommend that physicians use urine and plasma copper, and urine zinc, as primary monitoring tools. In contrast to the comfortable situation with maintenance therapy, the initial treatment of acutely ill Wilsons disease patients is not well worked out. Patients with neurological disease often get worse initially on penicillamine, and zinc acts more slowly than is ideal. We have initiated studies of tetrathiomolybdate for this purpose. Studies of biliary secretions of normal subjects suggest that they excrete regulatory (excess) copper packaged in a protease-resistant ceruloplasmin fragment. This fragment is missing in Wilsons disease bile. The gene for Wilsons disease is on chromosome 13, close to the retinoblastoma locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of an Undifferentiated Malignancy as a Mast Cell Tumor Using Mutation Analysis in the Proto-Oncogene c-KIT

A 6.5-year-old female Boxer was euthanized and presented for necropsy following rapid clinical decline concomitant with the development of numerous tumor masses. The largest of these masses was in the same location as a mast cell tumor that had been previously removed from this dog. Gross examination revealed the presence of nodules 5–200 mm in diameter throughout the body, including the lymph nodes. Histologic analysis showed an influx of round cells with no granules, leading to the provisional diagnosis of systemic lymphosarcoma. Immunohistochemical staining for B- and T-lymphocyte antigens was negative. Molecular tests were used to identify a tandem duplication in the c-KIT proto-oncogene from both the earlier mast cell tumor and the current nodules, implicating a common origin. Addition of molecular testing to conventional necropsy evaluations allowed a definitive diagnosis of mast cell tumors.

Bovine Hereditary Zinc Deficiency: Lethal Trait a 46

Bovine hereditary zinc deficiency, also referred to as Adema disease, is an autosomal recessive disorder which results in inadequate amounts of zinc being absorbed from the gastrointestinal tract and leads to a number of clinical abnormalities. Using semen from a homozygous affected bull and obligate heterozygote cows in embryo transfer studies, 7 offspring were obtained. These included 5 affected calves and 1 heterozygous carrier; the seventh calf died within 48 hours of birth undiagnosed. One unaffected, unrelated bull calf was raised as a control. All the calves were raised and maintained under similar management conditions designed to minimize secondary complications that would obscure the clinical and biochemical observations of a zinc deficient state. The first clinical manifestation of zinc deficiency was diarrhea, followed by skin lesions, poliosis, and a decreased ability to sustain a suckle reflex. Trace mineral analysis of plasma blood samples revealed that plasma zinc concentrations of all the calves were normal at birth; however, they gradually declined in affected calves over the course of 3–8 weeks postpartum to below 0.5 ppm. Biochemical analysis of serum samples showed alkaline phosphatase activity consistently paralleled changes in the plasma zinc concentrations. The oral administration of zinc acetate caused a reversal of all clinical, biochemical, and histologic abnormalities in affected calves. The study of these affected calves allows further insight into the biological role of zinc as well as provides an animal model for the continued investigation of the human homologue acrodermatitis enteropathica.

Human and Canine Inherited Copper Toxicosis: Copper Balance Regulation and Molecular Genetics of Its Impairment

In this paper we briefly summarize the evidence supporting the view that zinc acetate is an excellent, fully efficaceous, non-toxic therapy for the maintenance treatment of Wilson’s disease. The recommended dose is 50 mg three times per day with each dose separated from food and beverages, except water, by at least one hour. Zinc therapy is also excellent for the treatment of presymptomatic Wilson’s disease patients and for the pregnant patient. We also summarize our hypothesis and supporting data that Wilson’s disease results from a failure to secrete a copper-rich, protease-resistant fragment of ceruloplasmin into the bile. We have updated our research in the area of molecular genetics of both the human gene and the canine copper toxicosis gene.