Zinc Clinical and Biochemical Significance

Stephen C. Cunnane

• Publisher: CRC Press
• Year: 2018
• Print ISBN: 9781315898711
• eBook ISBN: 9781351094719
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

In keeping with the etiology theme, it also became apparent that the clinical aspects needed to be strictly separated from the animal aspects of zinc metabolism, a separation that has never previously been attempted. Although this division, like the separation of primary from secondary zinc depletion, may be somewhat arbitrary, it is the author's impression that current knowledge of the truly clinical aspects of zinc metabolism is too often confused with its effects in animals. The two will frequently be similar, but not always. In this book, therefore, animal studies are considered in part 2 (Biochemistry. Only a handful of references to animal studies has been included in part 1 (Clinical). The purpose of this separation is to clearly distinguish animal from human, experimental from clinical. Too many of the animal studies have involved severe and prolonged zinc deficiency or other exaggerated nutritional conditions that cannot be realistically applied in the clinical setting. Furthermore, animal studies are mainly or primary (dietary) zinc depletion, whereas in humans, secondary zinc depletion is more prevalent and has a more diverse etiology.

Part I — Clinical

Chapter 1

HISTORICAL

I. CLINICAL

The first definitive demonstration of clinical zinc deficiency was in the early 1960s in Iranian adolescent dwarfs.^1308,1309 The dwarfism was a consequence of protein-energy malnutrition, anemia, and zinc deficiency. Although increased growth and sexual maturation was observed in dwarfs fed a nutritionally adequate diet without zinc supplementation, zinc supplementation consistently shortened the period of time required to develop sexual maturity and improve growth.⁶⁷² It was these studies of the effects of zinc supplementation which finally demonstrated that zinc deficiency could and did exist in humans.

For the purpose of providing a background to clinical zinc studies, the period prior to 1961 will be considered as historical. The rest of the chapter is an outline of studies on zinc, both animal and human, which were carried out prior to 1961. By separating the period prior to 1961, one can see that the wide range of the biochemical importance of zinc was largely established during that period. Since 1961, we have refined, but not significantly extended, our understanding of zinc biochemistry. What certainly has been achieved is the establishment of zinc as a nutrient of critical clinical importance whose homeostasis is very finely regulated.

The use of zinc in such preparations as calamine (contains zinc oxide) and zinc ointment for skin irritations, abrasions, and bums, has been documented since pre-Christian times, e.g., in the Ebers papyrus.⁴³⁹ Oral zinc salts (zinc oxide and sulfate) have been given since the 18th century for the treatment of epilepsy⁷⁶⁵ and convulsive disorders.¹³⁵⁵ One of the earliest reports of the clinical use of zinc as a medication was by Graham.⁶²⁹ who described the use of zinc sulfate pills prepared with turpentine. These pills were fed orally to cure gleet and leukorrhea, conditions of vaginal infection. The biochemical effects of zinc oxide against staphylococci and streptococci were reported by Haxthausen⁷⁰² who also observed that the acid conditions produced by the bacteria enhanced the bactericidal effects of zinc oxide. Eggleton⁴⁵¹ noted that zinc levels in hair, skin, and nails of Chinese patients with beriberi were 50% of those of healthy controls and suggested that coexisting zinc deficiency might exacerbate beriberi.

Zinc was also shown to complex with uroporphyrin, the excretion of which is increased in idiopathic porphyria.¹⁶⁸⁴ The etiology of porphyria was later hypothesized to be zinc-related. Zinc chelating agents, e.g., 2,3-dimercaptopropanol and ethylenediaminetetraacetic acid (EDTA), were successfully used to treat porphyria.^1270,1271

Vallee and Gibson¹⁶³⁷ studied zinc levels in various anemias. With the exception of pernicious anemia in which erythrocyte zinc was found to be increased, anemia was not associated with a change in blood zinc. Treatment of pernicious anemia with liver extracts caused a decline in erythrocyte zinc, an effect suggested to be due to an increase in the rate of erythrocyte death.

A paper frequently quoted is that by Vikbladh¹⁶⁵⁷ on the analysis of zinc in human blood plasma, erythrocytes, and leukocytes. Vikbladh showed that about a third of plasma zinc transport proteins bound zinc tightly and two thirds bound it loosely. Transferrin was suggested as a possible zinc transport protein. Diurnal rhythms in plasma zinc were observed, as was the decrease in plasma zinc during pregnancy and increase in the newborn. Plasma zinc was also shown to decrease during acute infection, an effect that correlated well with the increase in body temperature. Vikbladh made the comment that zinc was “indispensable” for mammals, but its lack, however, causes no specific pathological syndrome (in humans).¹⁶⁵⁷

Vallee and Altschule¹⁶³⁶ published an excellent and detailed review on zinc. They made particular reference to effects of zinc toxicity, e.g., leukocytosis and anemia. The elevation of blood zinc in pernicious anemia was also noted. Vallee has published further reviews on zinc,^1634,1635 with extensive discussion of enzymes and zinc deficiency effects on plants.

The sharp decrease in serum levels of zinc concomitant with increased levels of malic and lactic dehydrogenase were suggested by Wacker et al.¹⁶⁶⁵ to be a reliable indicator of the occurrence of a myocardial infarction. Shortly after, Vallee’s group also demonstrated that serum zinc was decreased and urinary zinc excretion was increased in alcoholic cirrhosis.¹⁶⁴⁰ In this context, zinc was noted to be required for ethanol metabolism to acetaldehyde.

Zinc was implicated in the epidemiology of cancer by Stocks and Davies.¹⁵⁶¹ They found that both zinc and cobalt in the soil were positively correlated with the incidence of stomach cancer. Two tumor cell types, spindle cell sarcoma and mammary adenocarcinoma, when transplanted into mice, were shown to more rapidly take up zinc-65 than the normal surrounding tissue.⁷⁰³

II. ZINC MEASUREMENT

Prior to the application of atomic absorption spectrophotometry to trace element analysis in 1955, zinc analysis was done mainly by colorimetric methods using agents such as dithizone (diphenylthiocarbazone) or its analogs. Most of the methods used in the studies described below will have used the colorimetric method.

Birckner¹⁴⁵ demonstrated that human milk and cow’s milk contained zinc. Zinc was reported by Bertrand and Vladesco¹³⁴ to be present in the prostate of men, bulls, and pigs. The zinc content of the human body was calculated by Lutz¹⁰³⁰ to be about 2 g, a figure still quoted today. In human semen the majority of zinc was shown to be of prostatic origin.¹⁰⁷²

Incorporation of zinc-65 into tissues of the mouse and dog was studied by Sheline et al.¹⁴⁶⁰ They demonstrated that, after an oral dose, zinc-65 disappeared from the plasma within 10 hr. Uptake was continuous into the erythrocyte and liver with significant amounts also appearing in the pancreatic acinar cell.¹¹⁴³ Excretion was mainly via the feces. Similar studies by McCance and Widdowson¹⁰⁸⁰ using unlabeled zinc, corroborated these results. From zinc analysis of average diets, they suggested that a normal intake of zinc would be in the region of 10 to 15 mg/day. Spray and Widdowson¹⁵⁴² reported on the effect of maturation on tissue zinc levels in mammals. They observed that total body zinc (per gram of body weight) did not change significantly from birth to 300 days.

Feaster et al.⁵⁰¹ reported on the placental transfer of zinc-65 in the rat. They noted that ⁶⁵Zn was readily transferred across the placenta with peak amounts being...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Introduction
• PART I — CLINICAL
• PART II — BIOCHEMISTRY
• Conclusion
• References
• General Reading
• Index