The clinical manifestations of zinc deficiency in humans include growth retardation, male hypogonadism, skin changes, poor appetite, mental lethargy, abnormal neurosensory changes, delayed wound healing, and susceptibility to infection [3-5]. Zinc supplementation completely corrects all of these manifestations [3-5].

Nutritional zinc deficiency is prevalent throughout the world. Zinc deficiency in children has been reported from at least a dozen countries (including the United States) on all continents [6, 7]. The cereal proteins consumed by persons in developing countries contain large quantities of phytates, organic compounds that bind dietary zinc and iron and render them unavailable for absorption [4]. It is therefore not surprising that iron-deficiency anemia and zinc deficiency coexist in most developing countries and that these deficiencies are common problems throughout the world [4-6]. Zinc and iron in red meat are readily available for absorption. However, the Western world's shift away from consumption of red meat and toward consumption of cereal proteins containing high phytate levels may be conducive to the development of mild zinc deficiency in developed countries [8]. Our studies in elderly persons in the Detroit area [5] and the studies of Yokoi and colleagues [8] in premenopausal women in Galveston, Texas, show that mild zinc deficiency is relatively common, even in the United States.

Zinc deficiency is known to be associated with chronic diarrhea, growth failure, and immune deficiency [4]. In a double-blind, randomized, controlled trial of zinc supplementation administered to children in India who had acute diarrhea, zinc supplementation resulted in a 23% reduction in the risk for continued diarrhea and a 39% reduction in the mean number of watery stools per day [9].

It is now evident that not only nutritional but also conditioned deficiency of zinc may be seen in many clinical situations [4-6], including the malabsorption syndromes, chronic renal disease, chronic liver disease, sickle cell anemia, effects of penicillamine therapy, alcohol abuse, and various other chronic diseases. In most instances, a combination of decreased dietary intake, decreased absorption, and increased urinary excretion of zinc are responsible for the development of zinc deficiency [4-6].

Just as we have seen remarkable advances in clinical medicine with respect to zinc metabolism in humans, an explosion in the amount of knowledge about the roles of zinc in enzymology and molecular biology has occurred during the past three decades. Approximately 30 years ago, we knew of only three enzymes (carbonic anhydrase, carboxypeptidase, and alcohol dehydrogenase) that required zinc for their activities; now we know of more than 300 [10]. Zinc has three functions in zinc-dependent enzymes: catalytic, co-catalytic, and structural [10]. However, zinc may also be involved in regulating the amount of an enzyme that is synthesized and therefore available for catalytic activity. For example, our recent studies in the T-lymphoblastoid cell line show that zinc is involved in gene expression in deoxythymidine kinase [11]. This type of zinc action on the induction of an enzyme is a unique observation, but other such examples will probably be discovered in the future. The recent characterization of zinc finger-proteins and their involvement in the genetic expression of various growth factors and steroid receptors is another exciting development; it might even be said that this area of research is rapidly galvanizing biology and medicine [12].

In this issue, Mossad and colleagues [13] report the results of their study on the efficacy of zinc gluconate lozenges for the treatment of the common cold. Patients were instructed to take one lozenge (containing 13.3 mg of zinc) every 2 hours while awake as long as the cold symptoms persisted. The treatment group took a mean of 36 lozenges, a total intake of nearly 500 mg of zinc. The time to complete resolution of symptoms was significantly shorter in the treatment group (4.4 days compared with 7.6 days). The side effects of this treatment were nausea and bad taste. Inasmuch as the morbidity resulting from common colds is considerable [13], the therapeutic use of zinc lozenges appears to be acceptable. Because the bad taste was probably caused by the ligand gluconate, it might have been avoided had zinc acetate been used instead.

As suggested by Mossad and colleagues, zinc may exert its therapeutic effects on the duration of colds by acting as an inhibitor of the replication of rhinoviruses or by preventing virus entry into the cell [14], but other mechanisms are certainly possible. For example, therapeutic effects may in part be due to correction of subclinical zinc deficiency, at least in some patients. In this connection, it is important to note that, during the past decade, considerable knowledge has accumulated on the role of zinc in cellular immunity. In humans, zinc deficiency results in a selective decrease in the number of T4⁺ and CD8 ⁺CD73⁺ cytolytic cells, as well as decreases in serum thymulin activity, production of interleukin-2, natural killer cell lytic activity, and T-lymphocyte proliferation [15]. These basic developments, together with the results of Mossad and colleagues, raise the intriguing possibility that zinc supplementation in susceptible persons will decrease the incidence of common colds. Only carefully conducted clinical trials will answer this question.

Administering zinc in physiologic amounts to zinc-deficient persons is an accepted practice. The therapeutic use of zinc, however, is less common. In one study [16], administering zinc (25 mg as acetate orally every 4 hours) to patients with sickle cell anemia significantly decreased irreversible sickling. The mechanism proposed for this effect involves the cellular protein calmodulin, which is activated by binding calcium [17]. In sickle cells, calmodulin promotes retention of hemoglobin by erythrocyte ghosts and induces shrinkage of erythrocytes [17]. It has been shown that zinc inhibits these effects and thus acts as an antisickling agent by allowing cell membranes to expand [17]. These effects were seen in patients with sickle cell anemia only when large doses of zinc were administered, because plasma proteins avidly bind zinc.

Administration of zinc for 3 to 6 months in therapeutic doses (150 mg/d orally) to patients with sickle cell anemia resulted in neutropenia caused by an induction of copper deficiency [18]. This effect was easily corrected by oral administration of copper. This experience, however, suggested the possibility that zinc could be used to decrease the copper burden in Wilson disease [19]. Zinc induces synthesis of the low-molecular-weight protein metallothionein in the intestine, which avidly binds copper; metallothionein-bound copper is then excreted in the feces [20]. Zinc is effective as a therapeutic decoppering agent in Wilson disease, and it is also effective in preventing copper damage in genetically susceptible patients with Wilson disease if an early diagnosis is made [20].

This experience with the use of zinc in therapeutic doses over relatively long periods is reassuring. At the same time, the ingestion of gram quantities of zinc by many millions of persons as therapy for the common cold would represent a kind of uncontrolled nutritional experiment that is cause for concern [18, 21]. At the very least, therefore, surveillance for potential toxicity will be needed for a good many years if zinc therapy becomes widely adopted for one of mankind's most common and seemingly most intractable maladies.