Trace Elements in Nutrition of Children, edited by R. K. Chandra. Nestle Nutrition, Vevey/Raven Press, New York © 1985. Diagnostic Approaches to Trace Element Deficiencies Ananda S. Prasad Department of Medicine, Wayne State University School of Medicine, Harper-Grace Hospital, Detroit, Michigan 48202; and Veterans Administration Medical Center, Allen Park, Michigan 48101 Although several trace elements, such as iron, copper, zinc, chromium, selenium, manganese, cobalt, iodine, and fluorine, are considered to be essential for human health, only a few have clinical relevance. Manganese deficiency in human subjects has not been established beyond doubt. The only role of cobalt appears to be that related to the vitamin-B12 molecule. Although important for dental health, fluorine is not essential for life. The essentiality of iron, which is needed for heme synthesis, has been known for more than 100 years, and several reviews on this subject are available; therefore this topic is not considered here. The role of iodine in thyroid metabolism has also been well known for more than a century, and inasmuch as many books deal with this subject iodine is not covered in this review. Deficiencies of zinc and copper in human subjects have been recognized only during the past two decades (1-4), but a great deal of progress has been made in understanding their important roles in biochemical functions. Clinical problems of their deficiencies are being discovered with increasing frequency in association with several disease states. It is therefore important to deal with the diagnostic approaches of the deficiencies of zinc and copper in human subjects in detail. Although clinical deficiencies of chromium and selenium are not well established thus far, it is important to recognize their potentially useful roles in clinical medicine; as such, these topics are discussed in this chapter. ZINC DEFICIENCY Etiology It is becoming more apparent that deficiency of zinc is very prevalent, accom- panying inadequate protein intake, such as is seen in cases of protein—calorie malnutrition in populations subsisting on low incomes and in geriatric cases. Predominant use of cereal proteins by the majority of the world population is a very important predisposing factor for zinc deficiency. The availability of zinc in such diets is very poor because of high phosphate and phytate content. 17 18 DIAGNOSTIC APPROACHES Zinc deficiency in human subjects has been reported to occur in conditions where there is an increased requirement of zinc. Included here are infants and children during the rapid-growth-age period and women who are pregnant and lactating. The recommended dietary allowances for zinc in infants, adolescents, and pregnant women are relatively high and are unlikely to be met on an ordinary diet. Thus physicians have to be aware of this possibility and take proper preventive measures. Zinc deficiency has been reported to occur in patients with malabsorption syn- drome. In such cases, zinc deficiency is likely to occur in association with other deficiencies. Hyperzincuria over an extended period may lead to zinc depletion. Urinary excretion of zinc appears to vary with the amount of element bound to the plasma amino acid pool. Thus, in those conditions where histidine and cysteine increase in the plasma, one would expect to find hyperzincuria. Conditions associated with a hypercatabolic state, such as surgery, burns, multiple injuries, major fractures, diabetes mellitus, protein deprivation, and starvation, usually exhibit hyperzincuria (5). Proteinuria and use of chelating agents such as penicillamine also result in excessive zinc loss in the urine. Severe deficiency of zinc resulting from penicil- lamine therapy in a patient with Wilson's disease was reported by Klingberg et al. (6). Hyperzincuria is likely to occur after chlorothiazide administration. Thus, hypertensive patients on long-term therapy with chlorothiazide should be monitored for zinc deficiency. Glucagon is also known to cause hyperzincuria (7). Patients with chronic liver disease, nephrotic syndrome, and sickle cell disease are known to have hyperzincuria (8-10). It has been shown that several of the clinical manifestations of sickle cell disease and chronic liver disease are indeed due to zinc deficiency and that zinc supplementation corrects these manifestations (11,12). At present, two genetic disorders, acrodermatitis enteropathica and sickle cell disease, are known to be associated with zinc deficiency. All the clinical manifes- tations of acrodermatitis enteropathica seem to be reversible with zinc supplemen- tation (13). In sickle cell disease, clinical manifestations, such as growth retardation, hypogonadism in males, abnormal dark adaptation, hyperammonemia, general leth- argy, and poor appetite, appear to be related to a deficiency of zinc (14). Severe zinc deficiency in patients receiving long-term total parenteral nutrition without zinc supplementation has been reported by several investigators (15). Symptoms are similar to those seen in acrodermatitis enteropathica and include skin rashes, alopecia, diarrhea, and depression. The onset of symptoms usually 5 to 10 weeks after the start of total parenteral nutrition is related to the severity of zinc depletion in the patient. Clinical Manifestations Growth retardation, hypogonadism in males, poor appetite, mental lethargy, and skin changes were the typical clinical features of chronically zinc-deficient subjects DIAGNOSTIC APPROACHES 19 from the Middle East, as reported by the author during the early 1960s (1-3). These features were corrected by zinc supplementation. The mechanism of the characteristic enlargement of spleen and liver in this syndrome is not well under- stood at present. Abnormal dark adaptation in alcoholic cirrhotics has been related to a deficiency of zinc (16). Zinc administration to these patients corrected the abnormal dark adaptation. Similar clinical observations have been made in zinc-deficient sickle cell anemia patients (17). It has been proposed that the effect of zinc on the retina may be mediated by an enzyme, retinene reductase, which is known to be zinc- dependent. In sickle cell disease, delayed onset of puberty and hypogonadism in the male, characterized by decreased facial, pubic, and axillary hair, short stature, low body weight, rough skin, and poor appetite have been noted and related to a secondary zinc-deficient state (14). Many patients with sickle cell disease develop chronic leg ulcers that do not heal, and a beneficial effect of zinc supplementation in such cases has been reported. Some patients with celiac disease who failed to respond to diet, steroids, or nutritional supplements made remarkable recoveries when zinc was administered. They gained weight, the D-xylose-absorption test improved, and the steatorrhea was alleviated after zinc therapy (18). Zinc supplementation in a few subjects with malabsorption syndrome (other than celiac disease) has produced beneficial results with respect to growth retardation, hypogonadism in males, mental lethargy, skin changes, and loss of hair (19). One should therefore be aware of the occurrence of zinc deficiency as a possible complication of malabsorption syndrome. The conclusion that zinc can promote the healing of cutaneous sores and wounds has been controversial for several years. Most studies now provide evidence that zinc supplementation promotes wound healing in zinc-deficient patients and that zinc therapy in zinc-sufficient subjects is not an effective therapy for wound healing. Abnormalities of taste have been related to a deficiency of zinc in many clinical conditions by some investigators (20). Decreased taste acuity (hypogeusia) has been observed in zinc-deficient subjects with liver disease, malabsorption syndrome, thermal burns, or chronic uremia and in subjects following administration of penicillamine or histidine. Although a double-blind study failed to show the effec- tiveness of zinc in the treatment of hypogeusia in various diseases (21), another double-blind study indicated that zinc was effective in improving taste acuity in subjects with chronic uremia (22). This discrepancy suggests that depletion of zinc may lead to decreased taste acuity, but not all cases of hypogeusia are due to zinc deficiency. The role of zinc in hypogeusia needs to be delineated further. The dermatological manifestations of severe zinc deficiency include progressive bullous-pustular dermatitis of the extremities and the oral, anal, and genital areas, combined with paronychia and generalized alopecia, such as seen in acrodermatitis enteropathica. Infection with Candida albicans is a frequent complication. These manifestations are seen in patients with severe zinc deficiency. 20 DIAGNOSTIC APPROACHES Neuropsychiatric signs include irritability, emotional disorders, tremors, and occasional cerebellar ataxia. The patients generally have retarded growth, and males exhibit hypogonadism. Zinc therapy has been shown to produce remarkable improvements and is considered to be a life-saving measure in these subjects. A similar clinical picture has been reported in a patient receiving penicillamine therapy for Wilson's disease (6). After total parenteral nutrition and excessive ingestion of alcohol, clinical manifestations of zinc deficiency resemble acroder- matitis enteropathica. Once a deficiency of zinc is recognized, zinc therapy be- comes imperative in such cases. According to Jameson (23), zinc-deficiency syndrome during pregnancy is char- acterized