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Advances in Nutrition logoLink to Advances in Nutrition
. 2013 Jan 4;4(1):76–81. doi: 10.3945/an.112.003186

Human Zinc Deficiency: Discovery to Initial Translation1,2,3

Harold H Sandstead 1,*
PMCID: PMC3648742  PMID: 23319126

Abstract

Ananda S Prasad first suspected zinc deficiency in 1958 after he, at the request of James A Halsted, evaluated a patient with severe iron deficiency. In addition to iron deficiency, the patient appeared ∼10 y old and was severely stunted and prepubertal, though his chronological and bone age were much older. He also had hepatosplenomegaly and ate clay. The condition was not rare in that 11 cases were reported. In 1961 Prasad joined the Vanderbilt Nutrition Group led by William J. Darby at the US Naval Medical Research Unit-3, Cairo, Egypt. Prasad et al. studied 40 males similar to the index case. Contrasts with the index case included no clay eating and infection with schistosomiasis and hookworm. Zinc kinetics confirmed the zinc deficiency. Endocrine studies showed hypopituitarism. Treatment with zinc and an omnivorous diet was more efficacious for growth than no treatment, diet alone, or iron and diet. Later, Halsted et al. confirmed these findings in stunted Iranian farmers. The key role of diet in the illness became evident when Prasad found 16 severely stunted farmers from 2 oases who were not infected with schistosomiasis or hookworm. Later, Reinhold et al., in Halsted’s group, reported that phytate and other indigestible zinc-binding ligands in unleavened bread prepared from high-extraction wheat flour suppress zinc absorption.

Introduction

Hurrah, hurrah, hurrah for Ananda Prasad (Supplemental Fig. 1). The work summarized here was done long ago. The knowledge facilitated certain research and other processes that continue for human benefit.

Before Prasad’s discovery (1), human zinc deficiency was thought highly unlikely. This opinion seemed supported by the wide distribution of zinc in nature, the difficulties associated with the induction of zinc deficiency in rats (2), and the apparent absence of zinc deficiency among farm animals other than swine (3). A few studies of human zinc nutriture had been reported (47), including the association of hyperzincuria with severe liver disease (7), but the general significance was not appreciated. Acceptance of Prasad’s discovery was slow, consistent with the resistance to new discoveries by some members of the academy. This review summarizes the initial discovery, proof of the hypothesis, and early attempts to apply the new knowledge. Some perspectives are included.

Current status of knowledge

Prasad first encountered zinc deficiency (1) in the fall of 1958 when he evaluated a patient at James A. Halsted’s (8) request for the purpose of a discussion of iron deficiency at the Medical Grand Rounds of the Saadi Hospital in Shiraz, Iran (Supplemental Fig. 2).

Prasad was in Shiraz to assist Hobart A. Reimann, the previous Head of Medicine at the University of Minnesota, implement a new curriculum at Nemazee Hospital. This post provided the opportunity to study diseases that are unlikely in Minnesota. Prasad had recently completed postgraduate training in Internal Medicine and Hematology and research for his PhD, at the University of Minnesota School of Medicine, where his mentor was Cecil J. Watson.

The patient (index case) was a male farmer, aged 21 y, who had not worked for 4 y because of weakness and shortness of breath (Supplemental Fig. 3). He began eating clay as a child and had always been small. He was severely iron deficient and had hepatosplenomegaly and no identifiable cause of blood loss. His diet of was based on the village bread [Tanok, a paper thin unleavened rural bread prepared from 90–100% extraction wheat flour, containing ∼750 mg phytate/100 gm. For adults, it may provide 50–90% of diet energy (9)], potatoes, other vegetables, and fruit. Eggs and meat were infrequent.

Physically, there was an obvious disparity between growth and development and chronological age in that he appeared ∼10 y old, was 135 cm tall, and weighed 29.5 kg. His vital signs were: temperature of 37.4°C, respiration at 20 rpm, heart rate regular at 100 bpm, and blood pressure of 105/55 mm Hg. He was pale and his nails had a spoon-like deformity (koilonychia). Signs of early heart failure were present. The liver and spleen were large at 4 cm below the costal margin. His genitalia were juvenile and adult body and facial hair were absent. Bone age was <14 y. Mental acuity was not measured [zinc is essential for brain function (10, 11)].

Indices of iron status included a very low hemoglobin of 35 g/L. Urine and feces were not remarkable. Liver functions and biopsy were normal. The total serum protein concentration and the percentage albumin were normal, while gamma globulin was increased. There was no baseline free gastric acid after histamine stimulation or after 6 wk of treatment [zinc nutriture affects gastric parietal cell function (12)].

Ten days of treatment with bed rest, adequate diet, and oral pharmaceutical-grade iron (which probably contained zinc) resulted in an increase in blood reticulocytes to 8%. After 8 wk, hemoglobin was normal. Body temperature averaged 37.5°C for 8 wk [iron (13) and zinc (14) deficiencies impair temperature control] and then became normal. After 10 wk, weight increased to 7.25 kg, cardiac function improved, liver and spleen were nearly normal size, and strength, mental activity, and behavior seemed improved. The genitalia and body hair had not changed.

At the Grand Rounds, Prasad suggested the likely mechanism of iron deficiency involved binding of iron to clay [later reported from Turkey (15)] and dietary phosphate [the binding of iron by phytate and other indigestible plant ligands was later reported (16)]. He then discussed the poor growth and development. He noted that iron deficiency does not cause stunting in experimental animals and suggested that another essential metal, zinc, with chemical characteristics necessary for binding to clay and phosphate, was responsible [the binding of zinc by phytate and other indigestible plant ligands in human diets was later reported (16)]. He based his suggestion on phenomena in other species that were cited in a review of zinc (17). According to Prasad, some attendees laughed with derision and one said it was well known that such patients were common in rural villages [∼3% of 19 y olds (18)] and that they were afflicted with hypopituitarism. Prasad asked if there was an epidemic and there was more laughter. To answer this and other questions, Prasad et al. (1) confirmed the findings in the index case by studying 10 additional similar patients.

In 1961 Prasad moved to Cairo, Egypt to join the newly organized Vanderbilt University Nutrition Group (VNG) at the US Naval Medical Research Unit-3 (NAMRU-3), led by William J. Darby (19) (Supplemental Fig. 4). The 1961–1963 VNG included Darby, Assistant Professor of Medicine Prasad, Assistant Professor of Biochemistry Arthur Schulert, PhD, and 2 technicians, Richard P. Koshakji and Mustafa A. Mansour. Cooperating NAMRU-3 personnel included Lieutenant Commander August Miale Jr., Medical Corps, US Navy, Head, Medical Department; US Public Health Service Senior Assistant Surgeon Harold H. Sandstead, MD; Zoheir Farid, MD, Director, Clinical Research Division; Samier Bassilly, MD, Clinician, Clinical Research Division; and 2 senior male nurses.

Prasad soon found farmers in Nile delta villages that were similar in appearance and age to the subjects he reported from Shiraz (1). Prasad showed them to Darby, who expressed surprise and said he had missed such patients in his studies of malnourished populations. Darby agreed that Prasad’s hypothesis should be tested. Arnold E. Schaefer, the responsible nutrition scientist at NIH, agreed (20) (Supplemental Fig. 5).

Forty males, aged 12–20 y, from Nile delta farming communities were studied (2125). They resided in primitive conditions with their families and animals. None were married. Parasites were common. Nearly all had Schistosoma mansoni and/or hematobium [stunting and hypogonadism associated with schistosomiasis occurs in China (2628)]. Levels of Ancylostoma duodenale (hookworm) infection varied widely, perhaps because of prior treatment [associations of hookworm with stunting, hypogonadism, and decreased cognitive performance had been known since the late 19th and early 20th centuries (2932)].

The home diets of the subjects were based on flat bread prepared from high-extraction wheat and/or maize flour. Other foods included rice, beans (Vicia fava), okra, squash, and greens. Less frequent were milk, eggs, and cheese. Meat was seldom available. Later VNG research by Carter et al. (33) on 279 Nile delta middle school village boys, 90 of which were stunted, measured the nutrients (energy, protein, fat, calcium, iron, retinol, thiamine, riboflavin, niacin, and zinc) in 2 composite meals that were prepared from the diets of 25 stunted and 9 nonstunted boys. Energy, retinol, and riboflavin were low, while iron content was 44 and 64 mg daily, and zinc content was 14 and 13 mg daily (such amounts in Western omnivorous diets are considered more than adequate).

At NAMRU-3 the subjects resided in the metabolic unit and were fed a diet that included meat (beef or lamb), eggs, cheese, milk, vegetables, and flat bread. All received treatment for hookworm.

Physical examinations found that some subjects had signs consistent with micronutrient deficiencies, such as facial pallor that might reflect deficiencies of micronutrients essential for hematopoiesis; dry, flaking, hyperpigmented skin of the extremities of unknown cause; koilonychia associated historically with iron deficiency; cheilosis of the lips and corners of the mouth, historically associated with deficiencies of riboflavin and pyridoxine [an association with zinc deficiency would not be surprising, because Zn-ATP is essential for flavokinase and pyridoxal kinase (3437)]; and atrophic lingual papillae, historically associated with iron deficiency. In addition, severely anemic subjects had tachycardia, 2 had dependent edema that cleared after treatment with iron, and 1 had edema associated with hypoalbuminemia. For comparison, later VNG research by Carter et al. (33) also found signs of micronutrient deficiencies in some of the 279 middle school Nile delta boys regardless of stature, such as cheilosis of the lips and corners of the mouth in 44% and papillary atrophy of the tongue in 21%. Also, 18% had hepatosplenomegaly. In addition, eggs of Schistosoma hematobium were present in the urine of 80%, but feces of only 2.2% of the subjects had eggs of Ankylostoma duodenale (perhaps the boys had been wearing of shoes, and/or had received recent treatment). Hypoferremia without anemia was present in some and plasma zinc concentrations were low in many.

Early in the research, zinc kinetics were measured in 12 of the subjects and 10 controls, normally grown men (Table 1). Zinc deficiency was confirmed: from 0 to 10 h, the subjects showed more rapid disappearance of tracer from plasma, but later the disappearance slowed; their zinc turnover was greater and their 24-h exchangeable zinc pool was small.

Table 1.

Zinc kinetics of stunted males from the Nile delta12

n Plasma 65-Zn disappearance, % remaining Turnover rate/60 min Exchangeable/d
0–60 min 0–10 h 0–7 d mg/kg body weight ± SD mg/kg body weight ± SD
Controls 10 42 11.7 4.9 1.00 ± 0.09 7.0 ± 1.6
Subjects 12 29 7.6 5.9 1.50 ± 0.029 4.6 ± 1.2
P <0.01 <0.01 <0.01 <0.05 <0.01
1

Data adapted from (22).

2

Turnover rate values are mean ± SD mg zinc/kg body weight/60 min; exchangeable is the mean ± SD mg tissue zinc/kg body weight/d.

The blood plasma or serum of the subjects was analyzed for concentrations of vitamins A, C, B-6, folate, and B-12 and calcium, phosphorus, magnesium, copper, sodium, potassium, iron, and zinc. Only the latter 2 were frequently low. Data from the 22 in whom endocrine functions were measured are presented in Table 2. Notable is the variability of the 3 indices. Some had normal values.

Table 2.

Baseline concentrations of hemoglobin, serum iron, and plasma zinc in stunted male farmers from the Nile delta of Egypt1

Index n Range Mean ± SD CV Normal2
Hemoglobin, g/L 22 34–150 91 ± 29 32 112–165
Serum iron, μmol/L 22 1.969–9.129 4.797 ± 2.238 47 4.833–31.325
Plasma zinc, μmol/L 22 5.355–12.393 9.899 ± 1.897 19 15.606 ± 1.989
1

Data adapted from (24).

2

Range of values observed in healthy control participants.

Zinc concentrations were also measured in hair, sweat, and urine. Hair zinc concentrations of 9 subjects ranged from 0.459 to 1.147 μmol/g (reported normal, 1.912 μmol/g) (25). Subjects lost less zinc in sweat; the whole arm sweat of 12 compared to 10 controls had zinc concentration of 7.341 ± 1.835 and 17.587 ± 4.588 μmol/L, respectively, while zinc concentrations in cell free sweat of 6 subjects and 8 controls were 44.35 ± 19.88 and 142.22 ± 39.76 μmol/L, respectively (38). The urine zinc excretions of 8 subjects and 9 controls were 6.010 ± 0.703 and 9.375 ± 1.422 μmol/d, respectively, 10.384 ± 3.104 and 6.836 ± 1.652 μmol/g creatinine, and 0.219 ± 0.044 and 0.150 ± 0.037 μmol/kg body weight (23).

Endocrine evaluations were done in 22 of the subjects. Their reported mean ± SD chronological age was 17.2 ± 1.8 y (Supplemental Fig. 6). Their height age was 9.7 ± 1.9 y and bone age was 10.6 ± 1.2 y. In 18 of them, the 24-h urine creatinine excretion/cm height was consistent with normal muscle mass.

Hypopituitarism [mechanisms are incompletely defined: e.g., Pit-1 is a pituitary-specific transcription factor that acts with other factors to influence pituitary development and hormone expression (39)] was present in subjects from the Nile delta (24) and from desert oases, later studied by VNG members Coble et al. (40, 41). At baseline, the Nile delta subjects had juvenile genitalia, and urinary follicle stimulating hormone was low in the 20 measured (Supplemental Fig. 7). Eighteen individuals from desert oases with juvenile genitalia also had low plasma concentrations of pituitary luteinizing hormone (40). At baseline, the Nile delta subjects had low normal resting urinary 17-hydoxysteroids. After i.v. administration of adrenocorticotropic hormone and/or methopyrapone to stimulate adrenal glands, their excretion of 17-hydroxysteroids did not increase appropriately. In 14 subjects and 4 normal men from desert oases, plasma concentrations of pituitary growth hormone were inappropriately low after insulin-induced hypoglycemia (41).

Three of the 22 Nile delta subjects had goiter. In 17 of 18 subjects measured, the protein-bound iodine was normal (the low concentration occurred in a hypoalbuminemic individual) and 6 of the 17 measured had thyroid 131I uptakes >45%, consistent feedback stimulation by thyroid-stimulating hormone secretion caused by low iodine availability to thyroid tissue from low intake and/or suppression of iodine utilization.

Oral glucose tolerance tests in 20 Nile delta subjects resulted in patterns of plasma glucose concentration consistent with delayed absorption. In contrast, i.v. glucose tolerance tests in 16 subjects resulted in the expected decrease in plasma glucose caused by adequate sensitivity to insulin.

Thirteen of the Nile delta subjects allowed measurements of growth and development. Twenty evaluations of growth were done (24). Height was measured using a stadiometer constructed by NAMRU carpenters that included a horizontal bar lateral to the head for constant positioning of the head so that a line from the lateral angle of the eye to the opening of the ear was horizontal relative to the ground. The treatments were: home diet, the maintenance diet, reagent grade ferrous sulfate, 300 mg by mouth 3 times/d with the maintenance diet, or reagent grade zinc sulfate, 30 mg by mouth 3 times/d with the maintenance diet. Three subjects resided in their village without treatment for parasites for 279, 300, and 395 d. The shortest interval was associated with a 1-y growth increment of nearly 2 cm and the 2 longer intervals were associated with 0 growth. Four subjects returned to their village and then returned to NAMRU and the maintenance diet; their average growth increment was 4.6 cm. Four were treated with iron and the maintenance diet; their average growth increment was 7.4 cm. Nine were treated with zinc and the maintenance diet; their average 1-y growth increment was 12.7 cm. For example, a subject lived at home nearly 279 d before admission for treatment with zinc and maintenance diet (Supplemental Fig. 8). His zinc-associated growth increment was nearly 17.8 cm.

Genitalia as well as body and facial hair changed little after treatment with diet alone or diet with iron. Changes associated with zinc were surprising. Pigmented pubic hair appeared as early as 3 wk. The penis appeared to have increased in size. Some subjects became boisterous. Fathers were impressed and other fathers requested treatment for their sons. The efficacy of zinc and diet is shown in Supplemental Figures 9 and 10.

Later, Halsted et al. (42) confirmed the efficacy of zinc for growth and development in 15 subjects, aged 19 y, who appeared similar to the index case. They were studied in a controlled environment and fed a nutritious diet and zinc compared with diet and placebo.

The importance of diet in the pathogenesis of the condition became obvious after Prasad et al. (21) studied 16 stunted males from 2 desert oases who were free of hookworm and schistosomiasis. Iron deficiency with mild anemia was present and plasma zinc was low in the 8 measured. Three and one-half years later, VNG scientists, Coble et al. (40), found 8 of the subjects. Growth and puberty had occurred, though they were still small. Iron status was improved, but the plasma zinc concentrations remained low. More adequately grown farmers also had low plasma zinc concentrations. A later comparison of stunted with adequately grown Nile delta farmers found both had low concentrations of plasma zinc, whereas affluent omnivorous Egyptians and Americans had normal plasma zinc concentrations (43). That zinc deficiency was associated with other illnesses in Egypt became evident when low concentrations of plasma zinc were found in infants with thalassemia (44) and infants recovering from protein-energy malnutrition (45).

The adverse effects of phytate and other indigestible zinc-binding ligands in the pathogenesis of zinc deficiency were not appreciated when “Prasad’s Syndrome” was first studied. O’Dell et al. (46) reported that phytate suppressed zinc absorption by chicks and his student, Oberleas, showed this was also true in swine (47). However, their reports apparently did not come to the attention of Prasad et al. in Iran or Egypt. Carter et al. did mention phytate in the discussion of their findings. Later, Reinhold et al. (4853) in Iran showed that dietary phytate and other indigestible zinc-binding ligands suppress zinc absorption [this phenomenon is central to the high risk of zinc deficiency worldwide (5456)].

Carter et al. (33) attempted the translation of knowledge from the metabolic unit to patient care. They conducted a 5.5-mo, double-blind, randomized, controlled treatment trial of zinc in the 279 middle school village boys noted above. The main outcome was growth. Treatments were 60 mg of reagent grade zinc sulfate, 333 mg reagent grade ferrous sulfate, or placebo administered at school 6 d/wk. Zinc had no apparent effect on growth or development. Ronaghy et al. (57) confirmed these findings in Iranian middle school village boys.

An ad hoc committee led by Halsted evaluated the negative outcomes. In attendance was Mattie-Ray Spivey-Fox, PhD. She noted the high likelihood that the subjects were deficient in other micronutrients and proposed that treatment include a broad mixture of other micronutrients (58). Later studies of Iranian middle-school village boys showed that zinc given with a broad mixture of other micronutrients was efficacious for growth (59, 60).

Conclusion

When human zinc deficiency was first reported and confirmed, the meaning was not widely understood. Some observers considered the condition esoteric. Others were dismissive and/or derisive. In my experience, most misunderstanding was among clinicians. Others with different interests were busy with other issues. This was expected. Fortunately, the current understanding of zinc’s many roles in metabolism has progressed to a stage where new discoveries are expected. Wise application of knowledge is now the challenge. The causes of human zinc deficiency in populations at high risk are known. One hopes that a greater understanding of in vivo zinc chemistry will galvanize the medical and public health communities to develop means for prevention.

Acknowledgments

Reminiscences with my friend and colleague Ananda Prasad inspired this review. He introduced me to zinc and welcomed me to his research team. That experience led to my subsequent career. The opinions expressed are my own. The author had sole responsibility for the final manuscript.

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