Zinc deficiency - has been known of for 40 years but ignored by global health organisations - OT

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http://bmj.com/cgi/content/full/326/7386/409

Zinc deficiency

Has been known of for 40 years but ignored by global health organisations

Although it has been known for more than six decades that zinc is essential

for the growth of micro-organisms, plants, and animals, until 1961 it was

believed that zinc deficiency in humans could never occur. It is now clear

that nutritional deficiency of zinc is widely prevalent and its morbidities

are severe. This article describes the history of the study of zinc

deficiency from a single case report in 1961 to its current state.

In 1958, a 21 year old male patient in the Iranian city of Shiraz presented

with dwarfism, hypogonadism, hepatosplenomegaly, rough and dry skin, mental

lethargy, geophagia, and iron deficiency anaemia.1 This patient had an

unusual diet. His intake of animal protein was negligible, and he ate only

unleavened bread. In addition, he consumed 0.5 kg of clay daily. His total

intake of calories and protein (cereal) was adequate, and except for iron

deficiency no other deficiency in micronutrients was documented

consistently. In the following three months 10 more patients with a similar

illness were seen in the same hospital. The growth retardation and

testicular hypofunction in all these patients could not be explained on the

basis of iron deficiencythese manifestations are not observed even in iron

deficient animals. In animals, among the transitional elements known to have

adverse effects on health due to deficiency (Cr, Mn,Co,Cu, and Zn), only

zinc deficiency was known to cause growth retardation and testicular

hypofunction.

I speculated that some dietary factors responsible for the decreased

availability of iron in geophagic patients might also have decreased the

availability of zinc.1 Later it became known that phytate in cereals

markedly impairs the absorption of zinc and also iron.2 With a well balanced

animal protein diet and administration of iron, all the clinical features in

the Iranian patients were corrected.

I saw similar patients in Egypt. The evidence for zinc deficiency in these

patients was that their concentrations of zinc in plasma, red blood cells,

hair, and a 24 hour urine sample were decreased compared with controls; 65Zn

studies showed that the plasma disappearance curve of zinc was more rapid

and the 24 hour exchangeable pool was decreased. Further, the rate of growth

in patients who received zinc supplements (average 12.7 cm per year) was

much greater compared with those who received iron instead or only an

adequate animal protein diet. 3 4 Gonadal changes were also reversed by zinc

supplementation only. Patients who had iron supplementation corrected their

anaemia, but no effect was noted on growth or gonads. In 1973, and

Moynahan noted that acrodermatitis enteropathica, a fatal genetic disorder,

was cured by supplementation with zinc.5 It is now known that patients with

acrodermatitis enteropathica do not absorb dietary zinc normally.

The discovery that zinc is essential for humans made a notable impact. In

1974 the Food and Nutrition Board of the US National Academy of Sciences

made a landmark decision, to declare zinc an essential nutrient and

establish recommended dietary allowances for humans. Later, including zinc

in total parenteral nutrition fluids was made mandatory, which undoubtedly

saved many lives. Dietary zinc deficiency is very prevalent in the

developing world (affecting nearly two billion people), where mainly cereals

are consumed by the population. A meta-analysis of 33 prospective

intervention trials of zinc supplementation and its effects on children's

growth in many countries showed that zinc supplementation alone had a

statistically significant effect on linear growth and body weight gain,

indicating that other deficiencies that may have been present were not

responsible for growth retardation.6 Zinc supplementation has been shown to

improve neuropsychological functions in Chinese children with zinc

deficiency.7 It reduces the incidence and duration of acute and chronic

diarrhoea and acute lower respiratory tract infections in children in

developing countries, resulting in decreased mortality.8 Zinc deficiency in

pregnant women causes abnormal labour, retarded fetal growth, and fetal

abnormalities.9

The immunological effects of zinc deficiency during the early 1960s were not

known, although I knew that patients with zinc deficiency in the Middle East

died of infection before the age of 25 (personal observation). It has now

been shown that in people with zinc deficiency, activity of serum thymulin

(a thymus specific hormone involved in T cell function) is decreased, an

imbalance between T helper cell (Th1) and Th2 function develops, and lytic

activity of natural killer cells and the percentage of precursors of

cytolytic T cells is decreased. 10 11

Zinc deficiency has now been recognised to be associated with many

diseasesfor example, malabsorption syndrome, chronic liver disease, chronic

renal disease, sickle cell disease, diabetes, malignancy, and other chronic

illnesses.9 In these conditions, deficiencies of other micronutrients such

as vitamins and other trace elements may also be associated. It should be

emphasised that nutritional zinc deficiency in the developing countries does

not occur in isolation.

Recently the National Institutes of Health's Eye Institute conducted a large

double blind clinical trial including 3640 elderly participants, which

showed that antioxidants and zinc supplements delayed progression of age

related macular degeneration and reduced the risk of loss of vision.12 Zinc

deficiency is also common in elderly people.9

Zinc decreases the copper burden in humans; as such it has been used

effectively to treat 's disease.9 In therapeutic doses, zinc has been

shown to be beneficial in the treatment of hepatic encephalopathy, sickle

cell disease, and the common cold.

More than 300 catalytically active zinc metalloproteins and more than 2000

zinc dependent transcription factors involved in gene expression of various

proteins have been recognised. 13 14

We have recently shown in cell culture studies that zinc activates nuclear

factor-kappa B in T helper cells and in zinc deficiency binding of nuclear

factor-kappa B to deoxyribonucleic acid is decreased, leading to decreased

gene expression of interleukin 2 and its production.15

The problem has been known for 40 years and a solution is still outstanding.

Despite all the evidence practically no attention has been given to the

problem of zinc deficiency by the world's organisations. Growth retardation,

increased susceptibility to infectious and cognitive impairment are common

in developing countries where nutritional deficiency of zinc is also

prevalent. Thus a correction of zinc deficiency is likely to have a great

impact on the health of a large population in the developing world and it is

imperative that the World Health Organization must include this problem in

its top priorities.

Ananda S Prasad, distinguished professor of medicine.

Wayne State University School of Medicine, Internal Medicine, University

Health Center 5-C, 4201 St Antoine, Detroit, MI 48201 USA

(prasada@...)

Footnotes

Competing interests: None declared.

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1. Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency anemia,

hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 1961; 31:

532-546[iSI].

2. Oberleas D. Phytates. In: Strong FM, ed, Toxicants occurring naturally

in foods. 2nd edition. Nat Acad Sci: Washington DC, pp 363-371, 1973.

3. Prasad AS, Miale A, Farid Z, Sandstead HH, Schulert AR. Zinc metabolism

in patients with the syndrome of iron deficiency anemia, hypogonadism, and

dwarfism. J Lab Clin Med 1963; 61: 537-549[iSI].

4. Sandstead HH, Prasad AS, Schulert AR, Farid Z, Miale A, Bassily S, et

al. Human zinc deficiency, endocrine manifestations and response to

treatment. Am J Clin Nutr 1967; 20: 422-442[iSI][Medline].

5. PM, Moynahan EJ. Zinc deficiency in acrodermatitis enteropathica:

multiple dietary intolerance treated with synthetic zinc. Proc R Soc Med

1973; 66: 327-329[iSI][Medline].

6. Brown KH, Peerson JM, J, LH. Effect of supplemental zinc on

the growth and serum zinc concentrations of prepubertal children: a

meta-analysis of randomized controlled trials. Am J Clin Nutr 2002; 75:

1062-1071[Abstract/Free Full Text].

7. Sandstead HH, Penland JG, Alcock NW, Dayal HH, Chen XC, Li JS, et al.

Effects of repletion with zinc and other micronutrients on neuropsychologic

performance and growth of Chinese children. Am J Clin Nutr 1998; 68(2

suppl): S470-S475[Abstract].

8. Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S. Zinc

supplementation in young children with acute diarrhea in India. N Eng J Med

1995; 338: 839-844.

9. Prasad AS. Clinical spectrum of human zinc deficiency. In: Prasad AS,

ed. Biochemistry of zinc. New York: Plenum Press, 1993:219-258.

10. Prasad AS, Meftah S, Abdallah J, Kaplan J, Brewer GJ, Bach JF. Serum

thymulin in human zinc deficiency. J Clin Invest 1988; 82:

1202-1210[iSI][Medline].

11. Beck FWJ, Prasad AS, Kaplan J, Fitzgerald JT, Brewer GJ. Changes in

cytokines production and T cell subpopulations in experimentally induced

zinc-deficient humans. Am J Physiol 1997; 272: E1002-E1007[iSI][Medline].

12. Age-Related Eye Disease Study Research Group (AREDS) Report No. 8. A

randomized, placebo-controlled, clinical trial of high-dose supplementation

with vitamins C and E, beta-carotene, and zinc for age-related macular

degeneration and vision loss. Arch Ophthalmol 2001; 119:

1417-1436[CrossRef][iSI].

13. Prasad AS. Zinc and enzymes. In: Prasad AS, ed. Biochemistry of Zinc.

New York: Plenum Press, 1993:17-53.

14. Prasad AS. Zinc and gene expression. In: Prasad AS, ed. Biochemistry of

Zinc: New York. Plenum Press, 1993:55-76.

15. Prasad AS, Bao B, Beck FWJ, Sarkar FH. Zinc activates NF-kB in HUT-78

cells. J Lab Clin Med 2001; 138: 250-255[CrossRef][iSI][Medline].