Free radicals in the pathogenesis of kwashiorkor.

The skeletal spectre of the marasmic child clearly results from a lack of intake of the bulk nutrients. It can be easily and consistently reproduced in any convenient species of experimental animal. In stark contrast, the other major form of malnutrition, kwashiorkor, has only once been convincingly reproduced in experimental animals. Coward & Whitehead (1972) produced oedema, fatty liver, skin lesions, hair discoloration and friability, hypoproteinaemia and mental changes in baboons by feeding the animals exactly the same diets that children with kwashiorkor received in Uganda. The authors demonstrated that the syndrome could be reproduced experimentally but made no attempt to discover the factor or factors in the diet responsible for the disease. In other studies the individual features of kwashiorkor had been singly and inconsistently reproduced in animals using a whole variety of, often extreme, experimental manipulations. The conditions necessary to give a ‘model’ for kwashiorkor oedema, for instance, are quite different from those used to give experimental fatty liver or hair discoloration. Why should the kwashiorkor syndrome be so difficult to reproduce experimentally I Why have the applied programmes designed to prevent kwashiorkor been so uniformly unsuccessful? The obvious first answer to be considered is that all the hypotheses that have been proposed, tested experimentally and used as the conceptual framework for the applied programmes, are incorrect. Certainly the extant hypotheses of protein deficiency (Williams, I 935)’ niacin deficiency (Gillman & Gillman, 195 I), antidiurectic-hormone-like action of free ferritin (Srikantia, 1958), dysadaptation to protein deficient stress (Gopalan, 1968), hormonal dysadaptation (Whitehead, 1979), or aflatoxin intoxication (Hendrickse, 1984), do not adequately explain more than a few of the features of kwashiorkor listed in Table I. These features must all be reconciled in any unifying hypothesis. Recently we have proposed that kwashiorkor results from an imbalance between the production of free radicals and their safe disposal (Golden, 1985). It is the purpose of the present paper to examine the evidence for such a hypothesis. The hypothesis, illustrated in Fig. I, states that in kwashiorkor, various noxae are imposed on the subject. These noxae produce free-radical-mediated lipid peroxides and toxic carbonyls. Under normal metabolic and nutritional