To understand the myriad changes of endocrine function that occur in systemic disease, an attempt has been made to classify some of the better defined ones into several categories (see Table 1). However, there remains for each category, and the group considered in toto, the nagging question of why such changes of endocrine function should occur with systemic disease? Such changes are not rare and indeed may be the rule rather than the exception. A growing awareness of their frequency has led the author to wonder whether Bricker's concept of pathophysiological 'trade-offs', initially advanced to explain adaptations to chronic uraemia, could not be applied equally to the endocrine changes of systemic disease. Bricker has proposed that the changes of chronic uraemia occur not as the result of toxic substances as initially proposed, but as the necessary and life saving 'trade-off' adaptations required for survival (Bricker, 1972). For example, in considering the kidney, it is evident that single nephrons in renal failure have the capacity to equal in excretory capacity the normal function of 10 to 60 nephrons. A critical premise of Bricker's thought is that this potential is realized only under external influence (Bricker, 1972). Since the adaptation represents a shift from reabsorption to excretion for many substances, logical candidates for roles in mediating the adaptation for the kidney would be circulating hormones capable of inhibiting or otherwise affecting solute transport. It is thus conceivable to postulate that the uraemic abnormalities are induced by rising concentrations of such hormones and not by formation of specific, unknown toxins. The trade-off hypothesis suggests that hormones which reach a critical blood level will affect cell types other than the tubular epithelial cells of the kidney, and in this way lead to changes in the function of extra-renal organs and organ systems. Although the trade-off hypothesis for the kidney remains hypothetical, there is considerable evidence to support it. For example, in regard to the excretion of phosphate: in the pre-uraemic nephron, some 85 per cent of the filtered phosphate is reabsorbed with the remaining 15 per cent excreted. In the nephron responding to the conditions of uraemia in which the majority of the total nephron population has been destroyed, only a small percentage is excreted. It has been suggested that the principal basis for this adaptation is an increase in the amount of circulating parathyroid hormone (Bricker, 1972). This change has life-saving advantages in terms of the ability to maintain external phosphate balance. However, parathyroid hormone has effects that transcend those on the kidney, and the peptide hormone can induce a variety of changes in bone architecture. The pathogenesis of secondary hyperparathyroidism in advancing renal disease is illustrative of this change: glomerular filtration rate which is directly related to the number of functioning nephrons decreases in a quantum fashion as each nephron is destroyed in progressive disease. With each reduction in glömerular filtration rate, there must occur a transient period of phosphorus retention until the residual nephrons increase their rate of excretion of phosphorus into the urine. During this lag period total phosphorus excretion must decrease. As the serum phosphate concentration rises there should occur a reciprocal fall in the ionized calcium concentration in the blood. The latter in turn stimulates the parathyroid gland to secrete an increased amount of parathyroid hormone. The increment in parathyroid hormonal activity would promote an increase in the rate of phosphate excretion per residual nephron, and the result would be restoration of serum phosphate concentrations to normal. Can a similar sequence of events be seen in systemic disease with other endocrine changes? A consideration of GH and somatomedin, and of thyroxine and its conversion to T3, would strongly suggest so. In any disease process in which caloric deprivation is prolonged, the body's primary need is for adequate fuel substrate. The body normally adapts to this need by mobilizing fatty acids from adipose tissue and by diverting amino acids from muscle to the production of glucose. The normal action of GH mediated via somatomedin is to enhance protein synthesis, and either indirectly or directly to promote cellular proliferation. However, in disease states with caloric deprivation, this would divert vital substrates from fuels for existing tissues into pathways directed to the synthesis of new protein. A decreased formation of somatomedin and a resulting tonic increase in the secretion of GH, however, would prevent this. Furthermore, the increased levels of GH associated with decreased somatomedin levels could be predicted to inhibit glucose uptake by peripheral tissues as this is one action mediated directly by GH and not requiring somatomedin. This latter action would allow vital substrates to be available for the brain, which has an obligatory requirement for glucose. In a similar manner, a decrease in conversion of thyroxine to T3 with the reciprocal increase of reverse T3 can be viewed as a mechanism to protect the body from excess catabolism in states where this could be dangerous, for example, in the elderly person, with a superimposed acute or chronic disease. Viewed in the manner just described, the endocrine aberrations of systemic disease might best be considered as alterations in the signals responsible for producing the necessary trade-off adaptations. At times, however, these alterations may cause a disease complex itself, such as the metabolic bone disease of secondary hyperparathyroidism. The practical implications of this knowledge are not totally evident at present, but at least one caution seems reasonable: the simple presence of abnormal laboratory values for a circulating hormone does not necessarily indicate endocrine disease. Elevated T4 and decreased T3 concentrations in the elderly, chronically ill, for example are best viewed as adaptations. Judged from one perspective (the T4 value) such patients could be classified as hyperthyroid; from the perspective of T3, they could be considered hypothyroid. Similar examples could be cited for parathyroid hormone, GH, insulin and glucagon. Possibly the general implication is the need to reemphasize an early dictum of medicine, that it is the total assessment of the patient which must be considered in the final analysis and management of disease. © 1979 W. B. Saunders Company Ltd. 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