Clinics in Endocrinology and Metabolism最新文献

Genetic disorders of trace element transport are now known in humans, mice, dogs and cattle. Those involving copper have been known longest and are best known clinically. Effects due to copper deficiency are seen in Menkes' disease, in X-linked cutis laxa and in the X-linked series of mottled mutants in the mouse. Copper accumulation is also harmful, causing damage initially to the liver and later to the kidneys and brain in Wilson's disease, in some Bedlington terriers and in toxic milk mice. Zinc deficiency is seen in acrodermatitis enteropathica and in premature babies born to women who seem to secrete milk that is zinc-deficient, as is seen in lethal milk mice. Study of animal mutants, especially mutant mice, is helpful in understanding the human diseases and identification of the basic defects in trace element transport in these diseases is improving knowledge relevant to trace element nutrition.

Basically, epidemiology is the making of measurements of known reproducibility, in a bias-free manner, on representative samples of subjects drawn from defined communities. Epidemiology has become a relatively precise science and its value in medicine is widely appreciated. So too are its limitations: the difficulties in achieving a high response rate, in identifying and controlling confounding factors in the examination of an association, and the ultimate difficulties in distinguishing causation from association. While the value of community-based studies seems to be recognized by those interested in man and his environment, the need for the strict application of epidemiological procedures, and the limitations imposed on conclusions drawn from studies in which these procedures have been compromised, does not seem to be adequately understood.

There are certain known links between trace elements in the environment and disease: for example the level of iodine in soil and water and the prevalence of goitre; the level of fluoride in water and the prevalence of dental caries. The investigation of other possible associations is difficult for a number of reasons, including interrelationships between trace elements, confounding of trace element levels (and disease) with social and dietary factors, and the probability that relationships are generally weak.

Two conditions in which associations are likely are cardiovascular disease and cancer. Despite research along a number of lines, the relevance of trace elements to cardiovascular disease is not clear, and certainly the apparent association with hardness of domestic water supply seems unlikely to be causal. The same general conclusion seems reasonable for cancer, and although there are a very few well established associations which are likely to be causal, such as exposure to arsenic and skin cancer, the role of trace elements is obscure, and likely to be very small.

Biochemical and clinical investigations involving trace elements are made (1) for the diagnosis of inherited or acquired deficiencies of essential trace elements and their treatment, (2) to monitor the efficacy of the therapeutic administration of non-essential trace elements in order to achieve maximum clinical response with minimum toxicity, and (3) for the early detection of excessive ingestion of non-essential toxic trace elements.

The wide range of tests used to assess trace element status in these three areas of clinical importance is discussed with examples of essential and of toxic trace elements since therapeutic use of trace elements is discussed elsewhere in this issue. Particular attention is given to zinc, copper, selenium, lead and cadmium because the various tests used to assess the status of these elements encompass the principles of all currently available tests.

Although trace element analysis of body fluids and tissues is the most useful and most commonly used method of assessment of trace element status, this is of limited value and no single test may be considered as ideal for any element. The provision of more detailed information from elemental analysis of cellular and subcellular fractions and of protein fractions from plasma leads inexorably to measurements of element-dependent enzymes, metalloproteins and of low molecular weight element-binding ligands. Even at this level of discrimination the choice of body tissue or tissue fluid for investigation is determined by the trace element and its principal metabolic targets.

Man depends on at least nine trace elements—iron, zinc, copper, manganese, iodine, chromium, selenium, molybdenum and cobalt—for optimum metabolic function. These elements serve a variety of functions including catalytic, structural and regulatory activities in which they interact with macromolecules such as enzymes, pro-hormones, presecretory granules and biological membranes. These micronutrients are involved, therefore, in all major metabolic pathways at levels which are so fundamental that the features of deficiency of many of them are protean and non-specific. In considering the metabolism of the elements themselves, they fall into two groups: those which exist normally as cations and those present as anions. The latter group are absorbed relatively easily and whole-body homeostasis is mediated mainly by renal excretion. The cations need specific pathways for absorption and their homeostasis is effected by gastrointestinal and biliary secretion. Some elements are absorbed more efficiently as organic complexes. The net achievement of the metabolic pathways for each element is to deliver it to its functional site(s) by exploiting its physicochemical characteristics to avoid interactions with other inorganic nutrients.

Recent studies investigating the association between low levels of lead and children's IQ, behaviour and educational attainment are reviewed. The main emphasis is on the methodological issues and problems which face researchers carrying out these cross-sectional epidemiological studies, and in particular the problem of confounding social factors.

It is concluded that body lead levels in children do to some extent act as a marker for socially disadvantageous factors, and that when these are controlled adequately, if there are any functional effects due to lead, then these are so small that they cannot be detected with any certainty, and they may not exist at all.

The properties of trace elements which feature in their therapeutic activity are: binding to macromolecules (enzymes, nucleic acids, etc.) with disturbance of biological function, and interaction with other elements. These properties, particularly the binding to large molecules, are far from specific, an observation which is reflected in the very wide range of diseases in which trace elements are employed.

While metal compounds have been administered for several centuries, the scientific basis for treatment with trace elements began with the use of gold compounds, initially in patients with tuberculosis and later those with rheumatoid arthritis. Although many other drugs have been developed, some of which also include metal complexes, gold has retained an important position in the treatment of this condition. The gold-induced effects upon the immunological aspects of RA are also observed in other conditions with autoimmune involvement. The antineoplastic potential of metal complexes will be further exploited by the development of less toxic compounds—of platinum and possibly also of other metals. At the same time there are improvements in the protocols for administration which increase the range of cancers responding to treatment. Perturbation of gastrointestinal activity represents another area where trace elements have an important therapeutic role, both in the control of intraluminal acidity and in the adjustment of nutrient availability. A fourth significant area of trace element therapeutics involves the central nervous system where the use of lithium has provided spectacular results in the treatment of affective and other disorders.

With a very wide range of other conditions in which they are employed, therapeutic uses provide somewhat unusual illustrations of the importance of trace elements in human disease.

Selenium is undoubtedly an essential trace element: its involvement in GPx structure, the presence of deleterious effects of selenium deficiency in animals, and the recognition of deficiency states in man attest to its importance.

However, if the consequences of selenium deficiency in man are now widely recognized, the mechanisms underlying these conditions are poorly understood. The definition of the exact role of selenium in human homeostasis has been hampered by the lack of a sensitive parameter, usable in routine investigation, to assess selenium status. Measurements of plasma and urinary levels, although useful in clinical practice, are inadequate indicators. The only true evidence of selenium deficiency lies in a positive response to selenium therapy.

Deficiency states have been demonstrated for inhabitants of regions where selenium supply is limited, in protein-energy malnutrition, and in patients maintained on total parenteral nutrition without selenium supplementation.

The benefit of selenium supplementation, together with other antioxidant drugs, in non-deficient subjects is still a matter of debate; its protective effect in neoplastic, cardiovascular and neurological degenerative diseases is not yet proven.