Nutrition and chronic disease.

© 2006 Mayo Foundation for Medical Education and Research See also page 353 The first victories of human clinical nutrition were the conquests of the classic deficiency diseases (eg, beriberi and pellagra). Each nutrient was associated with a specific disease, the approximate mechanism of its action was elucidated, and programs of supplementation or fortification that led to control or virtual elimination of the disease were implemented, more or less in that order. Most of this occurred more than half a century ago, and with those gains to its credit, nutrition has virtually disappeared from the radar screens of many, perhaps most, medical specialties. Except for alleged negative effects (eg, fat, salt, cholesterol), what more did nutrition have to offer human medicine? In essentially every instance, the index disease for each of the classic micronutrients had a short latency; otherwise the connection between cause (deficient intake) and effect (deficiency disease) could not have been discerned. Deficiency conditions that have long latencies are not precluded, and expanded understanding of cell biology suggests that they may, perhaps must, exist. Nevertheless, they have proved difficult to recognize, as have deficiency states that develop through mechanisms different from those understood to mediate the index disease. Today, at the beginning of its second century as a science, clinical nutrition faces 2 major and very different problems: (1) the need to develop investigative approaches to define the role nutritional deficiency plays in a broad array of chronic diseases and (2) the fact that American medicine tends either to ignore or to dismiss nutritional evidence relating to the diseases it treats. In the current issue of Mayo Clinic Proceedings, Holick summarizes a massive body of data indicating that vitamin D, in addition to its classic role in the calcium economy, is involved in many other systems and diseases. It is now known, for example, that more than 200 human genes contain vitamin D response elements, only a fraction of which are directly involved in operation of the calcium economy or in bone biology. We now know that vitamin D is intimately involved in regulating gene expression for such basic cell biologic processes as proliferation, differentiation, and apoptosis, in addition to various aspects of both primary and acquired immunity. The ubiquity of vitamin D involvement suggests that deficiency of the nutrient could be expressed in myriad ways distinct from rickets and osteomalacia. Defining optimal vitamin D status in this context will prove challenging because most chronic diseases typically share 2 characteristics that make investigation difficult: long latency and multifactorial causation. The challenge is not only to determine whether changing vitamin D status will alter development or severity of any of the conditions concerned but also to figure out how to show efficacy in a context of long latency, a problem not readily attacked by randomized controlled trials. There are also the lesser problems of determining how much vitamin D is needed to optimize a given system and how most effectively to improve vitamin D status for whole populations. At stake are far-reaching consequences for nutritional policy. Current micronutrient intake recommendations are pegged to preventing only the index disease. That will have to change. For vitamin D, current recommendations are sufficient to prevent only rickets. We already know that that is not enough to prevent the portion of the osteoporosis burden caused by low vitamin D status. Vitamin D is actually a sort of poster child for a broad array of essential nutrients, many of which are now known to function in diverse systems and, for some of their effects, to exhibit latencies varying from days to years (the latter of course not recognizable in the early days of nutritional science). Calcium is a good example because both its multiple system involvement and mechanisms of some of its manifold actions are now reasonably well worked out. Inadequate calcium intake depletes or limits skeletal mass, which functions as the body’s calcium nutrient reserve, thereby causing or aggravating osteoporosis. Of course, low calcium intake is not the only cause of osteoporosis; nevertheless, osteoporosis is the index disease for calcium, just as rickets (which also has other causes) is the index disease for vitamin D. Gradually we have come to recognize that calcium has nonskeletal health effects as well, many with shorter latencies. For example, unabsorbed calcium in the gut lumen (which averages about 90% of intake) complexes and neutralizes certain potentially harmful byproducts of digestion, such as oxalic acid, free fatty acids, and bile acids. The effect is purely chemical and is immediate; however, optimal complexation requires a high calcium intake. Reducing absorption of food oxalate decreases kidney stone risk in those susceptible, a benefit that has zero latency. Complexation of fatty acids serves at least 2 useful functions: (1) it reduces absorbed energy and thereby helps with weight control, and (2) it reduces cancer promotion by uncomplexed free fatty acids. For these intralu-