Most of the discussion to this point has centered around amino acid and protein metabolism in normal individuals. Although the effect of disease on amino acid and protein requirements is beyond the limits of this introductory chapter, a few important general points need to be made. The first is that energy and protein needs are tied together, as illustrated in Figure 2,16. When metabolic rate rises, body protein is mobilized for use as a fuel (amino acid oxidation) and for supply of carbon for gluconeogenesis. Several disease states increase metabolic rate. The first is infection, in which the onset of fever is a hallmark of increased metabolic rate. The second is injury, be it trauma, burn injury, or surgery per se. Along with onset of a hypermetabolic state comes a characteristic increase in the loss of protein measured by increased urea production. Sir David Cuthbertson observed over 60 years ago that a simple bone fracture causes significant loss of N in the urine ( 181). Since then, numerous studies of the hypermetabolic state of injury and infection have been performed. For most people, the injuries suffered are minimal and self-limiting, i.e., the fever goes away in a couple of days or the injury heals. In normal, healthy people the impact of the injury on overall protein metabolism is as minimal as a bout of fasting. However, in chronic, long-term illness or in patients otherwise weakened by age or other factors, onset of a hypermetabolic state may produce a significant and dangerous loss of body N.
The second point is that while the diagnosis of a metabolic condition that needs correcting may be straightforward (e.g., finding an increased loss of N and wasting of body protein), correcting the problem by administration of nutritional support is not as simple. The underlying illness usually resists or complicates simple nutritional replacement of amino acids. Trauma and infection are classic problems in which prevention of N loss is very difficult. Supplying additional nutrients either enterally (by mouth or feeding tube) or parenterally (by intravenous administration) may blunt, but will not reverse, the N loss seen in injury ( 182, 183).
Simple tools have been used to identify the hypermetabolic state: indirect calorimetry to measure energy expenditure, and N balance to follow protein loss. These measurements have shown that blunting the N loss in such patients is not as simple as supplying more calories, more amino acids, or different formulations of amino acids. What becomes clear is that although a nutritional problem exists, nutritional replacement will not correct the problem; instead, the metabolic factors that cause the condition must be identified and corrected. Wilmore has categorized the factors that produce the hypermetabolic state into three groups: stress hormones (cortisol, catecholamines, glucagon), cytokines (tumor necrosis factor, interleukins, etc.), and lipid mediators (prostaglandins, thromboxanes, etc.) ( 182). Strategies have been developed to address these various components. For example, insulin and growth hormone have been administered to provide anabolic hormonal stimuli to improve N balance. Alternatively, studies have been conducted in healthy individuals in which one or more of the potential mediators are administered to determine its effect on amino acid and protein metabolism (183, 184). For example, studies of the infusion of individual hormones while isotopically labeled amino acid tracers are also infused have given us some insight into the mechanisms of hormone action upon the regulation of amino acid oxidation and protein breakdown and synthesis in humans (184).
There are areas in which administration of a specific amino acid may produce a pharmacologic effect in ameliorating the disease state; for example, administration of glutamine and arginine or limiting sulfur amino acid intake. Glutamine is the most highly concentrated amino acid in muscle cells and plasma ( 89). Glutamine is an important nutrient to many cells, especially the gut and white cells, where it may be used both as a source of energy and for such critical processes as the synthesis of nucleotides (185). Glutamine is an essential nutrient for cell culture media. Because a hallmark of injury is a drop in the intracellular level of muscle glutamine, presumably because of increased use by other tissues, glutamine has been proposed as a nutrient that becomes conditionally essential in trauma and infection ( 182).
Arginine is another nonessential amino acid with important properties for promoting immune system function. Arginine is the precursor for nitric oxide synthesis ( 186) and has been proposed as a nutrient for altering immune function and improving wound healing ( 187, 188). We believe that adequate ornithine is synthesized to maintain arginine supplies under normal conditions, but we do not know whether additional demands for arginine can be met endogenously or whether arginine becomes a conditionally indispensable nutrient. For example, Yu et al. (189) used stable isotope tracers to measure arginine kinetics in pediatric burn patients and determined little net de novo arginine synthesis, suggesting that under conditions of burn injury, insufficient arginine is made to meet the body's presumed increased need when the immune system is under challenge.
Elevated plasma homocysteine is an independent risk factor for vascular disease (19,0). Homocysteine is produced by hydrolysis of S-adenosylhomocysteine, which is derived from S-adenosylmethionine, a major methyl group donor (e.g., in creatine synthesis in Fig 2.5). Homocysteine may be "remethylated" to methionine or degraded via condensation with serine to form cystathionine, which then goes on to form cysteine ( Fig,.,,,,2.,,4). High concentrations of homocysteine occur when either or both of the disposal pathways of homocysteine are impaired. Because these reactions of homocysteine metabolism depend upon vitamin B 6 (pyridoxal 5'-phosphate) and folate, supplementation of the diet with vitamin B 6 and folate often is effective in lowering plasma homocysteine levels (190). Alternatively, the dietary intake of sulfur amino acids may be reduced by ingesting relatively more of a sulfur amino acid-poor dietary protein, such as soy protein.
While supplementation of specific amino acids or cofactors may produce beneficial responses, there may be occasions when supplementation produces undesirable effects on the disease state. Supplementing glutamine in the diets of cancer patients may be counterproductive because the glutamine (which is essential for fast-growing cell lines in culture) may promote accelerated tumor growth (191). Similarly, arginine supplementation may stimulate nitric oxide synthesis because of the increased availability of the precursor for its formation. However, nitric oxide production produces both helpful and detrimental effects ( 186). In these and other applications of specific nutrients, the use of isotopically labeled tracers is particularly helpful because the metabolic fate of the administered nutrient may be followed (labeled nitrate production from nitric oxide synthesis from 15N-labeled arginine) as well as measurement of the promotion or suppression of protein synthesis and proteolysis in specific tissues. Amino acid and protein requirements in various diseases are quite difficult to assess and require a multifactorial approach. These are the real challenges facing us in nutrition today and in the days ahead.
Abbreviations: ADP—adenosine diphosphate; AMP—adenosine monophosphate; ATP—adenosine triphosphate; A-V—arteriovenous; BCAA—branched-chain amino acid; GMP—guanosine monophosphate; IMP—inosine monophosphate; KIC—a-ketoisocaproate; mRNA—messenger RNA; N—nitrogen; PER—protein efficiency ratio; PRPP—phosphoribosylpyrophosphate; RDA—recommended dietary allowance; TCA—cycle, tricarboxylic acid cycle; TML—trimethyllysine; tRNA—transfer RNA; WHO/FAO/UNU—World Health Organization/Food and Agriculture Organization/ United Nations University.
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