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Department of Surgery, Maastricht University, 6200 MD, Maastricht, The Netherlands
3 To whom correspondence should be addressed. E-mail: pb.soeters{at}ah.unimaas.nl.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • nutrition • supplementation • amino acid toxicity • stress • disease
Introduction
Amino acid adequacy is much better defined in growing and healthy organisms than during illness, because endpoints for growth and health are much easier to define than endpoints for amino acid adequacy during disease states. During disease, endpoints do not only indicate amino acid adequacy with respect to preserving the composition and function of the entire organism; more specifically, endpoints pertain to sustaining an adequate metabolic response to allow an organism to successfully deal with the disease process itself. Such an endpoint is difficult to assess, and it is not easy to find large populations with standardized disease to make this study possible.
In healthy organisms, amino acid adequacy does not only depend on amino acid composition and the digestibility of the protein under study, but also on the quality and quantity of other components of the meal. During critical illness, food handling by the gut is compromised, which may require adaptations to the route and mode of administration as well as the composition and quantities of food constituents. Similarly, in disease, metabolism appears to be specifically directed to generate a healing response rather than to preserve muscle mass; this influences amino acid requirements with respect to composition and quantity.
In this article, we briefly review the concept of protein adequacy during healthy states. Subsequently, we try to review changes in organ function and metabolism that occur in disease. These changes preclude application of the principles acquired from nondiseased organisms and lead to altered requirements. Application of these principles has led to the administration of nonessential amino acids in excess of the requirements for healthy organisms. This raises the question of whether this practice can lead to amino acid toxicity. In this context, we predominantly discuss generalized disease states such as sepsis or the systemic inflammatory response syndrome and only briefly address mono-organ diseases like renal or hepatic diseases.
Amino acid adequacy in healthy states
Concepts. For several decades, the quality of a protein as part of a bolus meal has been defined by its digestibility and absorption and by the amino acid composition of the protein in the meal (1–3). In recent decades, it was proposed that another important factor in determining protein quality and amino acid adequacy (4–6) is the suitability of the protein in the meal to be very gradually delivered into the portal and subsequently into the systemic circulation. On the basis of available evidence, it was also proposed that the mechanism by which the organism achieves slow release of amino acids into the portal circulation consists of the utilization of meal protein–derived amino acids for protein synthesis in the gut lumen or wall (7). Indirect evidence for this proposition is derived from knowledge that nutritional factors that promote protein synthesis decelerate the postprandial appearance of amino acids in the portal vein, diminish urea synthesis, and improve nitrogen balance. An example is the supplementation of isoleucine to hemoglobin ingested in the gut during gastrointestinal hemorrhage (4,5). Hemoglobin lacks the essential amino acid isoleucine. Consequently, an organism is presented with a protein of very low biological value during gastrointestinal bleeding or bleeding outside the gut. This leads to the possibility that optimizing the protein composition promotes temporary retention of its amino acids as protein in the gut. Another example is that addition of carbohydrate to protein, which is known to promote protein synthesis, delays amino acid appearance in the portal vein and importantly also diminishes urea formation (8).
Application of this concept to soy and casein proteins showed that amino acid appearance was much slower with casein and induced less urea formation (9). According to this concept, the best protein is therefore the protein that after digestion, resorption, and resynthesis to protein is slowly degraded and released as amino acids into the portal vein. In turn, this leads to better utilization of these amino acids in the liver or elsewhere in the body and to low levels of urea production.
The temporary pool of protein, which has been known for decades (10) to accumulate after a meal, is therefore considered to reside largely in the gut and is generally called the labile protein pool (7). The biological correlate of this labile protein pool may consist of enzymes synthesized in the process of digestion and secreted into the gut, mucus, enterocytes, and bacterial protein (11) in the gut lumen. This arrangement may be viewed to ascertain gradual amino acid release to the systemic circulation and maximally efficient use of protein from the feed (7).
Slow release of amino acids into the portal vein after digestion of meal-derived protein is not only the result of the ability of protein to be retained in the labile protein pool, but may also result from slow stomach emptying or slow digestion. Casein is considered to be a slow protein partly because of its coagulation in the stomach and subsequent slow passage and digestion (12). In view of the kinetics of the body's protein uptake from a bolus meal, amino acid requirements differ depending on the presence of other meal components, whether the meal contains fast or slow proteins, and the composition and digestibility of the protein (7).
Assessment. Although the experiments yielding the views outlined above provide some insight into the mechanisms involved, they are not suitable for elucidating amino acid adequacy in greater detail. This is because they are costly and unable to assess the values of discrete modifications of amino acid composition or structure with great accuracy. In the cattle-raising industry, large-scale feeding experiments are feasible for assessing growth and health. Although such experiments in healthy human populations are difficult, time consuming, and expensive, the endpoints are relatively straightforward and consist of growth in children or preservation of body mass and function in adults. Growth appears to be possible only when an organism is metabolically stable and is not subject to inflammation (13–17), stress, or severe organ dysfunction (18,19). Although these abnormalities are listed here as separate entities, it is very likely that a common underlying denominator exists in the form of an inflammatory response to these abnormalities. It also appears likely that this response is modulated by mediators that optimize the response to disease (20–22) but at the same time inhibit growth (13,23,24).
Application of this concept. Application of the proposed concept in daily life means that to spare protein, the human organism should eat balanced meals with high-quality protein that is combined with other nutrients including macronutrients such as carbohydrates. It is very likely that consumption of equal-sized meals spread over the day is preferable to one big meal at the end of the day with small meals in the morning and at lunch time. When most of the protein is eaten during one meal, the gut is unable to assimilate a large proportion of it because the capacity of the labile protein pool is exceeded (25,26). Consequently, a large portion of the amino acids derived from protein digestion are oxidized, or amino acid–derived carbon is used for glucose and fat synthesis (26). To a large extent, the nitrogen moiety is converted to urea.
Amino acid adequacy in disease states
Concepts. In clinical practice, there is not always consensus regarding the specific role of an organism's metabolic response to disease. In fact, many aspects of the metabolic response to disease are considered harmful and result in endeavors to counter this response; for instance, the cooling of patients with fever, administration of norepinephrine to counteract vasodilatation in septic states, and administration of hormones (27–31) or inhibitors (28,32) to counteract the stress response and the resulting muscle catabolism. This is rather unscrupulously done without real knowledge of whether fever, vasodilatation, and muscle catabolism in critical illness fulfill adaptive roles or whether they are harmful disturbances that deserve to be inhibited. Many therapeutic interventions in intensive care can be considered to be based on simplified and primitive reasoning rather than solid evidence, or part of an intelligent review of the available (albeit circumstantial) evidence leading to a protocol that can be evaluated. To devise meaningful therapy, clear insight should exist into the purpose of the various responses to disease; specifically, whether they are beneficial or deleterious; and consequently, whether they should be promoted or inhibited.
During chronic or acute disease, growth is inhibited (13,16,17,23,24,33–35) and the organism becomes catabolic, which is specifically exemplified by muscle atrophy. It is now clear that the neuroendocrine response including the cytokine response to disease leads to an obligatory loss of muscle that cannot be blocked by nutrition (36,37). In fact, the normal response to moderate trauma or disease includes immobility, anorexia, and catabolism. Muscle tissue disappears, but at the site of the injury or in tissues such as liver and the immune system, there is protein accumulation that is modulated by proinflammatory cytokines (38). Although the individual is anorectic, the anabolic accumulation of tissue in the liver, immune system, and site of injury can only occur with substrate that is derived from other tissues such as muscle (39,40). This is an easily-detectable situation that occurs in injured or ill patients, and it clearly indicates that muscle catabolism during acute trauma or disease is a useful adaptive phenomenon because the substrate derived from this catabolism is utilized for the healing response. As a consequence, modulation of the "catabolic" hormonal pattern with the intention of blocking muscle catabolism should not block the anabolic actions in the wound and immune system (41,42).
We have known for more than 30 y that metabolism during stress is crucially different from metabolism during pure starvation (43,44). During pure starvation, the reutilization of amino acids derived from protein degradation is efficient in the sense that essential amino acids are degraded to a very limited degree and are largely reused for protein synthesis. Whole-body protein turnover decreases, and very little protein is lost at the whole-body level (44). During starvation accompanied by disease, amino acids derived from muscle catabolism are not released in the circulation as such, but a large part [especially the branched-chain amino acids (BCAAs)4] are irreversibly degraded to yield other amino acids such as glutamine and alanine, which are avidly used at the site of the injury and in the liver and immune system (40,45–47). This precludes efficient reutilization of amino acids and obligatorily leads to increased protein catabolism at the whole-body level. It follows that the substrate mix and specifically the amino acid mix that is utilized during disease is essentially different from the substrate mix that is used during pure starvation.
Conceptually our aim to satisfy amino acid requirements in disease should be to infuse a substrate mix, or to allow the organism to produce a substrate mix, that the previously healthy organism produces when acutely diseased. Similarly, the goal should be to produce and certainly not to interfere with a hormonal milieu that is achieved by the organism when he or she is acutely ill or traumatized.
What is the actual substrate mix used by the body after trauma or in acute disease? One of the major reasons why reutilization of amino acids derived from muscle proteolysis leads to net catabolism at the whole-body level is that the increased glutamine and alanine efflux from muscle, which is demonstrated under these conditions (48–55), is derived in part from the irreversible degradation of BCAAs (56). This precludes reutilization of BCAAs for protein synthesis and leads to a catabolic rate that is more pronounced than during starvation unaccompanied by disease or trauma. Contrary to expectations, glutamine appearance is not always increased in disease (45,53,57–61). This may be due to methodological problems in research or to unexpected changes in glutamine turnover at the level of individual organs (62). The observation that more glutamine and alanine are released from peripheral (muscle) tissues implies that more alanine and glutamine are consumed in central (nonperipheral) organs such as liver, immune system, and possibly the site of injury (40,47).
Fluxes of other nonessential amino acids do not change to a similar degree as glutamine and alanine. It was proposed that arginine may become limiting under conditions of severe metabolic stress and that kidney may become an important arginine producer (63–68). Failure to produce sufficient quantities of arginine was claimed to occur in patients with short-bowel syndrome or during renal failure (66,68–70). Short-bowel syndrome is accompanied by low citrulline levels (71) supposedly because citrulline is produced in the intestine as one of the glutamine degradation products, and because citrulline can subsequently act as an arginine precursor in kidney (72). Data proving the importance of this pathway are lacking, however. Low arginine levels were also reported for severely traumatized or infected patients and were suggested to limit nitric oxide production (73). Whether these low plasma levels reflect a shortage is questionable, because most amino acids exist in low concentrations during these disease states (74) and also because low amino acid levels do not invariably point to decreased appearance and flux. Apart from de novo synthesis, arginine is derived from protein degradation, which is increased in disease states and exceeds protein synthesis. This leads to a substantial autoinfusion of arginine. Another substantial source of arginine is food; however, arginase activity in liver is extremely high, which precludes the escape of substantial amounts of arginine to the systemic circulation. It therefore was questioned whether much of the food-derived arginine and the de novo–synthesized arginine in the gut wall gains access to the general circulation (75). However, it was shown that enteral arginine supplementation can increase systemic arginine levels in rats (76) and humans (77). It is possible that arginine produced in kidney contributes significantly to its systemic appearance in the postprandial state, during which arginine is taken up in the process of net protein synthesis. Taking this into account, a more-efficient alternative for the enhancement of arginine levels is enteral citrulline supplementation. This hypothetically would provide substrate for renal de novo arginine synthesis without loss of administered arginine to the arginase system in liver and thereby limit urea synthesis. Recent studies (73) employing stable isotopes suggest that arginine appearance is increased in intensive-care patients to a similar degree as in moderately and severely ill patients. De novo synthesis in the kidney was lower in septic patients than in moderately ill patients (73). There is, however, no indication that the arginine requirement cannot be satisfied in this way.
Cysteine is suggested to play an important role in maintaining the redox state during disease. It is produced by the body via the transsulfuration pathway starting from methionine. However, estimates are that only a small proportion of cysteine is derived via this pathway (78,79). Most of the cysteine that appears in the circulation is derived from protein breakdown and food. Although a substantial appearance of cysteine from net protein catabolism can be estimated, claims have been made that cysteine may become the rate-limiting amino acid in glutathione synthesis. An indirect suggestion that cysteine may become deficient is derived from knowledge that administration of N-acetylcysteine has beneficial effects on the redox state and may enhance scavenging of reactive oxygen species (80).
Many other nonessential amino acids are proposed to play important roles in host response. Glycine was recently proposed (81) to be an anti-inflammatory, immunomodulatory, and cytoprotective agent. It was also proposed that tyrosine may become deficient in severely ill patients. Among the essential amino acids, BCAAs may become deficient due to increased degradation during severe disease, and histidine may become deficient during renal failure. Taurine has also received some attention and may have potential value when supplemented in neonates (82). Little is known, however, regarding the rate of appearance of taurine and the fluxes across individual organs.
The difficulty of assessing amino acid adequacy of the diet during disease and (surgical) trauma has led to the identification of surrogate markers using a pharmacokinetic approach (83,84). On the basis of increases or decreases of plasma levels of amino acids during a constant parenteral infusion of different amino acid mixtures together with carbohydrates, estimates are made whether individual amino acids are infused in sufficient or deficient quantities. The validity of such an approach should be proven by demonstrating that adaptation of the amino acid mixture according to these pharmacokinetic data improves nitrogen retention and clinical outcome.
What metabolic goals should be achieved in traumatized and critically ill patients? The acutely traumatized organism is known to increase its protein turnover (59,85–92). From the foregoing, it is clear that muscle-protein degradation must increase, and this has been confirmed clinically and experimentally. In contrast to what one would expect, whole-body protein synthesis also increases provided the organism was previously healthy and is well resuscitated (59). Experimentally, muscle-protein synthesis does not decrease; it may even modestly increase (33,91,93). Protein synthesis in liver was shown to increase (33,39,40,46,93–95). Although plasma concentrations of albumin are known to decrease, the fractional synthesis rate of albumin has also been demonstrated by several groups (96–98) to increase after trauma and in the intensive-care setting. The fractional synthesis rate of fibrinogen has been demonstrated (98,99) to increase. For some proteins, such as C-reactive proteins (CRPs) and globulins, no kinetic data are available yet. That their plasma concentrations, distribution spaces, and consequently, their pool sizes increase must imply that there is increased synthesis (38). Similarly the accumulation of white cells, macrophages, granulation tissue, collagen, and bone matrix at fracture sites is proof of increased synthetic processes at the site of injury and in the immune system. Summarizing the available kinetic data and the changes in concentration and pool size for different proteins within the organism, it appears that the organism's natural adaptive response to trauma and acute illness consists of an increase in protein turnover at the whole-body level. Increased protein turnover in muscle with increased protein synthesis but even higher protein degradation provides amino acids to the systemic circulation that are taken up by central organs. These considerations imply that one of the metabolic goals of therapeutic intervention should be to support increased protein turnover.
Another goal of therapy is to exogenously furnish the specific nonessential amino acids that the previously healthy organism produces in excess after trauma and acute illness. This may especially apply to patients who are unable to produce these substances themselves even when given adequate nutrition of conventional composition. It is likely that this is even more true in severely and chronically septic patients or in patients who have become depleted and lack the machinery to produce these amino acids. Proof of a deficient production of glutamine and alanine as nonessential amino acids that may become conditionally essential is lacking, however, because plasma flux of these amino acids seems to increase (100). Only decreased plasma and tissue concentrations have been reported (74,100), whereas fluxes in depleted states are not well established. In the "unphysiological" pathophysiology of severe sepsis and multiple organ failure, the primarily adaptive responses of the organism to increase transcapillary escape of fluid, white cells, and protein into the extravascular compartments and to increase membrane permeability may be so severe that cellular metabolism is compromised by intracellular dehydration, which precludes adequate upregulation of protein turnover (101).
A final goal of therapy is to preserve and, in the depleted state, to enhance the differential changes in protein kinetics as observed in the previously healthy organism subject to trauma or acute disease. Endeavors to inhibit net muscle catabolism in patients with burns by the use of growth hormone have been successful (30,31,102–107). Nevertheless, application of growth hormone in intensive-care patients greatly increased morbidity and mortality (27). It is possible that successful inhibition of muscle catabolism was paralleled by inhibition of the anabolic response in central tissues such as liver, immune system, and the site of injury (41,42). It appears, therefore, that our first priority is to preserve central anabolic responses and inhibit muscle catabolism only when this does not interfere with the central response.
Assessment. It may be considered a result of evolutionary survival that growth stops when organisms are stressed, traumatized, or in an inflammatory state (16–18,34,35,108). All substrate is directed to the healing response and not to growth or maintenance of muscle mass. One of the reasons that the present younger generations in western Europe have become taller than their parents may be the absence of childhood diseases and epidemics (specifically, diarrhea) (16). Growth and maintenance of muscle mass is therefore not a valid endpoint of amino acid adequacy. Although difficult to measure, an adequate response to trauma consists of an increase and subsequent subsiding of the inflammatory response. Initially, an adequate inflammatory response is necessary to overcome an infection or to deal with traumatized tissues. When this response is adequate, the inflammation gradually subsides. This makes it difficult to judge the merits of nutritional interventions. Some authors (109) base their claim of benefit on the observation of more-pronounced release of interleukin (IL)-6, whereas others (110) claim benefit on the basis of a lesser rise of CRP. These claims are contradictory but may result because measurements were taken during different phases. The behaviors of metabolic mediators and inflammatory parameters should therefore be judged with diligence and caution.
Although the first response to trauma or disease is obligatorily catabolic despite nutritional support, nutrition may limit nitrogen losses (111). The rare data that exist indicate that increasing the protein content of the food administered to 1.5 g of protein·kg–1·24 h–1 limits nitrogen losses (112). A fair amount of data (113–116) also suggests that glutamine enrichment limits nitrogen loss and improves outcome for intensive-care and surgical patients. Not all data are unequivocal, however. Similarly, dietary arginine enrichment was suggested (117) to be beneficial for surgical patients but not for critically ill patients. However, in most studies, arginine was part of a multimodality treatment, which precludes our generating conclusions regarding the individual role of arginine. Primary endpoints consist of septic morbidity and mortality, which are, however, influenced by several factors. Clinically, it is clear that healthy granulation tissue, solid epithelialization of granulating defects, high fever [in contrast to the prognostic unfavorable hyporesponsiveness of hypothermia (118)], growth of hair, loss of tissue edema, and regaining of muscle tonicity are all convincing signs of benefit.
At this point, it must be mentioned that severely ill patients have variable symptomatology. To study the effects of individual amino acid supplementation and define amino acid adequacy, large homogenous populations are required, and these are very difficult to collect.
Application of these concepts. The concepts outlined above may have important bearing on the use of bolus feeding during pathophysiological states. During critical illness, digestion and absorption are compromised, and enteral bolus feeding leads to intestinal paralysis and diarrhea in the majority of these patients (119–121). First-pass protein extraction and the labile protein pool capacity in the gut are therefore likely compromised, which necessitates continuous feeding over 24 h. Similar reasoning may apply when the bowel is short, stagnant, or diseased, or in situations in which gradual release of the bolus from the stomach into the small bowel is impossible, for instance, after gastrectomy or gastric bypass.
In parenteral nutrition, bolus feeding leads to severe metabolic instability. Also, if the healthy body is organized to guarantee a gradual release of amino acids into the systemic circulation (7), it is illogical to do otherwise when the organism is nourished directly into this systemic circulation.
On the basis of the studies previously mentioned, increasing the protein content of the feed to 1.5 g of protein·kg–1·24 h–1 is beneficial with regard to nitrogen balance and protein synthesis and degradation (112). There is some indirect scientific support for the increase in requirements, including the fact that during illness, organisms degrade more of the essential amino acids derived from protein degradation than during the healthy state, during which reutilization of amino acids for protein synthesis is more efficient (44). This specifically applies to muscle protein.
In this article, we approach the subject of amino acid adequacy from the viewpoint of metabolism rather than what has empirically been proven with supplementation of parenteral or enteral diets in ill patients.
The increased flux and rate of appearance of glutamine from peripheral to central tissues after trauma is such that supplementing the nutritional regimen with as much as 20 or even 40 g/d can still be considered in the physiological range. This may also apply to alanine, although no specific beneficial effects have been attributed to this amino acid.
Endogenous new formation of arginine is not substantial, and as yet there is no convincing evidence that it may be lacking. Although cysteine flux in the stressed state has only been studied in children (122), its increased rate of appearance in these patients and the beneficial effects of cysteine supplementation in other patients signify the importance of this amino acid. A potential lack of methionine (a precursor of cysteine) and threonine is suggested to exist in patients with AIDS on the basis of a pharmacokinetic approach (83,123). A similar approach in critically ill patients or in surgical patients identified cysteine, tyrosine, glutamine, arginine, glutamic acid, aspartic acid, as well as serine, proline, and glycine as amino acids that should be furnished in excess of their presence in dietary protein (84). Apart from glutamine, the kinetics of these amino acids have not been studied sufficiently to support these claims.
Amino acid toxicity during disease
The administration to patients of amino acids in excess of requirements carries the risk of inducing amino acid toxicity. In the 1950s, it was reported by Sherlock and colleagues (124,125) that patients with liver disease developed encephalopathy after receiving methionine.
Glutamine has been administered to patients in quantities (20–40 g/24 h) that are four- to eightfold higher than the amount present in a normal diet. These quantities are, however, less than half of the glutamine turnover for healthy and diseased human organisms. In addition, glutamine concentrations in tissues and plasma are known to vary widely without apparent toxic side effects. There are only a few reports regarding the potential toxicity of these increased amounts of glutamine. Liver-enzyme abnormalities were reported for patients who received parenteral nutrition at home; these values normalized when glutamine supplementation was discontinued (126,127). In addition, anecdotal reports mention precipitation of hepatic encephalopathy (128). In view of the large number of studies and the free administration of glutamine-enriched enteral and parenteral nutrition to different patient groups, the paucity of reports suggests that glutamine toxicity is rare if present at all.
In both health and disease, new formation of arginine is modest compared to glutamine, and its relevance is uncertain. The fate of arginine released into the portal vein, derived from either food or new formation in the gut wall, is not well established. It is possible that most if not all of this arginine is immediately degraded in the liver by arginase, which would result in little escaping into the systemic circulation (75). It was suggested that low citrulline production in the gut of patients with short-bowel syndrome (66,71,129) presents little citrulline to the kidney and leads to low levels of renal arginine production (68). Reports (69) indicate that this may lead to nephrosclerosis, which responds favorably to arginine supplementation. Few reports exist in which supplementation exclusively with arginine was studied. A number of studies were executed in which arginine supplementation was part of a multimodality intervention that also included (n-3) fatty acids and RNA. In the most recent meta-analyses, it was concluded that septic morbidity and mortality increase in critically ill intensive-care patients who received this multimodality treatment, and arginine most likely was the causative agent (117). Although the conclusions of this meta-analysis may be debated (130), there does not appear to be a clear-cut beneficial effect of arginine supplementation to critically ill patients.
In renal and hepatic failure, limitation of protein ingestion is generally dissuaded (131). In the past, protein restriction was suggested for patients with renal failure to limit urea production. At present, the unanimous recommendation for these patients is to ingest normal amounts of protein (132–134), and if necessary, to dialyze more frequently, as protein restriction may contribute to malnutrition. In the past, patients with liver disease were instructed to limit their protein intake because increased protein ingestion was believed to induce hepatic encephalopathy. This approach aggravated the nutritional depletion that is typically present in patients with bad liver function (133). Patients with liver disease should therefore consume diets containing normal amounts of protein, and only a small group of patients with end-stage liver disease cannot tolerate normal diets. Ingestion of liberal amounts of dietary protein is shown (135) to induce urea-cycle enzymes and allow adequate protein metabolism. One clear situation in which amino acid toxicity occurs is hemorrhage from esophageal varices, which was shown (136) to precipitate encephalopathy in patients with liver disease. It was demonstrated (137) that this is because hemoglobin lacks the essential amino acid isoleucine, which makes hemoglobin a protein with a low biological value that therefore cannot be used for protein synthesis and must be degraded and metabolized to carbon chains and urea. It is likely that intestinal hemorrhage is the only known disease state in clinical practice in which BCAA antagonism is present. The lack of protein synthesis leads to extremely elevated plasma amino acid levels including leucine and valine with the exception of isoleucine. The high levels of valine and especially leucine induce the common BCAA dehydrogenase, which leads to degradation of all BCAAs including isoleucine; this aggravates the amino acid imbalance even further.
Conclusion
Amino acid adequacy during disease is far from settled. There are several reasons for this including a lack of complete understanding of which components of the stress response should be supported and which should be inhibited. It appears that during disease, active metabolism and increased protein synthesis in central organs such as liver and in the immune system and wounds is a first priority. The substrate mix utilized for this process is crucially different from that used in the nondiseased state of starvation in healthy individuals. It is clear that glutamine and alanine are produced in excess during stressed conditions, and it appears logical to supplement these amino acids during chronic disease states or in situations where the organism cannot produce them due to depletion.
Convincing evidence is lacking that other nonessential amino acids such as arginine and cysteine are produced and utilized in excess. Similarly, there is no solid evidence that during severe illness, production rates are insufficient to raise an adequate host response. The effects of N-acetylcysteine have generated favorable responses in many clinical conditions. It may therefore be possible that cysteine supplementation in some form, e.g., as methionine, is advantageous. This is unclear for arginine in severely ill patients.
An additional problem consists of the variability of patient populations and the difficulty in quantitatively measuring endpoints such as wound healing or immune response.
Empirical and theoretical evidence exists that bolus feeding is ineffective during severe illness. Continuous or frequent but small meals are advisable during almost every severe disease state and for patients with compromised gut function, stomach capacity, or liver function.
Amino acid toxicity during disease may occur under exceptional conditions such as end-stage liver disease, whereby liberal amounts of protein and especially intestinal bleeding may lead to toxicity. It is possible that the pharmacological effects of arginine may be deleterious in critically ill intensive-care patients.
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FOOTNOTES |
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2 The work of C.H.C. Dejong is supported by Nederlandse organisatie voor Wetenschappelijk Onderzoek (Dutch Organization for Scientific Research).
4 Abbreviations used: BCAA, branched-chain amino acid; CRP, C-reactive protein; IL, interleukin.
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