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Supplement

Assessment of the Safety of Glutamine and Other Amino Acids¹

State University of New York at Stony Brook, Stony Brook, NY 11794-8191

	ABSTRACT

TOP ABSTRACT INTRODUCTION Published studies of glutamine... Evaluating the intake of... High protein intake Effects of high intakes... Conclusions and suggestions for... LITERATURE CITED

 
Glutamine is used to supplement intravenous and enteral feeding. Although there have been many human studies of its efficacy, there have been very few studies with safety as a primary goal. This article analyzes the literature on the safety of glutamine and also examines the available information on high intakes of total protein and other amino acids, so that additional indicators of potentially adverse effects can be suggested. Four studies that specifically addressed glutamine safety were identified, from which it was concluded that glutamine is safe in adults and in preterm infants. However, the published studies of safety have not fully taken account of chronic consumption by healthy subjects of all age groups. To help identify potential undetected hazards of glutamine intake, the literature on adverse effects of high dietary intake of protein and other amino acids was examined. High protein is reputed to cause nausea, vomiting and ultimately death in adults, and has been shown to result in neurological damage in preterm infants. Individual amino acids cause a variety of adverse effects, some of them potentially fatal, but neurological effects were the most frequently observed. Because glutamine is metabolized to glutamate and ammonia, both of which have neurological effects, psychological and behavioral testing may be especially important.

KEY WORDS: • protein intake • glutamine toxicity

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Published studies of glutamine... Evaluating the intake of... High protein intake Effects of high intakes... Conclusions and suggestions for... LITERATURE CITED

 
During the last decade, there has been increasing research interest in the amino acid, glutamine, particularly in regard to its potential clinical use in intravenous and enteral feeding. To date there have been hundreds of human studies of the efficacy of glutamine, with few if any reported adverse effects. A review by Sacks (1999) concluded that glutamine is safe, with the possible exception of specific patient groups such as those with liver or kidney disease and preterm neonates. However, there have been very few studies with safety as a primary goal. Moreover, in those studies that have investigated safety, the treatments were of relatively short duration; thus, information on the possible adverse effects of glutamine over periods longer than 1 mo is lacking. This may be important because it is becoming increasingly likely that in various groups of the population, enhanced glutamine intake [e.g., in total parenteral nutrition (TPN)² ] might occur for extended periods of time. Of potential importance is the burgeoning use of dietary supplements in the general population, without any medical supervision.

This article analyzes the available literature on the safety of glutamine to determine whether the currently used indicators of adverse effects are adequate for chronic consumption by the general population, as well as by medically supervised patients. The available information on high intakes of total protein and other amino acids will be examined so that additional indicators of potentially adverse effects can be suggested.

	Published studies of glutamine safety

TOP ABSTRACT INTRODUCTION Published studies of glutamine... Evaluating the intake of... High protein intake Effects of high intakes... Conclusions and suggestions for... LITERATURE CITED

 
A literature search revealed only four studies that specifically addressed glutamine safety. By far the most comprehensive is that of Ziegler et al. (1990) , who performed five separate experiments to examine safety under different circumstances, as follows: 1) six volunteers given oral glutamine at three different doses (0, 0.1, 0.3 g/kg), and monitored for 4 h; 2) nine volunteers, given intravenous infusions of glutamine at three doses [0, 0.0125, 0.025 g/(kg · h)] for 4 h; 3) seven volunteers given TPN plus glutamine at three doses [0, 0.285, 0.570 g/(kg · d)] over 5 d; 4) eight bone marrow transplant patients given glutamine at 3 doses (0, 0.285, 0.570 g/(kg · d)] over 30 ± 2 d; and 5) a pharmacokinetic analysis performed over 4 h in three volunteers. Measurements that were used to assess possible toxicity were as follows: blood glutamine, glutamate, other amino acids, glucose, insulin, glucagon and growth hormone; urinary creatinine, ammonia, urea and total nitrogen; standard clinical chemistry, complete blood counts, mental status, vital signs, temperature and clinical and subjective evidence of toxicity. However, these careful studies, including treatments between 4 h and 30 d, doses of glutamine up to 0.57 g/(kg · d) (40 g/d) and both healthy volunteers and sick patients, were not able to detect any sign of adverse effects.

A later study by Hornsby-Lewis et al. (1994) examined the effects of glutamine supplementation in Home TPN patients. Seven patients were monitored for 4 wk while receiving TPN plus glutamine at a dose of 0.285 g/(kg · d). To monitor safety, the following were measured: blood ammonia, bilirubin, urea nitrogen, creatinine, glucose, amino acids, complete cell count, serum glutamic oxaloacetic transaminase, glutamic pyruvate transaminase (GPT), alkaline phosphatase and lactic acid dehydrogenase. Of note was the withdrawal from the study of two patients who developed high concentrations of liver enzymes; these resolved, however, after discontinuing treatment. No other adverse effects were observed, but the authors noted their concern regarding the possibility of liver toxicity. The elevated liver enzymes might, however, have been a complication of intravenous nutrition, rather than of the glutamine per se, because no control group without supplementation was studied in parallel.

Jiang et al. (1999) studied the effect of the dipeptide, alanyl-glutamine, on clinical safety in a randomized, double-blind, controlled study of 120 postoperative patients. Patients (n = 60) were given normal TPN; the other 60 were given isonitrogenous TPN, including alanyl-glutamine [0.5 g/(kg · d)] for 6 d. They measured hemoglobin, white blood cell count (plus differential), platelets, blood glutamine, sodium, potassium, chloride, GPT, alkaline phosphatase, glucose, cholesterol, urea, creatinine, bilirubin, triglycerides, bicarbonate, urine volume, N balance and infection rate. The comparison between control and glutamine-treated patients revealed no indications of adverse effects.

All of the above studies were performed in adult subjects. Lacey et al. (1996) , however, investigated the effects of glutamine-supplemented parenteral nutrition [20% of amino acids, equivalent to 0.4 g/(kg · d) glutamine maximum] for 15 d in 44 preterm neonates, who might possibly be more sensitive to adverse effects than adults. Plasma glutamine level rose by 50%, but glutamate and ammonia remained within the normal range. On the basis of the measurements of plasma ammonia and glutamate and the absence of clinical signs of neurotoxicity, it was concluded that glutamine at this dose is safe in preterm infants.

To summarize, there have been very few indications of adverse effects in the studies described above that explicitly investigated safety. Moreover, despite the large number of published investigations in which glutamine has been administered to patients or healthy subjects, no adverse effects have been reported. However, the published studies of toxicity have not fully taken account of the following:

1) Both acute and chronic treatment must be investigated. As pointed out above, there is a possibility that glutamine supplements may be consumed by healthy people for extended periods of time, but there is no information on chronic consumption.

2) Most of the literature at present involves people who are ill and under medical supervision, but supplement usage by healthy subjects should be investigated further. Moreover, the possibility of specific susceptibilities has to be considered. For example, children with Crohn’s disease were given a polymeric diet containing 4 or 42% [0.1 or 1.0 g/(kg · d)] of amino acids as glutamine (Akobeng et al. 2000 ). Because of intolerance to the glutamine-supplemented diet, two patients were withdrawn. Furthermore, in the remainder, there was significantly less improvement in the Pediatric Crohn’s Disease Activity Index than in the control group. A similar observation was made in rats with experimental colitis induced by trinitrobenzenesulfonic acid. Glutamine supplementation at 12% of amino acids was without effect, but glutamine at 24% resulted in significantly more damage to the colon (Shinozaki et al. 1997 ).

3) The limited literature on safety does not include studies employing doses higher than 0.3 g/kg orally as a single dose, or 0.57 g/(kg · d) given intravenously over 30 d. There have been some brief reports in which larger doses than those in the studies described above (20–40 g/d) have been given. For example, 24 intensive care patients were randomized into four groups receiving 0, 0.28, 0.56 and 0.86 g/(kg · d) of glutamine intravenously for 3 d (Tjäder et al. 2000 ). In other studies, six children with cystic fibrosis were given oral glutamine [0.7 g/(kg · d)] for 4 wk (Hayes et al. 2000 ), and eight very-low-birth-weight infants were given enteral supplements of glutamine [0.6 g/(kg · d); Poulet-Young et al. 2000 ]. Although no information about safety was presented in these studies, no adverse effects were reported, suggesting that higher doses than those given in the more detailed descriptions of safety studies may be tolerated, but this requires further investigation.

4) Specific age groups. The very young or the elderly might have specific susceptibilities. Although the study in preterm infants described above (Lacey et al. 1996 ) showed no ill effects at a dose of 0.4 g/(kg · d)g/kg/d, this is lower than the doses used in a number of studies in adults. In another study, very-low-birth-weight infants were given enteral supplements of glutamine for 17 d [0.6 g/(kg · d); Poulet-Young et al. 2000 ] and no adverse affects were noted. This suggests that doses higher than 0.4 g/(kg · d) may be safe, but this brief report contained no safety evaluation. No information is available in the elderly; it is possible that with high doses they might not be able to process the increased nitrogen load through the liver and kidney.

Because there are still areas of uncertainty about the safety of glutamine, it is therefore appropriate that the investigation of potentially adverse effects should continue. The remainder of this article will therefore examine the approach that has been used to assess the toxicity of nutrients, and specifically the evidence of adverse effects of high intakes of protein and other amino acids, as a guide for future studies to fully assess the safety of glutamine.

	Evaluating the intake of a nutrient

TOP ABSTRACT INTRODUCTION Published studies of glutamine... Evaluating the intake of... High protein intake Effects of high intakes... Conclusions and suggestions for... LITERATURE CITED

 
The Food and Nutrition Board of the Institute of Medicine (USA) provides assessments of the intake of specific nutrients required to maintain health, which include a recommendation for the maximum amount to be consumed. Intake for healthy individuals in a particular life stage or group is evaluated in terms of four Dietary Reference Intakes (DRI) (Institute of Medicine 2000 ), which are used to define a range of intakes that is consistent with optimum health. At the lower end of the scale, the RDA (Recommended Dietary Allowance) and EAR (Estimated Average Requirement) define the intake below which deficiency is likely to occur, and at the high end of the scale, the UL (Tolerable Upper Level) defines the intake above which adverse or toxic effects are likely to occur. The last-mentioned DRI, the UL, is the one that is appropriate for assessing the safety of glutamine. The process for determining the UL involves risk assessment, which is undertaken in four steps as follows: 1) hazard identification, to reveal specific adverse effects, 2) dose response, to identify the UL, 3) the exposure, to characterize the population distribution of dietary intakes, and 4) risk characterization, to identify the proportion of the population at risk.

The risk assessment process must take account of the specific populations under consideration. For example, risk is likely to vary with age and with route of administration (i.e., oral vs. intravenous intake). It is also generally assumed that the risk occurs only at or above a certain threshold level, so that lower levels are associated with no risk. For the purposes of quantifying the risk, two further parameters are used, i.e., the Lowest Observed Adverse Effect Level (LOAEL) and the No Observed Adverse Effect Level (NOAEL). Ideally, both of these values are needed to set a UL with confidence, but often only one of these can be determined from the literature; thus, the derivation of the UL value must be approached with more caution.

Application of the DRI process to glutamine does not immediately give very useful insights. Because glutamine is not an indispensable amino acid, there is no clear EAR and RDA. Moreover, the evidence suggesting benefits of glutamine supplements was obtained at doses well above the normal dietary intake. In particular, there is an absence of data from which to identify a specific hazard or hazards. The studies to date have shown no effects of glutamine (NOAEL) for a range of clinical measurements, including the following: blood hemoglobin, white blood cell counts (including differential), platelets, plasma/serum Na, K, Cl, bicarbonate, NH₄⁺, GPT, glutamate oxaloacetate transaminase, alkaline phosphatase, lactate dehydrogenase, glucose, cholesterol, triglycerides, urea, creatinine, bilirubin, total protein, albumin, insulin, glucagon, growth hormone, glutamine, glutamate, amino acid profile, mental status, attention span, infection rate (blood cultures), temperature, blood pressure, pulse and respiration. Although none of these indices have suggested that glutamine has toxic effects, there remains the possibility that a real hazard has not been identified, and that the wrong measurements have been made. The question posed in this article, therefore, is whether we can use evidence derived from high dietary intakes of protein or of other amino acids, some of which are known to be toxic at high levels, to help select indicators of toxicity of glutamine.

	High protein intake

TOP ABSTRACT INTRODUCTION Published studies of glutamine... Evaluating the intake of... High protein intake Effects of high intakes... Conclusions and suggestions for... LITERATURE CITED

 
There is evidence from historical records that very high intakes of protein (>200 g/d), might be toxic, and that consumption of more than 40% of the dietary energy as protein results in nausea and diarrhea within 3 d and to death in a few weeks; this condition is known as "rabbit starvation" and refers to the very low fat content of rabbit meat (Speth and Spielmann 1983 ). However, it is possible to remain healthy while living on an exclusively meat diet, providing it contains enough fat to maintain a protein intake that is <40% of energy, and preferably in the range 15–25% (Lieb 1929 , McClellan and DuBois 1931 ). It has been suggested that the reason for this toxicity is the limited capacity of the liver to synthesize urea. It was shown by Rudman et al. (1973) that as the protein content of meals was increased, the rate of urea synthesis reached a maximum, so that with meals containing more than this maximum, the plasma amino acid and ammonia levels increased, and the duration of maximum urea synthesis was prolonged. The maximum rate corresponded to a protein intake of 230 g/d for a 70-kg person, or 40% of dietary energy. It seems unlikely that glutamine would be taken in sufficiently large amounts to exceed this limit for urea synthesis.

There is more direct evidence of protein toxicity in preterm neonates. Goldman et al. (1969) studied 304 preterm infants given diets containing either 3.0–3.6 or 6.0–7.2 g/(kg · d) of cow’s milk protein. The higher protein intake was associated with more fever, lethargy and poor feeding, as well as higher plasma protein levels and less edema than the lower protein group. A follow-up study of these children for physical and psychological testing was made after 3 and 6 y (Goldman et al. 1971 and 1974 ). The results showed that at both 3 and 6 y, there was an excess incidence of strabismus and low IQ scores in the children with lowest birth weight who had been fed the high protein diet.

High protein diets have also been suggested to be associated with a variety of other pathological conditions. It is well recognized that urinary calcium excretion increases in proportion to the protein content of the diet (Linkswiler et al. 1981 ). However, it has been suggested that there is little risk of bone loss because calcium intake is usually increased with higher protein diets, and bone loss does not occur if calcium intake is adequate (Heaney 1998 ). There is also the possibility that calcium oxalate stone formation in the kidney might be increased. Although there have been several studies that support this hypothesis, the only long-term prospective trial of chronic protein restriction (4.5 y) on stone formation in patients who were newly diagnosed with calcium stones did not confirm the hypothesis (Hiatt et al. 1996 ). In addition, high protein intakes have also been implicated in the progression of renal disease. However, although it is standard practice to lower the protein intake in patients diagnosed with renal disease to delay its progression, it is not now believed that the intake of protein has any influence on the incidence of renal disease in healthy people (Walser 1993 ).

	Effects of high intakes of individual amino acids: lessons to be learned regarding glutamine safety

TOP ABSTRACT INTRODUCTION Published studies of glutamine... Evaluating the intake of... High protein intake Effects of high intakes... Conclusions and suggestions for... LITERATURE CITED

 
Table 1 summarizes reported adverse effects and some metabolic products of individual amino acids given to animals or humans. From this list, a number of factors that are of relevance for determining the toxicity of glutamine become apparent.

For several amino acids, it is probable that adverse effects are direct consequences of the elevated concentration in blood or target tissue, e.g., glutamate (Takasaki et al. 1979 ) or phenylalanine (Batshaw et al. 1981 ). The measurements of plasma glutamine concentrations in the studies described above, showing little change from normal, therefore suggest a low chance of adverse effects.

Metabolic end products.

Products of metabolism are important because these might in themselves be toxic at increased levels (e.g., branched-chain keto acids from branched-chain amino acids). Alternatively, a large increase in the concentration of a product might provide an indication that the normal metabolism of that amino acid was overloaded. However, studies of high intakes of glutamine have shown that concentrations of ammonia and glutamate are not much increased (see above).

Competition/antagonism.

It is recognized that some amino acids given as supplements inhibit growth in animals, possibly by interfering with the metabolism of other amino acids by competing for transport or for common pathways of metabolism (Sauberlich 1961 ) e.g., lysine/arginine antagonism, because these amino acids share a transporter for cellular uptake. Measurement of the amino acid profile in plasma and/or tissues would enable competition for transport to be detected. Glutamine does not appear to alter the plasma amino acid profile to any extent, which is consistent with the biochemical data showing that glutamine has a specific transporter that is not shared with any other amino acid.

Effects on metabolism.

An amino acid supplement could cause alterations of metabolism of both related and unrelated systems. For example, arginine has been shown to cause hypotension, through its conversion to NO (Petros et al. 1991 ), which acts directly on blood vessels (closely related), whereas high tyrosine intake has been reported to cause eye and skin lesions (Goldsmith and Reed 1976 ), which are more distantly related. For glutamine, closely related systems that might be monitored are gluconeogenesis and blood glucose; increases in those systems could possibly lead to diabetes in the long term. In addition, the possibility of effects on more distantly related systems, e.g., cardiovascular disease (plasma cholesterol and triglycerides) and immune function, should not be ignored because they have been shown to be altered by high intakes of other amino acids.

Hormone secretion.

A variety of amino acids have well-described effects on the secretion of specific hormones, when given in large quantities (e.g., leucine and arginine stimulate secretion of insulin and growth hormone, respectively). The consequences of this might have short-term [e.g., leucine-induced hypoglycemia (Table 1) ], or long-term effects (e.g., the potential for activating cell division and thus promoting malignancy). However, glutamine administration has not been demonstrated to result in elevated secretion of any hormone.

Neurological effects.

Of the 15 amino acids represented in Table 1 , 9 are associated with neurological or neurotoxic effects, as is high protein intake. Glutamine degradation yields glutamate and ammonia, both of which are known to be neurotoxic, although glutamate has only been shown to be neurotoxic in animal studies (Airoldi et al. 1979 ). However, in those studies of glutamine safety in which neurological symptoms were assessed, no signs of adverse effects were detected (see above).

Electrolyte disturbances.

A large dose of a single amino acid can give rise to electrolyte disturbances, such as the hyponatremia resulting from glycine administration (Table 1) and the acidosis and hyperkalemia resulting from consumption of arginine hydrochloride (Table 1) . Moreover, an amino acid given in free form without food might be absorbed very quickly and have osmotic consequences. However, glutamine administration does not seem to result in any pronounced effects on electrolyte concentrations.

Effects due to impurities.

Although it is generally believed that the outbreak of eosinophilia-myalgia syndrome in subjects given tryptophan was caused by an impurity in the product of a single supplier, the evidence is not definitive (Young 1991 ). Although glutamine is stable as a dry solid, it is known to be unstable in solution, resulting in a toxic product (Fürst et al. 1997 ). However, such problems can be avoided by preparing solutions freshly from solid or by administering in the form of a dipeptide, in which form it is completely stable (Fürst et al. 1990 ).

Immunity.

Some amino acids, including glutamine, have been shown to stimulate aspects of the immune system, e.g., arginine and ornithine (Barbul 1986 ). However, the studies of glutamine safety described above, including only white blood cell counts (including differential), infection rate (blood cultures) and body temperature, have been of short duration. Much longer-term studies, including more specialized methods of assessment (e.g., delayed hypersensitivity, activation markers, response to vaccination) are required to show whether these effects persist with chronic consumption.

Clinical and physiologic signs.

Arginine has been shown to cause diarrhea in some subjects (Barbul 1986 ) and glutamate is believed by some to cause "Chinese Restaurant Syndrome" (Geha et al. 2000 ). There appear to be no similar effects associated with glutamine, and vital signs have been shown to be unaltered (see above).

	Conclusions and suggestions for future studies to confirm the safety of glutamine

TOP ABSTRACT INTRODUCTION Published studies of glutamine... Evaluating the intake of... High protein intake Effects of high intakes... Conclusions and suggestions for... LITERATURE CITED

 
From the above discussion, the following conclusions can be made:

1) A number of individual amino acids show characteristic patterns of toxicity when given in excess, whereas no adverse effects of glutamine have been demonstrated when given in doses of 50–60 g/d. However, this assessment, made in short-term studies in hospital patients, may not be appropriate for chronic supplementation in healthy subjects of all age groups.

2) The possibility of cancer has been dismissed previously because studies in animals have shown that glutamine supports the host metabolism in preference to the tumor (Klimburg and McClellan 1996 ). However, by analogy with arginine, for which supplements have been shown to either inhibit or stimulate the tumor growth, depending on the tumor type and immunogenicity (Levy et al. 1954 , Reynolds et al. 1988 ), continued research in this area is suggested.

3) A number of short-term studies have demonstrated beneficial effects of glutamine on the immune system, but it is not known whether there may be detrimental effects with chronic usage. There is a need for more specialized methods for assessing immune status to answer this question.

4) Modification of intermediary metabolism by glutamine could potentially lead to the development of metabolic diseases such as diabetes or coronary artery disease. These could be monitored by such measurements as plasma glucose or homocysteine, or by isotopic tracer studies of glucose or lipoprotein kinetics.

5) Neurological effects have been demonstrated for glutamate and ammonia, the two products of glutamine degradation, as well as for a number of other amino acids and total protein. Therefore, psychological and behavioral testing is especially important.

	FOOTNOTES

 
¹ Presented at the International Symposium on Glutamine, October 2–3, 2000, Sonesta Beach, Bermuda. The symposium was sponsored by Ajinomoto USA, Incorporated. The proceedings are published as a supplement to The Journal of Nutrition. Editors for the symposium publication were Douglas W. Wilmore, the Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School and John L. Rombeau, the Department of Surgery, the University of Pennsylvania School of Medicine.

² Abbreviations used: DRI, Dietary Reference Intakes; EAR, Estimated Average Requirement; GPT, glutamic pyruvate transaminase; LOAEL, Lowest Observed Adverse Effect Level; NOAEL, No Observed Adverse Effect Level, RDA, Recommended Dietary Allowance; TPN, total parenteral nutrition; UL, Tolerable Upper Level.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION Published studies of glutamine... Evaluating the intake of... High protein intake Effects of high intakes... Conclusions and suggestions for... LITERATURE CITED

 

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