Glutamine in total parenteral nutrition

Glutamine in total parenteral nutrition

Susan Grable Shipley

PHYSIOLOGICAL ROLES OF GLUTAMINE

Glutamine is the most abundant amino acid in the bloodstream. Because of its high circulating concentration of 0.5 to 0.8 mm, glutamine is delivered, via the bloodstream, to the various tissues in the body at higher rates than other amino acids. In addition, it has two nitrogen side chains, which explains why it is the most important nitrogen shuttle, accounting for 30 to 35% of all amino acid nitrogen transported in the blood. Glutamine transports ammonia in a nontoxic form from skeletal muscle to the kidneys and the liver. It is estimated that as much as 50% of the nitrogen excreted in the urine, as ammonium or urea, is derived from glutamine Fig. 1).

Glutamine plays a key role in a number of metabolic pathways. It serves as a precursor for the biosynthesis of a number of important compounds such as nucleotides, amino sugars, proteins, and some other amino acids (eg citrulline and alanine). In addition, glutamine is the most important substrate for renal ammonia production, a regulator of hepatic glycogen metabolism and muscle protein turnover, and a principal fuel for many metabolically active cells, including lymphocytes. Under normal physiologic conditions, sufficient glutamine is synthesized in the body to meet physiologic requirements. However, an increase in glutamine requirement could exceed the level normally produced in the body when severe infection or trauma alters metabolism. During these physiologic alterations associated with severe illness or injury, glutamine utilization is increased, and it plays an important role in the metabolic processes related to recovery. Thus, several studies have shown that, after surgery, trauma, and sepsis, glutamine depletion occurs in plasma and skeletal muscle.

It is known that T cells are critically dependent on glutamine for optimal growth and function.[1] As a result, glutamine deficiency has been implicated as a possible cause of the T-cell, suppression seen in injured patients. It has been speculated that a reason why intracellular free glutamine in skeletal muscle becomes depleted under stressful conditions is to provide glutamine for the cells of the immune system.[2] In addition to its position in lymphocyte function, glutamine also plays a key role in macrophage metabolism.[3] Some evidence has suggested that, in times of stress, glutamine also may support the production of the cytokines (mediators of the catabolic response) by macrophages.[4] Glutamine is required for the production of interleukin 1 (IL-1) by cultured macrophages, and probably other proinflammatory cytokines, such as IL-6 or tumor necrosis factor (TNF).[5] Glutamine also improves gut barrier function, which may indirectly reduce the production of proinflammatory cytokines (IL-6 and TNF), by the peripheral blood monocytes or related cells of the reticuloendothelial system.[2]

The majority of glutamine absorption occurs in the small intestine under postabsorptive conditions, extracting approximately 20 to 30% of circulating glutamine. The major glutamine-utilizing cell type in the small intestine is the enterocyte. Uptake of glutamine by the enterocytes occurs from the blood stream by capillaries adjacent to the basement membrane and from the gut lumen across the brush border. The avid uptake of glutamine by the mucosal cells is due in part to the high activity of glutaminase, the first enzyme in a series of reactions that produces energy by oxidizing glutamine. Gut glutamine requirements increase during critical illness. An important function of glutamine metabolism in the small intestine is the production of citrulline, the precursor in the renal synthesis of arginine.

TOTAL PARENTERAL NUTRITION

The development of total parenteral nutrition (TPN) was intended to reduce the risk of malnutrition in hospitalized patients. The traditional TPN solution was free of glutamine because of its chemical instabilities under the high temperature and high pressure of sterilization conditions. This problem has been solved by using glutamine dipeptides such as L-alanyl-1-glutamine and glycyl-1-glutamine. TPN has radically changed the approach to the patient with dysfunctional gastrointestinal (GI) tract. The, use of TPN has prevented malnutrition associated with prolonged recuperation from surgery, injury, and infection. However, the therapeutic efficiency of TPN has usually been measured by improvements in body composition and weight gain. Several studies have failed to demonstrate significant benefits of TPN on outcome from specific disease states. Alverdy et al.[7] hypothesize that, although TPN may be nutritionally beneficial in terms of body composition, it may be immunologically counterproductive during the host response to infection.

The effects of TPN on the GI tract have been thoroughly investigated by Johnson et al.[8] They found that prolonged TPN use led to several problems such as mucosal hypoplasia, reduction in intestinal hormone production, fatty liver infiltration, and decreases in brush border enzyme activity. In addition, increased permeability of the gut has been implicated as a critical component in the multiple-systems organ failure that often follows sepsis.[9] Thus, it is possible that any factor that can cause weakening of the gut membrane barrier can have serious consequences to the patient. TPN has been shown to give rise to gut atrophy. Sepsis patients are often fed by TPN. The combination of systemic sepsis of nongut origin and Tpn-mediated atrophy of the GI mucosa might lead to greater damage to the gut wall than TPN alone.[9]

In addition, TPN has been shown to cause hepatic steatosis in rats, as a result of enhanced hepatic synthesis of fatty acid and impaired triglyceride release.[10] Shujung and associates[10] have demonstrated that this enhanced hepatic synthesis of fat and impaired triglyceride release is related to an elevation of the portal venous insulin/glucagon molar ratio. By inhibition of hepatic fat accumulation and stimulation of hepatic lipid export, the addition of glucagon to TPN in concentrations that correct the ratio to control levels has been reported to prevent and reverse hepatic steatosis.[10]

ADVANTAGES OF GLUTAMINE IN TPN

Under certain circumstances, glutamine may be required in the diet, even though the body has glutamine-synthesizing enzymes in numerous tissues. During such conditions, there appears to be an inability to keep up with the accelerated rate of glutamine consumption. This has led to a number of studies that have examined the impact of glutamine-supplemented diets. Hammarqvist et al.[11] randomized patients after cholecystectomy to TPN with and without glutamine (20 g/day). The group receiving TPN with glutamine had less pronounced postoperative fall in skeletal muscle intracellular glutamine. At the same time, the total muscle ribosome concentration did not fall in the glutamine-fed patients, whereas it fell by 27% in controls. Furthermore, during the study period, the cumulative nitrogen loss was significantly less in the glutamine group compared with that in the control group. However, in a study performed by O’Riordain et al.,[2] a group of postoperative patients, who had undergone colonic resection, received glutamine-supplemented TPN and showed no improvement in nitrogen balance. They speculated that the patients in the study were only mildly catabolic, and glutamine may be unable to further improve nitrogen reserves in patients already in neutral nitrogen balance.

Most studies evaluating the nutritional impact of glutamine have focused on the gut. In a study performed by Van der Hulst et al.,[12] after 2 weeks of parenteral nutrition the addition of glutamine to TPN solution helped to maintain intestinal integrity, which was impaired in the standard parenteral nutrition group. In addition, villus height was unaltered in the glutamine TPN group, but it decreased in the standard TPN group. These results indicate that the addition of glutamine to parenteral nutrition prevents deterioration of gut permeability and preserves mucosal structure.

Alverdy et al.[7] made an important observation that glutamine-supplemented TPN, compared with standard formulas, reduces bacterial translocation from the gut in rats. This decrease in translocation was associated with a normalization of secretory immunoglobulin A (S-Ig A) levels, a decrease in bacterial adherence to enterocytes, and maintenance of both B- and T-cell populations in the lamina propria of the terminal ileum.[7] These results suggest that glutamine-supplemented TPN may improve gut immune function. Austgen et al.[13] found a significant increase in gut mucosal glutathione levels in the animals receiving the glutamine-enriched solutions. Glutathione (GSH) is a tripeptide consisting of glycine, glutamate, and cysteine. Clinically, this is significant, because it has been demonstrated that glutathione is required for intestinal function and is protective against oxidant stresses.

Another benefit of the use of glutamine-enriched TPN is maintenance of hepatic glutamine levels and increased survival in rats exposed to a chemotherapeutic drug called 5-fluorouracil (5-FU).[13] Similar benefits were shown by Jacobs and associates 14 who corroborated that accelerated healing of the gut mucosa in rats receiving 5-FU was due to a glutamine-enriched intravenous diet. O’Dwyer[15] also reported that, after 5-FU treatment, rats maintained on glutamine-enriched TPN demonstrated greater mean jejunal villus height and an increase in mucosal DNA content. There was a more marked effect on mucosal cellularity and a significantly lower mortality when glutamine-supplemented TPN was given before the administration of 5-FU than in animals maintained on standard TPN without glutamine. Similarly, Yoshida et al.[9] reported that addition of glutamine to the TPN solution decreased the endotoxin-induced damage to the jejunum and ileum. They also found an increase in protein synthesis and a decrease in tissue damage in glutamine-supplemented rats. Because 25% of the mucosal cells are immune cells, which have a critical need for glutamine, it becomes apparent why these cells benefit from supplemental glutamine.[16]

In addition, Ziegler et al.[17] have shown a reduction in the susceptibility to infection in critically ill patients undergoing bone marrow transplantation who received glutamine-supplemented TPN. These studies have suggested that glutamine supplementation may reduce the incidence of clinical infection by enhancing immune function. Furthermore, in cancer patients, maintaining nutritional status allows more aggressive treatments such as chemotherapy, radiotherapy, and surgical interventions. However, in patients with advanced cancer, conventional nutritional support usually fails to improve their nutritional status. Several observations suggest that glutamine supplementation might facilitate the nutritional management of the malnourished or fasting cancer patient. Kaibara et al.[6] found the addition of supplemental glutamine to a glutamine-free standard TPN solution significantly improved protein synthesis of muscle, colon, and jejunum and reduced whole body protein breakdown in tumor-bearing rats compared with those given standard TPN. However, the effects of nutritional supplementation on the malignancy itself are poorly understood. Austgen and associates’3 found that glutamine-enriched TPN does not affect tumor weight, tumor DNA content, or tumor glutaminase activity. However, increased cell proliferation has been observed in vitro after glutamine supplementation in hematopoietic, gastric, pancreatic, and breast cancer lines.[18]

Thus, glutamine-enriched TPN may be beneficial to host tissues by repleting muscle intracellular glutamine concentration, by supporting gut glutathione levels, and by maintaining muscle glutamine efflux. However, caution must be taken during nutritional management of cancer patients because of the inconsistencies between observations of glutamine supplementation and tumor growth.

WHO SHOULD RECEIVE SUPPLEMENTAL GLUTAMINE IN TPN?

There is adequate glutamine in the body during states of health, but when glutamine depletion is severe and when cells that have a substantial glutamine requirement under normal circumstances are damaged, additional glutamine appears to be beneficial. The intravenous administration of glutamine has been shown to be safe and well tolerated, and appears to better preserve gut function and integrity. In addition, hepatic steatosis is eliminated in rats when glutamine is added to the TPN solution.[10] Glutamine-enriched TPN prevented the reduction of muscle protein synthesis and reduced whole body protein breakdown, suggesting that nutritional support with glutamine may be beneficial to preserve host nitrogen.[6] In addition, it was suggested that glutamine supplementation may be a method of enhancing T-cell response in patients who are immunosuppressed before major surgery and who are at increased risk of postoperative sepsis.[2] It appears that glutamine supplementation in TPN is generally beneficial for patients under catabolic conditions. Further studies are required to determine which individuals are the best candidates for such therapy.

ACKNOWLEDGMENT

The assistance of Dr. Guoyao Wu and Dr. J. Martyn Gunn in the preparation of this manuscript is gratefully acknowledged.

REFERENCES

[1.] Ardawi M. Glutamine and glucose metabolism in human peripheral lymphocytes. Metabolism 1988;37:99-103.

[2.] O’Riordain M, Fearon K, Ross J, Rogers P, Falconer J, Bartolo D, Garden O, Carter D. Glutamine-supplemented total parenteral nutrition enhances T-lymphocyte response in surgical patients undergoing colorectal resection. Ann Surg 1994;220:212-21.

[3.] Newsholme P, Newsholme E. Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture. Biochem J 1989;261: 211-18.

[4.] Souba W, Klimberg V, Plumley D, Salloum R, Flynn T, Bland K, Copeland E. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990,48:383-91.

[5.] Wallace C, Keast D. Glutamine and macrophage function. Metabolism 1992;41:1016-20.

[6.] Kaibara A, Yoshida S, Yamasaki K, Ishibashi N, Kakegawa T. Effect of glutamine and chemotherapy on protein metabolism in tumor-bearing rats. J Surg Res 1994;57:143-9.

[7.] Alverdy J, Aoys E, Weiss-Carrington P, Burke D. The effect of glutamine-enriched TPN on gut immune cellularity. J Surg Res 1992;52: 34-8.

[8.] Johnson L, Copeland E, Dudrick S, Lichtenberger L, Castro G. Structural and hormonal alterations in the gastrointestinal tract of parenterally fed rats. Gastroenterology 1975;68:117.

[9.] Yoshida S, Leskiw M, Schluter M, Bush K, Nagele R, Lanza-Jacoby S, Stein T. Effect of total parenteral nutrition, systemic sepsis, and glutamine on gut mucosa in rats. Am J Physiol 1992;263:E368-E373.

[10.] Shujun L, Nussbaum M, McFadden D, Zhang F, LaFrance R, Dayal R, Fischer J. Addition of L-glutamine to total parenteral nutrition and its effects on portal insulin and glucagon and the development of hepatic steatosis in rats. Surg Res 1990;48:421-6.

[11.] Hammarqvist F, Wernerman J, Ali R, Von der Decken A, Vinnars E. Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis and improves nitrogen balance. Ann Surg 1989;209:455-61.

[12.] Van der Hulst R, Van Kreel B, Von Meyenfeldt M, Brummer R, Arends J, Deutz N, Soeters P. Glutamine and the preservation of gut integrity. Lancet 1993;334:1363-5.

[13.] Austgen T, Dudrick P, Sitren H, Bland K, Copeland E, Souba W. The effects of glutamine-enriched total parenteral nutrition on tumor growth and host tissues. Ann Surg 1992; 215:107-13.

[14.] Jacobs D, Evans D, O’Dwyer S, Smith R, Wilmore D. Disparate effects of 5-fluorouracil on the ileum and colon of enterally fed rats with protection by dietary glutamine. Surg Forum 1987;38:45-7.

[15.] O’Dwyer S, Scott T, Smith J, Wilmore D. 5-fluorouracil toxicity on small intestinal mucosa but not white blood cells is decreased by glutamine (abstract). Clin Res 1987;35:369a.

[16.] Ardawi M, Newsholme E, Glutamine, the immune system, and the intestine (editorial). f Lab Clin Med 1990;115:654-5.

[17.] Ziegler T, Young L, Benfell K, Scheltinga M, Hortos K, Bye R, Morrow F, Jacobs D, Smith R, Antin J, Wilmore D. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. Ann Intern Med 1992;116:821-8.

[18.] Ollenschlager G, Simmel A, Roth E. Availability of glutamine from peptides and acetylglutamine for human tumor-cell lines. Metabolism 1989;38(Suppl 1):40-2.

FOR REVIEW

[1.] Souba W. The use of glutamine enriched nutrition. In: Glutamine Physiology, Biochemistry and Nutrition in Critical Hiness. Florida: CRC Press, 1992:93-105.

RELATED ARTICLE: CALL FOR NOMINATIONS

The International Life Sciences Institute of North America (ILSI N.A.) is soliciting nominations of persons to be considered as recipients of the 1997/98 Future Leader Awards. The deadline for receipt of nominations is June 1, and selected nominees must submit applications by September 1. For nomination information, contact: Lili C. Merritt, ILSI North America, 1126 Sixteenth Street, NW, Washington, DC 20036. Phone: 202-659-0074; fax: 202-659-3859; E-mail: meeting@dc.ilsi.org.

Susan Grable Shipley is a graduate of Texas A&M University with a B.S. in scientific nutrition and is currently enrolled in Texas A&M University’s combined dietetic internship program while pursuing an M.S. in nutrition. Ms. Shipley is investigating the metabolism of colon cells under the supervision of Dr. J. Martyn Gunn. Correspondence can be directed to her at 508 Burlwood Road, Round Rock, TX 78664.

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