Role of Glutamine in Health and Disease
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Transcript of Role of Glutamine in Health and Disease
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Vol. 22, No. 12 December 2000
Refereed Peer Review
FOCAL POINT
KEY FACTS
#Glutamine, a conditionally
essential amino acid, can become
depleted during critical illness,
thereby precipitating metabolic
and organ dysfunction.
Role of Glutamine inHealth and DiseaseColorado State University
Elisa Mazzaferro, DVM, MSTimothy Hackett, DVM, MS Wayne Wingfield, DVM, MSGreg Ogilvie, DVMMartin Fettman, DVM, PhD
ABSTRACT: Glutamine maintains tissue function. Intestinal mucosal integrity, immune cell ac-
tivation, renal buffering mechanisms, DNA and protein synthesis, and generation of metabolic
fuels are dependent on body glutamine stores. During states of illness (e.g., sepsis, trauma,
neoplasia), glutamine use can exceed the body’s synthetic capacity, thereby causing its deple-
tion. Glutamine depletion can have negative consequences, including protein catabolism, de-
pressed immune function, intestinal mucosal atrophy, and metabolic acidosis. Dysfunction of
the intestinal tract and immune system can lead to bacteremia, sepsis, and multiorgan failure.
Glutamine supplementation during critical illness may be associated with improved clinical
outcome.
Glutamine, the most abundant amino acid in plasma and the extracellularfluid compartment,1 constitutes the largest labile source of nitrogen inthe body.2 Traditionally classified as a nonessential amino acid, glutamine
serves a variety of functions in healthy individuals, including transporting nitro-gen and carbon between tissue2–4; regulating protein synthesis5,6; generating sub-strates for renal ammoniagenesis7; synthesizing nucleic acid; and providing fuelfor gastrointestinal (GI),8 renal tubular,9 immune,10 and vascular endothelialcells11 (Figure 1). Glutamine also plays a central role in carbohydrate metabolismas a gluconeogenetic precursor.5 Because of its involvement in various metabolicevents, glutamine is essential for optimal cell growth and function.
The classification of glutamine as a nonessential amino acid is misleading be-
cause numerous studies have demonstrated that it is indispensable during criticalillness. In disease states, glutamine becomes a conditionally essential aminoacid.12 In human medicine, there is an intense interest in glutamine metabolism.This paper describes glutamine synthesis and degradation, glutamine flux be-tween tissue, consequences of glutamine depletion during critical illness, and po-tential benefits of glutamine therapy in critically ill animals.
GLUTAMINE SYNTHESIS AND DEGRADATIONIn animals, glutamine is readily synthesized from glutamic acid and ammonia
CE
V
I In disease states, when glutamine
requirements often exceed
synthesis, glutamine becomes a
conditionally essential amino acid
that must be supplemented.
I Glutamine depletion occurs early
during critical illness.
I Glutamine depletion may
contribute to sepsis, multiorgan
failure, and even death in
critically ill humans.
I Feeding glutamine-enriched diets
to human cancer patients and
some animal models has been
shown to have significant positive
effects.
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in an ATP-dependent reaction catalyzed by glutaminesynthetase, an enzyme found in most tissue (e.g., mus-cle, liver, lung, brain, adipocytes, lymphocytes, heart,small intestine).13 In humans, skeletal muscle is themain site of glutamine synthesis and storage in thepostabsorptive state.2 Under normal conditions, intra-muscular glutamine synthesis and proteolysis balancethe release of glutamine into the circulation, where it istransported for use by other tissue.13
Glutamine is degraded by the enzyme glutaminase.Most organs have glutamine synthetase and glutami-nase activity and are, therefore, capable of synthesis anddegradation.2 In most cases, the activity of one of theenzymes predominates, thus making the organ a netproducer or net consumer of glutamine. In healthy hu-mans, intracellular glutamine synthesis exceeds glu-tamine use during states of health, resulting in a netproduction of glutamine.13 Organs that consume glu-tamine include the GI tract, pancreas, kidney, and im-mune cells.2 Depending on metabolic conditions, theliver can be a net producer or net consumer of glu-tamine. Under normal physiologic conditions duringstates of health, the balance of glutamine synthesis andbreakdown by the liver is almost equal.7
GLUTAMINE FLUXCirculating glutamine concentration is dependent onrelative rates of glutamine uptake, synthesis, and re-lease.3 During states of health, the plasma glutaminepool is maintained at a fairly constant level. In mam-mals, the plasma glutamine concentration normally ranges from 0.6 to 0.9 mmol/L.1 Intracellular glu-tamine concentration in humans (i.e., 20 mmol/L) isapproximately 30 times its serum concentration.14 Cat-
abolic states (e.g., metabolic acidosis, sepsis, starvation)elicit significant changes in interorgan glutamine flowand can cause the redistribution of glutamine betweentissue.15
NORMAL GLUTAMINE FUNCTIONSNitrogen Transport
Glutamine contains two amine groups that allow thetransportation of carbon and nitrogen through thebody. Glutamine reactions serve to scavenge and trans-port ammonia in a nontoxic form from peripheral tis-sue to the liver and kidneys, where gluconeogenesis andureagenesis occur, respectively.2,3,16,17 Glutamine alsoplays a role in renal acid–base balance by transportingnitrogen and acting as a buffer, thereby facilitating ex-cretion of acid equivalents (e.g., ammonium) in theurine.17
Gastrointestinal FunctionThe importance of glutamine as a competence factor
for enterocytes is unequivocal.18 Glutamine is the mainmetabolic substrate that exerts trophic effects on entero-
cytes, thereby supporting their normal function (Figure2). Enterocytes can extract as much as 25% of glu-tamine from circulation or obtain it via luminal absorp-tion.19 A small amount of glutamine synthesis can alsooccur within enterocytes. The overall synthetic capaci-ty, however, is small and often inadequate to meet themetabolic needs of enterocytes, particularly duringstates of illness or stress. The maintenance of intestinalmucosal integrity, therefore, is dependent primarily on
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Figure 1—Functions of glutamine during states of health.
Glutamine
Fuel forendothelial cells
Protein andnucleic acidsynthesis
Cell growthand division
Nitrogentransport
Renal and hepaticgluconeogenesis
Renalammoniagenesis
and buffering
Fuel for renaltubular cells
Fuel forenterocytes
Fuel forimmune cells
Figure 2—Glutamine, which is required for normal entero-cyte health and function, is used as a primary fuel for entero-cyte and immune cells and plays a role in glutathione and
mucin production.
Glutamine
Mucinproduction
Dilation ofsubmucosal
arteries
Enterocytesubstrate
Fuel forimmune cells
Mucus defenseagainstbacterial
translocation
Enhancedgastrointes-tinal blood
flow
Glutathionesynthesis
Free radicalscavenging
Upregulationof cytotoxic
T cells;enhanced
natural killercell activity;
inflammatorycytokine
production
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an adequate supply of glutamine fromother sources.20 Glutamine nitrogen isused for hexosamine synthesis, whichserves as a precursor for carbohydratemolecules used to form intracellulartight junctions needed for mucosal
barrier function.21
GI glutamine is alsoused for synthesis of a protective mu-cus gel, which provides the first line of defense against luminal pathogens.22
Immune FunctionGlutamine is an essential nutrient
for proper function of immune cellssuch as macrophages, lymphocytes,and neutrophils.23 It provides precur-sors for purine and pyrimidine synthe-sis during phagocytic cell activation,antigen-presenting cell stimulation and
differentiation, lymphocyte blastogene-sis, expression of cell-surface markers,and antibody production.23 Glutaminealso upregulates activation of cytotoxicT cells, which play a central role in de-fense against bacterial infection.24,25
Furthermore, glutamine is required forsynthesis of the inflammatory cy-tokines interleukin-1β, interleukin-2,interleukin-6, interferon-γ , and tumornecrosis factor-α (TNF-α).14,26
ALTERATIONS IN GLUTAMINEMETABOLISMCritical Illness
In critical illness, glutamine metabolism is altered intissue. Profound changes in amino acid distribution oc-cur as plasma and intracellular glutamine concentra-tions fall.2 The release of glucocorticoids and inflamma-tory cytokines (e.g., interleukin-1β, TNF-α) results in aunidirectional flux of glutamine from muscle and lungin excess of glutamine production.27,28 The release of glucocounterregulatory hormones (e.g., epinephrine,glucagon) during stress and disease stimulates glu-tamine uptake and use by the GI mucosa.29 The accel-
erated export of glutamine in excess of its synthesis de-pletes muscle glutamine concentrations by 30% ormore, causing protein catabolism and muscle wasting.Ultimately, body glutamine stores can become deplet-ed.14,30 This occurrence has been documented in hu-mans with trauma, sepsis, and necrotizing pancreati-tis.31 When glutamine synthesis does not meet diseaserequirements, it becomes a conditionally essential aminoacid that must be supplemented14 (Figure 3).
SepsisGut-specific nutrients (e.g., glutamine) are important
for normal GI homeostasis and immune function. 32
Glutamine depletion, therefore, can lead to dysfunc-tion. Healthy dogs given parenteral glutaminase to de-plete circulating glutamine developed emesis, diarrhea,intestinal villous atrophy, mucosal ulceration, andnecrosis.33 In vitro, glutamine-starved intestinal cellsupregulate protein synthesis, inducing apoptosis or pro-grammed cell death.34
Deterioration of the gut mucosal barrier and in-creased intestinal permeability have been reported in
various critically ill humans with endotoxemia, multi-ple trauma, and major burns.31 In states of health, theintestinal epithelium normally restricts the passage of bacteria and toxic macromolecules.35 Glutamine deple-tion can result in increased intestinal mucosal perme-ability, allowing migration of intestinal bacteria into thebloodstream. The circulating bacteria can then stimu-late mesenteric mononuclear cell activation. Known asthe second hit theory, this event may play a role in the
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Figure 3—In states of critical illness and neoplasia, glutamine requirements often ex-ceed synthesis; therefore, glutamine becomes a conditionally essential amino acid.Circulating glutamine pools must be maintained to support normal intestinal andimmune function, renal ammoniagenesis and buffer mechanisms, and whole-body protein synthesis. (Modified from Souba WW: Glutamine: Physiology, Biochemistry and Nutrition in Critical Illness . Georgetown, TX, RG Landes, 1992, p 84; withpermission.)
Sepsis,trauma
Inflammation
Endotoxemia
KidneysCombat acidosisby excretion of
ammonium
LiverGluconeogenesis,
ureagenesis
GutSupports energy
requirements,promotes
mucosal repair
FibroblastsSubstrate for energy
metabolismMononuclear cellsSubstrate for cell
proliferation
Endothelial cells,macrophages,lymphocytes
Tumor necrosis factor, interleukin-1, interleukin-6
Pituitary/adrenalaxis
Cortisol
Skeletalmuscle
Circulatingglutamine pool
Lungs
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development of multiorgan dysfunction syndrome(MODS) and systemic inflammatory response syn-drome (SIRS) in response to sepsis24,36 (Figure 4).
CancerIn cases of neoplasia, the cause of glutamine deple-
tion is multifactorial (e.g., increased utilization of glu-tamine, abnormal glutamine metabolism).1 Althoughhost glutamine depletion is normally a characteristic of advanced malignancy, depletion often occurs early inthe disease while the patient still appears healthy andhas a good appetite.1 Fibrosarcoma, mammary carcino-ma, and other tumors can consume glutamine as theirprincipal amino acid source, thus acting as glutaminetraps. Changes in interorgan glutamine metabolism oc-cur because malignant cells import glutamine faster
than do nonmalignant cells.3
In an adaptive response toincreased glutamine uptake and degradation by neo-plastic cells, muscle glutamine synthetase activity in-creases to maintain adequate circulating stores. Early inneoplasia, TNF-α stimulates enhanced glutamine re-lease from hepatocytes, causing the liver to switch froman organ of net glutamine extraction to one of net syn-thesis and release.
Over time, tumors become the primary tissue for glu-
tamine uptake, extracting as much as 50% of glutaminefrom the circulating pool.1 Tumor growth is positively correlated with increased glutaminase activity.37–40 Withprogressive tumor growth and advanced malignancy,muscle glutamine synthetic capacity and hepatic glu-tamine stores become exhausted.1,41 In human cancer
patients, glutamine transport activity into the tumor ismaintained even at the expense of the host when ca-chexia is present. Tumor glutaminase activity increaseseven when intestinal glutamine extraction decreases, de-pleting the supply of glutamine needed for normal entero-cyte function.42,43 The resulting defective GI mucosal in-tegrity can lead to increased bacterial translocation.
POTENTIAL BENEFITS OF GLUTAMINESUPPLEMENTATIONCancer
Feeding glutamine-enriched diets to human cancerpatients and some animal models has been shown to
have some significant positive effects, including replet-ing host glutamine stores, increasing glutamine syn-thetase activity, normalizing host catabolic changes, andimproving clinical outcome.43,44
Glutamine is required for the synthesis of glu-tathione, which in turn is needed for interleukin-2 acti-vation of cytotoxic T cells and natural killer cell activi-ty.25 Oral glutamine supplementation during exposureto radiation or chemotherapy increases glutathione lev-els in the gut, liver, heart, kidney, and muscle.45 In ratfibrosarcoma cells, glutamine supplementation is asso-ciated with increased tumor cell glutathione levels, re-sulting in increased susceptibility to chemotherapy anddecreased tumor expansion.46 Oral glutamine supple-mentation administered to tumor-bearing rats47 upreg-ulated host glutathione synthesis and natural killer cellactivity in a dose-dependent manner. This activity may improve host defense against blood-borne metastasis25
and decrease tumor growth.47
Glutamine supplementation in cancer patients may enhance tumoricidal effectiveness of antitumor drugsand improve patients’ tolerance to the toxic effects of chemotherapy and radiation therapy.48 Numerous studiesin humans undergoing chemotherapy have demonstrat-ed a significantly decreased incidence of mucositis and
stomatitis with glutamine supplementation.44,49
Otherstudies have failed to produce similar results.50–52 Supple-mental glutamine increases tumor glutamine concentra-tions and appears to decrease the efflux of methotrexatefrom tumor cells.43 These supplements, therefore, may help prevent the development of drug resistance. Clinicalstudies53,54 investigating supplemental glutamine in ani-mals with cancer are few in number and have demon-strated equivocal results. Marks and colleagues53 found
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Figure 4—Glutamine plays a critical role in various metabolicpathways throughout the body. Glutamine depletion canlead to many negative consequences, including multiorgandysfunction.
Glutamine depletion
Protein catabolism Decreasedgastrointestinalbarrier function
Immune systemdysfunction
Negative nitrogenbalance, proteolysis,
muscle wasting,cachexia
Increased bacterialtranslocation
Hypermetabolism, pyrexia,altered glucose kinetics,
impaired urinary acidexcretion, impaired
nitrogenous waste metabolism
Multiorgan dysfunctionsyndrome
Stimulation ofinflammatory
cytokines
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that glutamine supplementation provided no benefit incats with methotrexate-induced enterocolitis. Otherstudies54 have demonstrated that glutamine supplementsgiven to dogs undergoing radiation therapy showed posi-tive effects in reducing mucositis.
Critical IllnessIn critically ill humans and animals, decreased foodintake is deleterious to proper GI function and integri-ty. A growing trend has developed in human medicinetoward the use of supplemental nutrients that can be-come selectively depleted during catabolic states.55
These supplements can improve clinical outcome incritical illness. The dose of supplemental glutaminevaries widely. In human enteral and parenteral formu-las, glutamine supplementation (0.285 to 0.36 g/kg/day) has been shown to increase peripheral leukocytenumbers, increase fractional protein synthesis by theliver, restore muscle glutamine levels, and improve over-
all nitrogen balance.56–58 These supplements have alsobeen shown to reduce the incidence of infection, im-prove recovery from illness, decrease the length of hos-pital stay, and increase 6-month survival rates in criti-cally ill humans after MODS (see Potential Benefits of Glutamine Supplementation).58
In experimental models associated with bacterialtranslocation and sepsis, glutamine supplementationimproved intestinal barrier function by decreasing in-testinal villous atrophy and increasing intestinal IgA levels.12,45,48 Although numerous experimental modelshave demonstrated that glutamine supplementationmay be beneficial, other studies have found little bene-fit.59 Beneficial results have also been demonstrated
when glutamine has been added to total parenteral nu-trition (TPN) formulations for humans with multipletrauma, surgical trauma, neoplasia, and inflammatory bowel disease. The use of TPN in patients with nor-mally functioning GI tracts is controversial becauseTPN may not provide enough trophic stimuli to pre-vent enterocyte atrophy, even with glutamine supple-mentation.60 In patients with normally functioning GItracts, enteral nutrition is preferred.
Oral glutamine exerts trophic effects on the GI tractby increasing DNA content and mucosal protein syn-
thesis, both of which may serve to improve growth andrepair of small bowels and reduce the incidence of bac-terial translocation.43,45,61 The incidence of bacterialpneumonia, bacteremia, and sepsis are subsequently de-creased.62 Oral glutamine supplementation in humancolorectal surgery patients has been shown to preventmononuclear cell activation, which contributes to ex-cessive production of inflammatory cytokines and sub-sequent SIRS.63
RECOMMENDATIONS FORGLUTAMINE THERAPY
Previously, glutamine was not routinely included inmost parenteral and enteral formulations because of itsinstability during storage.20 However, the advent of
heat-stable glutamine dipeptides (e.g., L-alanine-L-glu-tamine, glycyl-L-glutamine), which are stable in solu-tion and readily hydrolyzed following infusion, hasmade it possible for glutamine to be added to humanenteral formulas and veterinary preparations. Gluta-mine powder is available in crystalline form and can beadded to enteral or parenteral formulas, provided thatsterile technique is used during preparation of TPN so-lution.64 Furthermore, recent evidence has demonstrat-
Small Animal/Exotics Compendium December 2000
O R A L G L U T A M I N E I T O T A L P A R E N T E R A L N U T R I T I O N I C R Y S T A L L I N E F O R M
Immune system
I Stimulates macrophage and lymphocyte function
I Improves natural killer cell activity
Nitrogen balance
I Increases muscle and liver protein synthesis
Gastrointestinal tract
I Improves intestinal barrier function
I Increases mucosal IgA levels
I Increases mucosal DNA synthesis
I Promotes mucin production
I Decreases bacterial translocation
I
Decreases incidence of bacteremia/sepsis
Cancer in humans
I Increases host glutathione production
I Enhances free radical scavenging
I Decreases chemotherapy-induced cardiotoxicity
I Decreases stomatitis and mucositis
I Enhances tumoricidal effects of chemotherapeutic
agents
Critical illness in humans
IDecreases infections and multiorgan dysfunctionsyndrome
I Decreases morbidity and mortality
I Decreases length of hospital stay
I Improves 6-month survival
Potential Benefits ofGlutamine Supplementation
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ed that L-glutamine is stable in TPN solution for atleast 22 days at room temperature.65
Glutamine is an essential nutrient during stress andcritical illness. Studies have validated its use as a nu-traceutical in human critical care and cancer patients as
well as in animal models of critical illness (e.g., sepsis).
Thus the concept that glutamine may be beneficial inanimals is not without reason. Its use in veterinary med-icine has not yet been emphasized.
Recommendations for glutamine therapy in veteri-nary medicine are speculative because only a limitednumber of studies have investigated the use of glu-tamine supplementation in animals with equivocal re-sults.53,54 Dosages of glutamine used in animals havelargely been extrapolated from those recommended inhumans. Cats may require larger doses of glutamine ormay be resistant to the potential benefits of its supple-mentation at a dose of 1.08 g/kg/day. One study 54
showed that L-glutamine (4 g/m2/day) in suspension
was beneficial to dogs undergoing radiation therapy,suggesting that L-glutamine is adequately absorbed inthe GI tract. Further, glutamine infusion in anes-thetized dogs failed to produce any detrimental effects,particularly to the liver or kidneys,66 indicating its safe-ty as a nutraceutical in dogs.
Additional clinical research must be conducted tovalidate the use of glutamine supplements in critically ill animals. Potential benefits are promising and meritfurther investigation. The doses we have used havebeen extrapolated from those recommended for hu-mans; therefore, further study is needed to determineefficacy in small animals. The addition of glutamine toenteral or parenteral formulations at a dose of 0.24 to0.32 g/kg/day may potentially have a positive effect by improving nitrogen balance and immune function, anddecreasing morbidity and mortality in critically ill ani-mals. Its use, therefore, may be beneficial in a variety of illnesses, including acquired or surgical trauma, inflam-matory conditions (e.g., sepsis, pancreatitis, SIRS), dis-ease states that promote ileus and subsequent bacterialtranslocation, and conditions associated with negativenitrogen balance (e.g., cancer).
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Compendium December 2000 Small Animal/Exotics
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I Captions discuss history, signs,
evaluation, and case highlights
I Separate index of all included
breeds
IHigh-gloss finish and spiral bind-
ing—ideal for use as a diagnostic
guide and client education tool
I Extensive current bibliography for further information
on treatment
Appropriatefor general
practitioners,students/residents
in training, andbreeders
Second in a seriesby the authors ofAtlas of FelineOphthalmology
A
Atlas of Breed-RelatedCanine Ocular Disorders
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About the AuthorDrs. Mazzaferro, Hackett, and Wingfield are affiliated with
the Critical Care Unit, Dr. Ogilvie with Oncology, and Dr.
Fettman with Clinical Pathology/Nutrition, Veterinary
Teaching Hospital, College of Veterinary Medicine, Col-
orado State University, Fort Collins. Drs. Hackett and
Wingfield are Diplomates of the American College of Vet-
erinary Emergency and Critical Care. Dr. Wingfield is also
a Diplomate of the American College of Veterinary Sur-geons. Dr. Ogilvie is a Diplomate of the American College
of Veterinary Internal Medicine (Oncology).
Small Animal/Exotics Compendium December 2000
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