Plasma Citrulline Concentrations Research Articles

Effect of Teduglutide, a Glucagon-like Peptide 2 Analog, on Citrulline Levels in Patients With Short Bowel Syndrome in Two Phase III Randomized Trials.

Objectives:In clinical trials, treatment with the glucagon-like peptide 2 analog teduglutide was associated with improved fluid and nutrient absorption and increased intestinal villus height and crypt depth in patients with short bowel syndrome (SBS). Plasma citrulline, an amino acid produced by enterocytes, is considered a measure of enterocyte mass. This analysis assessed changes in plasma citrulline levels in patients with SBS in 2 phase III clinical studies of teduglutide.Methods:Both teduglutide studies (0.05 or 0.10 mg/kg/day in CL0600-004 and 0.05 mg/kg/day in CL0600-020) were phase III, 24-week, double-blind, and placebo controlled. Plasma citrulline levels were analyzed and validated by liquid chromatography coupled to tandem mass spectrometry.Results:In both the CL0600-004 and CL0600-020 studies, change in mean plasma citrulline concentrations at Week 24 vs. baseline was significantly greater with teduglutide compared with placebo (10.9 (0.05-mg/kg/day dose) and 15.7 (0.10-mg/kg/day dose) vs. 2.0 μmol/L and 20.6 vs. 0.7 μmol/L, respectively, for each study (P≤0.0001 for each comparison with placebo)). Teduglutide treatment was associated with reductions from baseline in PS (parenteral support) volume requirements; however, a significant correlation between PS reduction and increase in plasma citrulline at Week 24 was observed in only one out of the three teduglutide treatment groups.Conclusions:In 2 phase III studies, patients receiving teduglutide had significant increases in plasma citrulline at Week 24 compared with patients receiving placebo. Increases in plasma citrulline concentrations likely reflect enterocyte mass expansion, but no clear correlation was detected between change in plasma citrulline and change in weekly PS volume.

Catecholamine use is associated with enterocyte damage in critically ill patients.

Small bowel damage is frequent but underdiagnosed among critically ill patients with shock. High catecholamine doses may have a deleterious effect on mesenteric blood flow. Plasma intestinal fatty acid-binding protein (I-FABP) concentration is a marker of enterocyte damage, whereas plasma citrulline concentration is a marker of functional enterocyte mass. We hypothesized that high doses of catecholamines in critically ill patients may be associated with enterocyte damage. This study aimed to determine the link between catecholamine use and dose with enterocyte damage. This is a prospective observational study performed in a large regional university teaching hospital. Critically ill patients requiring epinephrine and/or norepinephrine at admission to a medical intensive care unit (ICU) were included, as well as controls not receiving catecholamines. We evaluated at admission plasma I-FABP and citrulline concentrations, abdominal perfusion pressure (APP), and variables relating to prognosis and treatment. Patients were categorized according to the quartiles of catecholamine dose at ICU admission. Sixty critically ill patients receiving catecholamines and 27 not receiving catecholamines were included. Plasma I-FABP was higher among patients receiving catecholamine than in controls. Among patients receiving catecholamines, a dose of 0.48 γ kg min or more at ICU admission was associated with a higher I-FABP concentration. A Sepsis-related Organ Failure Assessment score higher than 11 and plasma I-FABP more than 524 pg mL at ICU admission were independently associated with 28-day mortality (odds ratio, 4.0 [1.24-12.95] and odds ratio, 4.90 [1.44-16.6], respectively). Catecholamine use is associated with I-FABP elevation in critically ill patients. Critically ill patients receiving more than 0.48 γ kg min of epinephrine and/or norepinephrine at ICU admission have high I-FABP concentrations. This suggests that enterocyte damage reflects the severity of shock, and an adverse effect of catecholamines per se is possible.

The relationship between fasting plasma citrulline concentration and small intestinal function in the critically ill.

IntroductionIn this study, we aimed to evaluate whether fasting plasma citrulline concentration predicts subsequent glucose absorption in critically ill patients.MethodsIn a prospective observational study involving 15 healthy and 20 critically ill subjects, fasting plasma citrulline concentrations were assayed in blood samples immediately prior to the administration of a liquid test meal (1 kcal/ml; containing 3 g of 3-O-methylglucose (3-OMG)) that was infused directly into the small intestine. Serum 3-OMG concentrations were measured over the following 4 hours, with the area under the 3-OMG concentration curve (AUC) calculated as an index of glucose absorption.ResultsThe groups were well matched in terms of age, sex and body mass index (BMI) (healthy subjects versus patients, mean (range) values: age, 47 (18 to 88) versus 49 (21 to 77) years; sex ratio, 60% versus 80% male; BMI, 25.2 (18.8 to 30.0) versus 25.5 (19.4 to 32.2) kg/m2). Compared to the healthy subjects, patients who were critically ill had reduced fasting citrulline concentration (26.5 (13.9 to 43.0) versus 15.2 (5.7 to 28.6) μmol/L; P < 0.01) and glucose absorption (3-OMG AUC, 79.7 (28.6 to 117.8) versus 61.0 (4.5 to 97.1) mmol/L/240 min; P = 0.05). There was no relationship between fasting citrulline concentration and subsequent glucose absorption (r = 0.28; P = 0.12).ConclusionsWhereas both plasma citrulline concentrations and glucose absorption were reduced in critical illness, fasting plasma citrulline concentrations were not predictive of subsequent glucose absorption. These data suggest that fasting citrulline concentration does not appear to be a marker of small intestinal absorptive function in patients who are critically ill.

Urine Beta2-Microglobulin Is an Early Marker of Renal Involvement in LPI.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive disorder affecting the transport of cationic amino acids. It has previously been shown that approximately one third of the Finnish LPI patients have impaired renal function. The aim of this study was to analyse in detail urine beta2-microglobulin values, renal dysfunction, oral L-citrulline doses and plasma citrulline concentrations in Finnish LPI patients. Of the 41 Finnish LPI patients, 56% had proteinuria and 53% hematuria. Mean plasma creatinine concentration was elevated in 48%, serum cystatin C in 62%, and urine beta2-microglobulin in 90% of the patients. Seventeen per cent of the patients developed ESRD, and five of them received a kidney transplant. L-citrulline doses and fasting plasma citrulline concentrations were similar in adult LPI patients with decreased and normal GFR (mean ± SD 79.5 ± 29.2 vs. 82.4 ± 21.9mg/kg/day, P = 0.619, and 80.3 ± 20.1 vs. 64.8 ± 23.0μmol/l, P = 0.362, respectively). Urine beta2-microglobulin is a sensitive early marker of renal involvement, and it should be monitored regularly in LPI patients. Weight-based oral L-citrulline doses and plasma citrulline concentrations were not associated with renal function. LPI patients with ESRD were successfully treated with dialysis and kidney transplantation.

Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study

Arginine plays a role in many different pathways in multiple cell types. Consequently, a shortage of arginine, caused by pathologic conditions such as cancer or injury, has the potential to disturb many cellular and organ functions. Glutamine is the ultimate source for de novo synthesis of arginine in humans via the intestinal-renal axis. Therefore, we hypothesized that parenteral glutamine supplementation may stimulate the interorgan pathway of arginine production. The objectives were to quantify arginine production from its precursor glutamine and to establish the contribution of the kidneys to de novo synthesis of arginine in patients receiving intravenous supplementation of glutamine dipeptide during major abdominal surgery. Whole-body and renal metabolism of glutamine, citrulline, and arginine was assessed by stable isotope techniques in 7 patients receiving a perioperative supplement of intravenous alanyl-glutamine (0.5 g · kg(-1) · d(-1)). Plasma glutamine, citrulline, and arginine concentrations increased significantly in patients receiving intravenous glutamine dipeptide. At whole-body level, 91% of total citrulline turnover was derived from glutamine, whereas 49% of whole-body citrulline turnover was used for de novo synthesis of arginine. The kidneys were responsible for 75% of whole-body arginine production from citrulline. Glutamine and citrulline are important sources for de novo arginine synthesis. The kidneys are the main production site for endogenous arginine. After comparison of these results with previous similar studies, our data suggest that an intravenous glutamine supplement doubles renal arginine production from citrulline. This trial was registered at www.trialregister.nl as NTR2914.

Enteral Nutrition in the Management of Pediatric Intestinal Failure

Intestinal failure is an uncommon but devastating condition whose natural history has dramatically improved over the past two decades (1). Infants with intestinal failure due to severe short bowel syndrome or other diagnoses previously considered incompatible with life are now routinely being saved and cared for in cutting edge, multidisciplinary programs. Enteral nutrition plays a central role in the management of children with intestinal failure. This review provides an overview of enteral nutrition in pediatric intestinal failure, with specific emphasis on recent advances in clinical management, patient outcomes, and emerging therapies.

Extrarenal citrulline disposal in mice with impaired renal function.

The endogenous synthesis of arginine, a semiessential amino acid, relies on the production of citrulline by the gut and its conversion into arginine by the kidney in what has been called the "intestinal-renal axis" for arginine synthesis. Although the kidney is the main site for citrulline disposal, it only accounts for ~60-70% of the citrulline produced. Because the only known fate for citrulline is arginine synthesis and the enzymes that catalyze this reaction are widespread among body tissues, we hypothesized that citrulline can be utilized directly by tissues to meet, at least partially, their arginine needs. To test this hypothesis, we used stable and radioactive tracers in conscious, partially nephrectomized (½ and ⅚) and anesthetized acutely kidney-ligated mouse models. Nephrectomy increased plasma citrulline concentration but did not affect citrulline synthesis rates, thus reducing its clearance. Nephrectomy (⅚) reduced the amount of citrulline accounted for as plasma arginine from 88 to 42%. Acute kidney ligation increased the half-life and mean retention time of citrulline. Whereas the rate of citrulline conversion into plasma arginine was reduced, it was not eliminated. In addition, we observed direct utilization of citrulline for arginine synthesis and further incorporation into tissue protein in kidney-ligated mice. These observations indicate that a fraction of the citrulline produced is utilized directly by multiple tissues to meet their arginine needs and that extrarenal sites contribute to plasma arginine. Furthermore, when the interorgan synthesis of arginine is impaired, these extrarenal sites are able to increase their rate of citrulline utilization.

Effects of a dietary sweetener on growth performance and health of stressed beef calves and on diet digestibility and plasma and urinary metabolite concentrations of healthy calves1

Two experiments were conducted to explore the effects of a sodium saccharin-based dietary sweetener (Sucram) on growth performance, health, and physiological responses of feedlot steers. In Exp. 1, 173 newly-received male calves purchased from auction barns were fed 0, 100, 200, or 300 g of Sucram/t of DM over 56 d. Overall, ADG and G:F (P > 0.10) were not different among treatments, but steers receiving 200 g Sucram/t displayed numerically greater ADG (23%). In addition, DMI was 17% greater for steers receiving 200 g of Sucram/t compared to steers fed the control diet (cubic effect, P = 0.09). The morbidity rate for respiratory disease did not differ (P > 0.50) among treatments. In Exp. 2, 15 steers (initial BW = 261 ± 28 kg) were used to evaluate the effects of Sucram on apparent total tract digestibility, plasma metabolite concentrations, and urine monoamine metabolite concentrations. Treatments consisted of ad libitum access to a 60% concentrate diet (Control), ad libitum access to Control + 200 g of Sucram/t of DM (Adlib), and Control + 200 g of Sucram/t of DM with feed intake paired to the Control (Paired). By design, steer DMI during the metabolism period did not differ (P = 0.34) between Paired and Control, but DMI tended (P = 0.14) to be 8.2% greater for Adlib than for Control. Treatments did not alter (P > 0.17) apparent total tract nutrient digestibility. Postprandial plasma citrulline concentration was lower (P = 0.03) for Adlib than for Control and tended to be lower (P = 0.13) for Paired than for Control. Plasma homocysteine concentration was reduced (P < 0.03) by feeding Sucram. Urinary concentrations of ethylmalonic acid, vanillymandelic acid, and 5-hydroxyindolacetic acid were greater (P < 0.06) for Adlib than for Control; Paired steers had a greater (P = 0.02) urine vanillymandelic acid concentration than Control steers and tended (P < 0.12) to have a greater urinary concentration of ethylmalonic and 5-hydroxyindolacetic acid than Control steers. Serum insulin was greater for Adlib than for Control steers (P = 0.04) and tended to be greater for Paired than for Control steers (P = 0.14), but serum prolactin area did not differ (P > 0.22) among treatments. Supplementation with Sucram may increase feed intake by newly-received, stressed feedlot calves. Saccharin supplementation reduced plasma homocysteine and increased urinary excretion of vanillymandelic acid, suggesting an improved activity of the dopamine reward system.

Serum metabolomics identifies citrulline as a predictor of adverse outcomes in an equine model of gut-derived sepsis

Acute laminitis is an inflammatory disease of the equine foot that often occurs secondarily to sepsis or systemic inflammation associated with gastrointestinal disease. It has been suggested that laminitis is similar to multiple organ dysfunction syndrome in humans, although in horses the weight-bearing laminar epithelium of the foot appears to be the tissue most sensitive to insult and the first "organ" to fail. Metabolomics performed on serum samples collected before (Con) and after (Lmn) experimental induction of gastrointestinal-associated sepsis in six horses detected 1,177 metabolites of both mammalian and bacterial origin in equine serum. Network and correlation analyses suggested a dysregulation of fatty acid metabolism in the Lmn group, as well as an accumulation of organic acids such as lactate. Furthermore, concentrations of the amino acid citrulline were decreased in Lmn samples from all study animals, suggesting that citrulline might be useful as a biomarker to identify critically ill animals that are at risk of developing laminitis. We therefore established normal ranges of plasma citrulline concentrations in a separate group of horses (n = 36) and tested the ability of citrulline to predict adverse outcomes (laminitis or death) in critically ill horses (n = 23). Plasma citrulline was significantly lower in critically ill horses that went on to experience adverse outcomes (n = 6). Further study is required to accurately determine a diagnostic cutoff, but the present data are suggestive of the predictive value of citrulline as a biomarker for laminar failure in equine sepsis.

Citrulline levels following proximal versus distal small bowel resection

PurposeCitrulline, a nonprotein amino acid synthesized by enterocytes, is a biomarker of bowel length and the capacity to wean from parenteral nutrition. However, the potentially variant effect of jejunal versus ileal excision on plasma citrulline concentration [CIT] has not been studied. This investigation compared serial serum [CIT] and mucosal adaptive potential after proximal versus distal small bowel resection. MethodsEnterally fed Sprague-Dawley rats underwent sham operation or 50% small bowel resection, either proximal (PR) or distal (DR). [CIT] was measured at operation and weekly for 8 weeks. At necropsy, histologic features reflecting bowel adaptation were evaluated. ResultsBy weeks 6–7, [CIT] in both resection groups significantly decreased from baseline (P<0.05) and was significantly lower than the concentration in sham animals (P<0.05). There was no difference in [CIT] between PR and DR at any point. Villus height and crypt density were higher in the PR than in the DR group (P≤0.02). Conclusion[CIT] effectively differentiates animals undergoing major bowel resection from those with preserved intestinal length. The region of intestinal resection was not a determinant of [CIT]. The remaining bowel in the PR group demonstrated greater adaptive potential histologically. [CIT] is a robust biomarker for intestinal length, irrespective of location of small intestine lost.

Gastrointestinal hormones and weight loss response after Roux-en-Y gastric bypass

BackgroundMechanisms underlying variable weight loss (WL) response after Roux-en-Y gastric bypass (RYGB) are poorly understood. The objective of this study was to compare gastrointestinal hormonal responses to meal intake, and fasting plasma concentrations of surrogate markers of enterocyte mass and bile acid effect between patients with failed (F-WL) or successful WL (S-WL) after RYGB. MethodsCross-sectional study including 30 nondiabetic patients, evaluated at≥24 months after RYGB. Cases (F-WL; n = 10) and controls (S-WL; n = 20) were selected based on percent of excess WL (%EWL)<50% or≥50% from 12 months onwards after surgery. Groups were matched for gender, age, presurgical BMI, and length of follow up. Glucagon-like peptide 1 (GLP-1), peptide YY (PYY), GLP-2, and ghrelin responses to a meal challenge, and fasting plasma concentrations of citrulline and serum fibroblast growth factor 19 (FGF-19) were compared. ResultsF-WL patients presented lesser suppression of ghrelin (incremental area under the curve [iAUC]: F-WL −12490±6530 versus S-WL −31196±4536 pg×mL-1×min; P<.01), and lesser increase in the GLP-1 (iAUC: F-WL 3354±737 versus S-WL 5629±542 pmol×L-1×min; P = .02) but not in the PYY and GLP-2, response to meal intake. Citrulline concentrations were significantly correlated with time after surgery (rho = .537; P<.01). However, citrulline was higher in S-WL compared to F-WL patients (P<.05). Serum FGF-19 concentration was similar between groups. ConclusionAlthough limited by the cross-sectional design, our data suggest a role of some gastrointestinal hormones as mediators of successful weight loss but argues against larger enterocyte mass after BS as determinant of failed weight loss after RYGB.

Whey Protein Processing Influences Formula-Induced Gut Maturation in Preterm Pigs

Immaturity of the gut predisposes preterm infants to nutritional challenges potentially leading to clinical complications such as necrotizing enterocolitis. Feeding milk formulas is associated with greater risk than fresh colostrum or milk, probably due to loss of bioactive proteins (e.g., immunoglobulins, lactoferrin, insulin-like growth factor, transforming growth factor-β) during industrial processing (e.g., pasteurization, filtration, spray-drying). We hypothesized that the processing method for whey protein concentrate (WPC) would affect gut maturation in formula-fed preterm pigs used as a model for preterm infants. Fifty-five caesarean-delivered preterm pigs were distributed into 4 groups given 1 of 4 isoenergetic diets: formula containing conventional WPC (filtration, multi-pasteurization, standard spray-drying) (CF); formula containing gently treated WPC (reduced filtration and pasteurization, gentle spray-drying) (GF); formula containing minimally treated WPC (rennet precipitation, reduced filtration, heat treatment <40°C, freeze-drying) (MF); and bovine colostrum (used as a positive reference group) (BC). Relative to CF, GF, and MF pigs, BC pigs had greater villus heights, lactose digestion, and absorption and lower gut permeability (P < 0.05). MF and BC pigs had greater plasma citrulline concentrations than CF and GF pigs and intestinal interleukin-8 was lower in BC pigs than in the other groups (P < 0.05). MF pigs had lower concentrations of intestinal claudin-4, cleaved caspase-3, and phosphorylated c-Jun than CF pigs (P < 0.05). The conventional and gently treated WPCs had similar efficacy in stimulating proliferation of porcine intestinal epithelial cells. We conclude that processing of WPC affects intestinal structure, function, and integrity when included in formulas for preterm pigs. Optimization of WPC processing technology may be important to preserve the bioactivity and nutritional value of formulas for sensitive newborns.

Diagnosing small bowel malabsorption

The review article published in the present issue of Intern Emerg Med, from Corazza’s group [1], is an in-depth description of the up-to-date clinical features of small bowel malabsorption, but at the same time offers a practical clinical approach to this difficult diagnosis. Small bowel malabsorption often overlaps complex clinical scenarios, and is one of the most challenging diagnoses in gastroenterology. A key factor is the differential diagnosis, and this is presented starting with the pathological mimics of coeliac disease (CD), where the interplay between genes and environment (i.e. gluten) is described, and finishing with irritable bowel syndrome (IBS). The relationships between IBS and non-motility-related gastrointestinal disorders continue to be the subject of much debate. Population-based studies have shown that many of the symptoms reported by IBS patients (particularly in the tertiary care setting) overlap with symptoms suggestive of coeliac disease or intestinal malabsorption, including lactose malabsorption [2]. One study shows that IBS-like symptoms are present in 20 % of the celiac disease population studied (n = 150) [3]. In a recent metaanalysis, no specific complaint could predict lactose malabsorption, with sensitivities ranging from 0 to 90 % and specificities ranging from 18 to 96 % for symptoms such as bloating, diarrhoea, flatulence, and abdominal pain in individual studies [4]. Upper gastrointestinal symptoms reported by patients with functional dyspepsia are described in CD. Prevalence of biopsy-proven CD in subjects with dyspepsia is around 1 % and is higher than in controls, but this difference is not statistically significant in a recent meta-analysis [5]. In this complex scenario, no serological clinical markers validated in clinical practice are available. However, in the review by Papadia et al., a new research tool that could change the fate of intestinal malabsorption diagnosis is described. Plasma citrulline concentration is a new single marker whose role in the field is widely debated. Papadia et al. [6] show that plasma citrulline is not affected by intestinal inflammation; moreover, the citrulline assay provides a reliable clinical index of global function, and so the nutritional prognosis, of a compromised intestine and is independent from the nutritional status. Other recent markers, such as IgA F-actin and intestinal fatty acid-binding protein (I-FABP), in the light of some recent interesting results, may also contribute to assessing the extent of villous atrophy. As awareness, detection, and treatment for small bowel atrophy and malabsorption all improve, the laboratory’s role in facilitating follow-up and monitoring is sure to increase in the near future.

Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1

Citrullinemia type 1 (CTLN1) is an autosomal recessive disorder of metabolism caused by a deficiency of argininosuccinate synthetase. Despite optimal management, CTLN1 patients still suffer from lethal metabolic instability and experience life threatening episodes of acute hyperammonemia. A murine model of CTLN1 (fold/fold) that displays lethality within the first 21 days of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy. An AAV serotype 8 (AAV8) vector was engineered to express the human ASS1 cDNA under the control of a liver-specific promoter (thyroxine binding globulin, TBG), AAV8-TBG-hASS1, and delivered to 7–10 day old mice via intraperitoneal injection. Greater than 95% of the mice were rescued from lethality and survival was extended beyond 100 days after receiving a single dose of vector. AAV8-TBG-hASS1 treatment resulted in liver specific expression of hASS1, increased ASS1 enzyme activity, reduction in plasma ammonia and citrulline concentrations, and significant phenotypic improvement of the fold/fold growth and skin phenotypes. These experiments highlight a gene transfer approach using AAV8 vector for liver targeted gene therapy that could serve as a treatment for CTLN1.

Enterocyte Damage in Critically Ill Patients Is Associated With Shock Condition and 28-Day Mortality*

Small bowel dysfunction in critically ill patients is frequent, underdiagnosed, and associated with poor prognosis. Intestinal fatty acid-binding protein is a marker of enterocyte damage, and plasma citrulline concentration is a marker of functional enterocyte mass. Primary objective was to identify factors associated with intestinal fatty acid-binding protein in critically ill patients. Secondary objectives were to study factors associated with plasma citrulline concentration and its correlation with intestinal fatty acid-binding protein. Prospective observational study. ICU in a University Hospital Critically ill patients 18 years old or older with an expected length of ICU stay 48 hours or more, without pregnancy, chronic small bowel disease, or chronic renal failure. None. Plasma intestinal fatty acid-binding protein and citrulline concentrations, and variables relating to prognosis and treatment, were measured at admission to the ICU. One hundred and three patients were included. Intestinal fatty acid-binding protein elevation at admission to the ICU was associated with catecholamine support, higher lactate concentration, higher Sequential Organ Failure Assessment score, and higher international normalized ratio (all p≤0.001). Plasma citrulline concentration less than or equal to 10 μmol/L at admission to the ICU was associated with higher intra-abdominal pressure, higher plasma C reactive protein concentration, and more frequent antibiotic use (all p≤0.005). There was no correlation between plasma levels of intestinal fatty acid-binding protein and citrulline. At ICU admission, Sequential Organ Failure Assessment score≥12, plasma citrulline≤12.2 μmol/L, and plasma intestinal fatty acid-binding protein concentration≥355 pg/mL were all independently associated with 28-day mortality (odds ratio, 4.39 [1.48-13.03]; odds ratio, 5.17 [1.59-16.86]; and odds ratio, 4.46 [1.35-14.74], respectively). In critically ill patients, enterocyte damage is frequent, and it is significantly associated with shock and 28-day mortality. The link between intestinal fatty acid-binding protein and plasma citrulline concentrations in critically ill patients needs to be further evaluated.

Associations between intestinal mucosal function and changes in plasma zinc concentration following zinc supplementation.

Subclinical environmental enteropathy is associated with malabsorption of fats, carbohydrates, and vitamins A, B12, and folate; however, little information is available on mineral absorption. We therefore investigated the relation between intestinal mucosal function (measured by the lactulose:mannitol permeability test and plasma citrulline concentration), and zinc (Zn) absorption, as estimated by the change in plasma Zn concentration (PZC) following short-term Zn or placebo supplementation. We conducted a randomized, partially masked, placebo-controlled trial among 282 apparently healthy children 6 to 23 months of age in Burkina Faso. After completing baseline intestinal function tests, participants received either 5 mg Zn, as zinc sulfate, or placebo, daily for 21 days. At baseline, mean ± standard deviation PZC was 62.9 ± 11.9 μg/dL; median (interquartile range) urinary lactulose:mannitol (L:M) recovery ratio and plasma citrulline concentrations were 0.04 (0.03-0.07) and 11.4 (9.0-15.6) μmol/L, respectively. Change in PZC was significantly greater in the Zn-supplemented versus placebo group (15.6 ± 13.3 vs 0.02 ± 10.9 μg/dL; P < 0.0001), and was negatively associated with initial urinary L:M recovery ratio (-1.1 μg/dL per 50% increase in urinary L:M recovery ratio; P = 0.014); this latter relation did not differ between supplementation groups (P = 0.26). Baseline plasma citrulline concentration was not associated with change in PZC. Although altered intestinal permeability may reduce dietary Zn absorption, it likely does not undermine the efficacy of Zn supplementation, given the large increases in PZC following short-term Zn supplementation observed in this study, even among those with increased urinary L:M recovery ratios.

Non‐invasive biological quantification of acute gastrointestinal graft‐versus‐host disease in children by plasma citrulline

Clinical grading of GI involvement during acute GVHD remains a challenging issue, especially in children. Plasma citrulline, a non-protein amino acid selectively produced and released by enterocytes, is a suitable surrogate endpoint for small intestinal epithelial cell mass, irrespective of the underlying cause of cell loss. Children referred for allogeneic bone marrow transplantation who were free from chronic malabsorption or constitutional disease involving the GI tract were consecutively included in this prospective study. Plasma citrulline and albumin concentration was measured every week between day 7 and day 28 of BMT until resolution of the aGVHD or occurrence of chronic GVHD. In total, 31 children were included between 2008 and 2011. After a CR, citrulline levels fell to a minimum level on day 7 and then increased to reach the initial value on day 28. After day 28, plasma citrulline but not albumin was strongly linked to the occurrence of GI GVHD, the threshold being set at 10μmol/L. The correlation with clinical grade of GI-aGVHD now needs to be assessed in larger populations. In pediatric patients, citrulline is valuable as a suitable non-invasive marker of GI involvement in acute GVHD.

PTU-187 Is Plasma Citrulline Concentration a Reliable Marker for Diagnosis and Clinical Management of Coeliac Disease ?

IntroductionIn chronic villous atrophy plasma citrulline concentration (PCC) is decreased at the same severity and extent of mucosal lesions of villous architecture. Marsh-Oberhuber classification is conventionally used for grading villous...

Changes in plasma citrulline concentration among young Malian children with moderate acute malnutrition following a 12‐week dietary intervention

BackgroundThe amino acid citrulline (Cit) is a biomarker of enterocyte mass and may be useful in assessing intestinal absorptive capacity of undernourished children in developing countries.ObjectiveTo evaluate changes in plasma Cit in Malian children aged 6–35 months with non‐edematous, moderate acute malnutrition (MAM) before and after nutritional rehabilitation.MethodsPlasma Cit was measured using ultra performance liquid chromatography and mass spectrometry in 128 children (mean age 15.5 mo) enrolled in a trial that provided 500 kcal/d of supplementary food for 12 wks.ResultsAt baseline, the mean weight‐for‐height Z (WHZ), height‐for‐ age Z, mid‐upper arm circumference (MUAC), C‐reactive protein (CRP), and plasma Cit concentration were −2.22, −2.16, 12.1 cm, 7.7 mg/L and 12.3 μmol/L, respectively. At 12 wks, mean ± SD Cit increased to 14.3 ± 5.8 μmol/L (p&lt;0.0001). Mean change in plasma Cit was greater among the 88 children who recovered from MAM vs. the 40 who did not (2.7 ± 5.2 μmol/L vs. 0.6 ± 4.8 μmol/L, p=0.03). After controlling for age, sex, baseline CRP and Cit, a 1 μmol/L increase in Cit was associated with increases of 0.037 in WHZ (p=0.005) and 0.029 in MUAC (p=0.04).ConclusionsCit increased with gains in WHZ and MUAC during nutritional rehabilitation and may reflect an improved ability to absorb essential nutrients.

Amino acid utilization by the hindlimb of warmblood horses at rest and following low intensity exercise

Background: In particular branched-chain amino acids might limit muscle protein loss in pathological conditions. Little is known on basic amino acid utilization of muscle in horses. Objective: To assess amino acid utilization by the hindlimb of horses at rest and following low intensity exercise. Animals & methods: Amino acid uptake by the hindlimb was investigated using the arteriovenous difference technique. Blood from six warmblood mares (mean age 12 ± 3 (SD) years and weighing 538 ± 39 kg) was collected simultaneously from the (transverse) facial artery and from the caudal vena cava. Food was withheld for 12 hours prior to exercise. Exercise comprised a standardized treadmill protocol consisting of 5 minutes of walk, 20 minutes of trot, and thereafter another 5 minutes of walk. Amino acids were determined quantitatively by means of anion exchange chromatography. Statistical analysis was performed using a general linear mixed model. Results: Amino acids with the largest average extraction at rest were citrulline (11.1 ± 9%), cystine (8.3 ± 36%), serine (7.9 ± 11%), and leucine (5.9 ± 9%). Of the 25 amino acids studied, none showed a significant difference following exercise. Glycine (485 ± 65 μmol/L), glutamine (281 ± 40 μmol/L), valine (183 ± 26 μmol/L), and serine (165 ± 22 μmol/L) showed highest plasma concentrations. The average extraction for α-aminobutyric acid at rest was 18.2 ± 26%. Arterial plasma citrulline concentration was higher than venously. Conclusion: Citrulline, cystine, serine, and leucine might be regarded as most important amino acids at rest in warmblood mares. Clinical importance: Further investigation is necessary into the specific role of leucine supplementation to preserve or restore body protein in horses.