Mechanisms of Kwashiorkor-Associated Immune Suppression: Insights From Human, Mouse, and Pig Studies.

Malnutrition refers to inadequate energy and/or nutrient intake. Malnutrition exhibits a bidirectional relationship with infections whereby malnutrition increases risk of infections that further aggravates malnutrition. Severe malnutrition (SM) is the main cause of secondary immune deficiency and mortality among children in developing countries. SM can manifest as marasmus (non-edematous), observed most often (68.6% of all malnutrition cases), kwashiorkor (edematous), detected in 23.8% of cases, and marasmic kwashiorkor, identified in ~7.6% of SM cases. Marasmus and kwashiorkor occur due to calorie-energy and protein-calorie deficiency (PCD), respectively. Kwashiorkor and marasmic kwashiorkor present with reduced protein levels, protein catabolism rates, and altered levels of micronutrients leading to uncontrolled oxidative stress, exhaustion of anaerobic commensals, and proliferation of pathobionts. Due to these alterations, kwashiorkor children present with profoundly impaired immune function, compromised intestinal barrier, and secondary micronutrient deficiencies. Kwashiorkor-induced alterations contribute to growth stunting and reduced efficacy of oral vaccines. SM is treated with antibiotics and ready-to-use therapeutic foods with variable efficacy. Kwashiorkor has been extensively investigated in gnotobiotic (Gn) mice and piglet models to understand its multiple immediate and long-term effects on children health. Due to numerous physiological and immunological similarities between pigs and humans, pig represents a highly relevant model to study kwashiorkor pathophysiology and immunology. Here we summarize the impact of kwashiorkor on children's health, immunity, and gut functions and review the relevant findings from human and animal studies. We also discuss the reciprocal interactions between PCD and rotavirus-a highly prevalent enteric childhood pathogen due to which pathogenesis and immunity are affected by childhood SM.

One-carbon metabolism in children with marasmus and kwashiorkor.

BACKGROUND: Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor's disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children. METHODS: Blood was collected from children aged 12-60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = 46). Serum concentrations of 16 one-carbon metabolites were quantified using LC/MS techniques, and then compared across participant groups. FINDINGS: Twelve of 16 measured one-carbon metabolites differed significantly between participant groups. Measured outputs of one-carbon metabolism, asymmetric dimethylarginine (ADMA) and cysteine, were lower in marasmic-kwashiorkor (median µmol/L (± SD): 0·549 (± 0·217) P = 0·00045 & 90 (± 40) P < 0·0001, respectively) and kwashiorkor (0·557 (± 0·195) P < 0·0001 & 115 (± 50) P < 0·0001), relative to marasmus (0·698 (± 0·212) & 153 (± 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor. INTERPRETATION: Kwashiorkor and marasmic-kwashiorkor were distinguished by evidence of one-carbon metabolism dysfunction. Correlative observations suggest that methionine deficiency drives this dysfunction, which is implicated in the syndrome's pathogenesis. The hypothesis that kwashiorkor can be prevented by fortifying low quality diets with methionine, along with nutrients that support efficient methionine use, such as choline, requires further investigation. FUNDING: The Hickey Family Foundation, the American College of Gastroenterology, the NICHD, and the USDA/ARS.

Aflatoxins in organs and biological samples from children affected by kwashiorkor, marasmus and marasmic-kwashiorkor: A scoping review.

Originally, the kwashiorkor is a pathology justified by the low consumption of proteins and high carbohydrates in weaned children. However, today, it can appear due to multifactorial causes, one of the hypotheses being the presence of aflatoxins in foods consumed by the child population and detected in biological fluids. The objective of this work is to scoping review the presence of aflatoxins in kwashiorkor, marasmus and marasmic-kwashiorkor from organs and biological samples in children. Results reflected that the presence of aflatoxins in kwashiorkor is greater compared to marasmic-kwashiorkor and marasmus in the organs and biological samples analyzed. The relationship of this mycotoxin with the pathology shows that it can affect both genders, even up to 12 years, in addition they are detected in eight biological samples and organs, except in the spleen, and in ten African countries and in the Philippines. The appearance of this pathology has been associated in children when after weaning they consume foods with low protein content and rich in carbohydrates, but coincidentally coincides with foods where the growth of aflatoxigenic fungi is more prevalent, and even the presence of other fungi that can generate other mycotoxins, such as ochratoxin A and fumonisin B1.

Lysosome-Rich Enterocytes Mediate Protein Absorption in the Vertebrate Gut.

The guts of neonatal mammals and stomachless fish have a limited capacity for luminal protein digestion, which allows oral acquisition of antibodies and antigens. However, how dietary protein is absorbed during critical developmental stages when the gut is still immature is unknown. Here, we show that specialized intestinal cells, which we call lysosome-rich enterocytes (LREs), internalize dietary protein via receptor-mediated and fluid-phase endocytosis for intracellular digestion and trans-cellular transport. In LREs, we identify a conserved endocytic machinery, composed of the scavenger receptor complex Cubilin/Amnionless and Dab2, that is required for protein uptake by LREs and for growth and survival of larval zebrafish. Moreover, impairing LRE function in suckling mice, via conditional deletion of Dab2, leads to stunted growth and severe protein malnutrition reminiscent of kwashiorkor, a devastating human malnutrition syndrome. These findings identify digestive functions and conserved molecular mechanisms in LREs that are crucial for vertebrate growth and survival.

Switching to normal diet reverses kwashiorkor-induced salivary impairments via increased nitric oxide level and expression of aquaporin 5 in the submandibular glands of male Wistar rats.

Kwashiorkor, a form of malnutrition, has been shown to cause impaired salivary secretion. However, there is dearth of information on the mechanism that underlies this complication. Also, whether returning to normal diet after kwashiorkor will reverse these complications or not is yet to be discerned. Thus, this study aimed at assessing the mechanisms that underlie kwashiorkor-induced salivary impairments and to evaluate the effects of switching back to normal-diet on kwashiorkor-induced salivary impairments. Weaning rats were randomly divided into 3 groups (control group, kwashiorkor group (KG), re-fed kwashiorkor group (RKG)) of 7 rats each. The control group had standard rat chow while the KG and RKG were fed 2% protein diet for 6 weeks to induce kwashiorkor. The RKG had their diet changed to standard rat-chow for another 6 weeks. Blood and stimulated saliva samples were collected for the analysis of total protein, electrolytes, amylase, immunoglobulin A (IgA) secretion rate, leptin, and ghrelin. Tissue total protein, nitric oxide level, expressions of Na+/K+-ATPase, muscarinic (M3) receptor, and aquaporin 5 in the submandibular glands were also determined. Data were presented as means ± SEM and compared using ANOVA with Tukey's post hoc test. RKG showed improved salivary function evidenced by reduced salivary lag-time and potassium and increased flow rate, sodium, amylase, IgA secretion rate, leptin, submandibular nitric oxide level, and aquaporin 5 expression compared with KG. This study for the first time demonstrated that kwashiorkor caused significant reduction in salivary secretion through reduction of nitric oxide level and aquaporin 5 expression in submandibular salivary glands. Normal-diet re-feeding after kwashiorkor returned salivary secretion to normal.

Choline Supplementation Prevents a Hallmark Disturbance of Kwashiorkor in Weanling Mice Fed a Maize Vegetable Diet: Hepatic Steatosis of Undernutrition.

Hepatic steatosis is a hallmark feature of kwashiorkor malnutrition. However, the pathogenesis of hepatic steatosis in kwashiorkor is uncertain. Our objective was to develop a mouse model of childhood undernutrition in order to test the hypothesis that feeding a maize vegetable diet (MVD), like that consumed by children at risk for kwashiorkor, will cause hepatic steatosis which is prevented by supplementation with choline. A MVD was developed with locally sourced organic ingredients, and fed to weanling mice (n = 9) for 6 or 13 days. An additional group of mice (n = 4) were fed a choline supplemented MVD. Weight, body composition, and liver changes were compared to control mice (n = 10) at the beginning and end of the study. The MVD resulted in reduced weight gain and hepatic steatosis. Choline supplementation prevented hepatic steatosis and was associated with increased hepatic concentrations of the methyl donor betaine. Our findings show that (1) feeding a MVD to weanling mice rapidly induces hepatic steatosis, which is a hallmark disturbance of kwashiorkor; and that (2) hepatic steatosis associated with feeding a MVD is prevented by choline supplementation. These findings support the concept that insufficient choline intake may contribute to the pathogenesis of hepatic steatosis in kwashiorkor.

Metabolomic Changes in Serum of Children with Different Clinical Diagnoses of Malnutrition.

BACKGROUND: Mortality in children with severe acute malnutrition (SAM) remains high despite standardized rehabilitation protocols. Two forms of SAM are classically distinguished: kwashiorkor and marasmus. Children with kwashiorkor have nutritional edema and metabolic disturbances, including hypoalbuminemia and hepatic steatosis, whereas marasmus is characterized by severe wasting. The metabolic changes underlying these phenotypes have been poorly characterized, and whether homeostasis is achieved during hospital stay is unclear. OBJECTIVES: We aimed to characterize metabolic differences between children with marasmus and kwashiorkor at hospital admission and after clinical stabilization and to compare them with stunted and nonstunted community controls. METHODS: We studied children aged 9-59 mo from Malawi who were hospitalized with SAM (n = 40; 21 with kwashiorkor and 19 with marasmus) or living in the community (n = 157; 78 stunted and 79 nonstunted). Serum from patients with SAM was obtained at hospital admission and 3 d after nutritional stabilization and from community controls. With the use of targeted metabolomics, 141 metabolites, including amino acids, biogenic amines, acylcarnitines, sphingomyelins, and phosphatidylcholines, were measured. RESULTS: At admission, most metabolites (128 of 141; 91%) were lower in children with kwashiorkor than in those with marasmus, with significant differences in several amino acids and biogenic amines, including those of the kynurenine-tryptophan pathway. Several phosphatidylcholines and some acylcarnitines also differed. Patients with SAM had profiles that were profoundly different from those of stunted and nonstunted controls, even after clinical stabilization. Amino acids and biogenic amines generally improved with nutritional rehabilitation, but most sphingomyelins and phosphatidylcholines did not. CONCLUSIONS: Children with kwashiorkor were metabolically distinct from those with marasmus, and were more prone to severe metabolic disruptions. Children with SAM showed metabolic profiles that were profoundly different from stunted and nonstunted controls, even after clinical stabilization. Therefore, metabolic recovery in children with SAM likely extends beyond discharge, which may explain the poor long-term outcomes in these children. This trial was registered at isrctn.org as ISRCTN13916953.

Niacin metabolism and indoleamine 2,3-dioxygenase activation in malnourished patients with flaky paint dermatosis.

Flaky paint dermatosis, characterized by extensive, often bilateral areas of flaking and pigmentation, mostly in sun unexposed areas is considered a feature of kwashiorkor in both children and adults, and must be differentiated from other dermatosis, including chapped and xerotica skin, and pellagra. In this case series we provide evidence that malnourished patients with flaky paint dermatosis and infection/inflammation shown laboratory data suggestive of indoleamine 2,3-dioxygenase (IDO) activation, besides decreased urinary excretion of N1-methylnicotinamide (N1 MN), a marker of pellagra. We study nine adult patients showing flaky paint dermatosis and clinical features of infection or inflammation, and increased serum C-reactive protein, characteristic of the presence of acute phase response syndrome. As a group, they had low or deficient urinary N1 MN excretion (0.52 ± 0.39 mg/g creatinine) compatible with pellagra. They also showed low serum tryptophan levels (<29 µmol/L) and a serum kynurenine/tryptophan ratio higher than 0.04, suggesting increased IDO expression and increase in the tryptophan oxidation. Findings suggest that some patients with flaky paint dermatosis showed laboratory data suggestive of IDO activation, besides decreased N1 MN urinary excretion. Taken together, the data support the idea that flaky paint dermatosis could be a skin manifestation of niacin deficiency.

Embryonic protein undernutrition by albumen removal programs the hepatic amino acid and glucose metabolism during the perinatal period in an avian model.

Different animal models have been used to study the effects of prenatal protein undernutrition and the mechanisms by which these occur. In mammals, the maternal diet is manipulated, exerting both direct nutritional and indirect hormonal effects. Chicken embryos develop independent from the hen in the egg. Therefore, in the chicken, the direct effects of protein deficiency by albumen removal early during incubation can be examined. Prenatal protein undernutrition was established in layer-type eggs by the partial replacement of albumen by saline at embryonic day 1 (albumen-deprived group), compared to a mock-treated sham and a non-treated control group. At hatch, survival of the albumen-deprived group was lower compared to the control and sham group due to increased early mortality by the manipulation. No treatment differences in yolk-free body weight or yolk weight could be detected. The water content of the yolk was reduced, whereas the water content of the carcass was increased in the albumen-deprived group, compared to the control group, indicating less uptake of nutrients from the yolk. At embryonic day 16, 20 and at hatch, plasma triiodothyronine (T3), corticosterone, lactate or glucose concentrations and hepatic glycogen content were not affected by treatment. At embryonic day 20, the plasma thyroxine (T4) concentrations of the albumen-deprived embryos was reduced compared to the control group, indicating a decreased metabolic rate. Screening for differential protein expression in the liver at hatch using two-dimensional difference gel electrophoresis revealed not only changed abundance of proteins important for amino acid metabolism, but also of enzymes related to energy and glucose metabolism. Interestingly, GLUT1, a glucose transporter, and PCK2 and FBP1, two out of three regulatory enzymes of the gluconeogenesis were dysregulated. No parallel differences in gene expressions causing the differences in protein abundance could be detected pointing to post-transcriptional or post-translational regulation of the observed differences.

Kwashiorkor and marasmus are both associated with impaired glucose clearance related to pancreatic ß-cell dysfunction.

Severe malnutrition is a major health problem in developing countries and can present as kwashiorkor or marasmus. Kwashiorkor is associated with septicaemia, profound metabolic changes including hepatic steatosis, altered protein metabolism and increased oxidative stress. Limited data suggest that children with kwashiorkor have an impaired glucose tolerance and insulin secretion. Our objective was to determine glucose tolerance in children with kwashiorkor compared to marasmus and its relation to insulin secretion and sensitivity. Six children with kwashiorkor and 8 children with marasmus were studied. We were also able to include 3 healthy children for comparison. They received a primed (13 mg/kg), constant infusion (0.15 mg/kg/min) of [6,6-(2)H(2)]glucose for 4 h with serial blood sampling. In addition, an oral glucose tolerance test (OGTT) was performed with labeled 10 mg/g [U-(13)C]glucose. Glucose clearance was determined using mathematical modeling. Glucose clearance rates during the OGTT were -392 (range 309) mL/kg in children with kwashiorkor, -156 (426) mL/kg in marasmus and 279 (345) mL/kg in the control group. Glucose clearance rates correlated with plasma albumin concentrations (r=0.67, P=.001). Insulin responses were strongly impaired in both kwashiorkor and marasmus. There was no indication of peripheral or hepatic insulin resistance in the malnourished groups. We show that glucose clearance rates are affected in both children with marasmus as well as kwashiorkor, which correlate with plasma albumin concentrations. The disturbed glucose clearance in malnutrition is related to an impairment in insulin availability.

Mechanisms behind decreased endogenous glucose production in malnourished children.

Severe malnutrition is a major health problem in developing countries and can present itself as kwashiorkor or marasmus. Although marasmus is characterized by clinical wasting, kwashiorkor is associated with peripheral edema, oxidative stress, hypoalbuminemia, and hypoglycemia. The etiology of the hypoglycemia is poorly understood. We determined endogenous glucose production (EGP) in children with severe malnutrition. Children with kwashiorkor, marasmus, and controls received a primed constant infusion of [6,6H2]glucose for 2 h. An i.v. bolus of 13C-ketoisocaproic acid (KIC) was given, and breath samples were obtained during 2 h. Isotope dilution was used to calculate EGP, and 13CO2/12CO2 production was determined. Mean EGP ± SEM was 5.5 ± 0.3 mg/kg/min in the kwashiorkor group and 6.9 ± 0.4 mg/kg/min and 7.6 ± 0.7 mg/kg/min in the marasmic and control group, respectively, (p < 0.05 kwashiorkor versus marasmus and controls). EGP correlated with serum albumin concentration (r = 0.67; p < 0.001) and urinary 8-hydroxydeoxyguanosine as a marker of oxidative stress (r = -0.62; p < 0.005). 13CO2 secretion as a marker of hepatic mitochondrial function was significantly higher in the marasmic group compared with kwashiorkor and controls. We conclude that decreased EGP in severely malnourished children is related to the degree of hypoalbuminemia and oxidative stress but is not associated with a clear defect in hepatic mitochondrial function.

A systematic review of pharmacokinetics studies in children with protein-energy malnutrition.

OBJECTIVE: protein energy malnutrition (PEM) is a nutritional problem affecting many children world-wide. Its association with a wide spectrum of infections necessitates multiple drug therapies. A systematic review was performed to determine the effects of PEM on drug pharmacokinetics. METHODS: literature searches in the MEDLINE and EMBASE databases (January 1960 to December 2009) were performed. Malnutrition, undernutrition, underweight, protein-energy malnutrition, protein-calorie malnutrition, marasmus, marasmic-kwashiorkor or kwashiorkor was the medical subject heading (MeSH) descriptor used. Inclusion criteria were abstracts that assessed or discussed absorption, distribution, metabolism, elimination, clearance, pharmacokinetics or pharmacodynamics of drugs, except micronutrients and appetite-stimulating drugs. RESULTS: altogether, 41 publications were identified. A total of 34 drugs were studied. The absorption of 18 drugs was studied; the extent of absorption (AUC) was unaffected for 10 drugs. The plasma protein binding of 20 drugs was evaluated; it was significantly reduced for 12 drugs. The volume of distribution (Vd) of 13 drugs was evaluated; it was, however, unaffected for most of the drugs. The effect of PEM on total clearance and the half-life of drugs primarily metabolised by the liver was studied for 8 drugs. There was decreased total clearance and an associated increased half-life of 5 drugs. For 2 drugs (chloramphenicol and quinine), different degrees of PEM affected total clearance differently. The total clearance of six drugs primarily eliminated by the kidneys was studied; it was unaffected for four drugs, but significantly decreased for two drugs (cefoxitin and penicillin). CONCLUSIONS: considering the proportion of children affected with PEM world-wide, there have been relatively few pharmacokinetic studies of drugs frequently used for their treatment. More studies are therefore required to establish the appropriate dose and safety of these drugs for PEM children. The studies need to recognise that PEM is a disease spectrum and should further look at the differential effects of kwashiorkor and marasmus on drug pharmacokinetics in children.

Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus.

BACKGROUND: Kwashiorkor, a form of severe malnutrition with high mortality, is characterized by edema and systemic abnormalities. Although extremely common, its pathophysiology remains poorly understood, and its characteristic physical signs are unexplained. OBJECTIVE: Because kwashiorkor can develop in protein-losing enteropathy, which is caused by a loss of enterocyte heparan sulfate proteoglycan (HSPG), and previous observations suggest abnormal sulfated glycosaminoglycan (GAG) metabolism, we examined whether intestinal GAG and HSPG are abnormal in children with kwashiorkor. DESIGN: Duodenal biopsy samples collected from Zambian children with marasmus (n = 18), marasmic kwashiorkor (n = 8), and kwashiorkor (n = 15) were examined for expression of HSPG, GAGs, and immunologic markers and compared against reference samples from healthy UK control children. GAG and HSPG expression density and inflammatory cell populations were quantitated by computerized analysis. RESULTS: The kwashiorkor group was less wasted and had a lower HIV incidence than did the other groups. All duodenal biopsy samples showed inflammation compared with the histologically uninflamed control samples. Biopsy samples from marasmic children had greater inflammation and greater CD3+ and HLA-DR (human leukocyte antigen DR)-positive cell densities than did samples from children with kwashiorkor. Expression of both HSPG and GAGs was similar between marasmic and well-nourished UK children but was markedly lower in children with kwashiorkor in both the epithelium and lamina propria. Although underglycosylated and undersulfated, epithelial syndecan-1 protein was normally expressed in kwashiorkor, which confirmed that abnormalities arise after core protein synthesis. CONCLUSIONS: Intestinal HSPG loss occurs in kwashiorkor, which may precipitate protein-losing enteropathy to cause edema. If occurring systemically, impaired HSPG expression could cause several previously unexplained features of kwashiorkor. We speculate that a genetic predisposition to reduced HSPG biosynthesis may offer a contrasting selective advantage, by both diminishing protein catabolism during transient undernutrition and protecting against specific infectious diseases.

Protein metabolism in severe childhood malnutrition.

The major clinical syndromes of severe childhood malnutrition (SCM) are marasmus (non-oedematous SCM), kwashiorkor and marasmic-kwashiorkor (oedematous SCM). Whereas treatment of marasmus is straightforward and the associated mortality is low, kwashiorkor and marasmic-kwashiorkor are difficult to treat and have high morbidity and mortality rates. Despite extensive research, the pathogenic factors which cause a child to develop the oedematous instead of the non-oedematous form of SCM in response to food deprivation are still not clear. Over the years, two attractive hypotheses have been put forward. The first proposed that a dysadaptation in protein metabolism was involved and the second proposed that free radical damage of cellular membranes might be involved. To address aspects of these hypotheses, in this article we have reviewed work done by our group and by others on protein metabolism and pro-oxidant/anti-oxidant homeostasis in children with the oedematous and non-oedematous syndromes of SCM. A significant finding is that when there is chronic food deprivation children with non-oedematous SCM can maintain body protein breakdown at the same rate as when they are well nourished, but children with oedematous SCM cannot. The slower protein breakdown rate of children with oedematous SCM reduces the supply of most amino acids, resulting in decreased availability for the synthesis of plasma proteins involved in nutrient transport and the acute phase response to infection. Another consistent finding is that children with oedematous SCM have oxidative stress as there is evidence of oxidant-induced cellular damage and impaired synthesis of the primary cellular anti-oxidant glutathione.

Arginine flux and intravascular nitric oxide synthesis in severe childhood undernutrition.

BACKGROUND: Although nutritionally dispensable amino acids are not essential in the diet, adequate synthesis is necessary for maintenance of good health. Whereas children with edematous severe childhood undernutrition (SCU) can maintain production rates of glycine and serine despite a slower body protein breakdown rate, it is unknown whether the same is true for the semidispensable amino acid arginine. OBJECTIVE: We aimed to measure arginine flux and intravascular nitric oxide synthesis in children with SCU. DESIGN: Arginine flux and the fractional and absolute synthesis rates of plasma nitrite plus nitrate were measured postabsorptively by using a 6-h infusion of [(15)N(2)]-arginine in 2 groups of children with edematous (n = 14) or nonedematous (n = 7) SCU when they were infected and malnourished (postadmission day approximately 3; clinical phase 1), when they were no longer infected (postadmission day approximately 15; clinical phase 2), and when they were recovered (postadmission day approximately 55; clinical phase 3). RESULTS: Arginine flux was slower (P < 0.01) and plasma arginine concentrations were lower in the edematous group than in the nonedematous group at clinical phase 1. At clinical phase 2, flux doubled to a value that was not significantly different from the value at clinical phase 3. There were no significant differences in the plasma concentration or fractional or absolute synthesis rate of plasma nitrite plus nitrate between the groups at any clinical phase and among clinical phases within each group. CONCLUSION: Whereas children with nonedematous SCU can maintain arginine flux at the same rate as when recovered, children with edematous SCU cannot. The slower arginine flux was not, however, associated with slower nitric oxide synthesis.

Childhood malnutrition is associated with a reduction in the total melanin content of scalp hair.

Childhood malnutrition is known to be associated with visible lightening of hair colour (hypochromotrichia). Nevertheless, no systematic investigations have been carried out to determine the biochemical basis of this change. We used an HPLC method to measure melanins in the scalp hair of thirteen Jamaican children, diagnosed as having primary malnutrition, during various stages of their treatment and after recovery. During treatment for malnutrition, a progressive decrease in total melanin content along the hair shaft from tip to root (root:tip ratio: 0.62 (sd 0.31)) was observed. This ratio was significantly different (P = 0.003) from the ratio observed among children sampled several months after discharge from hospital (0.93 (sd 0.23)) and among normal control children (0.97 (sd 0.12)). Thus, it appears that a decrease in melanin content is associated with periods of malnutrition. The low root:tip ratio during malnutrition presumably arises because the tips reflect prior hair growth during 'normal' nutrition and the roots reflect hair growth during malnutrition; a return of the root:tip ratio to that seen among controls reflects 'recovery' from malnutrition. It is possible that reduced intake or availability of tyrosine, a key substrate in melanin synthesis, may play a role in the reduction of hair melanin content during periods of malnutrition. The precise mechanisms by which melanin content is reduced, and the role of aromatic amino acid availability in hair colour change and other features of childhood malnutrition remain to be explored.

Sulfur amino acid metabolism in children with severe childhood undernutrition: cysteine kinetics.

BACKGROUND: Children with edematous but not nonedematous severe childhood undernutrition (SCU) have lower plasma and erythrocyte-free concentrations of cysteine, the rate-limiting precursor of glutathione synthesis. We propose that these lower cysteine concentrations are due to reduced production secondary to slower de novo synthesis plus decreased release from protein breakdown. OBJECTIVE: We aimed to measure cysteine production, de novo synthesis, and the rate of cysteine release from protein breakdown in children with SCU. DESIGN: Cysteine flux, de novo synthesis, and release from protein breakdown were measured in 2 groups of children with edematous (n = 11) and nonedematous (n = 11) SCU when they were infected and malnourished (clinical phase 1), when they were still severely malnourished but no longer infected (clinical phase 2), and when they had recovered (clinical phase 3). RESULTS: In clinical phase 1, cysteine production and its release from protein breakdown were slower in both groups of children than were the values in the recovered state. These kinetic variables were significantly slower, however, in the children with edematous SCU than in those with nonedematous SCU. De novo cysteine synthesis in clinical phase 1 was faster than the rate at recovery in the edematous SCU group, and there were no significant differences between the groups at any clinical phase. CONCLUSION: These findings suggest that cysteine production is reduced in all children with SCU because of a decreased contribution from protein breakdown and not from decreased de novo synthesis. The magnitude of this reduction, however, is much greater in children with edematous SCU than in those with nonedematous SCU.

Sulfur amino acid metabolism in children with severe childhood undernutrition: methionine kinetics.

BACKGROUND: Children with edematous but not nonedematous severe childhood undernutrition (SCU) have lower plasma and erythrocyte-free concentrations of cysteine and methionine, which suggests a decreased availability of methionine for cysteine synthesis. We propose that methionine production and metabolism will be slower in children with edematous SCU than in those with nonedematous SCU. OBJECTIVE: We aimed to measure methionine flux, its transmethylation and its transsulfuration, and homocysteine remethylation in children with SCU. DESIGN: Methionine kinetics were measured in 2 groups of children with edematous (n = 11) and nonedematous (n = 11) SCU when they were infected and malnourished (clinical phase 1), when they were still severely malnourished but no longer infected (clinical phase 2), and when they had recovered (clinical phase 3). RESULTS: At clinical phase 1, children with edematous SCU had rates of total methionine flux, flux from protein breakdown, and flux to protein synthesis that were slower than the rates of the nonedematous group. There were no significant differences in homocysteine remethylation or methionine transsulfuration and transmethylation between the groups at clinical phase 1. CONCLUSION: These findings suggest that, in the acutely malnourished and infected state, children with edematous SCU have slower methionine production than do children with nonedematous SCU because of a slower rate of release from protein breakdown. This slower methionine production is not, however, associated with slower rates of methionine transsulfuration and transmethylation or homocysteine remethylation.

Glycine production in severe childhood undernutrition.

BACKGROUND: Although nutritionally dispensable amino acids are not essential in the diet, from a biochemical standpoint, dispensable amino acids such as glycine are essential for life. This is especially true under unique circumstances, such as when the availability of labile nitrogen for dispensable amino acid synthesis is reduced, as in severe childhood undernutrition. OBJECTIVE: We aimed to measure glycine production in children with edematous and nonedematous severe childhood undernutrition. DESIGN: Glycine flux and splanchnic glycine extraction were measured in 2 groups of children with edematous (n = 8) and nonedematous (n = 9) severe childhood undernutrition when they were infected and malnourished (clinical phase 1), when they were still severely malnourished but no longer infected (clinical phase 2), and when they were recovered (clinical phase 3). RESULTS: Total and endogenous glycine flux and splanchnic glycine uptake did not differ significantly between the edematous and nonedematous groups during any clinical phase. In both groups of subjects, none of the glycine kinetic parameters changed significantly from clinical phase 1 through phases 2 and 3. Compared with the value at clinical phase 3, plasma glycine concentrations were not significantly lower during clinical phase 1 or 2 in either group. CONCLUSIONS: These findings suggest that children with severe childhood undernutrition can increase their de novo glycine synthesis to compensate for the reduced contribution from chronic food deprivation. The maintenance of the plasma glycine concentration suggests that the rate of glycine production was sufficient to satisfy metabolic demands in these children when they were acutely undernourished and infected.