Asha Badaloo

Protein metabolism in severe childhood malnutrition

Abstract 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.

Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man

1. The evidence is accumulating to suggest that glycine, the simplest amino acid, is conditionally essential in man. Benzoic acid, by conjugation with glycine to form hippuric acid, is known to deplete the free glycine pool of the body. Glycine is one substrate for the enzyme glutathione synthase (EC 6.3.2.3) and in the inborn error of metabolism in which glutathione synthase function is defective, increased quantities of 5-oxoproline are excreted in the urine. 2. An oral dose of 4-10 g sodium benzoate was given to six normal adults to deplete the metabolic pool of glycine, and the urinary excretion of 5-oxoproline was followed for 6 h. In five of the six, a significant increase in the urinary 5-oxoproline was seen within 3 h. 3. These findings show that 5-oxoprolinuria can result from limited glycine availability, and may provide a useful test for assessing glycine sufficiency in a range of physiological and pathological states.

The transfer of 15N from urea to lysine in the human infant.

To explore the nutritional significance of urea hydrolysis for human subjects, male infants being treated for severe undernutrition were given oral doses of 10 mg [15N15N]urea every 3 h for 36 h, on admission, during rapid growth and after repletion with either moderate or generous intakes of protein. Urea hydrolysis was calculated from the 15N enrichment of urinary urea, and where possible, lysine, alanine, glycine and histidine were isolated from urine by preparative ion-exchange chromatography for measurement of 15N enrichment. Sufficient N was obtained for 15N enrichment of lysine to be measured on fifteen occasions from six children. Urea hydrolysis accounted for half of all urea production with 130 (SD 85) mg N/kg hydrolysed per d, most of which appeared to be utilized in synthetic pathways. Of the samples analysed successfully, nine samples of lysine were enriched with 15N (mean atom percent excess 0.0102, range 0.0017-0.0208) with relative enrichment ratios with respect to lysine of 1.63 (range 0.18-3.15), 1.96 (range 0.7-3.73) and 0.9 (range 0.4-1.8) for glycine, alanine and histidine respectively. Enriched samples were identified at each treatment phase and 68% of the variation in lysine enrichment was explained by the variation in urea enrichment with 54% explained by the overall rate of delivery of 15N to the lower gastrointestinal tract. The results indicate a minimum of 4.7 mg lysine per kg body weight made available by de novo synthesis with the more likely value an order of magnitude higher. Thus, urea hydrolysis can improve the quality of the dietary protein supply by enabling an increased supply of lysine and other indispensable amino acids.

Comparison of urinary 5-L-oxoproline (L-pyroglutamate) during normal pregnancy in women in England and Jamaica

Urinary 5-L-oxoproline was measured during normal pregnancies in Southampton, England and Kingston, Jamaica. The CV of 5-L-oxoproline excretion in urine, determined over 7 d in a non-pregnant woman and three pregnant women, was 10-36%. Compared with non-pregnant women, urinary 5-L-oxoproline increased three to four times from early pregnancy in women in Southampton, a highly significant difference, and remained elevated at similar levels during mid and late pregnancy. For women in Kingston, the excretion of 5-L-oxoproline was similar to that of Southampton women in the non-pregnant group and during early pregnancy. However, there was a progressive increase in the excretion of 5-L-oxoproline as pregnancy advanced and by late pregnancy excretion was from three to ten times greater than the average for the non-pregnant women. There was a significant difference between the women in Southampton and the women in Kingston during mid and late pregnancy, with women in Kingston excreting twice as much 5-L-oxoproline during late pregnancy. If the excretion of 5-L-oxoproline is a measure of glycine insufficiency, the results would indicate that in some pregnancies the ability of the mother to provide glycine for herself and the developing fetus is marginal or inadequate and the constraint appears more marked in Jamaica than in England.

Maldigestion and malabsorption of dietary lipid during severe childhood malnutrition

Background: Diets rich in lipid are used to provide energy density in treating children with severe malnutrition, but the extent to which their digestion and absorption can cope with the load effectively is uncertain. Aim: To determine the extent of impaired digestion or absorption, in three groups of eight malnourished children (aged 5–23 months) using isotopic probes of the predominant fatty acids in coconut and corn oil used to fortify the diet. Methods: Each child received oral doses of one of three 13C labelled triglycerides (trilaurin, triolein, or trilinolein). The recovery of 13C label in stool either as triglyceride (TAG) or fatty acid (FA), was used to assess digestion and absorption. In a separate test, the recovery of label in stool following an oral dose of [13C]-glycocholate was measured to assess bile salt malabsorption. Results: The median recovery of label in stool was 9% (range 1–29%) of administered dose. Following treatment there was a reduction in stool 13C excretion for the labelled TAG (<1%). In half the subjects, label was recovered as TAG in stool (median 0.6%, range 0–44%). Most label in stool was recovered as FA (median 30%, range 0–100%). Following [13C]-glycocholate, label was recovered in excess in about one third of studies. Conclusion: Abnormalities in the gastrointestinal handling of lipid were observed in over 50% of children with severe malnutrition, reflecting problems in absorption, although impaired solubilisation or hydrolysis could also be contributory factors. The underlying lesion improves as treatment progresses, leading to concomitant improvement in function.

Dietary cysteine is used more efficiently by children with severe acute malnutrition with edema compared with those without edema

BACKGROUND Children with edematous severe acute malnutrition (SAM) produce less cysteine than do their nonedematous counterparts. They also have marked glutathione (GSH) depletion, hair loss, skin erosion, gut mucosal atrophy, and depletion of mucins. Because GSH, skin, hair, mucosal, and mucin proteins are rich in cysteine, we hypothesized that splanchnic extraction and the efficiency of cysteine utilization would be greater in edematous than in nonedematous SAM. OBJECTIVE We aimed to measure cysteine kinetics in childhood edematous and nonedematous SAM. DESIGN Cysteine flux, oxidation, balance, and splanchnic uptake (SPU) were measured in 2 groups of children with edematous (n = 9) and nonedematous (n = 10) SAM at 4.4 ± 1.1 d after admission (stage 1) and at 20.5 ± 1.6 d after admission (stage 2) when they had replenished 50% of their weight deficit. RESULTS In comparison with the nonedematous group, the edematous group had slower cysteine flux at stage 1 but not at stage 2; furthermore, they oxidized less cysteine at both stages, resulting in better cysteine balance and therefore better efficiency of utilization of dietary cysteine. Cysteine SPU was not different between groups but was ∼45% in both groups at the 2 stages. CONCLUSION These findings suggest that children with edematous SAM may have a greater requirement for cysteine during early and mid-nutritional rehabilitation because they used dietary cysteine more efficiently than did their nonedematous counterparts and because the splanchnic tissues of all children with SAM have a relatively high requirement for cysteine. This trial was registered at clinicaltrials.gov as NCT00069134.

Predictors of physical activity energy expenditure in Afro-Caribbean children

Background/Objectives:We hypothesized that maternal size during pregnancy and birth size are determinants of childhood physical activity energy expenditure (PAEE). Also, childhood PAEE is inversely related to adiposity and levels of cardiovascular risk factors.Subjects/Methods:The Vulnerable Windows Cohort Study is a longitudinal observational study of 569 Afro-Jamaican mothers recruited from the first trimester and their offspring. Anthropometry, bioelectrical impedance, PAEE (using the Actical monitor) and cardiovascular risk factors (blood pressure, fasting glucose, insulin and lipids) were measured in 124 boys and 160 girls at a mean age of 13.2 years.Results:Boys had more fat-free mass (FFM) and expended more energy than girls (12.3±3.3 vs 9.6±2.8 kcal/kg/day; P<0.001). Maternal weight was associated with childs PAEE (r=0.29; P<0.001). PAEE was not significantly associated with birth weight. Maternal weight, after adjusting for childs age and sex, was positively associated with the childs FFM, fat mass and %fat (P-values ⩽0.01). Age- and sex-adjusted PAEE was positively associated with FFM, fat mass and % fat (P-values <0.001), but not after adjusting for current weight. Age- and sex-adjusted PAEE was positively associated with triglycerides, insulin and systolic blood pressure (P-values <0.05), but not after adjusting for weight and height. PAEE was associated with fasting glucose after controlling for age, sex, weight and height (r=−0.12; P=0.02).Conclusions:Maternal size, but not birth weight, is a determinant of childhood PAEE. PAEE is not strongly associated with childhood body composition, but is inversely related to fasting glucose concentration.

The Effect of Splenectomy on Whole Body Protein Turnover in Homozygous Sickle Cell Disease

In individuals with homozygous sickle cell (SS) disease, haemolysis creates a demand for increased red cell production. In children with hypersplenism haemolysis may be further increased and in such cases the excessive red cell production may be reduced by splenectomy (1). Whole body protein turnover is increased in SS disease and a large part of this increase is the consequence of increased turnover of red blood cells (2). Whole body protein turnover has therefore been measured in children with SS disease before and after splenectomy to find out if the reduction of the haemolytic rate following splenectomy was associated with a decrease in protein turnover.

Developmental contributions to macronutrient selection: a randomized controlled trial in adult survivors of malnutrition

Birthweight in children who had kwashiorkor and marasmus showed no independent effect on the intake of protein and energy in adulthood. However, energy intake and weight gain increase as the percentage of energy derived from dietary protein (PEP) is reduced, hence risk of developing obesity with low PEP diets.

Glutathione S-transferase polymorphisms may be associated with risk of oedematous severe childhood malnutrition

It has been estimated that more than 50 % of deaths before the age of 5 years have undernutrition as an underlying cause. Severe childhood malnutrition, an extreme form of undernutrition, occurs as oedematous and non-oedematous syndromes. The reasons why only some children develop oedematous severe childhood malnutrition (OSCM) have remained elusive, but the heterogeneity of clinical appearances among children from relatively homogeneous backgrounds suggests that interindividual variation in susceptibility to OSCM may exist. We investigated variants of four glutathione S-transferase (GST) genes in a retrospective study among subjects (n 136) previously admitted to the Tropical Metabolism Research Unit, Jamaica, for the treatment of either OSCM (cases) or non-oedematous severe childhood malnutrition (controls). We found that GSTP1 Val(105) homozygotes were significantly more common among the cases (odds ratio (OR) 3.5; 95 % CI 1.1, 10.8). We also found an association of borderline significance between non-deletion GSTT1 genotypes (i.e. +/+ or +/0) and OSCM (OR 2.4; 95 % CI 1.0, 5.9). There was no significant association between OSCM and any of the other GST variants. These preliminary findings suggest that genetic variation within the GST superfamily may contribute to the risk of OSCM. Additional, larger data sets and studies of variants in other candidate genes are required in order to properly assess the true contribution, if any, of genetic variation to risk of OSCM. Such studies may improve our understanding of the causes of clinical heterogeneity in malnutrition.