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Protein kinetic differences between children with edematous and nonedematous severe childhood undernutrition in the fed and postabsorptive states^1,2,3

¹ From the US Department of Agriculture Agricultural Research Service, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX (FJ), and the Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica (AB, MR, and TF)

² Supported by NIH grant RO1 DK 056689 and by federal funds from the US Department of Agriculture Agricultural Research Service under Cooperative Agreement No. 58-6250-6001.

³ Address reprint requests to F Jahoor, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030-2600. E-mail: fjahoor{at}bcm.tmc.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background:Pathogenic factors that cause a child to develop the edematous instead of the nonedematous form of severe childhood undernutrition (SCU) during food deprivation are not clear. It was hypothesized that, in edematous but not nonedematous SCU, impaired protein breakdown leading to inadequate amino acids for maintenance of important organ systems was a factor.

Objective:We measured protein kinetics in children with edematous and nonedematous SCU.

Design:Endogenous leucine flux, an index of whole-body protein breakdown rate, was determined in 4 groups of children with edematous or nonedematous SCU in the malnourished and recovered states. Two groups were studied in the postabsorptive state, and 2 groups were studied in the fed state.

Results:In the postabsorptive state, leucine flux was slower (P < 0.01) in the edematous group than in the nonedematous group in the malnourished state, but in the recovered state, it was faster (P < 0.05) in the children who previously had edematous SCU. When compared with the malnourished state value, leucine flux at recovery doubled in the group that previously had edematous SCU, but it did not change in the other group. In the fed state, leucine flux was slower (P < 0.01) in the edematous group than in the nonedematous group in the malnourished state but not in the recovered state. In the recovered state, enteral leucine extraction by splanchnic tissues trended higher in the group that previously had edematous SCU than in the nonedematous group.

Conclusion:These findings indicate different protein breakdown responses to food deprivation between children with edematous and nonedematous SCU and inherent differences in protein metabolism when they have recovered.

Key Words: Leucine kinetics • protein breakdown • edematous and nonedematous severe childhood undernutrition

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The 3 main clinical syndromes of severe childhood undernutrition (SCU) are marasmus, the nonedematous syndrome, and the edematous syndromes kwashiorkor and marasmic kwashiorkor. Marasmus is relatively straightforward to treat and has a low mortality rate, but the edematous syndromes have a more complex cause, are difficult to treat, and have high rates of morbidity and mortality (1–3). In addition to the wasting seen in marasmus, kwashiorkor and marasmic kwashiorkor are characterized by edema, low plasma protein concentrations, dermatosis, hypopigmented hair, impaired immune and antioxidant capacities, neurologic abnormalities, and hepatomegaly caused by intense fatty infiltration (2). Despite extensive research, the pathogenic factors that cause a child to develop the edematous instead of the nonedematous form of SCU in response to food deprivation are still not clear.

In the late 1960s and early 1970s, 2 hypotheses suggested that a dysadaptation in protein metabolism was one such factor. First, Gopalan (4) hypothesized in 1968 that kwashiorkor resulted from a failure to adapt to reduced intakes of protein and energy because "biochemical mechanisms which are usually invoked to protect the essential tissues like the liver, pancreas and intestines at the expense of less essential muscle have failed" (p 57). In 1972, a modified version of the same hypothesis was expressed by Whitehead and Alleyne (5), who reasoned that adaptation to food deprivation, as seen in marasmus, involved the gradual wasting of muscle and fat to provide energy for survival and amino acids to protect various metabolic processes such as synthesis of the nutrient transport proteins. In contrast, in kwashiorkor, tissue catabolism does not occur to the same extent, perhaps because sufficient carbohydrate is consumed for energy maintenance. Although this hypothesis was attractive at the time, it was never tested.

Six years ago, data to support the hypothesis came from a study by Manary et al (6), who reported that, in the fasted state, children with kwashiorkor had slower rates of whole-body protein breakdown, which suggested impaired tissue catabolism, than did children with marasmus. Because distinct groups of children with edematous and nonedematous SCU have not been studied in both the acutely malnourished and recovered states, it is not known whether the difference in rates of protein breakdown between the 2 groups reflects a dysadaptation by the edematous group or an innate difference in protein metabolism between well-nourished children who subsequently develop kwashiorkor and children who develop marasmus during food deprivation. To answer this question, the current study aimed to ascertain whether differences in the rate of protein breakdown existed between children with edematous and nonedematous SCU and whether any such difference was due to different adaptive responses to food deprivation or to inherent differences in protein metabolism. In addition, studies were performed in both the fed and postabsorptive states to obtain a more complete picture of protein metabolism in and of possible differences between children with edematous and nonedematous SCU.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
Forty-six children who were admitted to the Tropical Metabolism Research Unit (TMRU) at the University of the West Indies for treatment of SCU participated in the study. During hospitalization, the children were managed according to a standard treatment protocol as previously described (7). Each subject had a deficit in body weight-for-age of >20%, which indicated severe undernutrition. The diagnosis of edematous SCU—that is, kwashiorkor or marasmic kwashiorkor—was based on the Wellcome Classification (8). Forty-two of the children had evidence of one or more infections at admission.

Written informed consent was obtained from at least one parent of each child enrolled. This study was approved by the Medical Ethics Committee of the University Hospital of the West Indies and the Baylor Affiliates Review Board for Human Subject Research of Baylor College of Medicine.

Treatment and diets
During hospitalization, the children's disease was managed according to a standard treatment protocol that divided the treatment into phases. The acute resuscitation and maintenance phases of treatment extended from admission until appetite returned, infection was cleared, and edema was lost in those children with the edematous forms of severe undernutrition. The mean duration of this phase was 14.9 d for the children who participated in the fed experiments and 15.4 d for the children who participated in the postabsorptive experiments. During this period, fluid and electrolyte imbalances were first corrected, and infections were treated with broad-spectrum antibiotics, usually parenteral penicillin and gentamicin, plus oral metronidazole. The children were fed a resuscitative diet that was made by using a commercial milk powder (61 g NAN; Nestlé SA, Vevey, Switzerland), 81 g glucose, and 858 g water. The energy content of the feed was 2623 kJ/kg, and the macronutrient composition was 7.6 g protein/kg feed, 16.5 g lipid/kg feed, and 112.6 g carbohydrate/kg feed. The energy distribution of the feed was 72% from carbohydrate, 23% from fat, and 5% from protein. The amount offered aimed to provide 417 kJ · kg^–1 · d^–1 and 1.2 g protein · kg^–1 · d^–1. The feed was given as boluses every 3 h throughout the day or as smaller boluses every 2 h if the child was having difficulty in tolerating the feed.

The next phase in the clinical care of the children was the rapid catch-up growth phase. In this phase of treatment, the children were fed an energy-dense, milk-based formula that provided 625–750 kJ · kg^–1 · d^–1 and 3 g protein · kg^–1 · d^–1 until the growth rate plateaued and weight-for-length reached 90% of expected. The high-energy feed given during rapid catch-up growth was made from coconut oil and the same commercial milk powder (NAN; Nestlé SA). The energy content was 6047 kJ/kg, and the macronutrient composition was 33.75 g protein/kg feed, 72.9 g lipid/kg feed, and 164.7 g carbohydrate/kg feed. The energy distribution of the feed was 45.4% from carbohydrate, 45.3% from fat, and 9.3% from protein. The children were fed every 4 h ad libitum. During this phase, energy intake may be as high as 626–750 kJ · kg^–1 · d^–1.

In addition, both diets were supplemented with vitamins (Tropivite; Federated Pharmaceuticals, Kingston, Jamaica) and a mineral mix prepared in the TMRU metabolic kitchen. Each child received 2 mL vitamin solution/d that contained 6000 IU vitamin A (palmitate), 1600 IU vitamin D (calciferol), 2 mg thiamine HCL, 3.2 mg riboflavin, 120 mg vitamin C (ascorbic acid), 4 mg vitamin B-6 (B-6 HCL), and 28 mg nicotinamide. They also received 5 mg folic acid/d and 2 mL mineral mix · kg^–1 · d^–1. The mineral mix consisted of 37.28 g KCl + 50.84 MgCl₂ · 6 H₂O + 3.36 g (CH₃COO)₂Zn · 2 H₂O/L H₂O (BDH Chemicals, Poole, United Kingdom). During the rapid catch-up growth phase but not during the maintenance phase, the children also received 60 mg FeSO₄/d.

Weight and length were monitored throughout the hospitalization. Weight was monitored daily by using an electronic balance (Sartorius model F150S, Göttingen, Germany), and length was monitored weekly by using a horizontally mounted stadiometer (Holtain Ltd, Crymych, United Kingdom).

Study design
The study consisted of 2 groups of children with SCU: one group was studied in the fed state (fed experiment), and the other group was studied in the postabsorptive state (postabsorptive experiment). Each group consisted of some children with edematous SCU and some children with nonedematous SCU, as shown in Table 1 and Table 2. Twenty-two subjects participated in the postabsorptive experiment: 7 with nonedematous and 15 with edematous SCU, 8 with kwashiorkor, and 7 with marasmic kwashiorkor (Table 1 and Table 3). Twenty-four subjects participated in the fed experiment: 9 with nonedematous and 15 with edematous SCU, 10 with kwashiorkor, and 5 with marasmic kwashiorkor (Table 2 and Table 4).

The diet that was fed during the resuscitative and maintenance phases of treatment was also fed to the subjects for 3 d before their second isotope infusion. That is, all subjects received the same diet, which aimed to provide 417 kJ · kg^–1 · d^–1 and 1.2 g protein · kg^–1 · d^–1, before each of the 2 tracer infusions.

In both the fed and postabsorptive experiments, total leucine flux (from which endogenous leucine flux is calculated) was measured by an intravenous infusion of [²H₃]leucine, and TBW [from which fat-free mass (FFM) was calculated] was measured by oral administration of ²H₂O. In the fed experiment, an intragastric infusion of [1-¹³C]leucine was used to measure splanchnic leucine kinetics.

Tracer infusion protocol
Sterile solutions of [²H₃]leucine and [1-¹³C]leucine (99.9%; Cambridge Isotope Laboratories, Woburn, MA) were prepared in 9 g NaCl/L. Two intravenous access sites were established in opposite arms by the insertion of 22-gauge or 24-gauge catheters after preparation of the access sites with a topical anesthetic (EMLA cream; Astra Pharmaceuticals Ltd, Langley, United Kingdom). One intravenous catheter was used for infusion of the labeled substrate (and glucose in the postabsorptive experiments), and the other was used for blood sampling.

Fed experiments
Measurements were made on 2 occasions, first in the malnourished state and second in the recovered state. In these experiments, a nasogastric tube was inserted into the child's stomach, and a Flexiflo Magna-Port Y-Port connector (Ross Products Division, Abbott Laboratories, Columbus, OH) was attached to the proximal end. Approximately 33% of the child's current daily dietary intake was then administered over the next 8 h by continuous intragastric infusion into one limb of the Y-port by using an enteral infusion pump (Flexiflo companion enteral nutrition pump; Ross Laboratories, Columbus, OH). This rate of feed administration provided 17.4 kJ · kg^–1 · h^–1 and 0.05 g protein · kg^–1 · d^–1.

After 2 h of intragastric feeding, a 3-mL blood sample was drawn, and a bolus of 100 mg ²H₂O/kg (99.9%; Cambridge Isotope Laboratories) was given intragastrically by using the other port of the nasogastric tube. This was followed by a 2-mL flush of 9 g NaCl/L. Immediately afterward, a primed-continuous intragastric infusion of [1-¹³C]leucine (prime: 6 µmol/kg; infusion rate: 6 µmol · kg^–1 · h^–1) and a primed-continuous intravenous infusion of [²H₃]leucine (prime: 8 µmol/kg; infusion rate: 8 µmol · kg^–1 · h^–1) were started and maintained for 6 h. Additional 1.5-mL blood samples were drawn hourly from 3 to 6 h. The infusion and blood sampling protocols were the same for the experiments performed in the children in the recovered state (weight-for-length 90% of expected).

Postabsorptive experiments
Again, measurements were made on 2 occasions, first in the malnourished state and second in the recovered state. Leucine kinetics were measured from blood samples taken in the 6–9 h postabsorptive period because each isotope infusion started 3 h after the subject's last bolus of feed, and the first sample used to calculate leucine flux was taken 3 h after the infusion started. To avoid possible hypoglycemia during the experimental period, a 0.278 mol glucose/L solution was infused intravenously at 3 mg · kg^–1 · min^–1 starting 1 h after the last bolus feed—that is, 2 h before the isotope infusion started. After 2 h of continuous glucose infusion, a 1-mL blood sample was drawn for baseline measurements, a priming dose of 8 µmol [²H₃]leucine/kg was administered and followed immediately by a continuous infusion of 8 µmol [²H₃]leucine · kg^–1 · h^–1 for 6 h. Additional 1-mL blood samples were drawn hourly during the infusion. The infusion and blood sampling protocols were the same for the experiments performed in the recovered children (weight-for-length 90% of expected).

Sample analyses
The blood samples were centrifuged immediately at 1000 x g for 15 min at 4 °C, and the plasma was removed and stored immediately at –70 °C for later analysis. Plasma concentrations of amino acids were determined by reverse-phase HPLC on a Hewlett-Packard 1090 HPLC equipped with a Model HP 1046A fluorescence detector (Hewlett-Packard, Avondale, PA). The ²H₂ content of plasma water was measured in the 3-h sample by reducing water extracted from 10 µL plasma with zinc in quartz vessels and measuring the ²H₂ abundance of the resulting hydrogen gas by gas isotope ratio mass spectrometry (Delta-E; Finnigan MAT, San Jose, CA). Plasma leucine was isolated by ion exchange (Dowex 200x) chromatography and converted to the n-propyl ester, heptafluorobutyramide derivative. The tracer-to-tracee ratio was measured by negative chemical ionization gas chromatography–mass spectrometric analysis by using a Hewlett-Packard 5890 quadrupole mass spectrometer (Palo Alto, CA) and selectively monitoring ions at mass-to-charge ratios (m:z) of 349 to 352. Plasma -keto isocaproic acid (-KICA) tracer:tracee was measured by negative chemical ionization gas chromatography–mass spectrometry of its pentafluorobenzyl derivative monitoring ions at m:z of 129 to 132. The -KICA pentafluorobenzyl ester was prepared by adding 0.1-mL volumes of 0.1 mol tetrabutylammonium hydrogen sulfate/L and 0.13 mol -bromo-2,3,4,5,6-pentafluorotoluene/L to 0.1 mL plasma and allowing the mixture to react overnight at room temperature. The esters were extracted next with a 9:1 mixture (by volume) of hexane and ethanol and dried under a stream of nitrogen gas.

Calculations
In the fed experiments, the percentage of dietary leucine extracted by the splanchnic tissues was obtained as previously described (7):

(1)

where E_pIG and E_pIV are the plateau tracer:tracee of the intragastric (IG) and intravenous (IV) tracers and i_IG and i_IV are the rates of infusion of the IG and IV tracers.

Splanchnic leucine utilization (LEU_splan) was obtained as the product of the percentage of LEU_splan and enteral leucine intake. In both the fed and postabsorptive experiments, total leucine flux (Q) was calculated as follows:

(2)

where E_p -KICA is the plateau isotopic enrichment of -KICA derived from the intravenous leucine tracer. Leucine derived from protein breakdown (LEU_brk) was calculated as the difference between total leucine flux and all sources of leucine intake. For the fed experiments, it was calculated as follows:

(3)

For the postabsorptive experiments, it was calculated as follows:

(4)

TBW was calculated as follows:

(5)

where E_D2O is the enrichment of the deuterium oxide dose, E_pD2O is the plasma water plateau enrichment, and 1.04 is the factor that converts deuterium dilution space to total water (9).

FFM was calculated as follows:

(6)

where K is the age- and sex-specific hydration constants for FFM as reported by Fomon et al (10). In the children with edematous SCU, TBW measured in the malnourished state was corrected by subtracting the contribution from edema fluid. Edema fluid was estimated as the difference between body weight on the day of the experiment and the lowest postexperiment weight observed during the maintenance treatment phase.

Similarly, to discount the contribution of edema fluid to total body weight in the malnourished state measurement, body weights obtained after loss of edema (ie, the lowest weight observed between the malnourished state measurement and end of the maintenance phase) were used. All kinetic data are expressed per kilogram of body weight and per kilogram of FFM.

Statistics
Data are expressed as means ± SEMs. Differences in outcome means were compared by using repeated-measures analysis of variance with diagnosis as the between-subject factor and clinical state as the repeated factor. In the analyses of anthropometric variables plasma concentrations of albumin and glucose, the categories for diagnosis were nonedematous SCU, kwashiorkor, and marasmic kwashiorkor, but, in the analyses of plasma concentrations of amino acids and leucine kinetics, there were only 2 categories: nonedematous and edematous SCU. The repeated factor, clinical state, had 2 categories: the malnourished state and the recovered state. If the interaction terms from the repeated-measures analysis of variance were significant, pairwise comparisons were made by using Tukey's method. For the clinical characteristic variables [eg, hemoglobin concentration, white blood cell (WBC) count, and body temperature], an unpaired t test was used to compare values between the edematous and nonedematous subjects in the malnourished state. Inferential tests were considered significant if P < 0.05 (2-tailed). Data analysis was performed with STATA statistical software (version 8; Stata Corp, College Station, TX).

	RESULTS

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Anthropometric characteristics
The mean values for the anthropometric characteristics of the study subjects are reported separately in Tables 1 and 2. In the postabsorptive study, significant differences by diagnosis were observed in the mean ages of subjects at the time they participated in the malnourished state experiment; the mean age of the marasmic kwashiorkor group was the lowest. The children had a mean weight-for-age between 46% of expected in the subjects with marasmic kwashiorkor and 71% in the subjects with kwashiorkor (Table 1). As expected in the malnourished state, significant differences by diagnosis were observed in mean values of weight-for-age, weight-for-length, and FFM. When the subjects had recovered, all anthropometric measurements except length increased significantly. In contrast, at recovery, the percentage of body weight composed of FFM had decreased by 7% compared with the malnourished values (P < 0.001). A significant diagnosis x clinical state interaction was observed for plasma concentrations of albumin. In the malnourished state, the mean plasma concentration of albumin was greater in the nonedematous group than in the kwashiorkor group (Table 1). Mean plasma concentrations of albumin increased significantly on recovery (P < 0.001).

In the fed experiment, significant differences by diagnosis were observed in the mean ages of subjects at the time they participated in the malnourished state experiment (Table 2); the mean age of the marasmic kwashiorkor group was the lowest. The children had a mean weight-for-age between 49% of expected in the marasmic kwashiorkor group and 67% in the kwashiorkor group (Table 2). As expected, in the malnourished state, significant differences by diagnosis were observed in mean values of weight-for-age, weight-for-length, and FFM. When the subjects had recovered, all anthropometric measurements except length increased significantly. In contrast, at recovery, the percentage of body weight composed of FFM had decreased by 7% compared with the malnourished values (P < 0.001). A significant diagnosis x clinical state interaction was observed for plasma concentrations of albumin. In the malnourished state, the mean plasma concentration of albumin was greater in the nonedematous group than in the kwashiorkor group (Tables 2). Mean plasma concentrations of albumin increased significantly on recovery (P < 0.001).

Clinical characteristics
In the postabsorptive experiment, the clinical characteristics of the subjects at admission are shown in Table 3. All subjects but one were anemic. Twenty-one of the 23 subjects had 1 infections, but the WBC count was elevated in only 14 subjects. Mean hemoglobin concentrations and WBC counts were significantly (P < 0.05) higher in the nonedematous group than in the edematous group.

The clinical characteristics at admission of the subjects who participated in the fed study are shown in Table 4. All of the subjects were anemic. Twenty-one of the 24 subjects had 1 infections, but the WBC count swas elevated in only 12 subjects.

Leucine kinetics
Postabsorptive experiment
A significant diagnosis x clinical state interaction was observed for endogenous leucine flux (Table 5). In the malnourished state leucine flux from protein breakdown was significantly (P < 0.05) slower in the edematous group than in the nonedematous group. When compared with the rate in the malnourished state, at recovery, leucine flux from protein breakdown did not change in the nonedematous group, but it increased significantly (P < 0.05) in the edematous group. As a consequence, leucine flux from protein breakdown was significantly (P < 0.05) faster in the edematous group than in the nonedematous group in the recovered state.

Table 6

(Table 7

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

The finding that endogenous leucine flux in the children with edematous SCU was 40% slower than that in the children with nonedematous SCU when they were malnourished and in the postabsorptive state corroborates the findings of Manary et al (6), who reported that leucine flux from protein breakdown was 55% slower in children with kwashiorkor than in children with marasmus. The finding that the rate of protein breakdown increased significantly in the edematous group when they recovered, but did not change in the nonedematous group when they recovered, suggests that, when chronic nutrient deprivation occurs, children with nonedematous SCU have the ability to maintain body protein breakdown at the same rate as when they are well nourished, but children with the edematous forms of SCU do not have that ability. This difference in protein breakdown between children with edematous and nonedematous SCU was seen in both the fed and the postabsorptive states.

Our observation that the rate of protein breakdown is lower in the children with edematous SCU in the malnourished state lends indirect support to the hypothesis of Gopalan (4) and Whitehead and Alleyne (5) that impaired breakdown of muscle protein may be a contributing factor in the pathogenesis of kwashiorkor. In nonedematous SCU, the breakdown of structural body proteins may produce enough amino acids to maintain the synthesis of proteins and other biomolecules that are more critical for survival, but that is not the case in edematous SCU. Is this difference, however, really due to a "dysadaptation" in protein breakdown in children with edema, as proposed by Gopalan? The current findings suggest quite the opposite. That is, the protein breakdown response of the children with edematous SCU seems to conform to the expected adaptation to food deprivation, but the response of the children in the nonedematous group does not.

The observation that protein turnover was slower in the malnourished state than in the recovered state in children with SCU has been interpreted by others (11, 12) as an adaptation necessary to conserve energy and protein and, hence, to prolong survival in the face of chronic reduced intake of food. For example, Golden et al (11) reported that, whereas a maintenance diet of 397 kJ and 0.6 g protein · kg^–1 · d^–1 was sufficient to facilitate a positive nitrogen balance and growth in children when they were malnourished, it was not sufficient to support nitrogen balance and growth when the children had recovered and their rate of protein turnover was faster. Our present data corroborate this down-regulation of protein breakdown in children with SCU. However, our data indicate that this down-regulation is not a universal response in both the edematous and nonedematous forms of SCU. Whereas the rate of protein breakdown of the edematous group was 50% slower in the malnourished state than in the recovered state in both the fed and postabsorptive experiments, the rates did not differ significantly between the malnourished state and the recovered state in the nonedematous group. Hence, children with nonedematous SCU break down body proteins at the same rate as when they are well nourished. This apparent lack of adaptation in protein breakdown in response to food deprivation seems to confer a metabolic advantage that enables children with nonedematous SCU to cope with and survive the stress of chronic nutrient deprivation better than do their edematous counterparts. If we are to assume that the slowing down of metabolic processes, such as protein kinetics, in response to food deprivation is the correct response (11–13), then the children with edematous SCU seem to have the correct response, but not the children with nonedematous SCU. Hence, a dysadaptation in protein catabolism seems to exist not in edematous SCU, as proposed by Gopalan (4), but rather in nonedematous SCU, in which the inability to down-regulate protein catabolism during food deprivation enables these children to supply sufficient amino acids to maintain the integrity and functional capacities of the organ systems that are critical to survival. This possibility may explain why the plasma concentrations of amino acids in children with nonedematous SCU are not as depleted as are those in children with edematous SCU (Table 7). It may also explain why children with nonedematous SCU are better able to cope with and survive chronic food deprivation.

Because the stress of infection is known to stimulate protein turnover, one can argue that the faster rate of protein turnover observed in the malnourished nonedematous group than in the malnourished edematous group is probably due to differences in the infected states of the subjects. However, this is highly unlikely, because, overall, more of the edematous subjects than of the nonedematous subjects were infected. For example, in the postabsorptive experiments, all but one of the subjects with nonedematous SCU were infected, and, in the fed experiments, whereas all of the 15 subjects with edematous SCU were infected, only 6 of the 9 subjects with nonedematous SCU were infected.

A surprising finding was the presence of inherent differences in protein metabolism between the children with edematous SCU and nonedematous SCU when they had recovered. In the postabsorptive state, children who had recovered from nonedematous SCU were breaking down their body proteins 25% slower than were children who previously had edematous SCU. In addition, in the recovered-state fed experiments, both the percentage and the amount of leucine extracted by the splanchnic tissues trended higher in the children who had edematous SCU than in those in the nonedematous group. Because of evidence that a slower rate of protein turnover improves the efficiency of dietary protein utilization—and thus nitrogen balance in children (11) and in adults (14, 15) with a marginal intake of protein—it can be argued that an inherently slower rate of protein turnover, as seen in the children who had recovered from nonedematous SCU, confers a metabolic advantage that enables their better adaptation to a chronically inadequate diet.

With respect to splanchnic protein metabolism, our results indicate that the children with edematous SCU tended to extract more dietary leucine than did those with nonedematous SCU. The meaning of this difference in splanchnic leucine uptake between children with different types of SCU is not obvious. Extracting more dietary protein in the malnourished state should reduce the extent to which the integrity and metabolic capacity of the splanchnic organs are impaired during chronic inadequate food intake. Yet our studies in children with SCU have shown that synthesis rates of hepatic secretory proteins are more compromised in children with edematous SCU than in children with nonedematous SCU (16).

	ACKNOWLEDGMENTS

 
We thank the physicians and nursing staff of the TMRU for their care of the children and to Hyacinth Gallimore, Bentley Chambers, Sharon Howell, Margaret Frazer, and Melanie Del Rosario for their excellent work and support in the conduct of the studies and analysis of the samples.

All of the authors contributed to all aspects of the production of this manuscript, from the design of the study to the collection, analysis, and interpretation of the data and to the writing of the manuscript. None of the authors had a personal or financial conflict of interest.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

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