One-carbon metabolism in children with marasmus and kwashiorkor

Abstract

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.

Keywords: Choline; Edematous malnutrition; Methionine; Methyl donors; Nutritional edema; Severe acute malnutrition.

Figure 1

One-carbon metabolism schematic, adapted with permission.

Figure 2

One-carbon metabolites in serum: Subject groups are reflected by gray-scale differences according to the legend: kwashiorkor (N = 94), marasmic-kwashiorkor (43), marasmus (N = 118), moderate acute malnutrition (N = 56) controls (N = 46). Box plots depict serum concentrations (y axis) of methionine, S-adenosyl methionine (SAMe), S-adenosyl homocysteine (SAH), homocysteine, asymmetric dimethylarginine (ADMA), cysteine, cystathionine, and betaine. Lower, middle, and upper boundaries of bars represent the 25th, 50th, and 75th percentiles respectively. Lower and upper whiskers represent the 5th and 95th percentiles respectively. Shared letters indicate that pairwise comparison of means was insignificant (i.e. Tukey post-hoc test P > 0·05), after adjusting for multiple comparisons.

Figure 3

Covariate regression analysis: Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. Depicted ORs and CIs reflect interquartile range effects for the prediction of kwashiorkor (including marasmic-kwashiorkor), before and after adjusting for mean upper arm circumference (MUAC), height for age Z score (HAZ), weight-for-height Z score (WHZ), age, sex, diarrhea, and fever. *N = 345: Kwashiorkor: 89, Marasmic-kwashiorkor: 22, Marasmus: 94, MAM: 55, Controls: 46. S-adenosyl-methionine (SAMe), S-adenosyl-homocysteine (SAH), asymmetric dimethylarginine (ADMA). † Cysteine, N = 306. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA).