SickKids-led study indicates malnutrition in children may lead to severe impairments in liver function

TORONTO - Malnourished children living in the same household who are given the same food to eat sometimes have stark differences in health, leading researchers to query why some severely malnourished children face death while others don’t.

Researchers and global health experts have come to understand that simply giving food to severely malnourished children often does not lead to recovery. This is because severely malnourished children’s bodies are affected on a deeper level that is poorly understood. To understand this further, an international team led by Dr. Robert Bandsma, Principal Investigator with the Centre for Global Child Health at The Hospital for Sick Children (SickKids), and Dr. Peter Kim, Senior Scientist in the Cell Biology program at SickKids, studied this phenomenon in animal models.

Together with Dr. Barbara Bakker, a basic scientist from the University of Groningen in the Netherlands, the research team found that severe malnutrition could lead to dysfunctional liver mitochondria, which are essential for energy production, and a loss of peroxisomes, which are important for normal liver metabolic function. They identified the gene, which, when turned on by malnutrition, causes the loss of peroxisome. This is the first study to demonstrate a diet-induced loss of peroxisomes in vivo. The study results could potentially lead to novel treatment strategies for severely malnourished children. The results are published in the Sept. 5 online edition of the Journal of Cell Biology and in the Journal of Hepatology.

“This project is a great example of successfully bringing together leading basic scientists and clinical researchers, with the goal of addressing severe malnutrition in children,” says Bandsma who is also an Assistant Professor in the Department of Paediatrics at the University of Toronto. “The results of this study have greatly enhanced our understanding of the metabolic disturbances that can develop in children with severe malnutrition. Ultimately, these insights could lead to more effective interventions to reduce mortality in malnourished children.”

Severe malnutrition is associated with a high risk of mortality related to severe metabolic disturbances. Malnutrition still contributes to 45 per cent of all global childhood deaths below the age of five. Despite great achievements in the management of severe malnutrition in children, for example, through the development of a World Health Organization (WHO) treatment guideline, the condition remains difficult to treat and in-hospital fatality rates are more than 30 per cent in the most affected regions. It is estimated that more than half a million children die each year from severe malnutrition around the world. What contributes to the high death rates is not well understood, but these children often have hypoglycemia or low blood sugar, which demonstrates that malnourished children are unable to maintain normal metabolic homeostasis.

“What surprised me in the beginning was how little we knew about the basic cellular processes that are affected during severe malnutrition. Our work is a starting point for us to understand what happens in the bodies of young children during severe malnutrition. Only by understanding these basic cellular processes will we be able to provide new and innovative interventions for critically ill malnourished children,” says Kim who is also an Associate Professor in the Department of Biochemistry at the University of Toronto.

The liver is a central organ in metabolism regulation. Children with severe malnutrition actually often have a build-up of fats in the liver, suggesting that these livers are unable to utilize nutrients effectively. In this study, animal models were placed on a low-protein or control diet. The low-protein diet-fed animal models developed liver steatosis or the infiltration of liver cells with fat, consistent with that observed in humans. The loss of peroxisomes and impaired mitochondrial function prevented the liver from utilizing nutrients effectively and led to a significant energy crisis in liver cells.

The malnourished animal models were then given the drug Fenofibrate, which restored peroxisomes and mitochondrial activity, and improved overall liver function.

The authors will next investigate whether in low-resource settings, where severe malnutrition is prevalent, whether supplementation with specific nutrients that promote peroxisome and mitochondria activity together with current nutrition rehabilitation diets could potentially improve metabolic stabilization in severely malnourished children.  

The study was supported by the Canadian Institutes of Health Research, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and SickKids Foundation.