Intravenous nutrition saves lives. Used long-term, though, it's also connected to cirrhosis and eventual liver failure. "We didn't know what caused it, how to treat it, or how to prevent the disease from progressing," says Ronald Sokol, MD, Chief of Pediatric Gastroenterology, Hepatology and Nutrition at Children's Colorado. "Without a way to chronicle the pathogenesis of the disease, we were stuck."
Until the advent of total parenteral (intravenous) nutrition, or TPN, a half century ago, patients with necrotizing enterocolitis, short bowel syndrome and other gastrointestinal malformations would not survive. While TPN increased survival and quality of life for many, physicians soon realized that long-term treatment came with grave side effects for infants and children with bowel problems, the most serious among them rapidly-progressing cirrhosis and liver failure. Often fatal without a liver or multivisceral transplant, this intestinal failure associated liver disease (IFALD), also called TPN-associated cholestasis (PNAC), was a major stumbling block for the field.
Seeing the toll it took on these young patients, Dr. Sokol, gut macrophage expert Karim El Kasmi, MD, and a team of researchers from Children's Colorado and the University of Colorado School of Medicine set out to develop an animal model, one that would replicate the human pathophysiology of parenteral nutrition-associated cholestasis in infants and allow researchers to develop and test new treatments.
Forming a hypothesis about TPN-associated cholestasis
"We hypothesized that intestinal injury was just as important as the application of TPN," says Dr. Sokol. "We speculated that the lack of enteral feeding may significantly reduce intestinal motility and favor bacterial overgrowth, subsequently aggravating underlying inflammation. This, together with the presumed increased intestinal permeability of infants, could compromise the intestinal barrier function."
With a poorly functioning intestinal barrier, bacterial proteins, lipids or nucleic acids could be entering the portal vein, they surmised, initiating inflammatory pathways in the liver and activating receptor signaling, thereby promoting injury to the liver cell along with cholestasis, cell death and necrosis. But this alone was not enough to explain the damage done to the liver. They also proposed that there was something in the intravenous nutrition that synergized with the intestinal failure to cause liver injury.
To study this phenomenon, they developed a mouse model to induce intestinal injury and increased permeability using dextran sulphate sodium (DSS) followed by a continuous infusion of soy-based lipid parenteral nutrition through a central venous catheter. They found that they could cause cholestasis and liver injury, but only with the combination of both intestinal injury and TPN infusion.