Research ArticleLiver disease

Phytosterols Promote Liver Injury and Kupffer Cell Activation in Parenteral Nutrition–Associated Liver Disease

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Science Translational Medicine  09 Oct 2013:
Vol. 5, Issue 206, pp. 206ra137
DOI: 10.1126/scitranslmed.3006898

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Solving the Mysteries of Intravenous Nutrition

Parenteral nutrition (PN), an intravenously delivered replacement for food, is a life-saving option for patients who cannot tolerate enteral feeding. These patients’ diagnoses vary widely, ranging from short-term illnesses like pancreatitis to long-term intestinal problems. Unfortunately, the use of PN takes a toll on the liver and can lead to cholestatic liver damage known as PN-associated liver disease (PNALD). The risk of PNALD is particularly high for premature infants and for children with intestinal failure or short bowel syndrome, who are often PN-dependent for months or years. It is well known that the duration of PN use contributes to the risk of PNALD, but other factors that cause this disease are not fully understood.

Clinical evidence had suggested that the use of soy lipids in PN increases the risk of PNALD compared to fish oil–based lipids, but an explanation for this difference had been elusive. Now, El Kasmi and colleagues have identified the likely culprit for this side effect of soy lipids, as well as its pathogenic mechanism. The authors designed a mouse model, which they treated with a variety of PN formulations. Some of these included stigmasterol, a phytosterol derived from soy. Only the mice that received stigmasterol, either alone or as a component of soy lipid infusion, developed cholestasis. To clarify the mechanism for this effect, the authors showed that stigmasterol decreased the expression of sterol transporters in hepatocytes, resulting in a buildup of phytosterols in the liver cells. The researchers also found evidence that gut microbiota contribute to the risk of PNALD through stimulation of Toll-like receptor 4 and that antibiotic treatment reduces this risk.

Additional work will be needed to investigate the role of other phytosterols and further details of the mechanism, including the effects of specific gut microbes on PNALD. However, the results of this study add to the accumulating evidence of PNALD risk associated with soy-based lipids, clarify the pathogenesis of this disease, and may help promote a shift away from stigmasterol-containing solutions for PN-dependent patients.