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Mechanisms of Disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis

Nature Clinical Practice Gastroenterology & Hepatology volume 4, pages 277–287 (2007)Cite this article

Abstract

Since its introduction into clinical practice, parenteral nutrition has revolutionized the care of premature neonates. Serum transaminase and bilirubin levels are commonly elevated in infants on parenteral nutrition, but their normalization is typical in the setting of short-term administration of parenteral nutrition uncomplicated by sepsis. Premature infants who require long-term parenteral nutrition are, however, at severe risk for developing life-threatening hepatic complications. These complications include cirrhosis, liver failure, and the concomitant risks of sepsis, coagulopathy and death. Premature infants and those with short-bowel syndrome are most susceptible to these morbid outcomes. Although it has been more than a quarter of a century since parenteral nutrition was first introduced and its association with hepatic complications described, the precise etiology of parenteral nutrition associated cholestasis (PNAC) remains a mystery; however, our understanding of the molecular components that contribute to PNAC has improved substantially. In this Review, we summarize the fundamentals of PNAC, describe animal models of the disease, review the hepatic bile acid transporters that are crucial for bile acid homeostasis, and define the roles that endotoxin, genetics, and the components of parenteral nutrition are likely to have in the molecular pathogenesis of this life-threatening condition.

Key Points

  • Parenteral nutrition provides valuable life-sustaining nutrients to patients unable to tolerate enteral nutrition, but prolonged administration is associated with severe, life-threatening liver disease, especially in premature neonates

  • The precise etiology of parenteral nutrition associated cholestasis (PNAC) is probably multifactorial, with risk factors including prematurity, history of bowel resection and/or lack of enteral feeds, catheter infections and/or sepsis, and a lack of or presence of specific components in the parenteral nutrition itself

  • Older children and adults are less prone to severe cases of PNAC than are neonates, and animal models suggest that there is a developmental component to bile acid transporter gene expression; these factors indicate that the expression of critical hepatic protective genes might be involved in susceptibility to PNAC

  • Animal models of parenteral nutrition administration suggest that parenteral nutrition itself and/or particular components of parenteral nutrition might affect key hepatic bile acid transporters, apoptotic signaling, and other detoxification mechanisms at the gene level, thereby promoting cholestasis and hepatocellular injury

  • Few therapeutic options are available for PNAC, with severe cases necessitating liver or combined liver–bowel transplantation

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Figure 1: Factors that contribute to the development of parenteral nutrition associated cholestasis
Figure 2: Pathological features of parenteral nutrition associated liver injury
Figure 3: Hepatocyte transporters and nuclear receptors involved in bile acid homeostasis

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Acknowledgements

We would like to thank Saul J Karpen, MD, PhD, and members of the Texas Children's Liver Center Laboratory for intellectual contributions to the experimental data present in this manuscript. The authors would also like to thank Milton J Finegold, MD, Chief of Pediatric Pathology at Texas Children's Hospital, Baylor College of Medicine, for allowing us to include in this manuscript slides of gross and histopathological PNAC from his personal collection. Work in BA Carter's laboratory has been supported by the American Gastroenterological Association/Roche, Child Health Research Center K12 HD41648-04, and the Children's Digestive Health and Nutrition Foundation.

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  1. BA Carter is an Assistant Professor of Pediatrics and Hepatologist, and RJ Shulman is a Professor of Pediatrics and Director of the Nutrition Support Team at Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.,

    Beth A Carter & Robert J Shulman

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Correspondence to Beth A Carter.

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Carter, B., Shulman, R. Mechanisms of Disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis. Nat Rev Gastroenterol Hepatol 4, 277–287 (2007). https://doi.org/10.1038/ncpgasthep0796

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