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

Author
item CARTER, BETH - BAYLOR COLLEGE MED
item Shulman, Robert

Submitted to: Nature Clinical Practice Gastroenterology and Hepatology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/6/2007
Publication Date: 5/5/2007
Citation: Carter, B.A., Shulman, R.J. 2007. Mechanisms of disease: Update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis. Nature Clinical Practice Gastroenterology & Hepatology. 4(5):277-287.

Interpretive Summary: Intravenous feeding (parenteral nutrition, PN) can be life saving for infants and children who are unable to take food into their digestive tracts. Unfortunately, PN can be associated with liver disease that can be life threatening. We do not fully understand how this happens, but part of the mechanism may be related to how the PN affects the normal flow of materials through the liver in some individuals. It has been found that there are differences among individuals in their ability to synthesize and move digestive fluids though the liver. These differences among individuals may influence their risk of getting liver disease from parenteral nutrition.

Technical Abstract: Since its introduction into clinical practice in the 1970s, 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 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 quarter of a century since parenteral nutrition was 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 play in the molecular pathogenesis of this life-threatening condition.