New insight into mechanisms of parenteral nutrition—Associated cholestasis: Role of plant sterols

doi:10.1016/S0022-3468(98)90349-9

Journal of Pediatric Surgery

Volume 33, Issue 1, January 1998, Pages 1-6

https://doi.org/10.1016/S0022-3468(98)90349-9 Get rights and content

Abstract

Background Purpose: Infants on long-term parenteral nutrition frequently will have progressive cholestatic liver disease, the cause of which remains largely unknown. The aim of this study is to establish a possible role for plant sterols (phytosterols) in the pathogenesis of parenteral nutrition-associated cholestasis (PNAC).

Methods: Two experimental studies were used: (1) A study on neonatal piglets involved the daily injection of plant sterols; measurement of their concentrations in serum, liver, and bile during a 14-day period; and determination of serum bile acid concentrations, bile acid secretion, and bile flow at the end of the 14-day period. (2) Isolated rat hepatocyte couplets were used to study the effects of sterols on canalicular secretion.

Results: The daily injection of phytosterols (in amounts similar to those given to infants who receive parenteral nutrition) led to their progressive accumulation in the piglets' serum, liver, and bile. Serum bile acid levels were significantly higher in the sterol-treated piglets. Maximal bile acid excretion was significantly lower in the sterol group. Phytosterols caused a significant inhibition of secretory function in isolated rat hepatocyte couplets.

Conclusion: Important contaminants of commercial lipid emulsions (phytosterols) have been identified as a possible cause of PNAC.

References (9)

EMM Quigley et al.
Hepatobiliary complications of total parenteral nutrition
Gastroenterology
(1993)
PT Clayton et al.
Phytosterolaemia in children with parenteral nutrition—Associated cholestatic liver disease
Gastroenterology
(1993)
R Coleman et al.
Hepatobiiary function and toxicity in vitro using isolated hepatocyte couplets
Gen Pharmac
(1995)
J Boyer et al.
Preparation and specific applications of isolated hepatocyte couplets
Methods Enzymol
(1990)

There are more references available in the full text version of this article.

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After the stop of LE, plasma total CAMP, STIGM and SITO concentrations decreased very slowly suggesting a very slow metabolism and/or a slow elimination by hepatic ABCG5/G8 transporters and scavenger receptor BI and/or possibly by tissue incorporation. Phytosterol accumulation in tissues was described in patients with phytosterolemia and xanthomatosis, in ABCG5/G8 knockout mice fed a high-phytosterol diet and in neonatal piglets involved the daily injection of phytosterols [22–24]. It is plausible that because of similar structure, phytosterols could substitute cholesterol in cell membranes and this may interfere with membrane function, signal transduction or membrane-bound enzyme activity [18,24].
Phytosterols in vegetable oil (VO)-based lipid emulsions (LE) likely contribute to parenteral nutrition-associated cholestasis (PNAC) in preterm infants. No characterization of plasma phytosterol half-lives has been done in very low birth weight (VLBW) preterm infants receiving parenteral nutrition (PN) with LE.
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VLBW preterm infants on PN with LE had rather long plasma phytosterol half-lives similar to hypercholesterolemic adults and phytosterolemic homozygotes patients. We speculate that the accumulation of phytosterols could contribute to their vulnerability to PNAC.
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A growing amount of evidence suggests that specific components of parenteral nutrition (PN) are involved in the pathogenesis of intestinal failure-associated liver disease (IFALD). For a number of reasons, intravenous lipid emulsions (ILEs) are thought to play a key role in IFALD. PN without the provision of any fat source results in a higher incidence of liver dysfunction compared with PN with fat, making it difficult to draw a correlation between the role of ILE and PN-associated liver disease (PNALD) as both its presence and absence can predispose patients to developing PNALD. Moreover, excessive lipid provision is also thought to increase the incidence of IFALD. This may, in part, be caused by the widespread use of soybean oil-derived ILEs. Soybean oil-based ILEs contain high levels of proinflammatory omega-6 poly unsaturated fatty acids that result in increased production of proinflammatory products that can cause liver damage. Other components present in soybean oil-based ILEs, such as phytosterols and vitamin E content, may also contribute to the risk of IFALD. Alternative ILEs, containing fish, olive, or coconut oils, are being used to prevent or treat this potentially fatal disease. This chapter will address how the inflammatory characteristics of each oil source, the dose, and amount of phytosterols and alpha-tocopherol can either predispose patients to IFALD or be used in its prevention or treatment.

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^☆: Presented at the 44th Annual International Congress of the British Association of Paediatric Surgeons, Istanbul, Turkey, July 22–25, 1997.

^☆☆: Winner of the 1996 BAPS Trainee Prize.

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BAPS prize lectureNew insight into mechanisms of parenteral nutrition—Associated cholestasis: Role of plant sterols☆,☆☆

Abstract

Gastroenterology

Gastroenterology

Gen Pharmac

Methods Enzymol

BAPS prize lecture
New insight into mechanisms of parenteral nutrition—Associated cholestasis: Role of plant sterols☆,☆☆