Kinetics of phytosterol metabolism in neonates receiving parenteral nutrition

Abstract

BackgroundPhytosterols in soybean oil (SO) lipids likely contribute to parenteral nutrition-associated liver disease (PNALD) in infants. No characterization of phytosterol metabolism has been done in infants receiving SO lipids.MethodsIn a prospective cohort study, 45 neonates (36 SO lipid vs 9 control) underwent serial blood sample measurements of sitosterol, campesterol, and stigmasterol. Mathematical modeling was used to determine pharmacokinetic parameters of phytosterol metabolism and phytosterol exposure.ResultsCompared to controls, SO lipid-exposed infants had significantly higher levels of sitosterol and campesterol (p<0.01). During SO lipid infusion, sitosterol and campesterol reached half of steady-state plasma levels within 1.5 days and 0.8 days, respectively. Steady-state level was highest for sitosterol (1.68 mg/dL), followed by campesterol (0.98 mg/dL), and lowest for stigmasterol (0.01 mg/dL). Infants born < 28 weeks gestational age had higher sitosterol steady-state levels (p=0.03) and higher area under the curve for sitosterol (p=0.03) during the first 5 days of SO lipid (AUC5) than infants born ≥ 28 weeks gestational age.ConclusionPhytosterols in SO lipid accumulate rapidly in neonates. Very preterm infants receiving SO lipid have higher sitosterol exposure, and may have poorly developed mechanisms of eliminating phytosterols that may contribute to their vulnerability to PNALD.

Plasma Phytosterol Half‐Life and Levels Are Increased in Very Low Birth Weight Preterm Infants with Parenteral Nutrition‐Associated Cholestasis

“…In our PNAC infants, plasma phytosterol concentrations on both PN d7 and d14 were up to twofold higher than CTRL, and, as reported in the literature, slightly higher than those in patients with heterozygous phytosterolemia (Clayton et al, 1993;Ellegard et al, 2005;Nghiem-Rao et al, 2015;Pianese et al, 2008;Pupillo et al, 2016;Savini et al, 2013;Wang et al, 2015). The high phytosterol concentrations observed in Fig.…”

“…In our PNAC infants, plasma phytosterol concentrations on both PN d7 and d14 were up to twofold higher than CTRL, and, as reported in the literature, slightly higher than those in patients with heterozygous phytosterolemia (Clayton et al, ; Ellegard et al, ; Nghiem‐Rao et al, ; Pianese et al, ; Pupillo et al, ; Savini et al, ; Wang et al, ). The high phytosterol concentrations observed in PNAC infants suggest that they may have poorly developed mechanisms of metabolizing phytosterols and that there might be a link between phytosterols and cholestasis (Bindl et al, ; Iyer et al, ).…”

“…Nghiem‐Rao et al found that phytosterols in preterm infants on PN reached steady median plasma concentrations within 3–5 days of starting LE. Moreover, in PNAC infants, changes in conjugated bilirubin closely resembled those of plasma phytosterols (Nghiem‐Rao et al, ). Pupillo et al reported that preterm infants without PNAC had a plasma phytosterol half‐life of about 10 days, which was similar to that reported in phytosterolemic adult patients (Bhattacharyya et al, ; Lin et al, ; Pupillo et al, ).…”

Potential Hepatotoxicities of Intravenous Fat Emulsions in Infants and Children

“…In a prospective study of 45 infants, we found that infants who received a short duration of soy oil–based IVFEs had significantly higher levels of sitosterol and campesterol versus control infants who did not receive soy oil–based IVFE. In those who received soy oil–based IVFE, very preterm infants born <28 weeks of gestational age had a significantly higher steady state level and area under the curve for sitosterol as compared with more mature infants 54 . These findings indicate that very preterm infants accumulate more sitosterol than more mature infants, suggesting a developmental inability to regulate sterol levels that may contribute to the increased vulnerability of preterm infants to IFALD.…”

Phytosterol Esterification is Markedly Decreased in Preterm Infants Receiving Routine Parenteral Nutrition

“…These results could be explained by the different effect of phytosterol structure upon LCAT and ACAT activity resulting in different esterification rates. However, a faster incorporation of Ester-PHY into membranes cannot be excluded, even if all study patients received IV lipids for a quite long period of time before sampling and, thus, were likely at a steady state [30]. In vitro reconstitution of sterol transfer by G5 and G8 in a cell-free system showed a better sterol-free ABCG5/ABCG8-mediated transport than that of esterified sterols [31].…”