T. Hang Nghiem-Rao

Infants born to mothers with obesity have increased risk for later development of metabolic dysfunction-associated steatotic liver disease (MASLD); however early hepatic changes that occur in these infants remain unclear. We integrated metabolomic analysis of umbilical cord plasma and transcriptomic analysis of cord plasma-exposed hepatocytes to examine differences in the intrauterine environment of pregnancies with and without maternal obesity. We identified significantly higher abundance of fatty acids, bioactive lipids, and upregulation of glutathione metabolism in cord plasma from pregnancies with obesity compared to normal weight pregnancies. Hepatocytes exposed to cord plasma from pregnancies with obesity exhibited distinct transcriptional changes that favored cellular injury and inflammation, and impaired hepatocyte development compared to hepatocytes exposed to cord plasma of normal weight pregnancies. In integrated analysis, metabolite-gene relationships were distinct between pregnancies with and without obesity, and the abundance of lipids were positively correlated with the expression of KDM4D, DTX3, and NOTCH4 and negatively correlated with the expression of MT_TS1. Our findings provide novel insights into transcriptional changes induced in hepatocytes by circulating factors in the intrauterine environment of pregnancies with obesity. Excess intrauterine lipids may contribute to hepatic injury, inflammation, impaired mitochondrial function, and impaired hepatocyte development in infants of pregnancies with obesity.

Parenteral nutrition-associated cholestasis (PNAC) significantly limits the safety of intravenous parenteral nutrition (PN). Critically ill infants are highly vulnerable to PNAC-related morbidity and mortality, however the impact of hepatic immaturity on PNAC is poorly understood. We examined developmental differences between fetal/infant and adult livers, and used human induced pluripotent stem cell-derived hepatocyte-like cells (iHLC) to gain insights into the contribution of development to altered sterol metabolism and PNAC. We used RNA-sequencing and computational techniques to compare gene expression patterns in human fetal/infant livers, adult liver, and iHLC. We identified distinct gene expression profiles between the human feta/infant livers compared to adult liver, and close resemblance of iHLC to human developing livers. Compared to adult, both developing livers and iHLC had significant downregulation of xenobiotic, bile acid, and fatty acid metabolism; and lower expression of the sterol metabolizing geneABCG8.When challenged with stigmasterol, a plant sterol found in intravenous soy lipids, lipid accumulation was significantly higher in iHLC compared to adult-derived HepG2 cells. Our findings provide insights into altered bile acid and lipid metabolizing processes in the immature human liver, and support the use of iHLC as a relevant model system of developing liver to study lipid metabolism and PNAC.

Parenteral nutrition-associated cholestasis (PNAC) significantly limits the safety of intravenous parenteral nutrition (PN). Critically ill infants are highly vulnerable to PNAC-related morbidity and mortality, however the impact of hepatic immaturity on PNAC is poorly understood. We examined developmental differences between fetal/infant and adult livers, and used human induced pluripotent stem cell-derived hepatocyte-like cells (iHLC) to gain insights into the contribution of development to altered sterol metabolism and PNAC. We used RNA-sequencing and computational techniques to compare gene expression patterns in human fetal/infant livers, adult liver, and iHLC. We identified distinct gene expression profiles between the human feta/infant livers compared to adult liver, and close resemblance of iHLC to human developing livers. Compared to adult, both developing livers and iHLC had significant downregulation of xenobiotic, bile acid, and fatty acid metabolism; and lower expression of the sterol metabolizing gene ABCG8. When challenged with stigmasterol, a plant sterol found in intravenous soy lipids, lipid accumulation was significantly higher in iHLC compared to adult-derived HepG2 cells. Our findings provide insights into altered bile acid and lipid metabolizing processes in the immature human liver, and support the use of iHLC as a relevant model system of developing liver to study lipid metabolism and PNAC.

Background Animal studies suggest that total parenteral nutrition (TPN) may alter bacterial colonization of the intestinal tract and contribute to complications. Progressive changes in gut microbiome of infants receiving TPN are not well understood. Methods Infants with and without TPN/soy lipid were enrolled in a prospective, longitudinal study. Weekly fecal samples were obtained for the first 4 weeks of life. High throughput pyrosequencing of 16S rDNA was used for compositional analysis of the gut microbiome. Results 47 infants were eligible for analyses, 25 infants received TPN, and 22 infants did not (control). Although similar between TPN and control groups in the first week, fecal bacterial alpha diversity was significantly lower in the TPN group compared to controls at week 4 (Shannon index 1.0 vs 1.5, P-value = 0.03). The TPN group had significantly lower Bacteroidetes and higher Verrucomicrobia abundance compared to controls (P-values < 0.05), and these differences became more pronounced over time. At the genus level, TPN was associated with lower abundance of Bacteroides and Bifidobacterium in all weeks. Conclusions TPN is associated with significant loss of biodiversity and alterations in the pattern of gut microbial colonization of infants over time. TPN-associated dysbiosis may predispose infants to adverse NICU outcomes.

Background: The aim of this study was to determine the tube‐related complications and feeding outcomes of infants discharged home from the neonatal intensive care unit (NICU) with nasogastric (NG) tube feeding or gastrostomy (G‐tube) feeding. Materials and Methods: We performed a chart review of 335 infants discharged from our NICU with home NG tube or G‐tube feeding between January 2009 and December 2013. The primary outcome was the incidence of feeding tube–related complications requiring emergency department (ED) visits, hospitalizations, or deaths. Secondary outcome was feeding status at 6 months postdischarge. Univariate and multivariate analyses were conducted. Results: There were 322 infants discharged with home enteral tube feeding (NG tube, n = 84; G‐tube, n = 238), with available outpatient data for the 6‐month postdischarge period. A total of 115 ED visits, 28 hospitalizations, and 2 deaths were due to a tube‐related complication. The incidence of tube‐related complications requiring an ED visit was significantly higher in the G‐tube group compared with the NG tube group (33.6% vs 9.5%, P < .001). Two patients died due to a G‐tube–related complication. By 6 months postdischarge, full oral feeding was achieved in 71.4% of infants in the NG tube group compared with 19.3% in the G‐tube group (P < .001). Type of feeding tube and percentage of oral feeding at discharge were significantly associated with continued tube feeding at 6 months postdischarge. Conclusion: Home NG tube feeding is associated with fewer ED visits for tube‐related complications compared with home G‐tube feeding. Some infants could benefit from a trial home NG tube feeding.

Infants and children who depend on parenteral nutrition are among the most vulnerable to developing potentially devastating intestinal failure–associated liver disease. While the pathogenesis of intestinal failure–associated liver disease remains unclear, evidence for the contribution of fat emulsions to cholestasis and liver injury has rapidly increased in recent years. Data demonstrating the interaction among phytosterols, fatty acids, and antioxidants in cellular pathways that mediate bile flow and hepatic injury have led to the development of newer alternative fat emulsions. This article reviews recent studies that have provided insight into the potential hepatotoxicities of fat emulsions.

Background: Phytosterols 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. Methods: In 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. Results: Compared 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 and 0.8 d, 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 wk 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 d of SO lipid (AUC₅) than infants born ≥ 28 wk gestational age. Conclusion: Phytosterols 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.

Background: Cyclic parenteral nutrition (PN) is used for both the treatment and prevention of parenteral nutrition–associated liver disease (PNALD). Early initiation of prophylactic cyclic PN may not be well tolerated in young neonates. Our objective was to test the hypothesis that prophylactic cyclic PN initiated prior to the onset of hyperbilirubinemia is associated with younger age at initiation, lower bilirubin levels, and similar rates of adverse events compared to therapeutic cyclic PN initiated after established cholestasis in surgical neonates. Methods: A retrospective review of infants with gastrointestinal disorders requiring surgical intervention who received cyclic PN 2006‐2011 was performed. Results: Of the 43 infants eligible for analysis, 23 received prophylactic and 20 received therapeutic cyclic PN. Infants in both groups were comparable in demographics, surgical diagnoses, and illness severity. At initiation of cyclic PN, infants with prophylactic cyclic PN were significantly younger in chronologic (P = .003) and postmenstrual age (P = .029). Prophylactic cyclic PN was associated with a significantly lower incidence of hyperbilirubinemia (P = .001), lower maximum conjugated bilirubin (P < .0001), and lower last checked conjugated bilirubin (P = .032) compared to the therapeutic cyclic PN. The incidence of hypoglycemia, hyperglycemia, and hypertriglyceridemia was similar for the 2 groups. Conclusions: There may be a potential benefit to initiating cyclic PN prior to the development of hyperbilirubinemia in surgical neonates. Early initiation of prophylactic cyclic PN does not appear to increase the risk for adverse events.