**9. Changes in liver function during PN**

PN is a valuable clinical method supporting complete nutrition in the case of intestinal failure. However, PN can lead to serious metabolic complications including gut atrophy and dysfunction and hepatic abnormalities. Liver dysfunction is common in infant and adult patients receiving PN for both short- and long-term. Prolonged PN feeding can lead to PN associated liver disease (PNALD), fibrosis, steatosis, and eventually liver failure [99, 100].

Depending on the patient's age and duration of the PN administration, PNALD can be classified into three types: hepatic steatosis, cholestasis and gallbladder sludge [101, 102]. PN associated steatosis is mostly seen in adult patients with higher caloric intake from carbohydrates such as dextrose or carbohydratenitrogen imbalance with elevated triglyceride synthesis in the liver. PN associated cholestasis is more common among premature newborns (40–60%) and infants receiving short-term and long-term PN than adults. PN associated cholestasis was first reported in premature infants receiving TPN. Cholestasis occurs when bile flow is impaired with an elevation in bilirubin level > 2 mg/dL. Other hepatic enzymes including alkaline phosphatase (ALP) and gamma glutamyl aminotransferase (GGT) involved in the synthesis and secretion of bile are also impaired. This occurs within 1–5 weeks of PN administration [103]. Gallbladder sludge is seen in both adults and children and develops due to bile storage in the bladder for an extended period. Biliary sludge develops in patients having PN between 3 and 6 weeks [104].

Several risk factors have been shown to contribute to the development of PNALD including poor nutrition with inappropriate ratio of dextrose, lipid, and amino acid, premature birth, duration of PN, bacterial/fungal infection and short bowel syndrome. Evidence from the literature suggests that PN associated liver dysfunction can be improved by avoiding excess calories and maintaining dextrose/ lipid/amino acid balance. This will promote fatty acid oxidation, avoiding hyperinsulinemia in the liver and reducing the risk for the development of PN associated fatty liver disease [105].

Another key factor for the prevention or reversal of PNALD includes either fish oil-based lipid emulsion or lipid emulsion infusion of fish oil, soybean oil and olive oil mixture rather than a soybean oil-based formulation. Pro-inflammatory ω-6 fatty acids having a high amount of phytosterols in soybean oil promotes the proliferation of Kupffer cells and development of PNALD by impairing bile secretion and activating excessive secretion of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, IFN-γ, and reactive oxygen species (ROS) [106]. Soybean oil derived lipid component phytosterols alter the intestinal microbial composition including the overgrowth of specific bacterial components associated with PNALD [7]. Farnesoid X receptor (FXR) is known to inhibit bacterial overgrowth and induce the expression of genes involved in the protection of gut [107]. Soybean-derived phytosterols are FXR agonists. TPN studies in piglet and mouse models have suggested that alteration in the bile acid mediated FXR-FGF19 axis may lead to the pathophysiology of PNALD [108, 109].

*Parenteral Nutrition Modeling and Research Advances DOI: http://dx.doi.org/10.5772/intechopen.101692*

Alternatively, fish oil-based lipid emulsion or lipid emulsion of fish oil, olive oil and soybean oil mixture can reverse the development of PNALD. Anti-inflammatory ω-3 polyunsaturated fatty acids (PUFA) in fish oil, which have a high amount of omegaven and a low amount of phytosterols, can reduce the development of PNALD by suppressing the cytokine TNF-α [103, 110–114]. Additionally, a study from Harris, JK et al., shows that parenteral nutrition associated liver injury (PNALI) mice receiving fish oil derived lipid emulsion with a high amount of Omegaven harbor a specific composition of fecal microbiota. Specifically, there is a reduction in *Erysipelotrichaceae,* which appears to prevent the activation of Kupffer cells and subsequent PNALD as compared to soybean oil based lipid emulsions [32, 106]. Further, piglet studies have shown that replacing soybean oil based PN with fish oil based PN in neonatal piglets results in lower bilirubin, alanine transferase (ALT), aspartate transferase (AST) and improved PNALD [115, 116].

As mentioned, bacterial overgrowth and bacterial translocation is another potential cause of PNALD, which can be augmented with antibiotics such as metronidazole. Metronidazole administration in a rat model showed reduced fat accumulation with lower alkaline phosphatase (ALP), aspartate aminotransferase (AAT), and gamma glutamyl transpeptidase in the metronidazole treated group relative to the control group receiving PN [117, 118]. Further glutamine supplementation, an essential energy source for the gut, prevented liver steatosis in a PN rat model [119]. Considering the importance of a healthy gut microbiome in early life on immune development and metabolic growth, it remains unclear what the implications of antibiotic administration in neonates have on long-term growth and development.
