Parenteral nutrition emulsion inhibits CYP3A4 in an iPSC derived liver organoids testing platform.

OBJECTIVES: Parenteral nutrition (PN) is used for patients of varying ages with intestinal failure to supplement calories. Premature newborns with low birth weight are at a high risk for developing PN associated liver disease (PNALD) including steatosis, cholestasis, and gallbladder sludge/stones. To optimize nutrition regimens, models are required to predict PNALD. METHODS: We have exploited induced pluripotent stem cell derived liver organoids to provide a testing platform for PNALD. Liver organoids mimic the developing liver and contain the different hepatic cell types. The organoids have an early postnatal maturity making them a suitable model for premature newborns. To mimic PN treatment we used medium supplemented with either clinoleic (80% olive oil/20% soybean oil) or intralipid (100% soybean oil) for 7 days. RESULTS: Homogenous HNF4a staining was found in all organoids and PN treatments caused accumulation of lipids in hepatocytes. Organoids exhibited a dose dependent decrease in CYP3A4 activity and expression of hepatocyte functional genes. The lipid emulsions did not affect overall organoid viability and glucose levels had no contributory effect to the observed results. CONCLUSIONS: Liver organoids could be utilized as a potential screening platform for the development of new, less hepatotoxic PN solutions. Both lipid treatments caused hepatic lipid accumulation, a significant decrease in CYP3A4 activity and a decrease in the RNA levels of both CYP3A4 and CYP1A2 in a dose dependent manner. The presence of high glucose had no additive effect, while Clinoleic at high dose, caused significant upregulation of interleukin 6 and TLR4 expression.

Altered hepatic and intestinal homeostasis in a neonatal murine model of short-term total parenteral nutrition and antibiotics.

Parenteral nutrition (PN) prevents starvation and supports metabolic requirements intravenously when patients are unable to be fed enterally. Clinically, infants are frequently provided PN in intensive care settings along with exposure to antibiotics (ABX) to minimize infection during care. Unfortunately, neonates experience extremely high rates of hepatic complications. Adult rodent and piglet models of PN are well-established but neonatal models capable of leveraging the considerable transgenic potential of the mouse remain underdeveloped. Utilizing our newly established neonatal murine PN mouse model, we administered ABX or controlled drinking water to timed pregnant dams to disrupt the maternal microbiome. We randomized mouse pups to PN or sham surgery controls +/- ABX exposure. ABX or short-term PN decreased liver and brain organ weights, intestinal length, and mucosal architecture (vs. controls). PN significantly elevated evidence of hepatic proinflammatory markers, neutrophils and macrophage counts, bacterial colony-forming units, and evidence of cholestasis risk, which was blocked by ABX. However, ABX uniquely elevated metabolic regulatory genes resulting in accumulation of hepatocyte lipids, triglycerides, and elevated tauro-chenoxycholic acid (TCDCA) in serum. Within the gut, PN elevated the relative abundance of Akkermansia, Enterococcus, and Suterella with decreased Anaerostipes and Lactobacillus compared with controls, whereas ABX enriched Proteobacteria. We conclude that short-term PN elevates hepatic inflammatory stress and risk of cholestasis in early life. Although concurrent ABX exposure protects against hepatic immune activation during PN, the dual exposure modulates metabolism and may contribute toward early steatosis phenotype, sometimes observed in infants unable to wean from PN.NEW & NOTEWORTHY This study successfully established a translationally relevant, murine neonatal parenteral nutrition (PN) model. Short-term PN is sufficient to induce hepatitis-associated cholestasis in a neonatal murine model that can be used to understand disease in early life. The administration of antibiotics during PN protects animals from bacterial translocation and proinflammatory responses but induces unique metabolic shifts that may predispose the liver toward early steatosis.

Partially hydrolyzed guar gum alleviates hepatic steatosis and alters specific gut microbiota in a murine liver injury model.

PURPOSE: The gut microbiota, via the gut-liver axis, plays an important role in the development of intestinal failure-associated liver disease. Here, we investigated whether partially hydrolyzed guar gum (PHGG), a dietary fiber could alleviate liver damage and modulate the gut microbiota in a murine liver injury (LI) model. METHODS: Liver injury was induced in 6-week-old male C57BL/6 mice using an enteral liquid diet composed of parenteral nutrition (LI group) and treated with 5% PHGG (LI/PHGG group). Liver histopathology was examined using oil red O and a tumor necrosis factor-α (TNF-α) labeling. The gut microbiota was examined using 16S rRNA gene sequencing. RESULTS: Lipid accumulation was significantly decreased in the LI /PHGG group when compared with that of the LI group. The area of TNF-α-positive cells was significantly higher in the LI group when compared with that of the control. The principal coordinate analysis (PCoA) revealed pronounced changes in the gut microbiota after PHGG treatment. Linear discriminant analysis of effect size showed that PHGG treatment significantly increased cecal abundance of Parabacteroides. CONCLUSIONS: PHGG alleviated hepatic steatosis following liver injury in mice. The protective effect of PHGG treatment could be associated with increased abundance of Parabacteroides in the cecum.

The administration of hepatocyte growth factor prevents total parenteral nutrition-induced hepatocellular injury in a rat model.

PURPOSE: Total parenteral nutrition (TPN) sometimes induces parenteral nutrition-associated liver disease (PNALD). Hepatocyte growth factor (HGF) acts as a potent hepatocyte mitogen anti-inflammatory and antioxidant actions. We aimed to evaluate the effect of HGF on PNALD in a rat model of TPN. METHODS: A catheter was placed in the right jugular vein for 7-day continuous TPN. All rats were divided into three groups: TPN alone (TPN group), TPN plus intravenous HGF at 0.3 mg/kg/day [TPN + HGF (low) group], and TPN plus HGF at 1.0 mg/kg/day [TPN + HGF (high) group]. On day 7, livers were harvested and the histology, inflammatory cytokines and apoptosis were evaluated. RESULTS: Histologically, lipid droplets were apparent in the TPN group, but decreased in the TPN + HGF (low) and TPN + HGF (high) groups. The histological nonalcoholic fatty liver disease activity scores in the TPN + HGF (low) and TPN + HGF (high) groups were significantly lower than that in the TPN group (p < 0.01). There were no significant differences in the inflammatory cytokine levels of the three groups. The caspase-9 expression levels in the TPN + HGF (low) and TPN + HGF (high) groups were significantly decreased in comparison to that in the control group (p < 0.05). CONCLUSION: The intravenous administration of HGF attenuated hepatic steatosis induced by 7-day TPN dose dependently.

TGR5 signaling mitigates parenteral nutrition-associated liver disease.

Bile acid receptors regulate the metabolic and immune functions of circulating enterohepatic bile acids. This process is disrupted by administration of parenteral nutrition (PN), which may induce progressive hepatic injury for unclear reasons, especially in the newborn, leading to PN-associated liver disease. To explore the role of bile acid signaling on neonatal hepatic function, we initially observed that Takeda G protein receptor 5 (TGR5)-specific bile acids were negatively correlated with worsening clinical disease markers in the plasma of human newborns with prolonged PN exposure. To test our resulting hypothesis that TGR5 regulates critical liver functions to PN exposure, we used TGR5 receptor deficient mice (TGR5-/-). We observed PN significantly increased liver weight, cholestasis, and serum hepatic stress enzymes in TGR5-/- mice compared with controls. Mechanistically, PN reduced bile acid synthesis genes in TGR5-/-. Serum bile acid composition revealed that PN increased unconjugated primary bile acids and secondary bile acids in TGR5-/- mice, while increasing conjugated primary bile acid levels in TGR5-competent mice. Simultaneously, PN elevated hepatic IL-6 expression and infiltrating macrophages in TGR5-/- mice. However, the gut microbiota of TGR5-/- mice compared with WT mice following PN administration displayed highly elevated levels of Bacteroides and Parabacteroides, and possibly responsible for the elevated levels of secondary bile acids in TGR5-/- animals. Intestinal bile acid transporters expression was unchanged. Collectively, this suggests TGR5 signaling specifically regulates fundamental aspects of liver bile acid homeostasis during exposure to PN. Loss of TGR5 is associated with biochemical evidence of cholestasis in both humans and mice on PN.NEW & NOTEWORTHY Parenteral nutrition is associated with deleterious metabolic outcomes in patients with prolonged exposure. Here, we demonstrate that accelerated cholestasis and parental nutrition-associated liver disease (PNALD) may be associated with deficiency of Takeda G protein receptor 5 (TGR5) signaling. The microbiome is responsible for production of secondary bile acids that signal through TGR5. Therefore, collectively, these data support the hypothesis that a lack of established microbiome in early life or under prolonged parenteral nutrition may underpin disease development and PNALD.

Understanding triglyceride levels related to intravenous fat administration.

Lipid is an essential macronutrient in parenteral nutrition (PN) support. intravenous (IV) lipid provides essential fatty acids and a concentrated calorie source. Preterm infants are at risk for essential fatty deficiency early in life. Lipid administration is associated with some risks, and there are guidelines for administration to minimize complications. Lipid emulsions in the United States are derived from soybean oil. Outside of the United States, lipid emulsions made from fish oil or combinations of fish, soybean, olive, and medium-chain triglycerides (MCTs) are under investigation for improved tolerance, lower plasma lipid levels, and improved fatty acid profiles, all of which are considered beneficial. Triglyceride levels are an important measurement to assess patient tolerance.

Successful rehabilitation in pediatric ultrashort small bowel syndrome.

OBJECTIVE: To examine treatment outcomes in pediatric patients with ultrashort small bowel (USSB) syndrome in an intestinal rehabilitation program (IRP). STUDY DESIGN: We reviewed IRP records for 2001-2011 and identified 28 children with USSB (≤ 20 cm of small bowel). We performed univariate analysis using the Fisher exact test and Wilcoxon rank-sum test to compare characteristics of children who achieved parenteral nutrition (PN) independence with intact native bowel and those who did not. Growth, nutritional status, and hepatic laboratory test results were compared from the time of enrollment to the most recent values using the Wilcoxon signed-rank test. RESULTS: Of the 28 patients identified, 27 (96%) survived. Almost one-half (48%) of these survivors achieved PN independence with their native bowel. The successfully rehabilitated patients were more likely to have an intact colon and ileocecal valve (P = .01). Significant improvements in PN kcal/kg, total bilirubin, and height and weight z-scores were seen in all patients, but serum hepatic transaminase levels did not improve in the nonrehabilitated patients. CONCLUSION: Enrollment in an IRP provides an excellent probability of survival for children with USSB. The presence of an intact ileocecal valve and colon are positively associated with rehabilitation in this population, but are not requisite. Approximately one-half of patients with USSB can achieve rehabilitation, with a median time to PN independence of less than 2 years. The USSB population can attain reduced PN dependence, improvement of PN-associated liver disease, and enhanced growth with the aid of an IRP.

Home Parenteral Nutrition for Children: What Are the Factors Indicating Dependence and Mortality?

Parenteral nutrition (PN) in children with short bowel syndrome is crucial and lifesaving. Taking care of such patients requires interprofessional practice and multiple team resource management. Home PN (HPN) usage allows patients and families to live regular lives outside hospitals. We share our experiences for the last two decades and identify the risk factors for complications and mortality. A retrospective study of HPN patients was conducted between January 2000 and February 2022. Medical records of age, body weight, diagnosis, length of residual intestines, HPN period, central line attempts, complications, weaning, and survival were collected and analyzed. The patients were classified as HPN free, HPN dependent, and mortality groups. A total of 25 patients received HPN at our outpatient clinic, and one was excluded for the adult age of disease onset. There were 13 patients (54.1%) who were successfully weaned from HPN until the record-enroled date. The overall mortality rate was 20.8% (five patients). All mortality cases had prolonged cholestasis, Child Class B or C, and a positive Pediatric End-Stage Liver Disease (PELD) score. For HPN dependence, extended resection and multiple central line placement were two significant independent factors. Cholestasis, Child Class B or C, and positive PELD score were the most important risk factors for mortality. The central line-related complication rate was not different in all patient groups. The overall central line infection rate was 1.58 per 1000 catheter days. Caution should be addressed to prevent cholestasis and intestinal failure-associated liver disease during the HPN period, to prevent mortality. By understanding the risks of HPN dependence and mortality, preventive procedures could be addressed earlier.

Activity of aminotransferases as a marker of liver injury in home parenteral nutrition patients.

Aim of the study: Parenteral nutrition associated liver disease (PNALD) is a frequently reported complication of long-term parenteral nutrition. Early diagnosis and treatment of PNALD can help prevent end-stage liver disease. The aim of the study was to evaluate the activity of aminotransferases as a marker of liver dysfunction in patients receiving home parenteral nutrition under the care of a reference center. Material and methods: A comprehensive analysis of patients' medical records from a 9-year period (December 2012 - December 2021) was conducted and the following parameters were evaluated: parenteral nutrition mixture composition, total plasma bilirubin, activity of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), standardized time factor prothrombin (international normalized ratio [INR] factor) and serum albumin. The analysis covered 630,537 days of parenteral nutrition. The study included 251 patients (140 women and 111 men) included in the Home Parenteral Nutrition Program. Results: PNALD was diagnosed in 11 parenteral fed patients, which gives the frequency of 8.3%/9 years of treatment. Two deaths were classified as cause of death related to liver disease but not related to PNALD. None of the patients included in the analysis developed end-stage liver failure. Conclusions: The above analysis shows that individual selection of the composition of the mixture for intravenous nutrition significantly reduces the risk of PNALD and may prevent liver failure in this context.

Suppression of Bile Acid Synthesis in a Preterm Infant Receiving Prolonged Parenteral Nutrition.

Bile acid metabolism is altered in neonates on parenteral nutrition (PN), predisposing them to parenteral nutrition-associated liver disease. Cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the bile acid synthesis pathway, is repressed by fibroblast growth factor 19 (FGF19) and phytosterols (PS). We describe a case of a preterm infant who developed necrotizing enterocolitis (NEC) and received exclusive PN for over 2 months. Our objective was to serially assess CYP7A1 activity and plasma FGF19 and PS concentrations in this infant case compared to five healthy preterm infants. We found that CYP7A1 activity increased during the first 2 weeks of life in control infants but was undetectable in the infant case. FGF19 concentrations were high at birth in all infants and subsequently declined and did not differ between the case and control infants. As expected, PS concentrations were elevated in the infant case and continued to increase despite lipid minimization. In conclusion, CYP7A1 activity was gradually upregulated in healthy preterm infants but remained suppressed in the infant requiring prolonged PN. Preterm infants also had elevated FGF19 concentrations at birth, which decreased with advancing postnatal age.

Intravenous Lipid Emulsions in the Prevention and Treatment of Liver Disease in Intestinal Failure.

The development of intestinal failure-associated liver disease (IFALD) in pediatric and adult patients on parenteral nutrition is usually multifactorial in nature due to nutritional and non-nutritional causes. The role of lipid therapy as a contributing cause is well-established with the pathophysiological pathways now better understood. The review focuses on risk factors for IFALD development, biological effects of lipids, lipid emulsions and the mechanisms of lipid toxicity observed in laboratory animals followed by a synopsis of clinical studies in pediatric and adult patients. The introduction of fish oil-based lipid emulsions that provide partial or complete lipid replacement therapy has resulted in resolution of IFALD that had been associated with soybean oil-based therapy. Based on case reports and cohort studies in pediatric and adult patients who were at risk or developed overt liver disease, we now have more evidence that an early switch to partial or complete fish oil-based lipid therapy should be implemented in order to successfully halt and reverse IFALD.

Monitoring chronological change by liver-to-spleen attenuation ratio for secondary hepatic steatosis for a short term.

Parenteral nutrition-associated liver disease (PNALD) causes hepatic steatosis and moderate liver enzyme elevation due to lack of enteral nutrition and deficiency of some nutrients. However, the period for recovery from PNALD after a nutritional intervention is unknown with no report. Herein, we report a case of a 44-year-old Japanese woman with severe fatty infiltration of the liver due to malnutrition. Our nutritional support team administered appropriate total parenteral, especially fat and carnitine, nutrition to improve her malnutrition. Chronological changes in liver-to-spleen attenuation ratio were also considered because of her disease state. Computed tomography demonstrated improved attenuation of the liver, and the liver enzymes level normalized after 5 weeks from appropriate nutrition. Understanding the nutritional condition of a patient may help in elucidating an appropriate treatment strategy.

Effects of total parenteral nutrition on drug metabolism gene expression in mice.

Parenteral nutrition-associated liver disease (PNALD) is a liver dysfunction caused by various risk factors presented in patients receiving total parenteral nutrition (TPN). Omega-6 rich Intralipid® and omega-3 rich Omegaven® are two intravenous lipid emulsions used in TPN. TPN could affect the hepatic expression of genes in anti-oxidative stress, but it's unknown whether TPN affects genes in drug metabolism. In this study, either Intralipid®- or Omegaven®-based TPN was administered to mice and the expression of a cohort of genes involved in anti-oxidative stress or drug metabolism was analyzed, glutathione (GSH) levels were measured, and protein levels for two key drug metabolism genes were determined. Overall, the expression of most genes was downregulated by Intralipid®-based TPN (Gstp1, Gstm1, 3, 6, Nqo1, Ho-1, Mt-1, Gclc, Gclm, Cyp2d9, 2f2, 2b10, and 3a11). Omegaven® showed similar results as Intralipid® except for preserving the expression of Gstm1 and Cyp3a11, and increasing Ho-1. Total GSH levels were decreased by Intralipid®, but increased by Omegaven®. CYP3A11 protein levels were increased by Omegaven®. In conclusion, TPN reduced the expression of many genes involved in anti-oxidative stress and drug metabolism in mice. However, Omegaven® preserved expression of Cyp3a11, suggesting another beneficial effect of Omegaven® in protecting liver functions.

Incidence and risk factors of parenteral nutrition-associated liver disease in hospitalized adults: A prospective cohort study.

BACKGROUND AND AIMS: Parenteral nutrition-associated liver disease (PNALD) is a common complication in patients receiving parenteral nutrition (PN). Few studies have investigated the incidence and risk factors of PNALD in adult patients receiving PN with newer generation intravenous lipid emulsions. The aim of this study was to investigate the incidence and risk factors of PNALD in hospitalized adult patients. METHODS: Patients expected to receive PN for more than 14 days and have normal liver tests at baseline during September 2016 to February 2017 were enrolled. All patients were followed until there were liver test abnormalities. Incidence, onset and characteristics of PNALD, calories intake, amount of fat and carbohydrate, types of fat, nutrition status, and incidence of infection were evaluated. RESULTS: Forty-four adults were recruited. The incidence of PNALD was 59.1% (22.7% steatosis, 34.1% cholestasis, and 2.3% mixed type). Median onset of PNALD was 12.5 days (range: 4-42) and the onset was not significantly different between each subtype. In multiple regression analysis, severe malnutrition and amount of carbohydrate were independent risk factors for PNALD with an odds ratio of 13.25 (95% CI: 1.37-128.24; p = 0.026) and 21.61 (95% CI: 1.81-258.56; p = 0.015), respectively. CONCLUSIONS: PNALD was common in this group of patients. In contrast to previous studies, cholestasis was more common than steatosis, and the median onset was not different between each subtype. In severely malnourished patients, physicians need to exercise caution and monitor for PNALD intensively, and overfeeding of carbohydrate should be avoided to prevent PNALD from occurring.

The molecular impact of omega 3 fatty acids on hepatic pro-inflammatory cytokine signaling.

PURPOSE: Parenteral nutrition associated liver disease (PNALD) develops in a subset of children receiving parenteral nutrition for intestinal failure. Omegaven™ is an omega-3 fatty acid (Ω3FA) lipid emulsion high in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) that can lessen PNALD. Inflammatory cytokines (IL-1, TNF-α, TGF-ß) are elevated in PNALD and can decrease paraoxonase 1 protein expression (PON1). We sought to determine the effect of Omegaven™, EPA, and DHA on inflammatory cytokines TNF-α, IL-1, and TGF-ß via ERK1/2 and p-Smad2/3 signaling pathways as well as the changes in intracellular PON1 protein expression as a potential mechanism explaining the protective effects of Omegaven™ and Ω3FA. METHODS: HepG2 cells were cultured with each cytokine and Omegaven™, or EPA and DHA, or Intralipid™. P-Smad2/3 and PON1 protein levels were measured by Western blotting. ERK1/2 signaling was studied using homogenous time resolved fluorescence. RESULTS: Omegaven™ decreased TGF-ß mediated Smad2/3 signaling by 30% (70% of control ±12, p<0.03). Omegaven™ decreased IL-1 and TNF-α mediated ERK1/2 signaling (0.49 fold ±0.09, p<0.05 and 0.22±0.05, p<0.05) compared to control. CONCLUSION: Our results describe potential mechanisms by which Omegaven™ and Ω3FA can be hepatoprotective in the setting of PNALD by abating inflammatory cytokine signaling.

Liver Disease in Patients on Total Parenteral Nutrition.

Parenteral nutrition-associated liver disease (PNALD) spectrum ranges from liver enzyme abnormalities to steatosis to fibrosis, and, eventually, cirrhosis from total parenteral nutrition (TPN). The pathophysiology is postulated to be multifactorial. Diagnosis in adults is primarily by exclusion, eliminating other causes of chronic liver disease or cirrhosis, and other factors seen in critically ill or postoperative patients on TPN. Principal treatment is avoiding TPN. If this is not feasible, research supports fish oil-based lipid emulsions in TPN formulations to reduce risk and progression of PNALD. With liver and intestinal failure, liver and intestine transplant is an option.

Parenteral Nutrition-Associated Liver Disease: The Role of the Gut Microbiota.

Parenteral nutrition (PN) provides life-saving nutritional support in situations where caloric supply via the enteral route cannot cover the necessary needs of the organism. However, it does have serious adverse effects, including parenteral nutrition-associated liver disease (PNALD). The development of liver injury associated with PN is multifactorial, including non-specific intestine inflammation, compromised intestinal permeability, and barrier function associated with increased bacterial translocation, primary and secondary cholangitis, cholelithiasis, short bowel syndrome, disturbance of hepatobiliary circulation, lack of enteral nutrition, shortage of some nutrients (proteins, essential fatty acids, choline, glycine, taurine, carnitine, etc.), and toxicity of components within the nutrition mixture itself (glucose, phytosterols, manganese, aluminium, etc.). Recently, an increasing number of studies have provided evidence that some of these factors are directly or indirectly associated with microbial dysbiosis in the intestine. In this review, we focus on PN-induced changes in the taxonomic and functional composition of the microbiome. We also discuss immune cell and microbial crosstalk during parenteral nutrition, and the implications for the onset and progression of PNALD. Finally, we provide an overview of recent advances in the therapeutic utilisation of pro- and prebiotics for the mitigation of PN-associated liver complications.

Long-Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure-Associated Liver Disease [Formula: see text].

BACKGROUND: Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF-associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long-term PN and FOLE therapy due to chronic IF. MATERIALS AND METHODS: A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease. RESULTS: Of 215 patients with IFALD treated from 2004-2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight-for age and length-for-age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term. CONCLUSIONS: Children with IFALD who required long-term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation.

Pediatric parenteral nutrition-associated liver disease and cholestasis: Novel advances in pathomechanisms-based prevention and treatment.

Parenteral nutrition constitutes a life-saving therapeutic tool in patients unable to ingest/absorb oral or enteral delivered nutrients. Liver function tests abnormalities are a common therapy-related complication, thus configuring the so-called Parenteral Nutrition Associated Liver Disease (PNALD) or cholestasis (PNAC). Although the damage is frequently mild, and resolves after discontinuation of parenteral nutrition, in some cases it progresses into cirrhotic changes, especially in neonates and infants. We present a literature review focusing on the pathogenetic mechanisms-driven prevention and therapies for the cases where parenteral nutrition cannot be discontinued. Ursodeoxycholic acid has been proposed in patients with cholestatic hepatopathy, but its efficacy needs to be better established. Little evidence is available on efficacy of anti-oxidants, antibiotics, probiotics and anti TNFα. Lipid emulsions based on fish oil with a high content of long-chain polyunsaturated fatty acids ω-3 appear effective both in decreasing intrahepatic inflammation and in improving biliary flow. Most recent promising variations such as soybean/MCT/olive/fish oil emulsion [third generation lipid emulsion (SMOFlipid)] are under investigation. In conclusion, we remark the emergence of a number of novel pathomechanisms underlying the severe liver impairment damage (PNALD and PNAC) in patients treated with parenteral nutrition. Only few traditional and innovative therapeutic strategies have hitherto been shown promising.

Total Parenteral Nutrition-Induced Cholestasis: Prevention and Management.

When cholestasis occurs in patients receiving total parenteral nutrition, it is the result of many pathogenic pathways converging on the hepatic acinus. The result may be a temporary rise in liver function tests. The resulting fibrosis, portal hypertension, and jaundice are hallmarks of type 3 intestinal-associated liver disease to which children are more susceptible than adults. The key to prevention is in identifying high-risk scenarios, meticulous monitoring, and personalized prescription of parenteral nutrition solutions combined with an active approach in reducing the impact of inflammatory events when they occur by prompt use of antibiotics and line locks.