Search Results (46)

Background: Intestinal failure-associated liver disease (IFALD) is a serious complication in patients receiving parenteral nutrition, often exacerbated by inflammation, lipid overload, and oxidative stress. Nobiletin (NOB), a polymethoxylated flavone, is known for its anti-inflammatory and lipid-regulating properties. Methods: We employed an in vitro model using THLE-2 human hepatocytes and primary human cholangiocytes exposed to Intralipid (INT) and lipopolysaccharide (LPS) to simulate IFALD conditions. NOB was tested at non-toxic concentrations (10 and 25 µM) to assess its protective effects. MTT viability assays, multiplex bead-based immunoassays (MAGPIX), RT-qPCR, and Western blotting were used to evaluate changes in inflammation markers, gene expression, and protein signaling. Moreover, ALT and AST activities were used to assess hepatocellular injury. Results: NOB maintained high cell viability in THLE-2 hepatocytes and cholangiocytes, confirming its low cytotoxicity. NOB normalized ALT and AST activities in both tested cell lines, but the effect reached statistical significance only for ALT in cholangiocytes. Under IFALD-like conditions (LPS+INT), NOB significantly preserved metabolic activity in both cell types. In THLE-2 and cholangiocytes, NOB markedly reduced the phosphorylation of pro-inflammatory proteins JNK, NF-κB, and STAT3, indicating a broad inhibition of inflammatory signaling. Moreover, in THLE-2 cells, NOB upregulated lipid metabolism-related genes (PRKAA2, CYP7A1, and ABCA1) and decreased oxidative stress, thereby enhancing the nuclear translocation of Nrf2 and increasing SOD1 level, which supports the activation of antioxidant defenses. Conclusions: NOB exhibits hepatoprotective properties under IFALD-like conditions in vitro, likely through modulation of inflammation-related signaling and lipid metabolism pathways. Full article

Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a naturally occurring flavonol in fruits and vegetables. It exhibits diverse biological activities, including anti-inflammatory, antioxidant, senolytic, and lipid-lowering properties. This review explores the molecular mechanisms underlying fisetin’s hepatoprotective effects and evaluates its potential application in Intestinal Failure-Associated Liver Disease (IFALD), a severe complication associated with total parenteral nutrition (TPN). IFALD is characterized by inflammation, cholestasis, steatosis, oxidative stress, and dysregulated lipid and bile acid metabolism. Fisetin modulates several key signaling pathways, including NF-κB, Nrf2, AMPK, and SIRT1, leading to reduced inflammatory cytokine expression, enhanced antioxidant defenses, and improved lipid homeostasis. Fisetin shows potential anti-fibrotic and microbiota-modulating effects. More importantly, fisetin is recognized as a potent senolytic agent, selectively activating pro-apoptotic pathways in senescent cells, which are known sources of inflammation and tissue damage. However, despite its promising pharmacological profile, the poor bioavailability of fisetin remains a significant limitation, particularly for parenteral use. Emerging drug delivery systems such as liposomes and nanoparticles offer potential solutions. Given its broad spectrum of beneficial effects and favorable safety profile, fisetin represents a compelling candidate for future studies in the prevention and management of IFALD. Full article

Background: Liver transplant recipients are highly susceptible to invasive fungal infections, particularly candidemia, due to intensive immunosuppressive therapy and postoperative complications. However, few studies have comprehensively examined postoperative antimicrobial and immunosuppressive factors in this context. Aim: This study aimed to identify perioperative and postoperative factors associated with the development of candidemia in living donor liver transplant (LDLT) recipients, with a particular focus on antimicrobial and immunosuppressive regimens during initial hospitalization. Methods: A retrospective case–control analysis was conducted involving 36 LDLT recipients who developed candidemia (candidemia group) and 72 matched controls without candidemia (non-candidemia group) between January 2019 and November 2023. Demographic and clinical variables were compared using univariate and multivariate logistic regression analyses to identify independent associations. A post hoc power analysis demonstrated a high statistical power (97.3%) to detect large effect sizes. Results: Univariate analysis revealed significant associations with prolonged intubation (p < 0.001), bile leaks (p < 0.001), relaparotomy (p < 0.001), chronic renal disease (p = 0.011), hepatocellular carcinoma (p = 0.011), and the use of antimicrobials including meropenem (p = 0.048), linezolid (p = 0.005), tigecycline (p = 0.045), third-generation cephalosporins (p = 0.003), anidulafungin (p < 0.001), fluconazole (p = 0.006), mycophenolate (p = 0.011), and total parenteral nutrition (TPN) (p = 0.049). CMV prophylaxis (p < 0.001) and CMV-PCR positivity (p = 0.015) were also significantly associated with candidemia. Multivariate logistic regression analysis identified prolonged intubation (OR = 1.07; p = 0.019), bile leaks (OR = 10.9; p = 0.002), anidulafungin use (OR = 4.70; p = 0.032), fluconazole use (OR = 35.8; p = 0.005), and absence of CMV prophylaxis (OR = 11.7; p = 0.021) as independent factors associated with increased odds of candidemia. Conclusions: Prolonged intubation, bile leaks, antifungal exposure, and lack of CMV prophylaxis are independently associated with higher odds of candidemia after LDLT. Targeted prophylaxis, prudent antimicrobial stewardship, and timely biliary intervention may reduce fungal morbidity and mortality in post-transplant patients. Full article

Background: Manganese (Mn) is an essential trace element for humans. It has been recognized as a potential occupational toxin, but its danger as a toxin in patients under parenteral nutrition is often forgotten. Case Presentation: A 73-year-old man was logged for 210 days in the intensive care unit (ICU), receiving parenteral nutrition (PN) for a month, and was then transferred, first, to the internal medicine ward and, then, to the rehabilitation hospital, and 223 days after discharge from the ICU, he had current disease, chorea-type movements in the head and neck, and left hemibody. Diagnostic tests: The magnetic resonance imaging findings suggested manganese deposits, with a total blood manganese concentration of 34 µg·L⁻¹ (reference range: less than 13 µg·L⁻¹). Discussion: Abnormal movements can be caused by manganese poisoning due to parenteral nutrition and are associated with liver failure in the ICU. Our patient showed toxic Mn concentrations in whole blood after 31 days of receiving 300 μg·d⁻¹ of Mn in PN, a shorter duration than typically reported. Neurotoxicity was observed several months later (223 days). Factors such as liver dysfunction and iron deficiency can modulate neurotoxicity. Age may also be a susceptibility factor due to increased expression of Mn transport proteins. Magnetic resonance imaging (MRI) intensity in the globus pallidus is useful for detecting brain Mn accumulation, but it is not feasible for routine clinical practice. Conclusions: In this case, choreiform movements were attributed to manganese (Mn) accumulation in the basal ganglia. It is essential to monitor patients receiving parenteral nutrition (PN) solutions containing Mn, especially in those who have biomarkers of susceptibility, even if they have not yet shown neurological signs, and routinely measure whole-blood Mn concentrations, iron levels, age, and liver function. If Mn intoxication is suspected, a brain MRI examination should be conducted. Full article

Short bowel syndrome (SBS), usually resulting from massive small bowel resections or congenital defects, may lead to intestinal failure (IF), requiring intravenous fluids and parenteral nutrition to preserve patients’ nutritional status. Approximately 15% to 40% of subjects with SBS and IF develop chronic hepatic damage during their life, a condition referred to as intestinal-failure-associated liver disease (IFALD), which ranges from steatosis to fibrosis or end-stage liver disease. Parenteral nutrition has been largely pointed out as the main pathogenetic factor for IFALD. However, other elements, such as inflammation, bile acid metabolism, bacterial overgrowth and gut dysbiosis also contribute to the development of liver damage and may deserve specific treatment strategies. Indeed, in our review, we aim to explore IFALD pathogenesis beyond parenteral nutrition. By critically analyzing recent literature, we seek to delve with molecular mechanisms and metabolic pathways underlying liver damage in such a complex set of patients. Full article

Background/Objectives: Parenteral Nutrition-Associated Liver Disease (PNALD) is a significant complication in patients undergoing parenteral nutrition (PN). This study aims to explore the incidence, risk factors, and outcomes associated with PNALD, including abnormal liver function tests, in patients receiving parenteral nutrition, even in short-term PN recipients. Methods: A retrospective analysis of 500 patients receiving PN for at least 3 days at a tertiary medical center was conducted. Liver enzyme levels were monitored for 28 days, and PN duration, comorbidities, and metabolic factors were analyzed to identify independent risk factors of abnormal liver function tests and PNALD. Results: This study reported a 24.4% incidence of abnormal liver function tests and an 8.2% incidence of PNALD. Risk factors for abnormal liver function tests included liver disease (OR 2.064, 95% CI 1.224–3.479), infection (OR 1.654, 95% CI 1.075–2.546), PN duration (OR 1.035, 95% CI 1.014–1.056), and PN calories (OR 1.001, 95% CI 1.000–1.002). Significant PNALD risk factors comprised liver disease (OR 3.623, 95% CI 1.670–7.858), lung disease (OR 3.648, 95% CI 1.615–8.240), recent surgery (OR 3.719, 95% CI 1.645–8.407), PN duration (OR 1.041, 95% CI 1.016–1.068), total cholesterol (OR 1.005, 95% CI 1.000–1.010), and HDL-cholesterol (OR 1.012, 95% CI 1.001–1.023). The majority of PNALD cases (85.3%) showed improvement with PN modification or cessation. Conclusions: This study underscores that abnormal liver function tests and PNALD risks can emerge with short-term PN use. Identifying and addressing patient-specific risk factors is vital for predicting and preventing PNALD onset. Full article

Phytosterols in vegetable oils have gained attention for their nutritional benefits in foods and food supplements. However, the use of vegetable oils in emulsions for infant formulas and parenteral nutrition has raised some concerns, as phytosterols may contribute to phytosterolemia in the case of infant formulas and, in a second scenario, to parenteral nutrition-associated liver disease. The present study proposes removing phytosterols from soybean oil using a synthetic amorphous silica Trisyl^® (E551) as an adsorbent material. The process is simple and involves stirring the oil at a high temperature under vacuum conditions followed by filtration to remove the adsorbent. A rotational factorial design of experiments, considering the adsorbent/oil ratio, temperature, and time was carried out to determine the optimal conditions. Additionally, the effects on tocopherols levels and formation of trans fatty acids were explored. The total sterol content in the initial refined soybean oil was 2540 mg/kg, with 32% in ester form (813 mg/kg). The treatments effectively reduced the sterol concentration, achieving a reduction of nearly 70% when 10% Trisyl^®, 140 °C, and a 90-min treatment were applied. Under these conditions, nearly 80% of the oil was recovered. Campesterol and stigmasterol levels were almost halved. Tocopherol losses were found to be below 20%. Thermal degradation, as analyzed by triacylglycerol polymers and trans fatty acids, was not observed in the treatments. Full article

Intestinal failure (IF) is a debilitating condition characterized by the insufficient function of the gastrointestinal tract to absorb nutrients and fluids essential for life. This review consolidates recent advancements and challenges in managing IF among adult and pediatric populations, highlighting differences in etiology, management, and outcomes. Over the recent years, significant strides have been made in the nutritional and medical management of IF, significantly reducing mortality rates and improving the quality of life for patients. Key advancements include the development and availability of glucagon-like peptide-2 (GLP-2) analogs, improved formulations of parenteral nutrition, and the establishment of specialized interdisciplinary centers. Short bowel syndrome (SBS) remains the predominant cause of IF globally. The pediatric segment is increasingly surviving into adulthood, presenting unique long-term management challenges that differ from adult-onset IF. These include the need for tailored nutritional support, management of IF-associated liver disease, and addressing growth and neurodevelopmental outcomes. The therapeutic landscape for IF continues to evolve with the development of new treatment modalities and better understanding of the condition’s pathophysiology. However, disparities in treatment outcomes between children and adults suggest the need for age-specific management strategies. This review underscores the importance of a nuanced approach to IF, incorporating advancements in medical science with a deep understanding of the distinct needs. Full article

Pediatric chronic intestinal failure (PIF) is a rare and heterogeneous condition characterized by the inability of the patient’s intestine to adequately absorb the required fluids and/or nutrients for growth and homeostasis. As a result, patients will become dependent on home parenteral nutrition (HPN). A MEDLINE search was performed in May 2024 with keywords “intestinal failure”, “parenteral nutrition” and “pediatric”. Different underlying conditions which may result in PIF include short bowel syndrome, intestinal neuromuscular motility disorders and congenital enteropathies. Most common complications associated with HPN are catheter-related bloodstream infections, catheter-related thrombosis, intestinal failure-associated liver disease, small intestinal bacterial overgrowth, metabolic bone disease and renal impairment. Treatment for children with PIF has markedly improved with a great reduction in morbidity and mortality. Centralization of care in specialist centers and international collaboration between centers is paramount to further improve care for this vulnerable patient group. A recently promising medical therapy has become available for children with short bowel syndrome which includes glucagon-like peptide 2, a naturally occurring hormone which is known to delay gastric emptying and induce epithelial proliferation. Despite advances in curative and supportive treatment, further research is necessary to improve nutritional, pharmacological and surgical care and prevention of complications associated with parenteral nutrition use. Full article

Choline is an essential nutrient, with high requirements during fetal and postnatal growth. Tissue concentrations of total choline are tightly regulated, requiring an increase in its pool size proportional to growth. Phosphatidylcholine and sphingomyelin, containing a choline headgroup, are constitutive membrane phospholipids, accounting for >85% of total choline, indicating that choline requirements are particularly high during growth. Daily phosphatidylcholine secretion via bile for lipid digestion and very low-density lipoproteins for plasma transport of arachidonic and docosahexaenoic acid to other organs exceed 50% of its hepatic pool. Moreover, phosphatidylcholine is required for converting pro-apoptotic ceramides to sphingomyelin, while choline is the source of betaine as a methyl donor for creatine synthesis, DNA methylation/repair and kidney function. Interrupted choline supply, as during current total parenteral nutrition (TPN), causes a rapid drop in plasma choline concentration and accumulating deficit. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) defined choline as critical to all infants requiring TPN, claiming its inclusion in parenteral feeding regimes. We performed a systematic literature search in Pubmed with the terms “choline” and “parenteral nutrition”, resulting in 47 relevant publications. Their results, together with cross-references, are discussed. While studies on parenteral choline administration in neonates and older children are lacking, preclinical and observational studies, as well as small randomized controlled trials in adults, suggest choline deficiency as a major contributor to acute and chronic TPN-associated liver disease, and the safety and efficacy of parenteral choline administration for its prevention. Hence, we call for choline formulations suitable to be added to TPN solutions and clinical trials to study their efficacy, particularly in growing children including preterm infants. Full article

Many patients undergo small bowel and colon surgery for reasons related to malignancy, inflammatory bowel disease (IBD), mesenteric ischemia, and other benign conditions, including post-operative adhesions, hernias, trauma, volvulus, or diverticula. Some patients arrive in the operating theatre severely malnourished due to an underlying disease, while others develop complications (e.g., anastomotic leaks, abscesses, or strictures) that induce a systemic inflammatory response that can increase their energy and protein requirements. Finally, anatomical and functional changes resulting from surgery can affect either nutritional status due to malabsorption or nutritional support (NS) pathways. The dietitian providing NS to these patients needs to understand the pathophysiology underlying these sequelae and collaborate with other professionals, including surgeons, internists, nurses, and pharmacists. The aim of this review is to provide an overview of the nutritional and metabolic consequences of different types of lower gastrointestinal surgery and the role of the dietitian in providing comprehensive patient care. This article reviews the effects of small bowel resection on macronutrient and micronutrient absorption, the effects of colectomies (e.g., ileocolectomy, low anterior resection, abdominoperineal resection, and proctocolectomy) that require special dietary considerations, nutritional considerations specific to ostomized patients, and clinical practice guidelines for caregivers of patients who have undergone a surgery for local and systemic complications of IBD. Finally, we highlight the valuable contribution of the dietitian in the challenging management of short bowel syndrome and intestinal failure. Full article

Parenteral nutrition (PN), a vital therapy for patients with intestinal failure, can lead to the development of parenteral nutrition-associated liver disease (PNALD). In this study, we aimed to investigate the role of Lactobacillus johnsonii (L. johnsonii) in a rat model of PNALD. Total parenteral nutrition (TPN)-fed rats were used to assess the role of L. johnsonii in liver steatosis, bile acid metabolism, gut microbiota, and hepatocyte apoptosis. We observed a depletion of L. johnsonii that was negatively correlated with the accumulation of glycochenodeoxycholic acid (GCDCA), a known apoptosis inducer, in rats subjected to TPN. L. johnsonii attenuated TPN-induced liver steatosis by inhibiting fatty acid synthesis and promoting fatty acid oxidation. TPN resulted in a decrease in bile acid synthesis and biliary bile secretion, which were partially restored by L. johnsonii treatment. The gut microbial profile revealed depletion of pathogenic bacteria in L. johnsonii-treated rats. L. johnsonii treatment reduced both hepatic GCDCA levels and hepatocyte apoptosis compared with the TPN group. In vitro, L. johnsonii treatment inhibited GCDCA-induced hepatocyte apoptosis via its bile salt hydrolase (BSH) activity. Our findings suggest that L. johnsonii protects against liver steatosis, bile acid dysregulation, and hepatocyte apoptosis in TPN-fed rats. Full article

Intestinal failure-associated liver disease (IFALD) is a severe liver injury occurring due to factors related to intestinal failure and parenteral nutrition administration. Different approaches are studied to reduce the risk or ameliorate the course of IFALD, including providing omega-3 fatty acids instead of soybean oil-based lipid emulsion or administering active compounds that exert a hepatoprotective effect. This study aimed to develop, optimize, and characterize magnolol-loaded intravenous lipid emulsion for parenteral nutrition. The preformulation studies allowed for chosen oils mixture of the highest capacity of magnolol solubilization. Then, magnolol-loaded SMOFlipid was developed using the passive incorporation method. The Box–Behnken design and response surface methodology were used to optimize the entrapment efficiency. The optimal formulation was subjected to short-term stress tests, and its effect on normal human liver cells and erythrocytes was determined using the MTT and hemolysis tests, respectively. The optimized magnolol-loaded SMOFlipid was characterized by the mean droplet diameter of 327.6 ± 2.9 nm with a polydispersity index of 0.12 ± 0.02 and zeta potential of −32.8 ± 1.2 mV. The entrapment efficiency of magnolol was above 98%, and pH and osmolality were sufficient for intravenous administration. The magnolol-loaded SMOFlipid samples showed a significantly lower toxic effect than bare SMOFlipid in the same concentration on THLE-2 cells, and revealed an acceptable hemolytic effect of 8.3%. The developed formulation was characterized by satisfactory stability. The in vitro studies showed the reduced cytotoxic effect of MAG-SMOF applied in high concentrations compared to bare SMOFlipid and the non-hemolytic effect on human blood cells. The magnolol-loaded SMOFlipid is promising for further development of hepatoprotective lipid emulsion for parenteral nutrition. Full article

Intestinal failure-associated liver disease (IFALD) is a spectrum of liver disease including cholestasis, biliary cirrhosis, steatohepatitis, and gallbladder disease in patients with intestinal failure (IF). The prevalence of IFALD varies considerably, with ranges of 40–60% in the pediatric population, up to 85% in neonates, and between 15–40% in the adult population. IFALD has a complex and multifactorial etiology; the risk factors can be parenteral nutrition-related or patient-related. Because of this, the approach to managing IFALD is multidisciplinary and tailored to each patient based on the etiology. This review summarizes the current knowledge on the etiology and pathophysiology of IFALD and examines the latest evidence regarding preventative measures, diagnostic approaches, and treatment strategies for IFALD and its associated complications. Full article

In premature infants receiving parenteral nutrition, oxidative stress is a trigger for the development of bronchopulmonary dysplasia, which is an important factor in the development of adult lung diseases. Neonatal vitamin C and glutathione deficiency is suspected to induce permanent modification of redox metabolism favoring the development of neonatal and adult lung diseases. A total of 64 3-day-old guinea pigs were fed an oral diet that was either complete or deficient in vitamin C (VCD), cysteine (CD) (glutathione-limiting substrate) or both (DD) for 4 days. At 1 week of age, half of the animals were sacrificed while the other started a complete diet until 12 weeks of age. At 1 week, the decrease in lung GSH in all deficient groups was partially explained by the oxidation of liver methionine-adenosyltransferase. mRNA levels of kelch-like ECH-associated protein 1 (Keap1), glutathione-reductase (Gsr) and glutaredoxin-1 (Glrx) were significantly lower only in CD but not in DD. At 12 weeks, glutathione levels were increased in VCD and CD. Keap1, Gsr and Glrx mRNA were increased, while glutathione-reductase and glutaredoxin proteins were lower in CD, favoring a higher glutathionylation status. Both neonatal deficiencies result in a long-term change in glutathione metabolism that could contribute to lung diseases’ development. Full article