RARE DISEASE
Parenteral nutrition-associated cholestasis
Parenteral nutrition-associated cholestasis
Parenteral nutrition-associated cholestasis
Synonyms: PNAC
Synonyms: PNAC
Synonyms: PNAC
Drug discovery
3
drugs
With orphan designations
Overview
Parenteral Nutrition-Associated Cholestasis (PNAC) is intrahepatic cholestasis linked to prolonged parenteral nutrition (PN) use, particularly in neonates and infants with intestinal failure. It arises from multifactorial mechanisms, including immature hepatobiliary systems, nutrient composition (e.g., lipid overload), and gut dysmotility. PNAC manifests as persistent conjugated hyperbilirubinemia (>2 mg/dL) and may progress to fibrosis or cirrhosis. Management prioritizes enteral feeding initiation, lipid reduction/modification, and hepatoprotective strategies [1][4][16].
Burden
Prevalence: 18–30% in neonates on PN >2 weeks; higher in surgical infants (e.g., 30% in gastroschisis) [7][11].
Prolonged hospitalization, increased morbidity (e.g., sepsis), and elevated mortality (up to 34.7% in severe cases without intervention) [16].
Chronic PN dependency risks end-stage liver disease, necessitating transplantation in refractory cases [12][15].
Therapies
Enteral feeding: ≥10% caloric intake reduces cholestasis risk [1][8].
Lipid adjustments: Limit soybean oil (<1 g/kg/day), switch to fish oil–based emulsions (e.g., Omegaven®) to reverse cholestasis [12][16].
Adjuncts: Cyclic PN, ursodeoxycholic acid, and trace element avoidance (copper/manganese) [6][8].
Categories: rare hepatic diseases
Research Papers
853 drug discovery papers about Parenteral nutrition-associated cholestasis. Recent publications:
853 drug discovery papers about Parenteral nutrition-associated cholestasis. Recent publications:
categories:
Small molecules
small molecules
2026-06-26 | Fish oil emulsion for reversal of intestinal failure-associated liver disease in preterm infants: Three case reports and review of literature
BACKGROUND Prolonged parenteral nutrition (PN) is a major risk factor for intestinal failure-associated liver disease (IFALD), particularly in preterm infants. Plant-derived lipid emulsions, rich in phytosterols and ω-6 fatty acids, are considered key contributors. Fish oil lipid emulsions (FO-ILE) have emerged as a potential therapeutic alternative; however, the optimal dose for balancing efficacy and safety remains uncertain. CASE SUMMARY We report three preterm infants (gestational age, 31-36+2 weeks) with severe IFALD who were transitioned from soybean oil-based or multi-oil emulsions to FO-ILE. Fish oil was administered at a dose of 2 g/kg/day, a dosing approach for which limited data are available in this population. Prior to the transition, peak direct bilirubin (DB) levels ranged from 191.9 μmol/L to 356 μmol/L, with one patient exhibiting severe cholestasis and marked hepatosplenomegaly. Following 29-63 days of treatment, DB levels decreased to 30.7-89.9 μmol/L, resulting in a faster DB decline than that observed with the conventional 1 g/kg/day dosage. Full enteral feeding was achieved after 69-105 days of PN. The regimen was well tolerated, with no evidence of essential fatty acid deficiency, growth impairment, or bleeding complications. CONCLUSION FO-ILE up to 2 g/kg/day was well tolerated and improved liver function, which supports further investigation in PN-dependent infants.
2026-06-15 | Association between multi-oil fat emulsion and bronchopulmonary dysplasia in preterm infants <32 weeks.
Bronchopulmonary dysplasia (BPD) is a major respiratory morbidity in preterm infants and remains an important cause of adverse short- and long-term outcomes. Early postnatal nutrition may influence lung growth and injury repair, and intravenous lipid emulsions are a key component of parenteral nutrition in very preterm infants. Compared with conventional medium-chain/long-chain triglyceride fat emulsions (MCT/LCT), multi-oil fat emulsion (SMOF) contains fish oil and vitamin E, etc., and has a lower relative proportion of ω-6 fatty acids, and may theoretically attenuate inflammation and oxidative stress. However, current evidence regarding whether SMOF reduces the incidence of BPD remains inconsistent. This study aimed to evaluate the association between SMOF and BPD in preterm infants born at <32 weeks' gestation. A retrospective analysis included 171 preterm infants (<32 weeks) admitted to a tertiary neonatal intensive care unit, divided into SMOF (n=96) and MCT/LCT (n=75) groups. The outcome of respiratory system and other complications such as parenteral nutrition-related cholestasis (PNAC), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), late-onset of sepsis (LOS), brain injury and mortality were compared between the two groups. Among the 171 preterm infants in the study, the mean gestational age was 29.51±1.55 weeks, with birth weight of 1,229.39±299.06 g. Multivariate analysis identified SMOF as an independent protective factor against BPD [odds ratio (OR) =0.317, 95% confidence interval (CI): 0.128-0.784]. No significant differences were observed in PNAC, ROP, NEC, sepsis, brain injury, or mortality between groups. We preliminarily conclude that SMOF is a potentially protective factor for BPD in preterm infants <32 weeks without increasing complications such as PNAC, ROP, NEC, sepsis, and brain injury. These findings may support its clinical utility in this population.
2026-06-01 | OC51 Incidence and persistence of elevated vitamin A levels in paediatric patients on home parenteral nutrition
Vitamin A is an essential fat-soluble vitamin required for vision, bone growth, immune function, and differentiation of epithelial and nerve tissues.1 Both deficiency and toxicity are associated with significant morbidity in children, such as vision loss and increased intracranial pressure or headaches. Vitamin A has a long half-life; levels can remain elevated for extended periods.2 Regular monitoring is recommended for children receiving long-term parenteral nutrition (PN).3 The aim of the study was to review the frequency and duration of high serum vitamin A levels in children receiving home PN, and explore any associations between elevated levels with lipid provision or supplemental feeds. A retrospective review was conducted of all children currently receiving home PN under the care of the intestinal failure multidisciplinary team. Data were collected on demographic characteristics, underlying pathology leading to IF, time on PN, vitamin A levels, lipid and vitilipid doses, and any clinical symptoms suggestive of hypervitaminosis A. Episodes of high vitamin A were defined as levels above the laboratory reference range for at least three consecutive months over the last two years, while the child had a normal CRP. Thirty-nine children were on home PN (20 male, mean age 9 years, range 1–18 years). The main underlying conditions included short bowel syndrome (27/39, 69.2%), congenital diarrhoea (7/39, 17.9%), dysmotility (3/39, 7.7%), and other pathologies such as cystinosis (1/39, 2.6%) and eosinophilic colitis (1/39, 2.6%). Twenty-three of 39 (59%) children had elevated vitamin A lasting three months or more. Of these, 19/39 (48.7%) had one episode lasting at least three months and 4/39 (10.3%) had two prolonged episodes. None had more than two episodes. Four of 39 (10.3%) patients had prolonged elevation for the entire 24-month study despite reduced vitilipid dose (2/4 children (50%) had cholestasis). The median initial vitamin A concentration across all episodes was 2.05 (95% SD 3.32). Of all 27 episodes of raised vitamin A, 6/27 (22.2%) normalised after one reduction of vitilipid by 10%–25%. A further 4/27 (14.8%) resolved after multiple reductions in vitilipid content, ranging from a total reduction of 40%–55%. The remaining 13/27 (48.1%) episodes remained unresolved with levels above the reference range in September 2025, despite reductions in vitilipid on one (8/13) or more (5/13) occasions, ranging from 15% to 79% total reduction. Only one episode was associated with clinical symptoms compatible with hypervitaminosis A, including headache and irritability. Comparison between patients requiring a 10%–40% reduction of vitilipid (n=13) and those requiring >40% (n=8) did not differ in lipid nights per week (4.9 vs 4.6 nights, p=0.35) or the number on supplemental feeds (8/13 vs 3/8 respectively). Episodes of high vitamin A levels are common in children on home PN and may persist for several months. Although vitilipid provision should be amended, other factors—including interindividual variation in metabolism—may affect vitamin A levels. Any reduction in vitilipid should be made cautiously to avoid secondary deficiencies of other fat-soluble vitamins. Ross AC. Vitamin A. In: Ross AC, Caballero B, Cousins RJ, et al. editors. Modern Nutrition in Health and Disease. 11th ed. Baltimore (MD): Lippincott Williams & Wilkins; 2014. p. 260–277. Haskell MJ, Lembcke JL, Salazar M, et al. Population-based plasma kinetics of an oral dose of [2H4]retinyl acetate among preschool-aged Peruvian children. Am J Clin Nutr. 2003 Mar;77(3):681–686. Berger MM, Shenkin A, Schweinlin A, et al. ESPEN micronutrient guideline. Clin Nutr. 2022 Jun;41(6):1357–1424.
2025-12-28 | Mechanistic Analysis of Fisetin in Liver Diseases and Its Potential Therapeutic Application in IFALD—A Review of In Vitro and In Vivo Studies
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.
2025-09-04 | Association between mixed fatty acid emulsion and parenteral nutrition-associated cholestasis in extremely low-birth-weight infants: A retrospective cohort study.
Soybean oil lipid emulsions have been implicated in the development of parenteral nutrition-associated cholestasis (PNAC) in premature infants. A recent mixed fatty acid emulsion containing soybean oil, medium-chain triglycerides (MCTs), olive oil, and fish oil may reduce the incidence of PNAC, but evidence remains conflicting. The aim of this study was to evaluate the effect of mixed fatty acid emulsion on PNAC in extremely low-birth-weight (ELBW) infants. We performed a retrospective cohort study on ELBW infants from 2016 to 2022. ELBW infants who received MCT/long-chain triglyceride (LCT) lipid emulsion or mixed fatty acid emulsion were compared. The primary outcome was the incidence of PNAC. Secondary outcomes included peak levels of direct bilirubin and bronchopulmonary dysplasia. Multivariable analysis was performed to adjust for potential confounders. A total of 180 ELBW infants were reviewed in this study. Twenty-six of 99 patients (26.2%) in the mixed fatty acid emulsion group and 29 of 81 patients (35.8%) in the MCT/LCT lipid emulsion group developed PNAC (P = 0.17). There was no significant difference in median peak direct bilirubin and the rate of bronchopulmonary dysplasia. The results remained consistent after adjusting for potential confounders. Time to PNAC, rate of rise of direct bilirubin, and age of direct bilirubin normalization were not statistically different between groups. Compared with MCT/LCT lipid emulsion, mixed fatty acid emulsion did not reduce the incidence or degree of PNAC in ELBW infants.
antibodies
2024-02-20 | Inflammation drives pathogenesis of early intestinal failure-associated liver disease
Abstract Patients with intestinal failure who receive long-term parenteral nutrition (PN) often develop intestinal failure-associated liver disease (IFALD). Although there are identified risk factors, the early pathogenesis is poorly understood and treatment options are limited. Here, we perform a transcriptomic analysis of liver tissue in a large animal IFALD model to generate mechanistic insights and identify therapeutic targets. Preterm Yorkshire piglets were provided PN or bottle-fed with sow-milk replacer for 14 days. Compared to bottle-fed controls, piglets receiving PN developed biochemical cholestasis by day of life 15 (total bilirubin 0.2 vs. 2.9 mg/dL, P = 0.01). RNA-Seq of liver tissue was performed. Ingenuity Pathway Analysis identified 747 differentially expressed genes (343 upregulated and 404 downregulated) with an adjusted P < 0.05 and a fold-change of > |1|. Enriched canonical pathways were identified, demonstrating broad activation of inflammatory pathways and inhibition of cell cycle progression. Potential therapeutics including infliximab, glucocorticoids, statins, and obeticholic acid were identified as predicted upstream master regulators that may reverse the PN-induced gene dysregulation. The early driver of IFALD in neonates may be inflammation with an immature liver; identified therapeutics that target the inflammatory response in the liver should be investigated as potential treatments.
2022-07-13 | Interrupting tumor necrosis factor-alpha signaling prevents parenteral nutrition-associated cholestasis in mice.
We have recently reported a mouse model of PN-associated cholestasis (PNAC) in which combining intestinal inflammation and PN infusion results in cholestasis, hepatic macrophage activation, and transcriptional suppression of canalicular bile acid, bilirubin and sterol transporters Abcb11, Abcc2 and Abcg5/8. The aim of this study was to examine the role of TNFα in promoting PNAC in mice. First, recombinant TNFα was administered to mice as well as in hepatocyte cell culture. Second, Tnfr1/2KO or wild-type (WT) mice were exposed to dextran sulfate sodium (DSS) for 4 days followed by soy-oil lipid emulsion-based PN infusion through a central venous catheter for 14 days (DSS-PN). Finally, WT/DSS-PN mice were also infused with infliximab at 10 mg/kg on days 3 and 10 of PN. PNAC was defined by increased serum aspartate aminotransferase, alanine aminotransferase, total bile acids, and bilirubin. Intraperitoneal injection of TNFα into WT mice or TNFα treatment of Huh7 hepatocarcinoma cells and primary mouse hepatocytes suppressed messenger RNA (mRNA) transcription of bile (Abcb11, Abcc2]) and sterol transporters (Abcg5/8) and their regulators Nr1h3 and Nr1h4. DSS-PN mice with PNAC had increased hepatic TNFα mRNA expression and significant reduction of mRNA expression of Abcb11, Abcc2, Abcg5/8, Nr1h3, and Nr1h4. In contrast, PNAC development was prevented and mRNA expression normalized in both Tnfr1/2KO /DSS-PN mice and DSS-PN mice treated with infliximab. TNFα is a key mediator in the pathogenesis of PNAC through suppression of hepatocyte Abcb11, Abcc2, and Abcg5/8. Pharmacologic targeting of TNFα as a therapeutic strategy for PNAC thus deserves further investigation.
2018-04-11 | Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis
Abstract In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1β in PNAC. Pharmacological antagonism of IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1α and IL-1β) prevents PNAC in mice. IL-1β increases hepatocyte NF-κB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes ( Abcc2 , Abcb11 , and Abcg5/8 ), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1β, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC.
2017-06-01 | Case Report of Isolated Intestinal Transplantation from a Living Donor in Crossmatch Positive Recipient after Pre-transplant Immunomodulation
Introduction: Pre-transplant immunomodulation commonly used for highly sensitized renal recipient with living donor transplantation. However, living donor intestinal transplantation in highly sensitized recipient reported only in a few cases. In this study, we will report our experience of pre-transplant immunomodulation for a crossmach positive intestinal recipient with living donor. Case report: A 48-year-old female was presented with short bowel syndrome after massive small bowel resection because of internal herniation of small bowel resulting strangulation. She was underwent laparoscopic subtotal gastrectomy from gastric cancer one year ago. She received home parenteral nutrition after that, and was registered as a candidate for isolated intestinal transplantation (IITx). Her panel reactive antibodies was 91.7% for class-I and 0% for class-II. She wanted to receive living donor IITx. Her identical twin younger sister volunteered as a potential donor. However, the crossmatch result was positive. Therefore, we decided to do pre-transplant immunomodulation for the recipient as infusion of rituximab and repeated plasmapheresis (PP) followed by infusion of intravenous immunoglobulin until her donor-specific antibodies (DSA) level was decreased to optimal level to receive IITx.With reduction of DSA level after pre-transplant immunomodulation, she received IITx with segment of ileum donated from her identical twin younger sister. Induction immunosuppression was done using antithymocyte immunoglobulin (ATG). Tacrolimus was maintained and steroid was tapered. Intestinal donor was recovered without postoperative complication. During post-transplant recovery, the recipient was suffered from acute cellular rejection, which was treated with ATG, and multiple infection including cytomegalovirus (CMV) enteritis. CMV enteritis was managed with ganciclovir and reduction of immunosuppression level. Other infections were catheter-related infection and urinary tract infection which were treated with conservative management including proper antibiotics. The intestinal graft was recovering from ulcerative lesions after the rejection episode. Her need for parenteral nutrition was decreasing to about a half of daily caloric requirement at 8-month post-transplant. Conclusion: Pre-transplant immunomodulation using rituximab, IVIG and PP was successful in a crossmatch positive recipient who underwent IITx from a living-donor.
2012-01-24 | Anti–Tumor Necrosis Factor–α Monoclonal Antibody Alleviates Parenteral Nutrition–Associated Liver Disease in Mice
Background : The authors aimed to investigate the role of anti–tumor necrosis factor (TNF)–α monoclonal antibody treatment in a mouse model of parenteral nutrition–associated liver disease (PNALD). Methods : C57BL/6J male mice (aged 6–8 weeks) were randomly assigned to 3 groups: parenteral nutrition (PN), PN with anti–TNF‐α monoclonal antibody treatment (PN + mAb), and controls. A central venous catheter was inserted for intravenous infusion of a PN solution (PN and PN + mAb groups) or saline (controls) for 7 days. Liver pathology, hepatic biochemical indicators, and serum TNF‐α concentrations were analyzed. Levels of hepatic bsep, mdr1a / mdr1b, mdr2 , and mrp2 mRNA were also evaluated in each group. Results : The PN group showed significant increases in serum transaminase, direct bilirubin, and bile acids relative to the control group ( P < .05). Histopathological changes in this group were consistent with early stage cholestasis. The pathological score and serum alanine aminotransferase, total bilirubin, and direct bilirubin levels were improved in the PN + mAb group relative to the PN group ( P < .05). The PN group showed significantly lower hepatic bsep, mdr1a / mdr1b, mdr2 , and mrp2 mRNA expression than the controls ( P < .05), but these were significantly increased compared to the PN group ( P < .05). Conclusions : Infliximab administered at a single dose of 5 mg/kg body weight ameliorated the progression of PNALD and improved the expression of hepatic ABC transporter genes. Therefore, anti–TNF‐α monoclonal antibody may be a beneficial therapy for patients with PNALD.
cell therapies
2024-05-01 | The Use of Milk Bovine Extracellular Vesicles to Mitigate Gut-Liver Axis Dysfunction Under Pediatric Parenteral Nutrition
Parenteral Nutrition (PN) is a lifesaving strategy that provides intravenous nutrition in patients when enteral feeding is contraindicated, or access is insuffcient to prevent malnutrition. PN is used in low-birth-weight neonates whereprolonged use is associated with severe metabolic complications, including parenteral nutrition-associated liver disease (PNALD). PNALD is characterized by hepatitis, cholestasis, fibrosis, steatosis, and eventual organ failure. Elevated rates of PNALD in pediatric patients may be driven by liver immaturity, aberrant metabolic adaptation, and leaky gut barrier.To characterize the etiology of PNALD, we recently established a pediatric mouse model of PN. Using this model, we explored the intravenous use of bioactive milk components to augment hepatic immune response in pediatric mice without enteral milk intake. Extracellular vesicles (EVs) are involved in cell-to-cell communication, contain immune-augmenting microRNA, and are enriched in bovine milk. After isolating EVs from bovine milk and characterizing them, we explored EV use in vitro via M1 macrophage responses, showing TNF-alpha inhibition in the presence of LPS. Wethen hypothesized that EVs would protect the pediatric liver from hepatitis under PN feeding in vivo. Mouse pups were randomized to intravenous PN, PN + EV (1.39x10 9 particles/uL), or sham surgery control for 6 days. Flow cytometry showed PN elevated hepatic macrophages (CD11b+F4/80+), myeloid-derived suppressor cells (CD11b+GR1+) andreduced relative T cell populations compared with sham controls. PN+EV treatment restored hepatic immune profiles to patterns observed in sham controls. Spleen and liver cytokines also mirrored changes in hepatic flow results, where elevated proinflammatory IL-1 beta was induced with PN alone, but similar levels were found in sham and PN+EVanimals. MicroRNA sequencing showed the EV isolates contain 48% Let-7, a described myeloid suppressor microRNA. This data demonstrates that intravenous EV administration - or future synthetic microRNA - may provide a noveltherapeutic approach for patients requiring PN nutrition support, especially those with elevated risk of PNALD induced inflammation and organ dysfunction. Dairy Innovation Hub, UW-Madison. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
2016-03-03 | Production of tissue-engineered intestine from expanded enteroids
BackgroundShort bowel syndrome is a life-threatening condition with few solutions. Tissue-engineered intestine (TEI) is a potential treatment, but donor intestine is a limiting factor. Expanded epithelial surrogates termed enteroids may serve as a potential donor source.Materials and methodsTo produce TEI from enteroids, crypts were harvested from mice and enteroid cultures established. Enteroids were seeded onto polymer scaffolds using Matrigel or culture medium and implanted in immunosuppressed mice for 4 wk. Histology was analyzed using Periodic acid–Schiff staining and immunofluorescence. Neomucosa was quantified using ImageJ software. To determine whether TEI could be produced from enteroids established from small intestinal biopsies, 2 × 2–mm pieces of jejunum were processed for enteroid culture, enteroids were expanded and seeded onto scaffolds, and scaffolds implanted for 4 wk.ResultsEnteroids in Matrigel produced TEI in 15 of 15 scaffolds, whereas enteroids in medium produced TEI in 9 of 15 scaffolds. Use of Matrigel led to more neomucosal surface area compared to media (10,520 ± 2905 μm versus 450 ± 127 μm, P < 0.05). Histologic examination confirmed the presence of crypts and blunted villi, normal intestinal epithelial lineages, intestinal subepithelial myofibroblasts, and smooth muscle cells. Crypts obtained from biopsies produced an average of 192 ± 71 enteroids. A single passage produced 685 ± 58 enteroids, which was adequate for scaffold seeding. TEI was produced in 8 of 9 scaffolds seeded with expanded enteroids.ConclusionsEnteroids can be obtained from minimal starting material, expanded ex vivo, and implanted to produce TEI. This method shows promise as a solution to the limited donor intestine available for TEI production in patients with short bowel syndrome.
2008-11-28 | Preservation of extracorporeal tissue in closing gastroschisis augments intestinal length
Background Prenatal closure of the umbilical ring in gastroschisis may result in an amorphous, nonviable appearing extracorporeal tissue that is resected during the repair. However, it is unclear whether such remnant intestine is truly nonviable. Methods and Results We examined the outcomes of patients when this tissue is preserved. We identified 8 patients who presented with a closing gastroschisis and a mass of tissue connected by a vascular pedicle. Four patients underwent abdominal exploration with resection of the mass and gastroschisis closure. Histologic examination revealed normal intestinal wall architecture. All patients in this group developed short bowel syndrome, requiring long-term parenteral nutrition. Conversely, 4 patients underwent abdominal exploration with internalization of the remnant tissue, a maneuver referred to as "parking," along with either silo placement, or primary closure of the gastroschisis. At re-exploration, 3 of 4 patients were found to have viable intestine, and bowel continuity was reestablished. The mean parenteral nutrition requirement for this group was significantly shorter than the resected group. Conclusion In this series, we show that this amorphous tissue, when preserved, may exhibit normal intestinal architecture and absorptive function. Therefore, such remnant tissue should be preserved as it may significantly increase bowel length and minimize parenteral nutrition requirement.
2007-03-22 | Nutrition and Quality of Life Following Small Intestinal Transplantation
BACKGROUND The Outcome from small bowel transplantation (SBTx) has improved progressively over the past decade raising questions as to whether indications should be broadened from those currently followed based on “TPN (total parenteral nutrition) failure.” OBJECTIVE AND METHODS To assess current outcome, we studied the effect of transplantation on nutritional autonomy, organ function, and quality of life (QoL) measured by a validated self-administered questionnaire containing 26 domains and 130 questions, for a minimum of 12 months in a cohort of 46 consecutively transplanted patients between June 2003 and July 2004. The majority of transplanted patients (76%) had intestinal failure because of extreme short bowel, the remainder having either chronic pseudo-obstruction or porto-mesenteric vein thrombosis (PMVT). All but the PMVT patients were dependent on home TPN (HPN) (median 2, range 0–25 yr) and had developed serious recurrent infective complications with (25%) or without central vein thrombosis and liver failure. Sixty-one percent received a liver in addition to a small intestine. RESULTS Follow-up was for a mean of 21 (range 12–36) months. Five patients died, two with chronic graft rejection. All the remaining patients have graft survival with an average of 1.2 (range 0–5) episodes of acute rejection. All patients were weaned from TPN by a median of 18 days (range 1–117 days) and from tube feeding by day 69 (range 22–272 days). There was a significant improvement in overall assessment of QoL and in 13 of 26 of the specific domains examined. CONCLUSION Our results confirm the claim that a new era has dawned for SBTx, such that, with continued progress, it can potentially become an alternative to HPN for the management of permanent intestinal failure, rather than a last-chance treatment for “TPN failure.”
2006-12-01 | Recovery From Liver Dysfunction After Adult Isolated Intestinal Transplantation Without Liver Grafting
We sought to evaluate liver function recovery after isolated intestinal transplantation in adults with irreversible intestinal failure.Over a 5-year period, we transplanted 34 adult patients, 25 of whom received an isolated intestinal graft, 4 a multivisceral graft without a liver, and 5, a multivisceral graft with a liver. Among the group of patients transplanted with the isolated graft we selected 14 recipients with pretransplant liver dysfunction, namely, a serum bilirubin >2 mg/dL (normal value: 1.2) and/or transaminases >100 IU/mL (NV, 37/40). Other inclusion criteria were total parenteral nutrition, period > 3 months, no diagnosis of portal hypertension or cirrhosis. Two patients had biopsy-proven liver fibrosis.At discharge, all patients recovered liver function to normal values: mean bilirubin blood level was 0.9 +/- 0.96 mg/dL (range: 0.3-1.6) and mean transaminases were 26 +/- 9 and 31 +/- 18 IU/mL (range: 10-44/27-65). After a mean follow-up of 2 years, only one patient has an elevated alanine aminotransferase level without clinical signs of liver disease. Type of pretransplant liver disease did not impact on survival rates.In selected cases, an isolated intestinal or a multivisceral graft without a liver can represent a "liver salvage therapy" for an early failing liver in patients with irreversible intestinal failure. Pretransplant liver disease is not a negative prognostic factor.
gene therapies
2025-10-06 | MRPL35 Attenuates Neonatal Parenteral Nutrition-Associated Cholestasis by Modulating the ROS/JNK/NF-κB Pathway.
This study aimed to elucidate the role of the MRPL35/ROS/JNK/NF-κB signaling pathway in the pathogenesis of neonatal parenteral nutrition-associated cholestasis (PNAC) to identify underlying mechanisms and potential therapeutic targets. The study employed both human and animal models. Neonates receiving parenteral nutrition for at least 2 weeks were divided into PNAC (n=10) and control groups (n=13). A PNAC model was established in male Sprague-Dawley rats (parenteral nutrition for 14 days, n=6/group), with interventions including adenovirus-mediated MRPL35 overexpression and N-acetylcysteine (NAC) treatment. Inflammatory markers, oxidative stress indicators, and signaling pathway activation were assessed using ELISA, immunohistochemistry, qRT-PCR, and Western blotting. Clinically, neonates with PNAC exhibited elevated serum levels of AST, DBil, TBA, TNF-α, and IL-1β, along with reduced levels of anti-inflammatory cytokines (IL-4, IL-10), increased ROS, and higher apoptosis in peripheral blood mononuclear cells (PBMCs). MRPL35 expression was significantly downregulated and JNK and NF-κB pathways were activated. In the animal model, PNAC rats showed severe liver injury, elevated TNF-α, IL-1β and ROS in hepatocytes, and higher hepatocyte apoptosis; the expression of MRPL35 mRNA was significantly downregulated. Overexpression of MRPL35 reduced JNK/NF-κB activation, inflammatory cytokines, oxidative stress and liver injury, effects that were enhanced by co-treatment with N-acetylcysteine (NAC). The MRPL35/ROS/JNK/NF-κB signaling pathway plays a critical role in the pathogenesis of PNAC. Targeting MRPL35 is expected to alleviate liver injury by blocking mitochondrial ROS signaling, offering a novel precision treatment model targeting the mitochondrial-inflammation axis for PNAC.
small molecules
2026-06-26 | Fish oil emulsion for reversal of intestinal failure-associated liver disease in preterm infants: Three case reports and review of literature
BACKGROUND Prolonged parenteral nutrition (PN) is a major risk factor for intestinal failure-associated liver disease (IFALD), particularly in preterm infants. Plant-derived lipid emulsions, rich in phytosterols and ω-6 fatty acids, are considered key contributors. Fish oil lipid emulsions (FO-ILE) have emerged as a potential therapeutic alternative; however, the optimal dose for balancing efficacy and safety remains uncertain. CASE SUMMARY We report three preterm infants (gestational age, 31-36+2 weeks) with severe IFALD who were transitioned from soybean oil-based or multi-oil emulsions to FO-ILE. Fish oil was administered at a dose of 2 g/kg/day, a dosing approach for which limited data are available in this population. Prior to the transition, peak direct bilirubin (DB) levels ranged from 191.9 μmol/L to 356 μmol/L, with one patient exhibiting severe cholestasis and marked hepatosplenomegaly. Following 29-63 days of treatment, DB levels decreased to 30.7-89.9 μmol/L, resulting in a faster DB decline than that observed with the conventional 1 g/kg/day dosage. Full enteral feeding was achieved after 69-105 days of PN. The regimen was well tolerated, with no evidence of essential fatty acid deficiency, growth impairment, or bleeding complications. CONCLUSION FO-ILE up to 2 g/kg/day was well tolerated and improved liver function, which supports further investigation in PN-dependent infants.
2026-06-15 | Association between multi-oil fat emulsion and bronchopulmonary dysplasia in preterm infants <32 weeks.
Bronchopulmonary dysplasia (BPD) is a major respiratory morbidity in preterm infants and remains an important cause of adverse short- and long-term outcomes. Early postnatal nutrition may influence lung growth and injury repair, and intravenous lipid emulsions are a key component of parenteral nutrition in very preterm infants. Compared with conventional medium-chain/long-chain triglyceride fat emulsions (MCT/LCT), multi-oil fat emulsion (SMOF) contains fish oil and vitamin E, etc., and has a lower relative proportion of ω-6 fatty acids, and may theoretically attenuate inflammation and oxidative stress. However, current evidence regarding whether SMOF reduces the incidence of BPD remains inconsistent. This study aimed to evaluate the association between SMOF and BPD in preterm infants born at <32 weeks' gestation. A retrospective analysis included 171 preterm infants (<32 weeks) admitted to a tertiary neonatal intensive care unit, divided into SMOF (n=96) and MCT/LCT (n=75) groups. The outcome of respiratory system and other complications such as parenteral nutrition-related cholestasis (PNAC), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), late-onset of sepsis (LOS), brain injury and mortality were compared between the two groups. Among the 171 preterm infants in the study, the mean gestational age was 29.51±1.55 weeks, with birth weight of 1,229.39±299.06 g. Multivariate analysis identified SMOF as an independent protective factor against BPD [odds ratio (OR) =0.317, 95% confidence interval (CI): 0.128-0.784]. No significant differences were observed in PNAC, ROP, NEC, sepsis, brain injury, or mortality between groups. We preliminarily conclude that SMOF is a potentially protective factor for BPD in preterm infants <32 weeks without increasing complications such as PNAC, ROP, NEC, sepsis, and brain injury. These findings may support its clinical utility in this population.
2026-06-01 | OC51 Incidence and persistence of elevated vitamin A levels in paediatric patients on home parenteral nutrition
Vitamin A is an essential fat-soluble vitamin required for vision, bone growth, immune function, and differentiation of epithelial and nerve tissues.1 Both deficiency and toxicity are associated with significant morbidity in children, such as vision loss and increased intracranial pressure or headaches. Vitamin A has a long half-life; levels can remain elevated for extended periods.2 Regular monitoring is recommended for children receiving long-term parenteral nutrition (PN).3 The aim of the study was to review the frequency and duration of high serum vitamin A levels in children receiving home PN, and explore any associations between elevated levels with lipid provision or supplemental feeds. A retrospective review was conducted of all children currently receiving home PN under the care of the intestinal failure multidisciplinary team. Data were collected on demographic characteristics, underlying pathology leading to IF, time on PN, vitamin A levels, lipid and vitilipid doses, and any clinical symptoms suggestive of hypervitaminosis A. Episodes of high vitamin A were defined as levels above the laboratory reference range for at least three consecutive months over the last two years, while the child had a normal CRP. Thirty-nine children were on home PN (20 male, mean age 9 years, range 1–18 years). The main underlying conditions included short bowel syndrome (27/39, 69.2%), congenital diarrhoea (7/39, 17.9%), dysmotility (3/39, 7.7%), and other pathologies such as cystinosis (1/39, 2.6%) and eosinophilic colitis (1/39, 2.6%). Twenty-three of 39 (59%) children had elevated vitamin A lasting three months or more. Of these, 19/39 (48.7%) had one episode lasting at least three months and 4/39 (10.3%) had two prolonged episodes. None had more than two episodes. Four of 39 (10.3%) patients had prolonged elevation for the entire 24-month study despite reduced vitilipid dose (2/4 children (50%) had cholestasis). The median initial vitamin A concentration across all episodes was 2.05 (95% SD 3.32). Of all 27 episodes of raised vitamin A, 6/27 (22.2%) normalised after one reduction of vitilipid by 10%–25%. A further 4/27 (14.8%) resolved after multiple reductions in vitilipid content, ranging from a total reduction of 40%–55%. The remaining 13/27 (48.1%) episodes remained unresolved with levels above the reference range in September 2025, despite reductions in vitilipid on one (8/13) or more (5/13) occasions, ranging from 15% to 79% total reduction. Only one episode was associated with clinical symptoms compatible with hypervitaminosis A, including headache and irritability. Comparison between patients requiring a 10%–40% reduction of vitilipid (n=13) and those requiring >40% (n=8) did not differ in lipid nights per week (4.9 vs 4.6 nights, p=0.35) or the number on supplemental feeds (8/13 vs 3/8 respectively). Episodes of high vitamin A levels are common in children on home PN and may persist for several months. Although vitilipid provision should be amended, other factors—including interindividual variation in metabolism—may affect vitamin A levels. Any reduction in vitilipid should be made cautiously to avoid secondary deficiencies of other fat-soluble vitamins. Ross AC. Vitamin A. In: Ross AC, Caballero B, Cousins RJ, et al. editors. Modern Nutrition in Health and Disease. 11th ed. Baltimore (MD): Lippincott Williams & Wilkins; 2014. p. 260–277. Haskell MJ, Lembcke JL, Salazar M, et al. Population-based plasma kinetics of an oral dose of [2H4]retinyl acetate among preschool-aged Peruvian children. Am J Clin Nutr. 2003 Mar;77(3):681–686. Berger MM, Shenkin A, Schweinlin A, et al. ESPEN micronutrient guideline. Clin Nutr. 2022 Jun;41(6):1357–1424.
2025-12-28 | Mechanistic Analysis of Fisetin in Liver Diseases and Its Potential Therapeutic Application in IFALD—A Review of In Vitro and In Vivo Studies
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.
2025-09-04 | Association between mixed fatty acid emulsion and parenteral nutrition-associated cholestasis in extremely low-birth-weight infants: A retrospective cohort study.
Soybean oil lipid emulsions have been implicated in the development of parenteral nutrition-associated cholestasis (PNAC) in premature infants. A recent mixed fatty acid emulsion containing soybean oil, medium-chain triglycerides (MCTs), olive oil, and fish oil may reduce the incidence of PNAC, but evidence remains conflicting. The aim of this study was to evaluate the effect of mixed fatty acid emulsion on PNAC in extremely low-birth-weight (ELBW) infants. We performed a retrospective cohort study on ELBW infants from 2016 to 2022. ELBW infants who received MCT/long-chain triglyceride (LCT) lipid emulsion or mixed fatty acid emulsion were compared. The primary outcome was the incidence of PNAC. Secondary outcomes included peak levels of direct bilirubin and bronchopulmonary dysplasia. Multivariable analysis was performed to adjust for potential confounders. A total of 180 ELBW infants were reviewed in this study. Twenty-six of 99 patients (26.2%) in the mixed fatty acid emulsion group and 29 of 81 patients (35.8%) in the MCT/LCT lipid emulsion group developed PNAC (P = 0.17). There was no significant difference in median peak direct bilirubin and the rate of bronchopulmonary dysplasia. The results remained consistent after adjusting for potential confounders. Time to PNAC, rate of rise of direct bilirubin, and age of direct bilirubin normalization were not statistically different between groups. Compared with MCT/LCT lipid emulsion, mixed fatty acid emulsion did not reduce the incidence or degree of PNAC in ELBW infants.
antibodies
2024-02-20 | Inflammation drives pathogenesis of early intestinal failure-associated liver disease
Abstract Patients with intestinal failure who receive long-term parenteral nutrition (PN) often develop intestinal failure-associated liver disease (IFALD). Although there are identified risk factors, the early pathogenesis is poorly understood and treatment options are limited. Here, we perform a transcriptomic analysis of liver tissue in a large animal IFALD model to generate mechanistic insights and identify therapeutic targets. Preterm Yorkshire piglets were provided PN or bottle-fed with sow-milk replacer for 14 days. Compared to bottle-fed controls, piglets receiving PN developed biochemical cholestasis by day of life 15 (total bilirubin 0.2 vs. 2.9 mg/dL, P = 0.01). RNA-Seq of liver tissue was performed. Ingenuity Pathway Analysis identified 747 differentially expressed genes (343 upregulated and 404 downregulated) with an adjusted P < 0.05 and a fold-change of > |1|. Enriched canonical pathways were identified, demonstrating broad activation of inflammatory pathways and inhibition of cell cycle progression. Potential therapeutics including infliximab, glucocorticoids, statins, and obeticholic acid were identified as predicted upstream master regulators that may reverse the PN-induced gene dysregulation. The early driver of IFALD in neonates may be inflammation with an immature liver; identified therapeutics that target the inflammatory response in the liver should be investigated as potential treatments.
2022-07-13 | Interrupting tumor necrosis factor-alpha signaling prevents parenteral nutrition-associated cholestasis in mice.
We have recently reported a mouse model of PN-associated cholestasis (PNAC) in which combining intestinal inflammation and PN infusion results in cholestasis, hepatic macrophage activation, and transcriptional suppression of canalicular bile acid, bilirubin and sterol transporters Abcb11, Abcc2 and Abcg5/8. The aim of this study was to examine the role of TNFα in promoting PNAC in mice. First, recombinant TNFα was administered to mice as well as in hepatocyte cell culture. Second, Tnfr1/2KO or wild-type (WT) mice were exposed to dextran sulfate sodium (DSS) for 4 days followed by soy-oil lipid emulsion-based PN infusion through a central venous catheter for 14 days (DSS-PN). Finally, WT/DSS-PN mice were also infused with infliximab at 10 mg/kg on days 3 and 10 of PN. PNAC was defined by increased serum aspartate aminotransferase, alanine aminotransferase, total bile acids, and bilirubin. Intraperitoneal injection of TNFα into WT mice or TNFα treatment of Huh7 hepatocarcinoma cells and primary mouse hepatocytes suppressed messenger RNA (mRNA) transcription of bile (Abcb11, Abcc2]) and sterol transporters (Abcg5/8) and their regulators Nr1h3 and Nr1h4. DSS-PN mice with PNAC had increased hepatic TNFα mRNA expression and significant reduction of mRNA expression of Abcb11, Abcc2, Abcg5/8, Nr1h3, and Nr1h4. In contrast, PNAC development was prevented and mRNA expression normalized in both Tnfr1/2KO /DSS-PN mice and DSS-PN mice treated with infliximab. TNFα is a key mediator in the pathogenesis of PNAC through suppression of hepatocyte Abcb11, Abcc2, and Abcg5/8. Pharmacologic targeting of TNFα as a therapeutic strategy for PNAC thus deserves further investigation.
2018-04-11 | Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis
Abstract In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1β in PNAC. Pharmacological antagonism of IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1α and IL-1β) prevents PNAC in mice. IL-1β increases hepatocyte NF-κB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes ( Abcc2 , Abcb11 , and Abcg5/8 ), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1β, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC.
2017-06-01 | Case Report of Isolated Intestinal Transplantation from a Living Donor in Crossmatch Positive Recipient after Pre-transplant Immunomodulation
Introduction: Pre-transplant immunomodulation commonly used for highly sensitized renal recipient with living donor transplantation. However, living donor intestinal transplantation in highly sensitized recipient reported only in a few cases. In this study, we will report our experience of pre-transplant immunomodulation for a crossmach positive intestinal recipient with living donor. Case report: A 48-year-old female was presented with short bowel syndrome after massive small bowel resection because of internal herniation of small bowel resulting strangulation. She was underwent laparoscopic subtotal gastrectomy from gastric cancer one year ago. She received home parenteral nutrition after that, and was registered as a candidate for isolated intestinal transplantation (IITx). Her panel reactive antibodies was 91.7% for class-I and 0% for class-II. She wanted to receive living donor IITx. Her identical twin younger sister volunteered as a potential donor. However, the crossmatch result was positive. Therefore, we decided to do pre-transplant immunomodulation for the recipient as infusion of rituximab and repeated plasmapheresis (PP) followed by infusion of intravenous immunoglobulin until her donor-specific antibodies (DSA) level was decreased to optimal level to receive IITx.With reduction of DSA level after pre-transplant immunomodulation, she received IITx with segment of ileum donated from her identical twin younger sister. Induction immunosuppression was done using antithymocyte immunoglobulin (ATG). Tacrolimus was maintained and steroid was tapered. Intestinal donor was recovered without postoperative complication. During post-transplant recovery, the recipient was suffered from acute cellular rejection, which was treated with ATG, and multiple infection including cytomegalovirus (CMV) enteritis. CMV enteritis was managed with ganciclovir and reduction of immunosuppression level. Other infections were catheter-related infection and urinary tract infection which were treated with conservative management including proper antibiotics. The intestinal graft was recovering from ulcerative lesions after the rejection episode. Her need for parenteral nutrition was decreasing to about a half of daily caloric requirement at 8-month post-transplant. Conclusion: Pre-transplant immunomodulation using rituximab, IVIG and PP was successful in a crossmatch positive recipient who underwent IITx from a living-donor.
2012-01-24 | Anti–Tumor Necrosis Factor–α Monoclonal Antibody Alleviates Parenteral Nutrition–Associated Liver Disease in Mice
Background : The authors aimed to investigate the role of anti–tumor necrosis factor (TNF)–α monoclonal antibody treatment in a mouse model of parenteral nutrition–associated liver disease (PNALD). Methods : C57BL/6J male mice (aged 6–8 weeks) were randomly assigned to 3 groups: parenteral nutrition (PN), PN with anti–TNF‐α monoclonal antibody treatment (PN + mAb), and controls. A central venous catheter was inserted for intravenous infusion of a PN solution (PN and PN + mAb groups) or saline (controls) for 7 days. Liver pathology, hepatic biochemical indicators, and serum TNF‐α concentrations were analyzed. Levels of hepatic bsep, mdr1a / mdr1b, mdr2 , and mrp2 mRNA were also evaluated in each group. Results : The PN group showed significant increases in serum transaminase, direct bilirubin, and bile acids relative to the control group ( P < .05). Histopathological changes in this group were consistent with early stage cholestasis. The pathological score and serum alanine aminotransferase, total bilirubin, and direct bilirubin levels were improved in the PN + mAb group relative to the PN group ( P < .05). The PN group showed significantly lower hepatic bsep, mdr1a / mdr1b, mdr2 , and mrp2 mRNA expression than the controls ( P < .05), but these were significantly increased compared to the PN group ( P < .05). Conclusions : Infliximab administered at a single dose of 5 mg/kg body weight ameliorated the progression of PNALD and improved the expression of hepatic ABC transporter genes. Therefore, anti–TNF‐α monoclonal antibody may be a beneficial therapy for patients with PNALD.
cell therapies
2024-05-01 | The Use of Milk Bovine Extracellular Vesicles to Mitigate Gut-Liver Axis Dysfunction Under Pediatric Parenteral Nutrition
Parenteral Nutrition (PN) is a lifesaving strategy that provides intravenous nutrition in patients when enteral feeding is contraindicated, or access is insuffcient to prevent malnutrition. PN is used in low-birth-weight neonates whereprolonged use is associated with severe metabolic complications, including parenteral nutrition-associated liver disease (PNALD). PNALD is characterized by hepatitis, cholestasis, fibrosis, steatosis, and eventual organ failure. Elevated rates of PNALD in pediatric patients may be driven by liver immaturity, aberrant metabolic adaptation, and leaky gut barrier.To characterize the etiology of PNALD, we recently established a pediatric mouse model of PN. Using this model, we explored the intravenous use of bioactive milk components to augment hepatic immune response in pediatric mice without enteral milk intake. Extracellular vesicles (EVs) are involved in cell-to-cell communication, contain immune-augmenting microRNA, and are enriched in bovine milk. After isolating EVs from bovine milk and characterizing them, we explored EV use in vitro via M1 macrophage responses, showing TNF-alpha inhibition in the presence of LPS. Wethen hypothesized that EVs would protect the pediatric liver from hepatitis under PN feeding in vivo. Mouse pups were randomized to intravenous PN, PN + EV (1.39x10 9 particles/uL), or sham surgery control for 6 days. Flow cytometry showed PN elevated hepatic macrophages (CD11b+F4/80+), myeloid-derived suppressor cells (CD11b+GR1+) andreduced relative T cell populations compared with sham controls. PN+EV treatment restored hepatic immune profiles to patterns observed in sham controls. Spleen and liver cytokines also mirrored changes in hepatic flow results, where elevated proinflammatory IL-1 beta was induced with PN alone, but similar levels were found in sham and PN+EVanimals. MicroRNA sequencing showed the EV isolates contain 48% Let-7, a described myeloid suppressor microRNA. This data demonstrates that intravenous EV administration - or future synthetic microRNA - may provide a noveltherapeutic approach for patients requiring PN nutrition support, especially those with elevated risk of PNALD induced inflammation and organ dysfunction. Dairy Innovation Hub, UW-Madison. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
2016-03-03 | Production of tissue-engineered intestine from expanded enteroids
BackgroundShort bowel syndrome is a life-threatening condition with few solutions. Tissue-engineered intestine (TEI) is a potential treatment, but donor intestine is a limiting factor. Expanded epithelial surrogates termed enteroids may serve as a potential donor source.Materials and methodsTo produce TEI from enteroids, crypts were harvested from mice and enteroid cultures established. Enteroids were seeded onto polymer scaffolds using Matrigel or culture medium and implanted in immunosuppressed mice for 4 wk. Histology was analyzed using Periodic acid–Schiff staining and immunofluorescence. Neomucosa was quantified using ImageJ software. To determine whether TEI could be produced from enteroids established from small intestinal biopsies, 2 × 2–mm pieces of jejunum were processed for enteroid culture, enteroids were expanded and seeded onto scaffolds, and scaffolds implanted for 4 wk.ResultsEnteroids in Matrigel produced TEI in 15 of 15 scaffolds, whereas enteroids in medium produced TEI in 9 of 15 scaffolds. Use of Matrigel led to more neomucosal surface area compared to media (10,520 ± 2905 μm versus 450 ± 127 μm, P < 0.05). Histologic examination confirmed the presence of crypts and blunted villi, normal intestinal epithelial lineages, intestinal subepithelial myofibroblasts, and smooth muscle cells. Crypts obtained from biopsies produced an average of 192 ± 71 enteroids. A single passage produced 685 ± 58 enteroids, which was adequate for scaffold seeding. TEI was produced in 8 of 9 scaffolds seeded with expanded enteroids.ConclusionsEnteroids can be obtained from minimal starting material, expanded ex vivo, and implanted to produce TEI. This method shows promise as a solution to the limited donor intestine available for TEI production in patients with short bowel syndrome.
2008-11-28 | Preservation of extracorporeal tissue in closing gastroschisis augments intestinal length
Background Prenatal closure of the umbilical ring in gastroschisis may result in an amorphous, nonviable appearing extracorporeal tissue that is resected during the repair. However, it is unclear whether such remnant intestine is truly nonviable. Methods and Results We examined the outcomes of patients when this tissue is preserved. We identified 8 patients who presented with a closing gastroschisis and a mass of tissue connected by a vascular pedicle. Four patients underwent abdominal exploration with resection of the mass and gastroschisis closure. Histologic examination revealed normal intestinal wall architecture. All patients in this group developed short bowel syndrome, requiring long-term parenteral nutrition. Conversely, 4 patients underwent abdominal exploration with internalization of the remnant tissue, a maneuver referred to as "parking," along with either silo placement, or primary closure of the gastroschisis. At re-exploration, 3 of 4 patients were found to have viable intestine, and bowel continuity was reestablished. The mean parenteral nutrition requirement for this group was significantly shorter than the resected group. Conclusion In this series, we show that this amorphous tissue, when preserved, may exhibit normal intestinal architecture and absorptive function. Therefore, such remnant tissue should be preserved as it may significantly increase bowel length and minimize parenteral nutrition requirement.
2007-03-22 | Nutrition and Quality of Life Following Small Intestinal Transplantation
BACKGROUND The Outcome from small bowel transplantation (SBTx) has improved progressively over the past decade raising questions as to whether indications should be broadened from those currently followed based on “TPN (total parenteral nutrition) failure.” OBJECTIVE AND METHODS To assess current outcome, we studied the effect of transplantation on nutritional autonomy, organ function, and quality of life (QoL) measured by a validated self-administered questionnaire containing 26 domains and 130 questions, for a minimum of 12 months in a cohort of 46 consecutively transplanted patients between June 2003 and July 2004. The majority of transplanted patients (76%) had intestinal failure because of extreme short bowel, the remainder having either chronic pseudo-obstruction or porto-mesenteric vein thrombosis (PMVT). All but the PMVT patients were dependent on home TPN (HPN) (median 2, range 0–25 yr) and had developed serious recurrent infective complications with (25%) or without central vein thrombosis and liver failure. Sixty-one percent received a liver in addition to a small intestine. RESULTS Follow-up was for a mean of 21 (range 12–36) months. Five patients died, two with chronic graft rejection. All the remaining patients have graft survival with an average of 1.2 (range 0–5) episodes of acute rejection. All patients were weaned from TPN by a median of 18 days (range 1–117 days) and from tube feeding by day 69 (range 22–272 days). There was a significant improvement in overall assessment of QoL and in 13 of 26 of the specific domains examined. CONCLUSION Our results confirm the claim that a new era has dawned for SBTx, such that, with continued progress, it can potentially become an alternative to HPN for the management of permanent intestinal failure, rather than a last-chance treatment for “TPN failure.”
2006-12-01 | Recovery From Liver Dysfunction After Adult Isolated Intestinal Transplantation Without Liver Grafting
We sought to evaluate liver function recovery after isolated intestinal transplantation in adults with irreversible intestinal failure.Over a 5-year period, we transplanted 34 adult patients, 25 of whom received an isolated intestinal graft, 4 a multivisceral graft without a liver, and 5, a multivisceral graft with a liver. Among the group of patients transplanted with the isolated graft we selected 14 recipients with pretransplant liver dysfunction, namely, a serum bilirubin >2 mg/dL (normal value: 1.2) and/or transaminases >100 IU/mL (NV, 37/40). Other inclusion criteria were total parenteral nutrition, period > 3 months, no diagnosis of portal hypertension or cirrhosis. Two patients had biopsy-proven liver fibrosis.At discharge, all patients recovered liver function to normal values: mean bilirubin blood level was 0.9 +/- 0.96 mg/dL (range: 0.3-1.6) and mean transaminases were 26 +/- 9 and 31 +/- 18 IU/mL (range: 10-44/27-65). After a mean follow-up of 2 years, only one patient has an elevated alanine aminotransferase level without clinical signs of liver disease. Type of pretransplant liver disease did not impact on survival rates.In selected cases, an isolated intestinal or a multivisceral graft without a liver can represent a "liver salvage therapy" for an early failing liver in patients with irreversible intestinal failure. Pretransplant liver disease is not a negative prognostic factor.
gene therapies
2025-10-06 | MRPL35 Attenuates Neonatal Parenteral Nutrition-Associated Cholestasis by Modulating the ROS/JNK/NF-κB Pathway.
This study aimed to elucidate the role of the MRPL35/ROS/JNK/NF-κB signaling pathway in the pathogenesis of neonatal parenteral nutrition-associated cholestasis (PNAC) to identify underlying mechanisms and potential therapeutic targets. The study employed both human and animal models. Neonates receiving parenteral nutrition for at least 2 weeks were divided into PNAC (n=10) and control groups (n=13). A PNAC model was established in male Sprague-Dawley rats (parenteral nutrition for 14 days, n=6/group), with interventions including adenovirus-mediated MRPL35 overexpression and N-acetylcysteine (NAC) treatment. Inflammatory markers, oxidative stress indicators, and signaling pathway activation were assessed using ELISA, immunohistochemistry, qRT-PCR, and Western blotting. Clinically, neonates with PNAC exhibited elevated serum levels of AST, DBil, TBA, TNF-α, and IL-1β, along with reduced levels of anti-inflammatory cytokines (IL-4, IL-10), increased ROS, and higher apoptosis in peripheral blood mononuclear cells (PBMCs). MRPL35 expression was significantly downregulated and JNK and NF-κB pathways were activated. In the animal model, PNAC rats showed severe liver injury, elevated TNF-α, IL-1β and ROS in hepatocytes, and higher hepatocyte apoptosis; the expression of MRPL35 mRNA was significantly downregulated. Overexpression of MRPL35 reduced JNK/NF-κB activation, inflammatory cytokines, oxidative stress and liver injury, effects that were enhanced by co-treatment with N-acetylcysteine (NAC). The MRPL35/ROS/JNK/NF-κB signaling pathway plays a critical role in the pathogenesis of PNAC. Targeting MRPL35 is expected to alleviate liver injury by blocking mitochondrial ROS signaling, offering a novel precision treatment model targeting the mitochondrial-inflammation axis for PNAC.
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Drug Discovery Landscape
3 orphan drug designations for Parenteral nutrition-associated cholestasis, including 1 approved therapy.
3 orphan drug designations for Parenteral nutrition-associated cholestasis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
fish oil triglycerides [Omegaven] | other | FDA | 2008-02-27 | 2018-07-27 | Fresenius Kabi USA, LLC |
Choline chloride | — | FDA | 2006-07-20 | — | Protara Therapeutics, Inc. |
Multi-vitamin infusion (neonatal formula) | — | FDA | 1989-12-12 | — | Astra Pharmaceuticals, L.P. |
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