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Czerniel J, Gostyńska-Stawna A, Urbaniak N, Sommerfeld-Klatta K, Stawny M. Harnessing algae oil as a sustainable DHA source for parenteral nutrition in vegan patients. Sci Rep 2025; 15:18548. [PMID: 40425710 PMCID: PMC12116783 DOI: 10.1038/s41598-025-03319-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 05/20/2025] [Indexed: 05/29/2025] Open
Abstract
Parenteral nutrition (PN) is a life-saving intervention for patients unable to meet their nutritional needs through oral or enteral routes. However, long-term PN therapy is often associated with complications, including intestinal failure-associated liver disease (IFALD), largely attributed, among other factors, to oxidative stress induced by pro-inflammatory unsaturated fatty acids. To mitigate the risk of developing IFALD, NEs have been optimized by increasing the content of Ω-3 fatty acids, particularly docosahexaenoic acid (DHA). This study aimed to develop a novel NE utilizing algae oil as a sustainable source of DHA, along with soybean lecithin as an emulsifier, to create a fully animal-free alternative to commercial intravenous NEs. The formulated algae oil-based NEs met pharmacopeial and physicochemical standards for intravenous administration, achieving a mean droplet diameter below 166.2 nm, a narrow polydispersity index, and a minimal percentage of fat globules larger than 5 μm, capped at a maximum of 0.01%. They demonstrated excellent compatibility with commercial PN admixtures, biocompatibility with red blood cells, and stability over six months of storage. Among the formulations, NE P100, prepared using non-GMO soybean-derived phospholipids containing over 90% phosphatidylcholine, exhibited the most favorable properties, indicating its potential for further development. These findings highlight algae oil as a sustainable and effective source of DHA, offering a viable option for PN-dependent patients, including those following vegan diets, while reducing the risk of IFALD. Further in vitro and in vivo research is warranted to expand applications and refine this vegan alternative in PN therapy.
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Affiliation(s)
- Joanna Czerniel
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, 3 Rokietnicka, Poznan, 60-806, Poland
| | - Aleksandra Gostyńska-Stawna
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, 3 Rokietnicka, Poznan, 60-806, Poland.
| | - Natalia Urbaniak
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, 3 Rokietnicka, Poznan, 60-806, Poland
| | - Karina Sommerfeld-Klatta
- Department of Toxicology, Poznan University of Medical Sciences, 3 Rokietnicka, Poznan, 60-806, Poland
| | - Maciej Stawny
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, 3 Rokietnicka, Poznan, 60-806, Poland
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Wang SZ, O’Daniel EL. Updates in Intestinal Failure Management. J Clin Med 2025; 14:3031. [PMID: 40364063 PMCID: PMC12072433 DOI: 10.3390/jcm14093031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2025] [Revised: 04/23/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025] Open
Abstract
Short bowel syndrome (SBS) is a malabsorptive condition resulting from reduced functional small intestinal length. SBS is closely related to intestinal failure (IF), defined as the reduction of functional intestinal mass below that which can sustain life, resulting in parenteral nutrition (PN) support for 60 days or greater within a consecutive 74-day period. IF frequently results from intestinal resection necessitated by such diseases as necrotizing enterocolitis in children and Crohn's disease in adults. Clinical manifestations of IF may include diarrhea, growth failure, bacterial overgrowth, and vitamin deficiencies. Nutritional rehabilitation is the cornerstone of IF management. Surgical interventions are aimed at preserving intestinal length and restoring continuity. Medical management involves individualized enteral and parenteral nutrition therapy, GLP-2 agonists (e.g., teduglutide) that promote mucosal growth, and drugs for symptom management such as antidiarrheals. Experimental therapies such as the use of devices to induce intestinal growth through distraction enterogenesis are under development for the treatment of IF. An interdisciplinary approach involving surgeons, gastroenterologists, dietitians, nurses, and social workers is crucial in the management of these complex patients. Ultimately, a combination of nutritional, medical, and surgical management may be necessary to improve clinical outcomes in patients with IF.
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Affiliation(s)
- Sarah Z. Wang
- Department of Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA;
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Wang SZ, Hirsch TI, Fligor SC, Tsikis ST, Pan A, Quigley M, Mitchell PD, Gura KM, Fraser DA, Puder M. A medium-chain fatty acid analogue prevents endotoxin liver injury in a murine model. Sci Rep 2025; 15:13645. [PMID: 40254678 PMCID: PMC12009971 DOI: 10.1038/s41598-025-98200-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 04/10/2025] [Indexed: 04/22/2025] Open
Abstract
Parenteral nutrition (PN) is lifesaving for patients with short bowel syndrome and other gastrointestinal disorders, however long-term use may lead to complications including hepatosteatosis and sepsis. We have previously demonstrated the anti-steatotic, -fibrotic, and -inflammatory properties of SEFA-6179, an engineered medium-chain fatty acid analogue. We hypothesized that SEFA-6179 treatment would protect against endotoxin-induced liver injury in a murine model of PN-induced hepatosteatosis. C57Bl/6J mice were administered a high-carbohydrate liquid diet plus intravenous lipid emulsion (Intralipid, 4 g fat/kg/d) or intravenous saline for 19 days to induce hepatosteatosis. SEFA-6179 (100 mg/kg) or vehicle (MCT/medium-chain triglyceride) was administered via oral gavage for four days leading up to intraperitoneal challenge with lipopolysaccharide (15 mg/kg) or saline on day 19. Age-matched, chow-fed controls received the same treatments. The primary outcome was liver biomarkers: alanine aminotransferase and aspartate aminotransferase. Pro-inflammatory cytokines, IL-6, TNF-alpha, and monocyte chemoattractant protein (MCP1), were analyzed. Liver immunofluorescence staining was performed to evaluate macrophage phenotypes. In endotoxin-challenged mice, pre-treatment with SEFA-6179 lowered liver enzymes and pro-inflammatory cytokine levels compared to vehicle. On liver histology, SEFA-6179 pre-treatment led to greater polarization of M1/pro-inflammatory macrophages to an M2/anti-inflammatory phenotype compared to vehicle. SEFA-6179 is currently in Phase II clinical trials. These findings support the potential application of SEFA-6179 in high-risk, PN-dependent patients.
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Affiliation(s)
- Sarah Z Wang
- Boston Children's Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Department of Surgery and Vascular Biology Program, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.
| | - Thomas I Hirsch
- Boston Children's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Scott C Fligor
- Boston Children's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Savas T Tsikis
- Boston Children's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Amy Pan
- Boston Children's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Mikayla Quigley
- Boston Children's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Paul D Mitchell
- Boston Children's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Kathleen M Gura
- Boston Children's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | | | - Mark Puder
- Boston Children's Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Department of Surgery and Vascular Biology Program, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.
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Wolff J, Cober MP, Huff KA. Essential fatty acid deficiency in parenteral nutrition: Historical perspective and modern solutions, a narrative review. Nutr Clin Pract 2025; 40:350-367. [PMID: 39961748 PMCID: PMC11879921 DOI: 10.1002/ncp.11278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 01/16/2025] [Accepted: 01/16/2025] [Indexed: 03/06/2025] Open
Abstract
Essential fatty acid deficiency (EFAD) may occur in the setting of inadequate fat intake, malabsorption, malnutrition, and altered fat metabolism. Humans lack the enzymes to synthesize the essential acids linoleic acid and alpha-linolenic acid, so they must be obtained from the diet. Patients dependent on parenteral nutrition need adequate amounts of these essential fatty acids supplied in lipid injectable emulsions (ILEs). With the increasing use of multicomponent ILEs that are lower in linoleic and alpha-linolenic acid, it is imperative that clinicians understand appropriate dosing to prevent EFAD. An understanding of fatty acid composition and metabolic pathways is important, as the use of the Holman Index (triene:tetraene ratio) alone may lead to an inaccurate diagnosis of EFAD.
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Affiliation(s)
- Jodi Wolff
- Baxter Healthcare CorporationDeerfieldIllinoisUSA
| | - Mary Petrea Cober
- College of PharmacyNortheast Ohio Medical UniversityRootstownOhioUSA
| | - Katie A. Huff
- Division of Neonatal‐Perinatal Medicine, Department of PediatricsIndiana University School of MedicineIndianapolisIndianaUSA
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Abi-Aad SJ, Lovell M, Khalaf RT, Sokol RJ. Pathogenesis and Management of Intestinal Failure-Associated Liver Disease. Semin Liver Dis 2025; 45:66-80. [PMID: 40015320 PMCID: PMC12031023 DOI: 10.1055/a-2545-7370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 02/14/2025] [Indexed: 03/01/2025]
Abstract
Long-term parenteral nutrition (PN) has considerably improved the management of intestinal failure (IF) in children and adults, particularly those with short bowel syndrome; however, it carries a significant risk of hepatotoxicity, specifically, intestinal failure-associated liver disease (IFALD), also known as PN-associated liver disease. This review provides an update on the latest understanding of IFALD pathogenesis, emerging therapies, and ongoing challenges in the management of this complication. A number of factors are associated with the development of IFALD. PN lipid emulsions, phytosterol exposure, bacterial dysbiosis, an altered gut-liver axis, and episodes of sepsis disrupt bile acid homeostasis and promote liver inflammation in the active phase of IFALD, favoring the development of PN-associated cholestasis (PNAC) and the more chronic form of steatohepatitis with fibrosis. Based on the identification of pathophysiological pathways, potential therapies are being studied in preclinical and clinical trials, including lipid emulsion modifications; targeted therapies such as Farnesoid X receptor (FXR) and liver receptor homolog 1 (LRH-1) agonists, tumor necrosis factor inhibitors, glucagon-like peptide-2 analogs; microbiome modulation; and supplementation with choline and antioxidants. In conclusion, the pathogenesis of IFALD is complex, and PN dependence and liver injury remain challenging, particularly in patients with IF who cannot advance to enteral nutrition and be weaned off PN.
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Affiliation(s)
- Sasha-Jane Abi-Aad
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Mark Lovell
- Department of Pathology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
| | - Racha T. Khalaf
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Ronald J. Sokol
- Department of Pediatrics, Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado
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Povero M, Gura KM, Premkumar MH, Pradelli L, Puder M, Calkins KL. Fish oil lipid emulsion compared with soybean oil lipid emulsion in pediatric patients with parenteral nutrition-associated cholestasis: A cost-effectiveness study. JPEN J Parenter Enteral Nutr 2025; 49:180-188. [PMID: 39707865 DOI: 10.1002/jpen.2713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/06/2024] [Accepted: 11/21/2024] [Indexed: 12/23/2024]
Abstract
OBJECTIVES Evidence indicates that, in pediatric patients with parenteral nutrition-associated cholestasis (PNAC), the use of a 100% fish oil lipid emulsion (FOLE) increased the likelihood of PNAC resolution and reduced the likelihood of liver transplantation compared with a 100% soybean oil lipid emulsion (SOLE). To evaluate the potential economic benefit, we conducted a cost-effectiveness analysis comparing FOLE with SOLE. STUDY DESIGN A discrete event simulation model evaluated cost-effectiveness by simulating clinical outcomes and estimating associated healthcare costs in pediatric patients with PNAC receiving parenteral nutrition (PN) with FOLE (1 g/kg) or SOLE (1.9 g/kg) over a time horizon of 6 years. Model inputs for clinical outcomes were derived from the integrated analysis of two US Phase 3 trials (NCT00910104 and NCT00738101). Cost estimates were estimated from the perspective of the US payer including the cost of PN, transplantation, and adverse events. RESULTS The total cost associated with FOLE was $69,847 USD vs $141,605 USD for SOLE. The cost reduction of $71,757 USD was attributable to the avoidance of liver transplantation (-15.7%) and reduction in adverse events (-4.8%). Life-years and the quality-adjusted life-years were increased with FOLE compared with SOLE (by 0.248 and 0.295, respectively). CONCLUSION By reducing the need for liver transplant and providing time to transition to full enteral nutrition, FOLE leads to cost-savings, compared with SOLE, in pediatric patients with PNAC in the perspective of the US payer. These findings support the use of FOLE in pediatric patients with PNAC who require PN.
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Affiliation(s)
| | - Kathleen M Gura
- Department of Pharmacy, the Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Muralidhar H Premkumar
- Department of Pediatrics, Division of Neonatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
| | | | - Mark Puder
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kara L Calkins
- Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center of the Children's Discovery and Innovation Institute, David Geffen School of Medicine University of California Los Angeles, Los Angeles, California, USA
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Al Qurashi M, Mohammad H, Aga SS, Mustafa A, Alallah J, Al Hindi M, Al Harbi M, Hasosah M. Acquired Zinc Deficiency in Preterm Infant Post-Surgery for Necrotizing Enterocolitis (NEC) on Prolonged Total Parenteral Nutrition (TPN). Pediatr Rep 2024; 16:551-557. [PMID: 39051233 PMCID: PMC11270164 DOI: 10.3390/pediatric16030046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/20/2024] [Accepted: 06/20/2024] [Indexed: 07/27/2024] Open
Abstract
Zinc (Zn) is a vital trace element that plays a pivotal role in protein synthesis, cellular growth, and differentiation and is involved as a cofactor of metalloenzymes, performing a wide variety of metabolic, immune, and synthesis roles. Zn is required at all stages of an infant's and child's development, and severe Zn deficiency has been reported to lead to slower physical, cognitive, and sexual growth. Preterm neonates are at a higher risk of developing zinc deficiency for a variety of reasons, including low Zn intake from enteral feeds containing breast milk, relative malabsorption due to immaturity of the gastrointestinal tract with limited absorptive capacity, increased urinary loss of zinc, and increased demand during the early developmental stages. Moreover, premature infants are at risk of gastrointestinal diseases like necrotizing enterocolitis (NEC), which can limit absorption capacity and potentially lead to malabsorption. TPN is frequently used in preterm infants to provide them with sufficient nutrients and calories. However, it has its own complications, including cholestasis, especially if used for prolonged periods. In this case report, we are presenting the case of a male preterm infant who was delivered by caesarean section at 26 weeks' gestation. The baby developed an intestinal perforation due to NEC, for which he underwent surgery for resection of the necrotic bowel and the creation of a high ileal stoma and was put on prolonged total parenteral nutrition (TPN), which led to the development of zinc deficiency.
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Affiliation(s)
- Mansour Al Qurashi
- Department of Pediatrics, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdul Aziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia; (M.A.Q.); (H.M.); (A.M.); (J.A.); (M.A.H.); (M.A.H.); (M.H.)
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 21423, Saudi Arabia
| | - Hadeel Mohammad
- Department of Pediatrics, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdul Aziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia; (M.A.Q.); (H.M.); (A.M.); (J.A.); (M.A.H.); (M.A.H.); (M.H.)
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 21423, Saudi Arabia
| | - Syed Sameer Aga
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 21423, Saudi Arabia
- Basic Medical Sciences, College of Medicine, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia
| | - Ahmed Mustafa
- Department of Pediatrics, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdul Aziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia; (M.A.Q.); (H.M.); (A.M.); (J.A.); (M.A.H.); (M.A.H.); (M.H.)
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 21423, Saudi Arabia
| | - Jubara Alallah
- Department of Pediatrics, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdul Aziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia; (M.A.Q.); (H.M.); (A.M.); (J.A.); (M.A.H.); (M.A.H.); (M.H.)
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 21423, Saudi Arabia
| | - Mohammed Al Hindi
- Department of Pediatrics, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdul Aziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia; (M.A.Q.); (H.M.); (A.M.); (J.A.); (M.A.H.); (M.A.H.); (M.H.)
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 21423, Saudi Arabia
| | - Mohammed Al Harbi
- Department of Pediatrics, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdul Aziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia; (M.A.Q.); (H.M.); (A.M.); (J.A.); (M.A.H.); (M.A.H.); (M.H.)
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 21423, Saudi Arabia
| | - Mohammed Hasosah
- Department of Pediatrics, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdul Aziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia; (M.A.Q.); (H.M.); (A.M.); (J.A.); (M.A.H.); (M.A.H.); (M.H.)
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Jeddah 21423, Saudi Arabia
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Cheng SY, Jiang L, Wang Y, Cai W. Emerging role of regulated cell death in intestinal failure-associated liver disease. Hepatobiliary Pancreat Dis Int 2024; 23:228-233. [PMID: 36621400 DOI: 10.1016/j.hbpd.2022.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 12/08/2022] [Indexed: 01/10/2023]
Abstract
Intestinal failure-associated liver disease (IFALD) is a common complication of long-term parenteral nutrition that is associated with significant morbidity and mortality. It is mainly characterized by cholestasis in children and steatohepatitis in adults. Unfortunately, there is no effective approach to prevent or reverse the disease. Regulated cell death (RCD) represents a fundamental biological paradigm that determines the outcome of a variety of liver diseases. Nowadays cell death is reclassified into several types, based on the mechanisms and morphological phenotypes. Emerging evidence has linked different modes of RCD, such as apoptosis, necroptosis, ferroptosis, and pyroptosis to the pathogenesis of liver diseases. Recent studies have shown that different modes of RCD are present in animal models and patients with IFALD. Understanding the pathogenic roles of cell death may help uncover the underlying mechanisms and develop novel therapeutic strategies in IFALD. In this review, we discuss the current knowledge on how RCD may link to the pathogenesis of IFALD. We highlight examples of cell death-targeted interventions aiming to attenuate the disease, and provide perspectives for future basic and translational research in the field.
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Affiliation(s)
- Si-Yang Cheng
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China; Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Lu Jiang
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China; Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Ying Wang
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China; Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China; Shanghai Institute for Pediatric Research, Shanghai 200092, China.
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Mihajlovic M, Rosseel Z, De Waele E, Vinken M. Parenteral nutrition-associated liver injury: clinical relevance and mechanistic insights. Toxicol Sci 2024; 199:1-11. [PMID: 38383052 DOI: 10.1093/toxsci/kfae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2024] Open
Abstract
Intestinal failure-associated liver disease (IFALD) is a relatively common complication in individuals receiving parenteral nutrition (PN). IFALD can be manifested as different types of liver injury, including steatosis, cholestasis, and fibrosis, and could result in liver failure in some cases. The onset and progression of IFALD are highly dependent on various patient and PN-related risk factors. Despite still being under investigation, several mechanisms have been proposed. Liver injury can originate due to caloric overload, nutrient deficiency, and toxicity, as well as phytosterol content, and omega-6 to omega-3 fatty acids ratio contained in lipid emulsions. Additional mechanisms include immature or defective bile acid metabolism, acute heart failure, infections, and sepsis exerting negative effects via Toll-like receptor 4 and nuclear factor κB inflammatory signaling. Furthermore, lack of enteral feeding, gut dysbiosis, and altered enterohepatic circulation that affect the farnesoid x receptor-fibroblast growth factor 19 axis can also contribute to IFALD. Various best practices can be adopted to minimize the risk of developing IFALD, such as prevention and management of central line infections and sepsis, preservation of intestine's length, a switch to oral and enteral feeding, cyclic PN, avoidance of overfeeding and soybean oil-based lipid formulations, and avoiding hepatotoxic substances. The present review thus provides a comprehensive overview of all relevant aspects inherent to IFALD. Further research focused on clinical observations, translational models, and advanced toxicological knowledge frameworks is needed to gain more insight into the molecular pathogenesis of hepatotoxicity, reduce IFALD incidence, and encourage the safe use of PN.
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Affiliation(s)
- Milos Mihajlovic
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Zenzi Rosseel
- Department of Pharmacy, Universitair Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium
- Department of Clinical Nutrition, Universitair Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium
| | - Elisabeth De Waele
- Department of Clinical Nutrition, Universitair Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium
- Department of Intensive Care, Universitair Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium
- Faculty of Medicine and Pharmacy, Department of Clinical Sciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium
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10
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Zafirovska M, Zafirovski A, Rotovnik Kozjek N. Current Insights Regarding Intestinal Failure-Associated Liver Disease (IFALD): A Narrative Review. Nutrients 2023; 15:3169. [PMID: 37513587 PMCID: PMC10385050 DOI: 10.3390/nu15143169] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
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.
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Affiliation(s)
- Marija Zafirovska
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Association of General Practice/Family Medicine of South-East Europe (AGP/FM SEE), St. Vladimir Komarov No. 40/6, 1000 Skopje, North Macedonia
| | - Aleksandar Zafirovski
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- General Hospital Jesenice, Cesta Maršala Tita 112, 4270 Jesenice, Slovenia
- Clinical Institute of Radiology, University Medical Centre Ljubljana, Zaloška Cesta 7, 1000 Ljubljana, Slovenia
| | - Nada Rotovnik Kozjek
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Department for Clinical Nutrition, Institute of Oncology Ljubljana, Zaloška Cesta 2, 1000 Ljubljana, Slovenia
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11
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Kudo H, Wada M. Pediatric intestinal rehabilitation. Curr Opin Organ Transplant 2023; 28:237-241. [PMID: 37053076 DOI: 10.1097/mot.0000000000001062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
PURPOSE OF REVIEW The intestinal rehabilitation program (IRP) is a comprehensive treatment strategy that employs various approaches implemented by multidisciplinary teams to treat intestinal failure in children. This program has shown promising results, such as reducing complications and improving prognosis and quality of life (QOL). In this review, we discuss the current status of this program and relevant topics. RECENT FINDINGS IRP includes the prevention and treatment of various complications such as intestinal failure associated liver disease, catheter-related bloodstream infection or sepsis, and venous thromboembolism. In addition, treatment strategies such as glucagon-like peptide-2 analogs, surgical interventions, and intestinal transplantation have evolved over time and have contributed to improved outcomes. In addition, the scope and regions for IRP activities have expanded. SUMMARY IRP improves the prognosis and QOL of children with intestinal failure. The development of new drugs, surgical methods, and treatment strategies is expected to improve the current and future status of pediatric patients with intestinal failure. Furthermore, international institutions must collaborate, share knowledge, conduct joint research, and establish patient registries to advance IRP progress.
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Affiliation(s)
- Hironori Kudo
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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12
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Phelps HM, Warner BW. Intestinal adaptation and rehabilitation. Semin Pediatr Surg 2023; 32:151314. [PMID: 37276784 DOI: 10.1016/j.sempedsurg.2023.151314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Massive intestinal resection is a regrettably necessary but life-saving intervention for progressive or fulminant necrotizing enterocolitis (NEC). However, the resultant short bowel syndrome (SBS) poses its own array of challenges and complications. Within hours of such an abrupt loss of intestinal length, the intestine begins to adapt. Our ability to understand this process of intestinal adaptation has proven critical in our ability to clinically treat the challenging problem of short bowel syndrome. This review first highlights key data relating to intestinal adaptation including structural and functional changes, biochemical regulation, and other factors affecting the magnitude of intestinal adaptation responses. We then focus on intestinal rehabilitation as it relates to strategies to enhance intestinal adaptation while meeting nutritional needs and preventing complications of parenteral nutrition.
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Affiliation(s)
- Hannah M Phelps
- Division of Pediatric Surgery, Department of Surgery, Washington University in St. Louis School of Medicine, 9901 Wohl Hospital, Campus Box 8109, St. Louis, MO 63110, USA.
| | - Brad W Warner
- Division of Pediatric Surgery, Department of Surgery, Washington University in St. Louis School of Medicine, 9901 Wohl Hospital, Campus Box 8109, St. Louis, MO 63110, USA
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13
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Caporilli C, Giannì G, Grassi F, Esposito S. An Overview of Short-Bowel Syndrome in Pediatric Patients: Focus on Clinical Management and Prevention of Complications. Nutrients 2023; 15:nu15102341. [PMID: 37242224 DOI: 10.3390/nu15102341] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/26/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Short-bowel syndrome (SBS) in pediatric age is defined as a malabsorptive state, resulting from congenital malformations, significant small intestine surgical resection or disease-associated loss of absorption. SBS is the leading cause of intestinal failure in children and the underlying cause in 50% of patients on home parental nutrition. It is a life-altering and life-threatening disease due to the inability of the residual intestinal function to maintain nutritional homeostasis of protein, fluid, electrolyte or micronutrient without parenteral or enteral supplementation. The use of parenteral nutrition (PN) has improved medical care in SBS, decreasing mortality and improving the overall prognosis. However, the long-term use of PN is associated with the incidence of many complications, including liver disease and catheter-associated malfunction and bloodstream infections (CRBSIs). This manuscript is a narrative review of the current available evidence on the management of SBS in the pediatric population, focusing on prognostic factors and outcome. The literature review showed that in recent years, the standardization of management has demonstrated to improve the quality of life in these complex patients. Moreover, the development of knowledge in clinical practice has led to a reduction in mortality and morbidity. Diagnostic and therapeutic decisions should be made by a multidisciplinary team that includes neonatologists, pediatric surgeons, gastroenterologists, pediatricians, nutritionists and nurses. A significant improvement in prognosis can occur through the careful monitoring of nutritional status, avoiding dependence on PN and favoring an early introduction of enteral nutrition, and through the prevention, diagnosis and aggressive treatment of CRSBIs and SIBO. Multicenter initiatives, such as research consortium or data registries, are mandatory in order to personalize the management of these patients, improve their quality of life and reduce the cost of care.
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Affiliation(s)
- Chiara Caporilli
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Giuliana Giannì
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Federica Grassi
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Susanna Esposito
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
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14
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Miles JM. Hepatic dysfunction in patients receiving intravenous lipid emulsions. Curr Opin Clin Nutr Metab Care 2023; 26:278-283. [PMID: 36943142 DOI: 10.1097/mco.0000000000000924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
PURPOSE Until recently, intravenous lipid emulsions (ILEs) have consisted of soybean oil (SO) only. This review addresses recent developments in the field, including the problem of intestinal failure associated liver disease (IFALD) that can occur with the use of ILEs in children and adults, and newer ILEs that may minimize and reverse IFALD. RECENT FINDINGS Cholestasis is the primary manifestation of IFALD in premature infants receiving ILEs, whereas in older children and adults, steatosis is predominant. Two alternative ILEs have been extensively investigated for both safety and efficacy. SMOF, an ILE containing medium chain triglyceride, soybean oil, olive oil and fish oil (FO), is now widely used in both children and adults. A newer FO ILE is approved for use in children only. However, in case reports FO ILE has been shown to improve IFALD in adults. A number of new studies suggest that cholestasis from ILEs is dose-related. IFALD does not improve in many patients after transition from SO to SMOF, but partial or complete replacement with FO can halt and reverse IFALD. SUMMARY Adverse hepatic effects from ILEs are to some extent dose-related. Overfeeding with fat or with carbohydrate, or simply providing excessive calories in general, may be responsible. More research is needed investigating dose-related effects of macronutrients on liver injury.
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Affiliation(s)
- John M Miles
- Division of Endocrinology, Diabetes and Clinical Pharmacology, Department of Medicine, University of Kansas School of Medicine, Kansas City, Kansas, USA
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15
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Weylandt KH, Karber M, Xiao Y, Zhang IW, Pevny S, Blüthner E, von Schacky C, Rothe M, Schunck WH, Pape UF. Impact of intravenous fish oil on omega-3 fatty acids and their derived lipid metabolites in patients with parenteral nutrition. JPEN J Parenter Enteral Nutr 2023; 47:287-300. [PMID: 36164258 DOI: 10.1002/jpen.2448] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 08/08/2022] [Accepted: 09/15/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND Long-term parenteral nutrition (PN) can lead to intestinal failure-associated liver disease (IFALD). Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were shown to prevent IFALD. EPA-derived and DHA-derived oxylipins could contribute to this protective effect. METHODS We analyzed the effect of parenteral fish oil on oxylipins in patients with chronic intestinal failure receiving PN (n = 8). Patients first received no fish oil for 8 weeks and then switched to PN with 25% of fat as fish oil for another 8 weeks. Fatty acid profiles of red blood cells, PUFA-derived oxylipins generated by cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 (CYP) pathways, inflammatory markers, and liver function were assessed before and during fish-oil PN. RESULTS EPA plus DHA in erythrocytes (the Omega-3 Index) was high with a median of 11.96% at baseline and decreased to 9.57% without fish oil in PN. Addition of fish oil in PN increased the median Omega-3-Index to 12.75%. EPA-derived and DHA-derived CYP-dependent and LOX-dependent metabolites increased significantly with fish oil in PN, with less pronounced changes in arachidonic acid and its oxylipins. There were no significant changes of inflammation and liver function parameters. CONCLUSIONS This study shows that fish oil-containing PN leads to primarily CYP- and LOX-dependent n-3 PUFA-derived inflammation-dampening oxylipins arising from EPA and DHA. Within this short (16-week) study, there were no significant changes in inflammation and clinical readout parameters.
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Affiliation(s)
- Karsten H Weylandt
- Department of Gastroenterology, Metabolism and Oncology, Division of Medicine, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany.,Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany.,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Medical Department, Division of Medicine, Department of Gastroenterology, Campus Mitte, Berlin, Germany
| | - Mirjam Karber
- Department of Gastroenterology, Metabolism and Oncology, Division of Medicine, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany.,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Medical Department, Division of Medicine, Department of Gastroenterology, Campus Mitte, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Yanan Xiao
- Department of Gastroenterology, Metabolism and Oncology, Division of Medicine, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany.,Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany.,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Medical Department, Division of Medicine, Department of Gastroenterology, Campus Mitte, Berlin, Germany
| | - Ingrid W Zhang
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Medical Department, Division of Medicine, Department of Gastroenterology, Campus Mitte, Berlin, Germany.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Sophie Pevny
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Medical Department, Division of Medicine, Department of Gastroenterology, Campus Mitte, Berlin, Germany
| | - Elisabeth Blüthner
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Medical Department, Division of Medicine, Department of Gastroenterology, Campus Mitte, Berlin, Germany
| | | | | | - Wolf H Schunck
- Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany
| | - Ulrich F Pape
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Medical Department, Division of Medicine, Department of Gastroenterology, Campus Mitte, Berlin, Germany.,Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, Asklepios Tumorzentrum, Hamburg, Germany
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16
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Jaksic T. Current short bowel syndrome management: An era of improved outcomes and continued challenges. J Pediatr Surg 2023; 58:789-798. [PMID: 36870826 DOI: 10.1016/j.jpedsurg.2023.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 01/06/2023] [Indexed: 01/22/2023]
Abstract
Prior to the late 1960s, pediatric short bowel syndrome was a frequently fatal disease. Currently, pediatric interdisciplinary bowel rehabilitation centers report very high survival rates. The mortality trends, up-to-date definitions, incidence, causes, and clinical manifestations of short bowel syndrome are reviewed. Emphasis is placed upon the nutritional, medical, and surgical advances that have contributed to the dramatic improvement in outcomes for pediatric short bowel syndrome patients. Recent findings and remaining challenges are highlighted.
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Affiliation(s)
- Tom Jaksic
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, 333 Longwood Avenue, Boston MA, 02115, USA.
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17
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Berlana D. Parenteral Nutrition Overview. Nutrients 2022; 14:4480. [PMID: 36364743 PMCID: PMC9659055 DOI: 10.3390/nu14214480] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/17/2022] [Accepted: 10/22/2022] [Indexed: 09/10/2023] Open
Abstract
Parenteral nutrition (PN) is a life-saving intervention for patients where oral or enteral nutrition (EN) cannot be achieved or is not acceptable. The essential components of PN are carbohydrates, lipids, amino acids, vitamins, trace elements, electrolytes and water. PN should be provided via a central line because of its hypertonicity. However, peripheral PN (with lower nutrient content and larger volume) can be administered via an appropriate non-central line. There are alternatives for the compounding process also, including hospital pharmacy compounded bags and commercial multichamber bags. PN is a costly therapy and has been associated with complications. Metabolic complications related to macro and micronutrient disturbances, such as hyperglycemia, hypertriglyceridemia, and electrolyte imbalance, may occur at any time during PN therapy, as well as infectious complications, mostly related to venous access. Long-term complications, such as hepatobiliary and bone disease are associated with longer PN therapy and home-PN. To prevent and mitigate potential complications, the optimal monitoring and early management of imbalances is required. PN should be prescribed for malnourished patients or high-risk patients with malnutrition where the feasibility of full EN is in question. Several factors should be considered when providing PN, including timing of initiation, clinical status, and risk of complications.
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Affiliation(s)
- David Berlana
- Pharmacy Department, Vall Hebron Barcelona Campus Hospital, 08035 Barcelona, Spain;
- Pharmacology, Toxicology and Therapeutic Chemistry Department, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
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18
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Di Dato F, Iorio R, Spagnuolo MI. IFALD in children: What's new? A narrative review. Front Nutr 2022; 9:928371. [PMID: 35958249 PMCID: PMC9358220 DOI: 10.3389/fnut.2022.928371] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/27/2022] [Indexed: 11/19/2022] Open
Abstract
Intestinal failure-associated liver disease (IFALD) is a progressive liver disease complicating intestinal failure (IF). It is a preventable and reversible condition, but at the same time, a potential cause of liver cirrhosis and an indication to combined or non-combined liver and small bowel transplantation. The diagnostic criteria are not yet standardized, so that its prevalence varies widely in the literature. Pathophysiology seems to be multifactorial, related to different aspects of intestinal failure and not only to the long-term parenteral nutrition treatment. The survival rates of children with IF have increased, so that the main problems today are preventing complications and ensuring a good quality of life. IFALD is one of the most important factors that limit long-term survival of patients with IF. For this reason, more and more interest is developing around it and the number of published articles is increasing rapidly. The purpose of this narrative review was to focus on the main aspects of the etiology, pathophysiology, management, prevention, and treatment of IFALD, based on what has been published mainly in the last 10 years. Controversies and current research gaps will be highlighted with the aim to pave the way for new project and high-quality clinical trials.
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Affiliation(s)
| | | | - Maria Immacolata Spagnuolo
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy
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19
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Abstract
Intestinal failure (IF) secondary to short bowel syndrome is a challenging and complex medical condition with significant risk for surgical and medical complications. Significant advancements in the care of this patient population have led to improved survival rates. Due to their intensive medical needs children with IF are at risk for long-term complications that require comprehensive management and close monitoring. The purpose of this paper is to review the available literature emphasizing the surgical aspects of care for children with IF secondary to short bowel syndrome. A key priority in the surgical care of this patient population includes strategies to preserve available bowel and maximize its function. Utilization of novel surgical techniques and autologous bowel reconstruction can have a significant impact on children with IF secondary to short bowel syndrome related to the function of their bowel and ability to achieve enteral autonomy. It is also important to understand the potential long-term complications to ensure strategies are put in place to mitigate risk with early detection to improve long-term outcomes.
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Affiliation(s)
- Christina Belza
- Group for Improvement of Intestinal Function and Treatment (GIFT), The Hospital for Sick Children, University of Toronto, Canada
| | - Paul W Wales
- Division of General and Thoracic Surgery, Cincinatti Children's Hospital Medical Center, University of Cincinnati, Cincinnatii, USA; Cincinnati Children's Intestinal Rehabilitation Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, MLC 2023, Cincinnati, Ohio 45229, USA.
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20
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Khalaf RT, Ford SL. Intestinal failure-associated liver disease in the neonatal ICU: what we know and where we're going. Curr Opin Pediatr 2022; 34:184-190. [PMID: 35051980 DOI: 10.1097/mop.0000000000001105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Parenteral nutrition is an integral part of the care of infants in the neonatal ICU. However, prolonged use of parenteral nutrition can be associated with adverse outcomes, most notably parenteral nutrition-associated liver disease, now known as intestinal failure-associated liver disease (IFALD). This review highlights pertinent developments in the epidemiology of IFALD as it pertains to neonates and showcases recent advances in the pathophysiology, treatment, and outcomes of neonates with IFALD. RECENT FINDINGS The role of intravenous lipid emulsions in the pathogenesis, prevention, and treatment of IFALD remains a target for investigative studies. Recent data continues to support the use of fish-oil based intravenous lipids, but its use is limited due to concerns for essential fatty acid deficiency. Use of soy-based lipids and mixed lipids is not wrought with such concerns as these are often used at greater doses but their use is limited due to higher proinflammatory fatty acid content, increased phytosterols and decreased antioxidants, risk factors for the development of IFALD. SUMMARY Hepatic complications may limit the use of parenteral nutrition in the neonatal ICU. However, the pathophysiology of IFALD is continuing to be further elucidated and novel targets are being developed for the treatment of IFALD. As noninvasive disease monitoring strategies continue to be developed, early enteral nutrition ameliorates the risk of IFALD and should be considered when possible.
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Affiliation(s)
- Racha T Khalaf
- Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, Florida, USA
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Al-Alaiyan S, Elsaidawi W, Alanazi AM, Qeretli RA, Abdulaziz NA, Alfattani A. Ursodeoxycholic Acid and SMOFlipid for Treating Parenteral Nutrition Associated Cholestasis in Infants. Cureus 2022; 14:e22060. [PMID: 35295369 PMCID: PMC8916914 DOI: 10.7759/cureus.22060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2022] [Indexed: 11/20/2022] Open
Abstract
Background: Parenteral nutrition-associated cholestasis (PNAC) is frequently seen in preterm infants receiving total parenteral nutrition (TPN) for a long duration. The pathogenesis of PNAC is believed to be multifactorial; however, phytosterols are hepatotoxic, resulting in cholestasis. A novel lipid emulsion consisting of a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOFlipid) with a low level of phytosterols has been shown to improve cholestasis. Moreover, ursodeoxycholic acid (UDCA) has improved bile flow and normalized liver function tests. This study aimed to determine the effect of UDCA and SMOFlipid in preventing and treating PNAC in infants. Methods: We conducted a retrospective cohort study that included all infants who received TPN for at least five days between January 2010 and December 2018, who also received UDCA for the treatment of cholestasis, and infants who developed cholestasis but were not treated with UDCA. In addition, any infants who received SMOFlipid for parenteral nutrition during the same period were included. We recorded multiple variables, including neonatal demographic data, major medical diagnosis, liver function, medications, and maternal variables. Results: A total of 58 infants with cholestasis who received UDCA for treatment were identified. The infants were divided into two groups, Group 1 infants had gestational age (GA) of ≤32 weeks, and Group 2 had GA of >32 weeks. We found that combining SMOFlipid with UDCA resulted in a significant reduction in cholestasis duration in both groups. Infants in Group 1 who received SMOFlipid had cholestasis for a mean of 67 ± 57 days, and those who did not receive SMOFlipid had cholestasis for a mean of 145 ± 102 days (p=0.04). Infants in Group 2 who received SMOFlipid had cholestasis for a mean of 38.2 ± 28 days, and those who did not receive SMOFlipid had cholestasis for a mean of 117 ± 119 days (p=0.02). Conclusions: According to our results, the use of UDCA and SMOFlipid reduced the duration of parenteral nutrition-associated with cholestasis in very low birth weight infants.
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Goulet O, Lamazière A, Abi Nader E, Talbotec C, Wolf C, Lambe C. Erythrocyte fatty acid membrane composition in children on long-term parenteral nutrition enriched with ω-3 fatty acids. Am J Clin Nutr 2022; 115:422-431. [PMID: 34582547 DOI: 10.1093/ajcn/nqab263] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/19/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Composite lipid emulsions containing soybean oil (30%), medium-chain triglycerides (30%), olive oil (25%), and fish oil (15%) (SMOF) are now widely used. OBJECTIVES We aimed to evaluate the tolerance, the efficiency, and the erythrocyte fatty acid (FA) profile for children on long-term home parenteral nutrition (HPN) receiving a composite fish oil-based emulsion (FOLE). METHODS At baseline, children (n = 46) with severe intestinal failure highly dependent on parenteral nutrition (PN) for ≥1 y were included in the study when they had received the composite FOLE for >6 mo. Out of this baseline group, only 25 children remained highly PN-dependent (SMOF1, n = 25) and could be assessed a second time, 2.4 y later (SMOF2, n = 25). An independent control group ("weaned off PN" group; n = 24) included children who had been weaned off PN for >2 y (median: 4 y). RBC-FA composition was established by GC-MS. Growth parameters, plasma citrulline, conjugated bilirubin, FA profiles, and the Holman ratio (20:3ω-9/20:4ω-6) were compared between groups. RESULTS No difference for growth parameters, citrulline, and bilirubin was observed between the SMOF groups after 2.4 y (0.2 < P < 0.8). The weaned-off group did not differ from the SMOF groups for growth parameters (0.2 < P < 0.4) but citrulline was higher (P < 0.0001) and conjugated bilirubin lower (P < 0.01). The composite FOLE induced higher proportions of EPA (20:5n-3) (8.4% ± 2.9%) and DHA (22:6n-3) (11.7% ± 2.2%) than what was observed in weaned-off children (0.8% ± 0.4% and 6.6% ± 2.3%, respectively) but lower proportions of arachidonic acid (20:4n-6). However, the Holman ratio did not vary between groups (P = 0.9), whereas the PUFA concentrations varied widely. CONCLUSIONS Long-term use of the composite FOLE was well tolerated in HPN-dependent children. The RBC-FA profile alterations were consistent with the ω-3 PUFA-enriched composition of this emulsion without evidence of essential FA deficiency.
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Affiliation(s)
- Olivier Goulet
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition; Necker-Enfants Malades Hospital; University of Paris; Paris Descartes School of Medicine, Paris, France
| | - Antonin Lamazière
- Mass Spectrometry and Lipid Metabolism Laboratory, Research Center of Saint Antoine, Sorbonne University, Clinical Metabolomics Department, Sorbonne University, Research Center of Saint Antoine, DMU BioGeM, AP-HP, Paris, France
| | - Elie Abi Nader
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition; Necker-Enfants Malades Hospital; University of Paris; Paris Descartes School of Medicine, Paris, France
| | - Cécile Talbotec
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition; Necker-Enfants Malades Hospital; University of Paris; Paris Descartes School of Medicine, Paris, France
| | - Claude Wolf
- Mass Spectrometry and Lipid Metabolism Laboratory, Research Center of Saint Antoine, Sorbonne University, Clinical Metabolomics Department, Sorbonne University, Research Center of Saint Antoine, DMU BioGeM, AP-HP, Paris, France
| | - Cécile Lambe
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition; Necker-Enfants Malades Hospital; University of Paris; Paris Descartes School of Medicine, Paris, France
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23
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Zou TT, Li JR, Zhu Y, Wan CM, Liao Q. Fish oil-containing lipid emulsions prevention on parenteral nutrition-associated cholestasis in very low birth weight infants: a meta-analysis. World J Pediatr 2022; 18:463-471. [PMID: 35325398 PMCID: PMC9205820 DOI: 10.1007/s12519-022-00536-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/27/2022] [Indexed: 01/08/2023]
Abstract
BACKGROUND The effect of fish oil-containing lipid emulsions on preventing parenteral nutrition-associated cholestasis (PNAC) in very low birth weight (VLBW) infants is not known. Thus, we conducted a meta-analysis to identify any prevention effect. METHODS PubMed, EMBASE, and CENTRAL were searched up to 26 January 2021 for studies related to the preventive effect of fish oil-containing lipid emulsions and fish oil-free lipid emulsions on cholestasis in VLBW infants. Revman 5.3 was used to synthesize the results. A fixed-effect model was used to summarize the data when the heterogeneity was non-significant (I2 < 50%), and a random-effects model was used when the heterogeneity was significant (I2 > 50%). RESULTS Of 728 articles, 11 randomized controlled trials met the inclusion criteria. The meta-analysis indicated that fish oil-containing lipid emulsion reduced the occurrence of PNAC significantly with risk ratio (RR) = 0.53, 95% confidence interval (CI) 0.36-0.80, P = 0.002. The heterogeneity was non-significant with I2 = 23%. Subgroup analysis based on parenteral nutrition duration and median birth weight was performed. The synthesis results for patients with parenteral nutrition duration exceeding 14 days revealed I2 = 35% (P = 0.15) and pooled RR = 0.47, 95% CI 0.30-0.73, P = 0.0008; and for patients with duration less than 14 days revealed I2 = 0% (P = 0.72) and pooled RR = 1.14, 95% CI 0.39-3.35, P = 0.81. The synthesis for patients with birth weight more than 1000 g revealed I2 = 0% (P = 0.41) and pooled RR = 0.55, 95% CI 0.26-1.18, P = 0.12; and for patients with birth weight below 1000 g revealed I2 = 44% (P = 0.11) and pooled RR = 0.53, 95% CI 0.33-0.85, P = 0.009. CONCLUSIONS The fish oil-containing lipid emulsion can reduce the occurrence of PNAC in VLBW infants based on the available original randomized controlled trial studies, especially for patients with parenteral nutrition duration exceeding 14 days and extremely low birth weight infants. Future studies should be performed before a definitive conclusion can be established.
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Affiliation(s)
- Ting-Ting Zou
- grid.461863.e0000 0004 1757 9397Department of Pediatric Infectious Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041 China
| | - Jin-Rong Li
- Department of Child Healthcare, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Yu Zhu
- grid.461863.e0000 0004 1757 9397Department of Pediatric Infectious Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041 China
| | - Chao-Min Wan
- grid.461863.e0000 0004 1757 9397Department of Pediatric Infectious Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041 China
| | - Qiong Liao
- Department of Pediatric Infectious Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
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24
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Guthrie G, Stoll B, Chacko S, Mohammad M, Style C, Verla M, Olutoye O, Schady D, Lauridsen C, Tataryn N, Burrin D. Depletion and enrichment of phytosterols in soybean oil lipid emulsions directly associate with serum markers of cholestasis in preterm parenteral nutrition-fed pigs. JPEN J Parenter Enteral Nutr 2022; 46:160-171. [PMID: 33581699 PMCID: PMC8361868 DOI: 10.1002/jpen.2088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/24/2021] [Accepted: 02/09/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Clinical reports show a positive correlation between phytosterol concentrations and severity of cholestatic liver disease markers in infants during long-term administration of parenteral lipid emulsions. Establishing a causal link between phytosterols and cholestasis has been complicated by confounding factors of lipid emulsion load, fatty acid composition, and vitamin E in many of these studies. The goal of this study is to determine whether altering the phytosterol concentration within a common soybean oil-based emulsion will alter the onset and severity of cholestasis in parenterally fed preterm piglets. METHODS Preterm piglets were administered, for 21 days, either enteral nutrition (ENT) or parenteral nutrition (PN) prepared from a soybean oil-based emulsion containing either 24.0% (depleted [DEP]), 100% (Intralipid; normal phytosterol [NP] concentration), or 144% (enriched [ENR]) total phytosterol concentration. RESULTS At the end of the study, plasma and liver phytosterol concentrations were highest in the ENR group, followed by NP and then DEP and ENT. Serum direct bilirubin, serum bile acids, and γ-glutamyltransferase were higher in the ENR and NP groups compared with either DEP or ENT groups. All PN lipid groups showed evidence of mild hepatic steatosis but no change in hepatic expression of proinflammatory cytokines or Farnesoid X receptor target genes. CONCLUSION The increase in serum direct bilirubin was lower in the DEP group vs the lipid emulsions with normal or ENR phytosterols. Our results provide additional evidence that phytosterols are linked to an increase in serum markers of cholestasis in preterm PN-fed pigs.
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Affiliation(s)
- Greg Guthrie
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Barbara Stoll
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Shaji Chacko
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Mahmoud Mohammad
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Candace Style
- Nationwide Children’s Hospital, Department of Pediatric Surgery, Columbus, United States
| | - Mariatu Verla
- Nationwide Children’s Hospital, Department of Pediatric Surgery, Columbus, United States
| | - Oluyinka Olutoye
- Nationwide Children’s Hospital, Department of Pediatric Surgery, Columbus, United States
| | - Deborah Schady
- Baylor College of Medicine, Department of Pathology, Houston, United States
| | | | - Nick Tataryn
- Center for Comparative Medicine, Baylor College of Medicine, Houston, United States
| | - Douglas Burrin
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Section Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Houston, United States
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25
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Herrera Vielma F, Valenzuela R, Videla LA, Zúñiga-Hernández J. N-3 Polyunsaturated Fatty Acids and Their Lipid Mediators as A Potential Immune-Nutritional Intervention: A Molecular and Clinical View in Hepatic Disease and Other Non-Communicable Illnesses. Nutrients 2021; 13:3384. [PMID: 34684386 PMCID: PMC8539469 DOI: 10.3390/nu13103384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/11/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
In recent years, the beneficial effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) intake on human health has been widely accepted in the field of immunonutrition. Today, we find a diversity of supplements based on n-3 PUFAs and/or minerals, vitamins and other substances. The main objective of this review is to discuss the importance of n-3 PUFAs and their derivatives on immunity and inflammatory status related to liver disease and other non-communicable illnesses. Based on the burden of liver diseases in 2019, more than two million people die from liver pathologies per year worldwide, because it is the organ most exposed to agents such as viruses, toxins and medications. Consequently, research conducted on n-3 PUFAs for liver disease has been gaining prominence with encouraging results, given that these fatty acids have anti-inflammatory and cytoprotective effects. In addition, it has been described that n-3 PUFAs are converted into a novel species of lipid intermediaries, specialized pro-resolving mediators (SPMs). At specific levels, SPMs improve the termination of inflammation as well as the repairing and regeneration of tissues, but they are deregulated in liver disease. Since evidence is still insufficient to carry out pharmacological trials to benefit the resolution of acute inflammation in non-communicable diseases, there remains a call for continuing preclinical and clinical research to better understand SPM actions and outcomes.
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Affiliation(s)
- Francisca Herrera Vielma
- Department of Biomedical Basic Sciences, School of Health Sciences, University of Talca, Talca 3460000, Chile;
| | - Rodrigo Valenzuela
- Department of Nutrition, Faculty of Medicine, University of Chile, Santiago 8380000, Chile;
| | - Luis A. Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Science, Faculty of Medicine, University of Chile, Santiago 8380000, Chile;
| | - Jessica Zúñiga-Hernández
- Department of Biomedical Basic Sciences, School of Health Sciences, University of Talca, Talca 3460000, Chile;
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Mohanty PK, Zakiulla M, Som TK, Tripathy BB, Mohanty MK. Intestinal Failure in a Neonate: A Surgical Emergency and Medical Catastrophe. Cureus 2021; 13:e16890. [PMID: 34513464 PMCID: PMC8416567 DOI: 10.7759/cureus.16890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2021] [Indexed: 11/05/2022] Open
Abstract
In this case report, we present a female neonate referred to us, born to a primigravida mother at 39 weeks, who cried after birth, did not require any resuscitation, had a birth weight of 2.9 kg and developed abdominal distension and bilious vomiting on Day 1 of life. Ultrasound abdomen and X-ray imaging were suggestive of midgut volvulus with malrotation. The emergency explorative laparotomy revealed the small bowel to be gangrenous in extensive areas, and 10 cm of the small intestine was successfully preserved. The baby was admitted to the NICU and required three months of total parenteral nutrition. In between, the baby was managed successfully for sepsis, septic shock, diarrhea, and dehydration, Later, she was discharged, and is currently being followed up. At the first follow-up, the baby was noted to be gaining weight and has developed no complications to date.
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Affiliation(s)
- Pankaj Kumar Mohanty
- Neonatology, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Mohammad Zakiulla
- Neonatology, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | - Tapas Kumar Som
- Neonatology, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
| | | | - Manoj Kumar Mohanty
- Pediatric Surgery, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar, IND
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27
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Lipid-Free Parenteral Nutrition Is Associated with an Increased Risk of Hepatic Dysfunction in Surgical Critically Ill Patients: A Retrospective Observational Study. Healthcare (Basel) 2021; 9:healthcare9091096. [PMID: 34574872 PMCID: PMC8467940 DOI: 10.3390/healthcare9091096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/21/2021] [Accepted: 08/11/2021] [Indexed: 01/03/2023] Open
Abstract
To evaluate the effects of lipid-free parenteral nutrition (PN) and various intravenous fat emulsions (IVFEs) on hepatic function in surgical critically ill trauma/acute care surgery patients. We retrospectively reviewed trauma/acute care surgery patients without admission hepatic disorder that received PN. The PN groups include lipid-free, soybean oil/medium-chain triglyceride, olive oil-based, and fish-oil contained PN. We excluded patients with (1) age <18 years, (2) without surgery, (3) preexisting liver injury/diseases, (4) hyperbilirubinemia at admission, (5) received more than one type of PN, and (6) repeated ICU episodes in the same hospitalization. Hepatic dysfunction was considered as serum total–bilirubin >6.0 mg/dL. The demographics, severity score, comorbidities, blood stream infection, and mortality were collected for analyses. The major outcome is hepatic function. We also performed analyses stratified by separated lipid doses (g/kg/day). A total of 249 patients were enrolled. There were no demographic differences among groups. The lipid-free PN group had a higher incidence of hepatic dysfunction and mortality. Compared to the lipid-free group, the other three IVFEs had significantly lower risks of hepatic dysfunction, while the olive oil-based group had a significantly lower risk of 30 and 90-day mortality. After being stratified by separating lipid doses, the soybean oils showed a decreasing trend of hepatic dysfunction and mortality with increased dosage. Fish oil >0.05 g/kg/day was associated with lower hepatic dysfunction incidences. Our findings suggest that, when compared to IVFEs, surgical critically ill patients with trauma/acute care surgery that received lipid-free PN are associated with an increased risk of hepatic dysfunction. In addition, the olive oil-based group had a significantly lower risk of mortality, while fish oil >0.05 g/kg/day was associated with lower incidences of hepatic dysfunction; however, further studies are warranted.
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28
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Rochling FA. Intravenous Lipid Emulsions in the Prevention and Treatment of Liver Disease in Intestinal Failure. Nutrients 2021; 13:895. [PMID: 33801970 PMCID: PMC7999390 DOI: 10.3390/nu13030895] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 02/22/2021] [Accepted: 03/04/2021] [Indexed: 11/17/2022] Open
Abstract
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.
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Affiliation(s)
- Fedja A Rochling
- Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68198-2000, USA
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29
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Goulet OJ, Cai W, Seo JM. Lipid Emulsion Use in Pediatric Patients Requiring Long-Term Parenteral Nutrition. JPEN J Parenter Enteral Nutr 2021; 44 Suppl 1:S55-S67. [PMID: 32049395 DOI: 10.1002/jpen.1762] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/20/2019] [Accepted: 11/22/2019] [Indexed: 12/13/2022]
Abstract
The ability to deliver nutrients via parenteral nutrition (PN) has markedly improved the prognosis of infants and children with intestinal failure. Technical refinements and advances in knowledge have led to the development of highly sophisticated PN solutions that are tailored to meet the needs of pediatric patients. However, children who require long-term PN have an increased risk of complications such as catheter-related sepsis, liver disease, and bone disease. Although the pathogenesis of intestinal failure associated liver disease (IFALD) is multifactorial, studies have identified a possible link between the dose of lipid emulsions based on soybean oil and cholestasis, shown to occur with a significantly higher frequency in patients receiving >1 g lipids/kg/d. Potential contributing factors include oxidative stress, high ω-6 polyunsaturated fatty acid (PUFA) and phytosterol content, and relatively low α-tocopherol levels. Lipid emulsions containing fish oil offer potential advantages compared with traditional emulsions with a high soybean oil content, such as decreased ω-6 and increased ω-3 PUFA concentrations, high concentrations of α-tocopherol, and reduced phytosterol content. Studies in PN-dependent children at risk for IFALD have shown that lipid emulsions containing fish oil reduce the risk of cholestasis and improve biochemical measures of hepatobiliary function compared with pure soybean oil emulsions. This review summarizes evidence regarding the role of lipid emulsions in the management of pediatric patients with intestinal failure requiring long-term PN, with a particular focus on the prevention and treatment of IFALD.
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Affiliation(s)
- Olivier J Goulet
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Intestinal Failure Rehabilitation Center, National Reference Center for Rare Digestive Diseases, Hospital Necker-Enfants Malades, Paris-Descartes Medical School at the University of Sorbonne-Paris-Cité, Paris, France
| | - Wei Cai
- Department of Pediatric Surgery, Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jeong-Meen Seo
- Division of Pediatric Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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30
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Martindale RG, Berlana D, Boullata JI, Cai W, Calder PC, Deshpande GH, Evans D, Garcia-de-Lorenzo A, Goulet OJ, Li A, Mayer K, Mundi MS, Muscaritoli M, Pradelli L, Rosenthal M, Seo JM, Waitzberg DL, Klek S. Summary of Proceedings and Expert Consensus Statements From the International Summit "Lipids in Parenteral Nutrition". JPEN J Parenter Enteral Nutr 2021; 44 Suppl 1:S7-S20. [PMID: 32049392 DOI: 10.1002/jpen.1746] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/24/2019] [Accepted: 10/25/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND The 2018 Lipids in Parenteral Nutrition summit involved a panel of experts in clinical nutrition, lipid metabolism, and pharmacology, to assess the current state of knowledge and develop expert consensus statements regarding the use of intravenous lipid emulsions in various patient populations and clinical settings. The main purpose of the consensus statements is to assist healthcare professionals by providing practical guidance on common clinical questions related to the provision of lipid emulsions as part of parenteral nutrition (PN). METHODS The summit was designed to allow interactive discussion and consensus development. The resulting consensus statements represent the collective opinion of the members of the expert panel, which was informed and supported by scientific evidence and clinical experience. RESULTS The current article summarizes the key discussion topics from the summit and provides a set of consensus statements designed to complement existing evidence-based guidelines. Lipid emulsions are a major component of PN, serving as a condensed source of energy and essential fatty acids. In addition, lipids modulate a variety of biologic functions, including inflammatory and immune responses, coagulation, and cell signaling. A growing body of evidence suggests that lipid emulsions containing ω-3 fatty acids from fish oil confer important clinical benefits via suppression of inflammatory mediators and activation of pathways involved in the resolution of inflammation. CONCLUSIONS This article provides a set of expert consensus statements to complement formal PN guideline recommendations.
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Affiliation(s)
- Robert G Martindale
- Department of Surgery, Oregon Health and Science University, Portland, Oregon, USA
| | - David Berlana
- Pharmacy Service, Vall d'Hebron Barcelona Hospital Campus and Department of Nutrition, University of Barcelona, Barcelona, Spain
| | - Joseph I Boullata
- Department of Nutrition Sciences, Drexel University, Philadelphia, Pennsylvania, USA.,Clinical Nutrition Support Services, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Wei Cai
- Department of Pediatric Surgery, Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Philip C Calder
- Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.,NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
| | - Girish H Deshpande
- Neonatal NICU, Nepean Hospital, Kingswood, NSW, Australia.,Sydney Medical School, Nepean, University of Sydney, Australia
| | - David Evans
- Department of Surgery, Ohio State University Medical Center, Columbus, Ohio, USA
| | | | - Olivier J Goulet
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Intestinal Failure Rehabilitation Center, National Reference Center for Rare Digestive Diseases, Hospital Necker-Enfants Malades, University of Paris-Descartes, Paris, France
| | - Ang Li
- Department of General Surgery, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Konstantin Mayer
- Vidia Kliniken Karlsruhe, Medizinische Klinik IV, Karlsruhe, Germany
| | - Manpreet S Mundi
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Martin Rosenthal
- Department of Surgery, Division of Trauma and Acute Surgery, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Jeong-Meen Seo
- Division of Pediatric Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Dan L Waitzberg
- Department of Gastroenterology, Lim 35, School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Stanislaw Klek
- Department of General and Oncology Surgery, Intestinal Failure Unit, Stanley Dudrick's Memorial Hospital, Skawina, Poland
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31
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Prediction, identification and progression of histopathological liver disease activity in children with intestinal failure. J Hepatol 2021; 74:593-602. [PMID: 33002568 DOI: 10.1016/j.jhep.2020.09.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/22/2020] [Accepted: 09/18/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Diagnostic criteria, progression risk and optimal monitoring for intestinal failure (IF)-associated liver disease (IFALD) remain undefined. We assessed predictors, non-invasive markers and progression of histopathological liver disease in patients with IF. METHODS In total, 77 children with IF and median age of 1.7 years underwent diagnostic liver biopsy, which was repeated in 48 patients after 2.9 years with simultaneous evaluation of liver biochemistry, liver stiffness, serum citrulline (a surrogate for viable enterocyte mass), spleen size, esophageal varices and clinical data. Patients were staged according to histopathological liver disease activity: active IFALD (cholestasis and/or inflammation), chronic IFALD (significant fibrosis and/or steatosis), or no IFALD (none of these features). RESULTS Diagnostic liver biopsy revealed active, chronic or no IFALD in 48%, 21% and 31% of patients. Active IFALD was segregated by low serum citrulline, parenteral nutrition (PN) dependency and young age, while weaning off PN and older age predicted chronic IFALD. Although the liver histopathology in most patients either normalized (52%) or transformed to a less reactive (chronic) disease stage (23%), 19% of patients retained and 6.3% progressed to an active cholestatic/inflammatory IFALD phenotype. Decreased serum citrulline and PN-dependency also predicted active IFALD in follow-up biopsies. Increased median liver biochemistry values and liver stiffness only associated with active IFALD, which was accurately identified by gamma-glutamyltransferase (GGT), citrulline and liver stiffness, their combinations reaching diagnostic and follow-up AUROC values above 0.90. CONCLUSIONS Active IFALD, essentially predicted by intestinal disruption and PN-dependency, was accurately detected by GGT, liver stiffness and citrulline, which together with recent advances in clinical management options, provides new avenues for monitoring and targeted liver protection in patients with IF. LAY SUMMARY Liver disease is a common and critical complication in patients with intestinal failure, who require intravenous nutrition for survival due to severe intestinal dysfunction. We showed that both intravenous nutrition dependency and intestinal disruption essentially predicted development of active histopathological liver disease, which persisted in 25% of patients during long-term follow-up and could be accurately detected without the need for liver biopsy. Identification of the active and potentially progressive histopathology offers new possibilities for monitoring and targeted liver protection in patients with intestinal failure.
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32
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Gura KM, Premkumar MH, Calkins KL, Puder M. Fish Oil Emulsion Reduces Liver Injury and Liver Transplantation in Children with Intestinal Failure-Associated Liver Disease: A Multicenter Integrated Study. J Pediatr 2021; 230:46-54.e2. [PMID: 33038344 PMCID: PMC7914137 DOI: 10.1016/j.jpeds.2020.09.068] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To compare the aspartate aminotransferase to platelet ratio index, liver transplantation, and mortality rates between children with intestinal failure-associated liver disease who received fish oil lipid emulsion (FOLE) or soybean oil intravenous lipid emulsion (SOLE). STUDY DESIGN In this multicenter integrated analysis, FOLE recipients (1 g/kg/d) (n = 189) were compared with historical controls administered SOLE (≤3 g/kg/d) (n = 73). RESULTS Compared with SOLE, FOLE recipients had a higher direct bilirubin level at baseline (5.8 mg/dL vs 3.0 mg/dL; P < .0001). Among FOLE recipients, 65% experienced cholestasis resolution vs 16% of SOLE recipients (P < .0001). The aspartate aminotransferase to platelet ratio index scores improved in FOLE recipients (1.235 vs 0.810 and 0.758, P < .02) but worsened in SOLE recipients (0.540 vs 2.564 and 2.098; P ≤ .0003) when baseline scores were compared with cholestasis resolution and end of study, respectively. Liver transplantation was reduced in FOLE vs SOLE (4% vs 12%; P = .0245). The probability of liver transplantation in relation to baseline direct or conjugated bilirubin (DB) was lower in FOLE vs SOLE recipients (1% vs 9% at DB of 2 mg/dL; 8% vs 35% at DB of 12.87 mg/dL; P = .0022 for both). Death rates were similar (FOLE vs SOLE: 10% vs 14% at DB of 2 mg/dL; 17% vs 23% at a DB of 12.87 mg/dL; P = .36 for both). CONCLUSIONS FOLE recipients experienced a higher rate of cholestasis resolution, lower aspartate aminotransferase to platelet ratio index, and fewer liver transplants compared with SOLE. This study demonstrates that FOLE may be the preferred parenteral lipid emulsion in children with intestinal failure-associated liver disease when DB reaches 2 mg/dL. TRIAL REGISTRATION Clinicaltrials.gov: NCT00910104 and NCT00738101.
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Affiliation(s)
- Kathleen M. Gura
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pharmacy (KG); Department of Surgery and the Vascular Biology Program (MPU); Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Muralidhar H. Premkumar
- Baylor College of Medicine, Section of Neonatology, Department of Pediatrics, Texas Children’s Hospital, Houston TX, 77030, USA
| | - Kara L. Calkins
- Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Mattel Children’s Hospital, University of California Los Angeles, 757 Westwood Plaza, Los Angeles, CA 90095, USA
| | - Mark Puder
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pharmacy (KG); Department of Surgery and the Vascular Biology Program (MPU); Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
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33
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Impact of Parenteral Lipid Emulsion Components on Cholestatic Liver Disease in Neonates. Nutrients 2021; 13:nu13020508. [PMID: 33557154 PMCID: PMC7913904 DOI: 10.3390/nu13020508] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 12/30/2022] Open
Abstract
Total parenteral nutrition (TPN) is a life-saving intervention for infants that are unable to feed by mouth. Infants that remain on TPN for extended periods of time are at risk for the development of liver injury in the form of parenteral nutrition associated cholestasis (PNAC). Current research suggests the lipid component of TPN is a factor in the development of PNAC. Most notably, the fatty acid composition, vitamin E concentration, and presence of phytosterols are believed key mediators of lipid emulsion driven PNAC development. New emulsions comprised of fish oil and medium chain triglycerides show promise for reducing the incidence of PNAC in infants. In this review we will cover the current clinical studies on the benefit of fish oil and medium chain triglyceride containing lipid emulsions on the development of PNAC, the current constituents of lipid emulsions that may modulate the prevalence of PNAC, and potential new supplements to TPN to further reduce the incidence of PNAC.
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34
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Secor JD, Yu L, Tsikis S, Fligor S, Puder M, Gura KM. Current strategies for managing intestinal failure-associated liver disease. Expert Opin Drug Saf 2020; 20:307-320. [PMID: 33356650 DOI: 10.1080/14740338.2021.1867099] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Introduction: Intestinal failure-associated liver disease (IFALD) refers to hepatic dysfunction that results from prolonged parenteral nutrition (PN) use. IFALD is multifactorial in origin and remains a major cause of morbidity and mortality. Prior to 2004, IFALD was associated with mortality as high as 90% in infants who remained on PN greater than 1 year. The advent of new strategies for intravenous lipid emulsion (ILE) administration and improved catheter care now allow many patients to remain on PN and recover from this once fatal condition. Several additional treatment modalities are often used to further improve outcomes for IFALD patients and they are reviewed here.Areas covered: The etiology of IFALD is presented, as well as the rationale behind the use of ILEs that contain fish oil. Other management strategies are addressed, including the effects of several pharmacologic and nutritional interventions.Expert opinion: Like its etiology, the management of IFALD is multifactorial. Prompt recognition of patients at risk, avoiding macronutrient excess, and preventing central line associated bloodstream infections will improve outcomes. In patients who develop IFALD, the use of fish oil monotherapy seems to be efficacious. The most effective intervention, however, continues to be discontinuation of PN and achieving full enteral feedings.
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Affiliation(s)
- Jordan D Secor
- Harvard Medical School, Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.,Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Lumeng Yu
- Harvard Medical School, Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.,Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Savas Tsikis
- Harvard Medical School, Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.,Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Scott Fligor
- Harvard Medical School, Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.,Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Mark Puder
- Harvard Medical School, Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.,Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Kathleen M Gura
- Department of Pharmacy, Boston Children's Hospital, Boston, MA, USA.,Division of Gastroenterology, Hepatology and Nutrition, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
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Plasma and Red Blood Cell PUFAs in Home Parenteral Nutrition Paediatric Patients-Effects of Lipid Emulsions. Nutrients 2020; 12:nu12123748. [PMID: 33291478 PMCID: PMC7762095 DOI: 10.3390/nu12123748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 11/28/2020] [Accepted: 12/01/2020] [Indexed: 11/16/2022] Open
Abstract
Background: Mixed lipid emulsions (LE) containing fish oil present several advantages compared to the sole soybean oil LE, but little is known about the safety of essential fatty acids (EFA) profile in paediatric patients on long-term Parenteral Nutrition (PN). Aim of the study: to assess glycerophosfolipid polyunsaturated fatty acids (PUFA) levels on plasma and red blood cell (RBC) membrane of children on long term PN with composite LE containing fish oil (SMOF), and to compare it with a group receiving olive oil LE (Clinoleic®) and to the reference range for age, previously determined on a group of healthy children. Results: A total of 38 patients were enrolled, median age 5.56 (0.9-21.86) years, 15 receiving Clinoleic®, 23 receiving SMOF. Patients on SMOF showed significantly higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower levels of arachidonic acid (ARA) and Mead acid (MEAD)/ARA ratio in plasma and RBC compared with patients on Clinoleic® and with healthy children. Triene:tetraene (T:T) ratio of both groups of patients did not differ from that of healthy children-median plasma (MEAD/ARA: 0.01, interquartile rage (IQR) 0.01, p = 0.61 and 0.02, IQR 0.02, p = 0.6 in SMOF and Clinoleic® patients, respectively), and was considerably lower than Holman index (>0.21). SMOF patients showed no statistically significant differences in growth parameters compared with Clinoleic® patients. Patients of both groups showed stiffness class F0-F1 of liver stiffness measure (LSM) 5.6 (IQR 0.85) in SMOF patients and 5.3 (IQR 0.90) in Clinoleic® patients, p = 0.58), indicating absence of liver fibrosis. Conclusions: Fatty acids, measured as concentrations (mg/L), revealed specific PUFA profile of PN patients and could be an accurate method to evaluate nutritional status and eventually to detect essential fatty acid deficiency (EFAD). SMOF patients showed significantly higher EPA, DHA and lower ARA concentrations compared to Clinoleic® patients. Both LEs showed similar hepatic evolution and growth.
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Gura KM. The Power of Networking and Lessons Learned From Omegaven. J Pediatr Pharmacol Ther 2020; 25:663-674. [PMID: 33214777 DOI: 10.5863/1551-6776-25.8.663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2020] [Indexed: 01/19/2023]
Abstract
As more meetings become virtual, the impact of "live" meetings is being reevaluated. Here one example of how a chance meeting at a national pharmacy meeting led to the development of a new drug therapy that reinvented how parenteral nutrition is provided to infants and children is described. Along the way, many lessons were learned both in the lab and at home. Addressing the challenges raised by others, understanding how the FDA works, and the power of parental involvement are all considered. Until 2013, the only FDA-approved lipid emulsions were those composed of pure soybean oils. Starting with compassionate use protocol in 2004, it took 18 years and hundreds of patients to bring a pure fish oil lipid emulsion to the US market. First used off label to treat a soy-allergic patient dependent on parenteral nutrition, researchers at Boston Children's Hospital later conducted animal studies on its role in treating and preventing intestinal failure associated with liver injury and later translated it into clinical trials that led to the drug's approval in 2018. This is a recount of those efforts.
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Affiliation(s)
- Kathleen M Gura
- Department of Pharmacy, Boston Children's Hospital; Harvard Medical School, Boston, MA
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Administration of an Intravenous Fat Emulsion Enriched with Medium-Chain Triglyceride/ω-3 Fatty Acids is Beneficial Towards Anti-Inflammatory Related Fatty Acid Profile in Preterm Neonates: A Randomized, Double-Blind Clinical Trial. Nutrients 2020; 12:nu12113526. [PMID: 33207743 PMCID: PMC7698253 DOI: 10.3390/nu12113526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/09/2020] [Accepted: 11/12/2020] [Indexed: 12/26/2022] Open
Abstract
Intravenous administration of pure soybean oil emulsions high in linoleic acid may lead to inflammation and lipid peroxidation in preterm neonates. We aimed to investigate the effects of a medium-chain triglyceride (MCT)/ω-3 polyunsaturated fatty acid (PUFA)-enriched intravenous fat emulsion (IVFE) on plasma fatty acid (FA) profile and serum interleukin-6 (IL-6) in preterm neonates. In this double-blind randomized study, 92 preterm neonates (gestational age < 32 weeks, birth weight < 1500 g) were assigned to receive either MCT/ω-3 PUFA-enriched IVFE (Intervention Group) or soybean oil-based IVFE (Control Group). Levels of FAs were measured at baseline (day 0) and day 15 of parenteral nutrition with gas-chromatography mass-spectrometry. Serum IL-6 was measured with sandwich ELISA in 59 neonates. Plasma FAs changed significantly over time; the MCT/ω-3 PUFA-IVFE group showed higher ω-3 PUFAs (p = 0.031), eicosapentaenoic acid (p = 0.000), and oleic acid (p = 0.003), and lower ω-6/ω-3 PUFAs ratio (p = 0.001) and ω-6 PUFAs (p = 0.023) compared to control group. Linoleic acid was higher in the soybean oil (SO)-based IVFE arm compared to the MCT/ω-3 PUFAs-IVFE arm (p = 0.006). Both fat emulsion types decreased IL-6 compared to baseline, but changes were insignificant between groups. Administration of MCT/ω-3 PUFA-enriched IVFE in preterm neonates is beneficial in changing the FA profile consistent with attenuated inflammatory response.
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Mundi MS, Bonnes SL, Salonen BR, McMahon MM, Martindale R, Hurt RT. Clinical application of fish-oil intravenous lipid emulsion in adult home parenteral nutrition patients. Nutr Clin Pract 2020; 36:839-852. [PMID: 32970359 DOI: 10.1002/ncp.10581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 08/23/2020] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND High-ω-6 polyunsaturated fatty acids (PUFAs) are noted to contribute to development of intestinal failure-associated liver disease (IFALD) in home parenteral nutrition (HPN). Fish oil (FO) has been added to latest generation of lipid injectable emulsion (ILE) to increase ω-3:ω-6 PUFA ratio; however, appropriate dose of FO to treat IFALD is unknown. METHODS After approval of exclusive FO ILE in the US for pediatric patients, we noted 2 adult patients with ongoing IFALD despite transition to mixed-oil (MO) ILE. They were transitioned to off-label FO ILE after review of literature regarding use of FO ILE in adult HPN patients was conducted to guide management. RESULTS The first case involves a 40-year-old female receiving HPN with IFALD refractory to MO ILE. MO ILE (with 15% FO) was provided at 50 g/d for 3 d/wk and combined with FO ILE at 50 g/d for 4 d/wk. This combination resulted in improvement in liver studies and allowed for decrease in dextrose calories. The second case involves a 49-year-old male receiving HPN (secondary to complications of necrotizing pancreatitis) who developed IFALD. FO ILE was used as the sole source of lipids and led to improvement in liver function tests. No evidence of essential fatty acid deficiency was found in either case. CONCLUSIONS Current case presentations and review of literature support the use of FO ILE to increase ω-3 PUFAs in patients with IFALD refractory to MO ILE. Additional research is necessary to delineate the dose of FO ILE necessary to achieve benefit.
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Affiliation(s)
- Manpreet S Mundi
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Sara L Bonnes
- Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Bradley R Salonen
- Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - M Molly McMahon
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Robert Martindale
- Division of Gastrointestinal and General Surgery, Oregon Health Science University, Portland, Oregon, USA
| | - Ryan T Hurt
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.,Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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High Dose Intravenous Fish Oil Reduces Inflammation-A Retrospective Tale from Two Centers. Nutrients 2020; 12:nu12092865. [PMID: 32961695 PMCID: PMC7551918 DOI: 10.3390/nu12092865] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/09/2020] [Accepted: 09/16/2020] [Indexed: 12/19/2022] Open
Abstract
AIM Patients on parenteral nutrition (PN) are prone to inflammation. This may aggravate an existing proinflammatory state and become a critical factor in the development of liver dysfunction (LD). Intravenous fish oil may attenuate this inflammatory state, but data on its use in adults are scarce. The aim of this study was to investigate the effects of adding a pure fish oil intravenous lipid emulsion (ILE) into short- and long-term PN in patients either at risk of, or with existing, inflammation. METHODS A retrospective analysis of 61 patients (32 female, 29 male, mean age 51.5 ± 12.6 years) who received all-in-one PN, including amino acids, glucose, and lipids supplemented with pure fish oil ILE, was performed. Pure fish oil ILE (Omegaven®, Fresenius Kabi, Bad Homburg, Germany) was used along with the standard ILE to reach a fish oil dose of 0.4-0.5 g fish oil/kg/d. Diagnoses were chronic intestinal failure (CIF, n = 20), Crohn's disease (CD, n = 22), and ulcerative colitis (UC, n = 19). The observation period was 12 months for CIF and 21 days for UC and CD. RESULTS A reduction in inflammation was noticeable in all patients and became statistically significant in CD (hsCRP p < 0.0001, ESR p = 0.0034, procalcitonin p = 0.0014, Il-6 p = 0.001) and UC groups (hsCRP and ESR p < 0.0001, Il-6 p = 0.0001, TNF-α p = 0.0113). In the CIF group, the total bilirubin concentration (p = 0.2157) and aspartate transaminase SGOT (p = 0.1785) did not vary over time. CONCLUSIONS PN with pure fish oil ILE reduces some inflammatory parameters in IBD and maintains liver function parameters in CIF patients. Fish oil might become a valuable ingredient in both short- and long-term PN in patients at risk of liver dysfunction.
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Abstract
Intestinal failure-associated liver disease (IFALD) is common in neonates who suffer from intestinal failure and rely on parenteral nutrition. The etiology is multifactorial, relating to the infant's underlying cause of intestinal failure and other infant factors such as prematurity. Management of the disease includes transitioning to enteral feedings as soon as is safe for the infant. In infants who continue to rely on parenteral nutrition, alternative lipid emulsions and other medications may be used. This article reviews the epidemiology and factors that contribute to IFALD in neonates, in addition to management strategies.
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Affiliation(s)
- Jennifer Fundora
- Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Susan W Aucott
- Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD.,Division of Neonatology, Greater Baltimore Medical Center, Towson, MD
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Composite Lipid Emulsion for the Infant at Risk of Intestinal Failure-associated Liver Disease: The Canadian Perspective. J Pediatr Gastroenterol Nutr 2020; 71:283-287. [PMID: 32459744 DOI: 10.1097/mpg.0000000000002794] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Currently, in North America we are fortunate to have a number of available options for lipid emulsions to be used in the parenteral nutrition regimens for infants and children, including for long-term parenteral nutrition given intestinal failure. Neonates and infants in particular are at risk for intestinal failure-associated liver disease (IFALD). The choice of parenteral lipid emulsion will influence the risk and severity of IFALD. The purpose of this review is to discuss the rationale for the composite lipid emulsion SMOFlipid that includes soybean, medium-chain triglycerides, olive and fish oils for IFALD, with focus on the Canadian practice and experience.
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Choudhury RA, Yoeli D, Hoeltzel G, Moore HB, Prins K, Kovler M, Goldstein SD, Holland-Cunz SG, Adams M, Roach J, Nydam TL, Vuille-Dit-Bille RN. STEP improves long-term survival for pediatric short bowel syndrome patients: A Markov decision analysis. J Pediatr Surg 2020; 55:1802-1808. [PMID: 32345501 DOI: 10.1016/j.jpedsurg.2020.03.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 01/31/2020] [Accepted: 03/22/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Increasingly, for pediatric patients with short bowel syndrome (SBS), intestinal lengthening procedures such as serial transverse enteroplasty (STEP) are being offered with the hope of improving patients' chances for achieving enteral autonomy. However, it remains unclear to what extent STEP reduces the long-term need for intestinal transplant or improves survival. METHODS Based on existing literature, a decision analytic Markov state transition model was created to simulate the life of 1,000 pediatric SBS patients. Two simulations were modeled: 1) No STEP: patients were listed for transplant once medical management failed and 2) STEP: patients underwent STEP therapy and subsequent transplant listing if enteral autonomy was not achieved. Sensitivity analysis of small bowel length and anatomy was completed. Base case patients were defined as neonates with a small bowel length of 30cm. RESULTS For base case patients with an ostomy and a NEC SBS etiology, STEP was associated with increased rates of enteral autonomy after 10 years for patients with an ICV (53.9% [STEP] vs. 51.1% [No STEP]) and without an ICV (43.4% [STEP] vs. 36.3% [No STEP]). Transplantation rates were also reduced following STEP therapy for both ICV (17.5% [STEP] vs. 18.2% [No STEP]) and non-ICV patients (20.2% [STEP] vs. 22.1% [No STEP]). 10-year survival was the highest in the (+) STEP and (+) ICV group (85.4%) and lowest in the (-) STEP and (-) ICV group (83.3%). CONCLUSIONS For SBS patients, according to our model, STEP increases rates of enteral autonomy, reduces need for intestinal transplantation, and improves long-term survival. TYPE OF STUDY Economic/Decision Analysis or Modeling Studies LEVEL OF EVIDENCE: Level III.
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Affiliation(s)
- Rashikh A Choudhury
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO.
| | - Dor Yoeli
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Gerard Hoeltzel
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Hunter B Moore
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Kas Prins
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Mark Kovler
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Seth D Goldstein
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Stephan G Holland-Cunz
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Megan Adams
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Jonathan Roach
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Trevor L Nydam
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
| | - Raphael N Vuille-Dit-Bille
- University of Colorado Hospital, Department of Transplant Surgery, Aurora, CO; Johns Hopkins Hospital, Department of Pediatric Surgery, Baltimore, MD; Ann and Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Surgery, Chicago, IL; University Children's Hospital of Basel, Department of Pediatric Surgery, Basel, Switzerland; Colorado Children's Hospital, Department of Pediatric Surgery, Aurora, CO
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Dao DT, Anez-Bustillos L, Finkelstein AM, Mitchell PD, O’Loughlin AA, Fell GL, Baker MA, Potemkin AK, Gura KM, Puder M. Trends of INR and Fecal Excretion of Vitamin K During Cholestasis Reversal: Implications in the Treatment of Neonates With Intestinal Failure-Associated Liver Disease. JPEN J Parenter Enteral Nutr 2020; 44:951-958. [PMID: 31282035 PMCID: PMC6944781 DOI: 10.1002/jpen.1677] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/22/2019] [Accepted: 06/12/2019] [Indexed: 11/12/2022]
Abstract
BACKGROUND Vitamin K is a fat-soluble compound that plays important roles in coagulation. In children with intestinal failure-associated liver disease (IFALD), the disrupted enterohepatic circulation can lead to intestinal loss of vitamin K. Fish oil-based lipid emulsion (FOLE) has proven effective in treating IFALD. As biliary excretion is restored during cholestasis reversal, the accelerated vitamin K loss can pose a risk for deficiency. METHODS Ten neonates with IFALD and receiving FOLE monotherapy were prospectively enrolled in the study from 2016 to 2018. In addition to weekly measurements of international normalized ratio (INR) and direct bilirubin (DB), ostomy output was collected for determination of fecal concentrations of phylloquinone (PK). Trends of DB, INR, and fecal PK concentrations were summarized with locally estimated scatterplot smoothing. RESULTS The median time (interquartile range) from FOLE initiation to cholestasis reversal was 59 (19-78) days. During cholestasis reversal, INR remained relatively unchanged, whereas the mean (95% confidence interval) daily fecal excretion of PK increased from 25.1 (5.0-158.5) ng at the time of FOLE initiation to 158.5 (31.6-1000.0) ng at complete reversal. Examination of individual trends in fecal PK excretion and INR revealed little correlation between the 2 measurements (r = -0.10; P = 0.50). CONCLUSION Children with IFALD are at risk for vitamin K deficiency during cholestasis reversal. Close monitoring and quantified supplementation of vitamin K may be warranted during this period. However, this should not be guided by INR alone, as it is a poor indicator of vitamin K status.
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Affiliation(s)
- Duy T. Dao
- Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Lorenzo Anez-Bustillos
- Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Adam M. Finkelstein
- Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Paul D. Mitchell
- Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Alison A. O’Loughlin
- Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Gillian L. Fell
- Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Meredith A. Baker
- Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Alexis K. Potemkin
- Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Kathleen M. Gura
- Department of Pharmacy, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Mark Puder
- Vascular Biology Program and the Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
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Golonka RM, Xiao X, Abokor AA, Joe B, Vijay-Kumar M. Altered nutrient status reprograms host inflammation and metabolic health via gut microbiota. J Nutr Biochem 2020; 80:108360. [PMID: 32163821 PMCID: PMC7242157 DOI: 10.1016/j.jnutbio.2020.108360] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/07/2020] [Accepted: 02/08/2020] [Indexed: 02/07/2023]
Abstract
The metabolism of macro- and micronutrients is a complex and highly regulated biological process. An imbalance in the metabolites and their signaling networks can lead to nonresolving inflammation and consequently to the development of chronic inflammatory-associated diseases. Therefore, identifying the accumulated metabolites and altered pathways during inflammatory disorders would not only serve as "real-time" markers but also help in the development of nutritional therapeutics. In this review, we explore recent research that has delved into elucidating the effects of carbohydrate/calorie restriction, protein malnutrition, lipid emulsions and micronutrient deficiencies on metabolic health and inflammation. Moreover, we describe the integrated stress response in terms of amino acid starvation and lipemia and how this modulates new age diseases such as inflammatory bowel disease and atherosclerosis. Lastly, we explain the latest research on metaflammation and inflammaging. This review focuses on multiple signaling pathways, including, but not limited to, the FGF21-β-hydroxybutryate-NLRP3 axis, the GCN2-eIF2α-ATF4 pathway, the von Hippel-Lindau/hypoxia-inducible transcription factor pathway and the TMAO-PERK-FoxO1 axis. Additionally, throughout the review, we explain how the gut microbiota responds to altered nutrient status and also how antimicrobial peptides generated from nutrient-based signaling pathways can modulate the gut microbiota. Collectively, it must be emphasized that metabolic starvation and inflammation are strongly regulated by both environmental (i.e., nutrition, gut microbiome) and nonenvironmental (i.e., genetics) factors, which can influence the susceptibility to inflammatory disorders.
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Affiliation(s)
- Rachel M Golonka
- UT Microbiome Consortium, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614
| | - Xia Xiao
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ahmed A Abokor
- UT Microbiome Consortium, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614
| | - Bina Joe
- UT Microbiome Consortium, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614
| | - Matam Vijay-Kumar
- UT Microbiome Consortium, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614.
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Mezoff EA, Minneci PC, Dienhart MC. Intestinal Failure: A Description of the Problem and Recent Therapeutic Advances. Clin Perinatol 2020; 47:323-340. [PMID: 32439114 DOI: 10.1016/j.clp.2020.02.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Pediatric intestinal failure occurs when gut function is insufficient to meet the nutrient and hydration needs of the growing child. The commonest cause is short bowel syndrome with maldigestion and malabsorption following massive bowel loss. The remnant bowel adapts during the process of intestinal rehabilitation. Management promotes the achievement of enteral autonomy while mitigating the risk of comorbid disease. The future of care is likely to see expansion of pharmacologic methods for augmenting bowel adaptation, tissue engineering techniques enabling immune suppression-free autologous bowel transplant, and the development of electronic health record tools for efficient, collaborative study and care improvement.
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Affiliation(s)
- Ethan A Mezoff
- Division of Gastroenterology, Hepatology & Nutrition, The Ohio State University College of Medicine, Center for Intestinal Rehabilitation and Nutrition Support, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
| | - Peter C Minneci
- Department of Surgery, The Ohio State University College of Medicine, Center for Surgical Outcomes Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
| | - Molly C Dienhart
- Division of Gastroenterology, Hepatology & Nutrition, The Ohio State University College of Medicine, Center for Intestinal Rehabilitation and Nutrition Support, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
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Call L, Molina T, Stoll B, Guthrie G, Chacko S, Plat J, Robinson J, Lin S, Vonderohe C, Mohammad M, Kunichoff D, Cruz S, Lau P, Premkumar M, Nielsen J, Fang Z, Olutoye O, Thymann T, Britton R, Sangild P, Burrin D. Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs. J Lipid Res 2020; 61:1038-1051. [PMID: 32350078 DOI: 10.1194/jlr.ra120000652] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 04/07/2020] [Indexed: 01/10/2023] Open
Abstract
Multi-component lipid emulsions, rather than soy-oil emulsions, prevent cholestasis by an unknown mechanism. Here, we quantified liver function, bile acid pools, and gut microbial and metabolite profiles in premature parenterally fed pigs given a soy-oil lipid emulsion, Intralipid (IL), a multi component lipid emulsion, SMOFlipid (SMOF), a novel emulsion with a modified fatty-acid composition [experimental emulsion (EXP)], or a control enteral diet (ENT) for 22 days. We assayed serum cholestasis markers, measured total bile acid levels in plasma, liver, and gut contents, and analyzed colonic bacterial 16S rRNA gene sequences and metabolomic profiles. Serum cholestasis markers (i.e., bilirubin, bile acids, and γ-glutamyl transferase) were highest in IL-fed pigs and normalized in those given SMOF, EXP, or ENT. Gut bile acid pools were lowest in the IL treatment and were increased in the SMOF and EXP treatments and comparable to ENT. Multiple bile acids, especially their conjugated forms, were higher in the colon contents of SMOF and EXP than in IL pigs. The colonic microbial communities of SMOF and EXP pigs had lower relative abundance of several gram-positive anaerobes, including Clostridrium XIVa, and higher abundance of Enterobacteriaceae than those of IL and ENT pigs. Differences in lipid and microbial-derived compounds were also observed in colon metabolite profiles. These results indicate that multi-component lipid emulsions prevent cholestasis and restore enterohepatic bile flow in association with gut microbial and metabolomic changes. We conclude that sustained bile flow induced by multi-component lipid emulsions likely exerts a dominant effect in reducing bile acid-sensitive gram-positive bacteria.
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Affiliation(s)
- Lee Call
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Tiffany Molina
- Pediatrics-Neonatology, Baylor College of Medicine, Houston, TX
| | - Barbara Stoll
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Greg Guthrie
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Shaji Chacko
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Jogchum Plat
- Department Human Biology and Movement Sciences, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Jason Robinson
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Sen Lin
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, People's Republic of China
| | - Caitlin Vonderohe
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Mahmoud Mohammad
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Dennis Kunichoff
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
| | - Stephanie Cruz
- Division of Pediatric Surgery, Baylor College of Medicine, Houston, TX
| | - Patricio Lau
- Division of Pediatric Surgery, Baylor College of Medicine, Houston, TX
| | | | - Jon Nielsen
- Comparative Pediatrics and Nutrition, University of Copenhagen, Copenhagen, Denmark
| | - Zhengfeng Fang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, People's Republic of China
| | - Oluyinka Olutoye
- Division of Pediatric Surgery, Baylor College of Medicine, Houston, TX
| | - Thomas Thymann
- Comparative Pediatrics and Nutrition, University of Copenhagen, Copenhagen, Denmark
| | - Robert Britton
- Alkek Center for Microbiome and Metagenomics Research, Baylor College of Medicine, Houston, TX
| | - Per Sangild
- Comparative Pediatrics and Nutrition, University of Copenhagen, Copenhagen, Denmark
| | - Douglas Burrin
- Pediatrics, Gastroenterology, and Nutrition, United States Department of Agriculture-Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX. mailto:
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Khalaf RT, Sokol RJ. New Insights Into Intestinal Failure-Associated Liver Disease in Children. Hepatology 2020; 71:1486-1498. [PMID: 32003009 PMCID: PMC8245203 DOI: 10.1002/hep.31152] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 01/07/2020] [Indexed: 12/26/2022]
Abstract
Development of intestinal failure-associated liver disease (IFALD) is a common complication of long-term parenteral nutrition (PN) in children and adults. The molecular and cellular mechanisms and the phases of IFALD are now being delineated. Components of PN lipid emulsions, including plant sterols, interact with hepatic innate immune activation promoted by products of gut bacterial overgrowth/dysbiosis and altered intestinal barrier function (gut-liver axis) and by episodes of sepsis to cause cholestasis and IFALD. New therapeutic strategies, including modifications of intravenous lipid emulsions to reduce pro-inflammatory fatty acids and plant sterol content, can lower the risk of IFALD, reverse cholestasis, and reduce complications, although the significance of persisting hepatic fibrosis is unknown. This review will provide an update on advances in the pathogenesis of IFALD, newer therapeutic and preventative strategies, and challenges that confront managing patients with IFALD.
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Affiliation(s)
- Racha T Khalaf
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO
| | - Ronald J Sokol
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO
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Gura K, Premkumar MH, Calkins KL, Puder M. Intravenous Fish Oil Monotherapy as a Source of Calories and Fatty Acids Promotes Age-Appropriate Growth in Pediatric Patients with Intestinal Failure-Associated Liver Disease. J Pediatr 2020; 219:98-105.e4. [PMID: 32059815 DOI: 10.1016/j.jpeds.2019.12.065] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/15/2019] [Accepted: 12/30/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To compare growth in children with intestinal failure-associated liver disease (IFALD) who received a fish oil intravenous lipid emulsion (FOLE) to those who received a soybean oil intravenous lipid emulsion (SOLE). STUDY DESIGN This multisite, retrospective study pair-matched FOLE (n = 82) to SOLE recipients (n = 41) using baseline serum direct bilirubin levels and postmenstrual age. Study subjects received open-label FOLE (1 g/kg/day) until IFALD resolved or parenteral nutrition was stopped. Historical control subjects received SOLE (up to 3 g/kg/day). Growth measures (changes in body weight, height/length, and head circumference), prealbumin, triglycerides, and glucose were compared between groups over time using the Wilcoxon rank-sum test. RESULTS Although changes in all of the growth measures were similar for both groups (P > .05), FOLE recipients demonstrated an overall improved growth trajectory. After 28 weeks, FOLE recipients had a mean body weight within a z score range of -1 to 1 indicating age-appropriate growth. FOLE recipients consistently had higher prealbumin, lower triglyceride, and more normal glucose concentrations over time compared with SOLE recipients. CONCLUSIONS Children with IFALD who received FOLE had similar growth and fewer metabolic abnormalities compared with those who received SOLE. TRIAL REGISTRATION Clinicaltrials.gov: NCT00910104 and NCT00738101.
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Affiliation(s)
| | | | - Kara L Calkins
- Mattel Children's Hospital, University of California Los Angeles, Los Angeles, CA
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Current status of lipid emulsions in the prevention of intestinal failure-associated liver disease. Curr Opin Organ Transplant 2020; 24:188-192. [PMID: 30762667 DOI: 10.1097/mot.0000000000000620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW The current review provides a summary of available lipid products and discusses current literature and the limitations to the use of various lipid products for treatment and prevention of intestinal failure-associated liver disease (IFALD) in pediatric patients dependent on parenteral nutrition. RECENT FINDINGS Improvements in markers of cholestasis and liver function have been seen with minimizing soybean lipid, fish oil lipid, and mixed fish oil-containing lipid emulsions. Soybean-based lipid products are thought to be the biggest contributor to development of IFALD. Mixed fish oil-containing lipid emulsions are most promising for minimizing and improving IFALD. SUMMARY Several types of lipid-based products are available for parenteral nutrition. Newer products like the mixed fish oil-containing-based lipid emulsions, that closely mimic the lipid composition provided by enteral feeding, may impact prevention and treatment of IFALD. Limitations exist in the current literature regarding mixed fish oil-containing-based emulsions, as many of the studies were designed to show efficacy with regard to growth, not prevention or treatment of IFALD. Based on available literature, it is reasonable to make some recommendations with regard to product selection for lipid provision.
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Growth in Infants and Children With Intestinal Failure-associated Liver Disease Treated With Intravenous Fish Oil. J Pediatr Gastroenterol Nutr 2020; 70:261-268. [PMID: 31978030 DOI: 10.1097/mpg.0000000000002551] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Infants with intestinal failure (IF) and IF-associated liver disease (IFALD) are at risk for poor somatic growth because of increased metabolic demands, inadequate intake, intestinal malabsorption, chronic liver disease and other comorbidities. There are limited data on the nutritional adequacy of intravenous fish oil lipid emulsion (FOLE) compared with standard soybean oil lipid emulsion (SOLE) in the setting of intestinal failure. AIMS To describe growth patterns in a large cohort of infants with IFALD treated with FOLE. METHODS We compared growth data from infants enrolled in a single-center, prospective FOLE study to published norms, as well as to a multicenter, historical cohort of infants with IF treated with SOLE. RESULTS One hundred thirty-eight infants with IFALD were treated with FOLE and 108 with SOLE. Compared with normative growth curves from WHO and published preterm data, infants in both groups from 6 to 11 months postmenstrual age exhibited declines in mean weight- and length-for-age z scores. At 24 months postmenstrual age compared with WHO growth data, infants treated with FOLE had a mean (95% confidence interval [CI]) weight-for-age z-score of 0.13 (-0.18 to 0.45) and length-for-age z-score of 0.07 (-0.33 to 0.47). In comparison, at 24 months postmenstrual age, infants treated with SOLE had a mean weight for age z-score of -0.93 (-1.20 to -0.67) and mean length for age z-score of -2.33 (-2.75 to -1.91). Independent predictors of higher weight, length and head circumference z-scores included older postmenstrual age at baseline, fewer central line-associated blood stream infections, resolution of cholestasis, type of intravenous fat emulsion (FOLE vs SOLE) and female sex. CONCLUSIONS Infants with IFALD treated with FOLE showed comparable somatic growth to those treated with SOLE in early infancy, and improved somatic growth up to 24 months of age, supporting its wider use in this patient population.
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