Pathogenesis and Management of Intestinal Failure-Associated Liver Disease

Sasha-Jane Abi-Aad; Mark Lovell; Racha T. Khalaf; Ronald J. Sokol

doi:10.1055/a-2545-7370

Seminars in Liver Disease, Table of Contents

CC BY 4.0 · Semin Liver Dis 2025; 45(01): 066-080
DOI: 10.1055/a-2545-7370

Review Article

Pathogenesis and Management of Intestinal Failure-Associated Liver Disease

Sasha-Jane Abi-Aad

¹Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, Florida

,

Mark Lovell

²Department of Pathology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado

,

Racha T. Khalaf

¹Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, Florida

,

Ronald J. Sokol

³Department of Pediatrics, Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado

› Author Affiliations

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.

Keywords

intestinal failure-associated liver disease - cholestasis - intestinal failure - lipid emulsions - parenteral nutrition-associated liver disease

Full Text

References

References
1 Wichman BE, Nilson J, Govindan S. et al. Beyond lipids: Novel mechanisms for parenteral nutrition-associated liver disease. Nutr Clin Pract 2022; 37 (02) 265-273
2 Khalaf RT, Sokol RJ. New insights into intestinal failure-associated liver disease in children. Hepatology 2020; 71 (04) 1486-1498
3 Tabone T, Mooney P, Donnellan C. Intestinal failure-associated liver disease: Current challenges in screening, diagnosis, and parenteral nutrition considerations. Nutr Clin Pract 2024; 39 (05) 1003-1025
4 Zafirovska M, Zafirovski A, Rotovnik Kozjek N. Current insights regarding intestinal failure-associated liver disease (IFALD): A narrative review. Nutrients 2023; 15 (14) 15
5 Lauriti G, Zani A, Aufieri R. et al. Incidence, prevention, and treatment of parenteral nutrition-associated cholestasis and intestinal failure-associated liver disease in infants and children: a systematic review. JPEN J Parenter Enteral Nutr 2014; 38 (01) 70-85
6 Lal S, Pironi L, Wanten G. et al.; Home Artificial Nutrition & Chronic Intestinal Failure Special Interest Group of the European Society for Clinical Nutrition and Metabolism (ESPEN). Clinical approach to the management of Intestinal Failure Associated Liver Disease (IFALD) in adults: A position paper from the Home Artificial Nutrition and Chronic Intestinal Failure Special Interest Group of ESPEN. Clin Nutr 2018; 37 (6 Pt A): 1794-1797
7 Mutanen A, Lohi J, Merras-Salmio L, Koivusalo A, Pakarinen MP. Prediction, identification and progression of histopathological liver disease activity in children with intestinal failure. J Hepatol 2021; 74 (03) 593-602
8 Mutanen A, Heikkilä P, Lohi J, Raivio T, Jalanko H, Pakarinen MP. Serum FGF21 increases with hepatic fat accumulation in pediatric onset intestinal failure. J Hepatol 2014; 60 (01) 183-190
9 Spencer AU, Neaga A, West B. et al. Pediatric short bowel syndrome: redefining predictors of success. Ann Surg 2005; 242 (03) 403-409 , discussion 409–412
10 Mutanen A, Lohi J, Heikkilä P, Koivusalo AI, Rintala RJ, Pakarinen MP. Persistent abnormal liver fibrosis after weaning off parenteral nutrition in pediatric intestinal failure. Hepatology 2013; 58 (02) 729-738
11 Mutanen A, Lohi J, Sorsa T, Jalanko H, Pakarinen MP. Features of liver tissue remodeling in intestinal failure during and after weaning off parenteral nutrition. Surgery 2016; 160 (03) 632-642
12 Gattini D, Roberts AJ, Wales PW. et al. Trends in pediatric intestinal failure: a multicenter, multinational study. J Pediatr 2021; 237: 16-23.e4
13 Wang Y, Chen S, Yan W. et al. Congenital short-bowel syndrome: clinical and genetic presentation in China. JPEN J Parenter Enteral Nutr 2021; 45 (05) 1009-1015
14 Rangel SJ, Calkins CM, Cowles RA. et al.; 2011 American Pediatric Surgical Association Outcomes and Clinical Trials Committee. Parenteral nutrition-associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg 2012; 47 (01) 225-240
15 Gura KM, Calkins KL, Premkumar MH, Puder M. Use of intravenous soybean and fish oil emulsions in pediatric intestinal failure-associated liver disease: A multicenter integrated analysis report on extrahepatic adverse events. J Pediatr 2022; 241: 173-180.e1
16 Hao W, Wong OY, Liu X, Lee P, Chen Y, Wong KK. ω-3 fatty acids suppress inflammatory cytokine production by macrophages and hepatocytes. J Pediatr Surg 2010; 45 (12) 2412-2418
17 Gupta K, Wang H, Amin SB. Soybean-oil lipid minimization for prevention of intestinal failure-associated liver disease in late-preterm and term infants with gastrointestinal surgical disorders. JPEN J Parenter Enteral Nutr 2021; 45 (06) 1239-1248
18 Puder M, Valim C, Meisel JA. et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg 2009; 250 (03) 395-402
19 Lee Y-Y, Tang T-K, Chan E-S. et al. Medium chain triglyceride and medium-and long chain triglyceride: metabolism, production, health impacts and its applications - a review. Crit Rev Food Sci Nutr 2022; 62 (15) 4169-4185
20 Chen S, Xiao Y, Liu Y. et al. Fish oil-based lipid emulsion alleviates parenteral nutrition-associated liver diseases and intestinal injury in piglets. JPEN J Parenter Enteral Nutr 2022; 46 (03) 709-720
21 Diamond IR, Grant RC, Pencharz PB. et al. Preventing the progression of intestinal failure-associated liver disease in infants using a composite lipid emulsion: a pilot randomized controlled trial of SMOFlipid. JPEN J Parenter Enteral Nutr 2017; 41 (05) 866-877
22 Wassef J, Lipkin E, Hardigan P, Duro D. Trends in liver profile and nutrition outcomes in children undergoing intestinal rehabilitation using a mixed lipid injectable emulsion. Nutr Clin Pract 2022; 37 (05) 1180-1189
23 Hudson AS, Tyminski N, Turner JM, Silverman JA. Intestinal failure-associated liver disease and growth pre- and post-transition to a composite lipid emulsion. J Pediatr Gastroenterol Nutr 2023; 76 (06) 830-836
24 Hill NS, Cormack BE, Little BS, Bloomfield FH. Growth and clinical outcome in very low-birth-weight infants after the introduction of a multicomponent intravenous lipid emulsion. JPEN J Parenter Enteral Nutr 2020; 44 (07) 1318-1327
25 Yildizdas HY, Poyraz B, Atli G. et al. Effects of two different lipid emulsions on antioxidant status, lipid peroxidation and parenteral nutrition-related cholestasis in premature babies, a randomized-controlled study. Pediatr Neonatol 2019; 60 (04) 359-367
26 Gallini F, Pelosi MS, De Rose DU. et al. Neurodevelopmental outcomes in preterm infants receiving a multicomponent vs. a soybean-based lipid emulsion: 24 month follow-up of a randomized controlled trial. Nutrients 2022; 15 (01) 58
27 Nandivada P, Fell GL, Gura KM, Puder M. Lipid emulsions in the treatment and prevention of parenteral nutrition-associated liver disease in infants and children. Am J Clin Nutr 2016; 103 (02) 629S-634S
28 Clayton PT, Bowron A, Mills KA, Massoud A, Casteels M, Milla PJ. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology 1993; 105 (06) 1806-1813
29 Hukkinen M, Mutanen A, Nissinen M, Merras-Salmio L, Gylling H, Pakarinen MP. Parenteral plant sterols accumulate in the liver reflecting their increased serum levels and portal inflammation in children with intestinal failure. JPEN J Parenter Enteral Nutr 2017; 41 (06) 1014-1022
30 Fligor SC, Hirsch TI, Tsikis ST. et al. Intestinal failure-associated liver disease model: a reduced phytosterol intravenous lipid emulsion prevents liver injury. Pediatr Res 2024
31 El Kasmi KC, Anderson AL, Devereaux MW. et al. Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med 2013; 5 (206) 206ra137
32 Mutanen A, Nissinen MJ, Lohi J, Heikkilä P, Gylling H, Pakarinen MP. Serum plant sterols, cholestanol, and cholesterol precursors associate with histological liver injury in pediatric onset intestinal failure. Am J Clin Nutr 2014; 100 (04) 1085-1094
33 Ghosh S, Devereaux MW, Anderson AL. et al. NF-κB regulation of LRH-1 and ABCG5/8 potentiates phytosterol role in the pathogenesis of parenteral nutrition-associated cholestasis. Hepatology 2021; 74 (06) 3284-3300
34 El Kasmi KC, Vue PM, Anderson AL. et al. Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis. Nat Commun 2018; 9 (01) 1393
35 Mutanen A, Pakarinen MP. Featuring molecular regulation of bile acid homeostasis in pediatric short bowel syndrome. Clin Res Hepatol Gastroenterol 2023; 47 (09) 102220
36 Mutanen A, Lohi J, Heikkilä P, Jalanko H, Pakarinen MP. Liver inflammation relates to decreased canalicular bile transporter expression in pediatric onset intestinal failure. Ann Surg 2018; 268 (02) 332-339
37 Ghosh S, Devereaux MW, Liu C, Sokol RJ. LRH-1 agonist DLPC through STAT6 promotes macrophage polarization and prevents parenteral nutrition-associated cholestasis in mice. Hepatology 2024; 79 (05) 986-1004
38 Mutanen A, Lohi J, Heikkilä P, Jalanko H, Pakarinen MP. Loss of ileum decreases serum fibroblast growth factor 19 in relation to liver inflammation and fibrosis in pediatric onset intestinal failure. J Hepatol 2015; 62 (06) 1391-1397
39 Xiao Y, Maitiabula G, Wang H. et al. Predictive value of serum fibroblast growth factor 19 and liver stiffness for intestinal failure associated liver disease-cholestasis. Clin Nutr ESPEN 2024; 59: 89-95
40 Li X, Lu W, Kharitonenkov A, Luo Y. Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases. J Intern Med 2024; 295 (03) 292-312
41 Zhao Y, Wang Y, Jiang L, Cai W, Yan J. Impaired intestinal FXR signaling is involved in aberrant stem cell function leading to intestinal failure-associated liver disease in pediatric patients with short bowel syndrome. FASEB J 2024; 38 (15) e23847
42 Korpela K, Mutanen A, Salonen A, Savilahti E, de Vos WM, Pakarinen MP. Intestinal microbiota signatures associated with histological liver steatosis in pediatric-onset intestinal failure. JPEN J Parenter Enteral Nutr 2017; 41 (02) 238-248
43 Ralls MW, Miyasaka E, Teitelbaum DH. Intestinal microbial diversity and perioperative complications. JPEN J Parenter Enteral Nutr 2014; 38 (03) 392-399
44 Jiang L, Wang Y, Xiao Y. et al. Role of the gut microbiota in parenteral nutrition-associated liver disease: from current knowledge to future opportunities. J Nutr 2022; 152 (02) 377-385
45 El Kasmi KC, Anderson AL, Devereaux MW. et al. Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology 2012; 55 (05) 1518-1528
46 Fligor SC, Tsikis ST, Hirsch TI. et al. Inflammation drives pathogenesis of early intestinal failure-associated liver disease. Sci Rep 2024; 14 (01) 4240
47 El Kasmi KC, Anderson AL, Devereaux MW. et al. Interrupting tumor necrosis factor-alpha signaling prevents parenteral nutrition-associated cholestasis in mice. JPEN J Parenter Enteral Nutr 2022; 46 (05) 1096-1106
48 Jiang L, Wang N, Cheng S. et al. RNA-sequencing identifies novel transcriptomic signatures in intestinal failure-associated liver disease. J Pediatr Surg 2022; 57 (09) 158-165
49 Ghosh S, Devereaux MW, Anderson AL, El Kasmi KC, Sokol RJ. Stat3 role in the protective effect of FXR Agonist in parenteral nutrition-associated cholestasis. Hepatol Commun 2023; 7 (03) e0056
50 Wan S, Maitiabula G, Wang P. et al. Down regulation of NDUFS1 is involved in the progression of parenteral-nutrition-associated liver disease by increasing oxidative stress. J Nutr Biochem 2023; 112: 109221
51 Shores DR, Alaish SM, Aucott SW. et al. Postoperative enteral nutrition guidelines reduce the risk of intestinal failure-associated liver disease in surgical infants. J Pediatr 2018; 195: 140-147.e1
52 Sharman-Koendjbiharie M, Piena-Spoel M, Hopman WP, Albers MJ, Jansen JB, Tibboel D. Gastrointestinal hormone secretion after surgery in neonates with congenital intestinal anomalies during starvation and introduction of enteral nutrition. J Pediatr Surg 2003; 38 (11) 1602-1606
53 Dodge ME, Bertolo RF, Brunton JA. Enteral feeding induces early intestinal adaptation in a parenterally fed neonatal piglet model of short bowel syndrome. JPEN J Parenter Enteral Nutr 2012; 36 (02) 205-212
54 Pironi L, Arends J, Bozzetti F. et al.; Home Artificial Nutrition & Chronic Intestinal Failure Special Interest Group of ESPEN. ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr 2016; 35 (02) 247-307
55 Nehra D, Fallon EM, Carlson SJ. et al. Provision of a soy-based intravenous lipid emulsion at 1 g/kg/d does not prevent cholestasis in neonates. JPEN J Parenter Enteral Nutr 2013; 37 (04) 498-505
56 Levit OL, Calkins KL, Gibson LC. et al. Low-dose intravenous soybean oil emulsion for prevention of cholestasis in preterm neonates. JPEN J Parenter Enteral Nutr 2016; 40 (03) 374-382
57 Calkins KL, Havranek T, Kelley-Quon LI. et al. Low-dose parenteral soybean oil for the prevention of parenteral nutrition-associated liver disease in neonates with gastrointestinal disorders. JPEN J Parenter Enteral Nutr 2017; 41 (03) 404-411
58 Rollins MD, Ward RM, Jackson WD. et al. Effect of decreased parenteral soybean lipid emulsion on hepatic function in infants at risk for parenteral nutrition-associated liver disease: a pilot study. J Pediatr Surg 2013; 48 (06) 1348-1356
59 Sanchez SE, Braun LP, Mercer LD, Sherrill M, Stevens J, Javid PJ. The effect of lipid restriction on the prevention of parenteral nutrition-associated cholestasis in surgical infants. J Pediatr Surg 2013; 48 (03) 573-578
60 Arenas Villafranca JJ, Nieto Guindo M, Álvaro Sanz E, Moreno Santamaria M, Garrido Siles M, Abilés J. Effects of cyclic parenteral nutrition on parenteral-associated liver dysfunction parameters. Nutr J 2017; 16 (01) 66
61 Bae HJ, Shin SH, Kim EK, Kim HS, Cho YS, Gwak HS. Effects of cyclic parenteral nutrition on parenteral nutrition-associated cholestasis in newborns. Asia Pac J Clin Nutr 2019; 28 (01) 42-48
62 Josephson J, Turner JM, Field CJ. et al. parenteral soy oil and fish oil emulsions: impact of dose restriction on bile flow and brain size of parenteral nutrition-fed neonatal piglets. JPEN J Parenter Enteral Nutr 2015; 39 (06) 677-687
63 Chan AP, Rostas S, Rogers S, Martin CR, Calkins KL. Parenteral nutrition in the neonatal intensive care unit: intravenous lipid emulsions. Clin Perinatol 2023; 50 (03) 575-589
64 Gura KM, Lee S, Valim C. et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics 2008; 121 (03) e678-e686
65 Calkins KL, Dunn JC, Shew SB. et al. Pediatric intestinal failure-associated liver disease is reversed with 6 months of intravenous fish oil. JPEN J Parenter Enteral Nutr 2014; 38 (06) 682-692
66 Lapillonne A, Fidler Mis N, Goulet O, van den Akker CHP, Wu J, Koletzko B. ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Lipids. Clin Nutr 2018; 37 (6 Pt B): 2324-2336
67 Robinson DT, Calkins KL, Chen Y. et al. Guidelines for parenteral nutrition in preterm infants: The American Society for Parenteral and Enteral Nutrition. JPEN J Parenter Enteral Nutr 2023; 47 (07) 830-858
68 Mercer DF, Hobson BD, Fischer RT. et al. Hepatic fibrosis persists and progresses despite biochemical improvement in children treated with intravenous fish oil emulsion. J Pediatr Gastroenterol Nutr 2013; 56 (04) 364-369
69 Lucchinetti E, Lou PH, Holtzhauer G. et al. Novel lipid emulsion for total parenteral nutrition based on 18-carbon n-3 fatty acids elicits a superior immunometabolic phenotype in a murine model compared with standard lipid emulsions. Am J Clin Nutr 2022; 116 (06) 1805-1819
70 Bernhard W, Böckmann KA, Minarski M. et al. Evidence and perspectives for choline supplementation during parenteral nutrition-a narrative review. Nutrients 2024; 16 (12) 16
71 Zhu J, Lu T, Chen F. et al. Choline protects against intestinal failure-associated liver disease in parenteral nutrition-fed immature rats. JPEN J Parenter Enteral Nutr 2018; 42 (02) 436-445
72 Sokol RJ, Dahl R, Devereaux MW, Yerushalmi B, Kobak GE, Gumpricht E. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J Pediatr Gastroenterol Nutr 2005; 41 (02) 235-243
73 Sokol RJ, McKim Jr JM, Goff MC. et al. Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat. Gastroenterology 1998; 114 (01) 164-174
74 Mungala Lengo A, Mohamed I, Lavoie JC. Glutathione supplementation prevents neonatal parenteral nutrition-induced short- and long-term epigenetic and transcriptional disruptions of hepatic H₂O₂ metabolism in guinea pigs. Nutrients 2024; 16 (06) 16
75 Jiang S, Hu Q, Zhang J. Dexamethasone may affect the occurrence of parenteral nutrition-associated cholestasis in preterm neonates. Front Pediatr 2022; 10: 1023798
76 El Khatib M, Billiauws L, Joly F. The indications and results of the use of teduglutide in patients with short bowel. Curr Opin Clin Nutr Metab Care 2023; 26 (05) 449-454
77 Micic D, Robinson I, Kidd T, Terreri B, Raphael BP. Teduglutide improves liver chemistries in short bowel syndrome-associated intestinal failure: Post hoc analysis. Nutr Clin Pract 2024; 39 (03) 634-640
78 Sueyoshi R, Furuhashi N, Ishii J. et al. Decreased liver damage in rat models of short bowel syndrome through DPP4 inhibition. Pediatr Surg Int 2022; 39 (01) 21
79 El Kasmi KC, Ghosh S, Anderson AL. et al. Pharmacologic activation of hepatic farnesoid X receptor prevents parenteral nutrition-associated cholestasis in -mice. Hepatology 2022; 75 (02) 252-265
80 Jiang Y, Fang Z, Guthrie G. et al. Selective agonism of liver and gut FXR prevents cholestasis and intestinal atrophy in parenterally fed neonatal pigs. biioRxiv [Preprint]; 2024. Sep 7: 2024.09.03.611073. Accessed March 9, 2025
81 Hukkinen M, Mutanen A, Pakarinen MP. Small bowel dilation in children with short bowel syndrome is associated with mucosal damage, bowel-derived bloodstream infections, and hepatic injury. Surgery 2017; 162 (03) 670-679
82 Wang W, Wang Y, Liu Y. et al. Lactobacillus plantarum supplementation alleviates liver and intestinal injury in parenteral nutrition-fed piglets. JPEN J Parenter Enteral Nutr 2022; 46 (08) 1932-1943
83 Xu J, Zhou Y, Cheng S. et al. Lactobacillus johnsonii attenuates liver steatosis and bile acid dysregulation in parenteral nutrition-fed rats. Metabolites 2023; 13 (10) 13
84 Beath SV, Davies P, Papadopoulou A. et al. Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors. J Pediatr Surg 1996; 31 (04) 604-606
85 Hermans D, Talbotec C, Lacaille F, Goulet O, Ricour C, Colomb V. Early central catheter infections may contribute to hepatic fibrosis in children receiving long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 2007; 44 (04) 459-463
86 Lambe C, Poisson C, Talbotec C, Goulet O. Strategies to reduce catheter-related bloodstream infections in pediatric patients receiving home parenteral nutrition: the efficacy of taurolidine-citrate prophylactic-locking. JPEN J Parenter Enteral Nutr 2018; 42 (06) 1017-1025
87 Oliveira C, Nasr A, Brindle M, Wales PW. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics 2012; 129 (02) 318-329
88 Smith JM, Weaver T, Skeans MA. et al. OPTN/SRTR 2017 Annual Data Report: Intestine. Am J Transplant 2019; 19 (Suppl. 02) 284-322
89 Kaufman SS, Atkinson JB, Bianchi A. et al.; American Society of Transplantation. Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation. Pediatr Transplant 2001; 5 (02) 80-87
90 Squires RH, Duggan C, Teitelbaum DH. et al.; Pediatric Intestinal Failure Consortium. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. J Pediatr 2012; 161 (04) 723-8.e2
91 Norsa L, Artru S, Lambe C. et al. Long term outcomes of intestinal rehabilitation in children with neonatal very short bowel syndrome: Parenteral nutrition or intestinal transplantation. Clin Nutr 2019; 38 (02) 926-933