Partial liver resection alters the bile salt-FGF19 axis in patients with perihilar cholangiocarcinoma: Implications for liver regeneration
Language English Country United States Media electronic-ecollection
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
38836805
PubMed Central
PMC11155560
DOI
10.1097/hc9.0000000000000445
PII: 02009842-202406010-00024
Knihovny.cz E-resources
- MeSH
- Fibroblast Growth Factors * blood MeSH
- Hepatectomy * MeSH
- Liver metabolism surgery MeSH
- Klatskin Tumor * surgery pathology blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Bile Duct Neoplasms * surgery pathology blood MeSH
- Liver Regeneration * physiology MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Bile Acids and Salts * blood metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- FGF19 protein, human MeSH Browser
- Fibroblast Growth Factors * MeSH
- Bile Acids and Salts * MeSH
BACKGROUND: Extended liver resection is the only treatment option for perihilar cholangiocarcinoma (pCCA). Bile salts and the gut hormone FGF19, both promoters of liver regeneration (LR), have not been investigated in patients undergoing resection for pCCA. We aimed to evaluate the bile salt-FGF19 axis perioperatively in pCCA and study its effects on LR. METHODS: Plasma bile salts, FGF19, and C4 (bile salt synthesis marker) were assessed in patients with pCCA and controls (colorectal liver metastases), before and after resection on postoperative days (PODs) 1, 3, and 7. Hepatic bile salts were determined in intraoperative liver biopsies. RESULTS: Partial liver resection in pCCA elicited a sharp decline in bile salt and FGF19 plasma levels on POD 1 and remained low thereafter, unlike in controls, where bile salts rose gradually. Preoperatively, suppressed C4 in pCCA normalized postoperatively to levels similar to those in the controls. The remnant liver volume and postoperative bilirubin levels were negatively associated with postoperative C4 levels. Furthermore, patients who developed postoperative liver failure had nearly undetectable C4 levels on POD 7. Hepatic bile salts strongly predicted hyperbilirubinemia on POD 7 in both groups. Finally, postoperative bile salt levels on day 7 were an independent predictor of LR. CONCLUSIONS: Partial liver resection alters the bile salt-FGF19 axis, but its derailment is unrelated to LR in pCCA. Postoperative monitoring of circulating bile salts and their production may be useful for monitoring LR.
Department of General Visceral and Transplant Surgery University Hospital RWTH Aachen Aachen Germany
See more in PubMed
Michalopoulos GK, Bhushan B. Liver regeneration: Biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol. 2021;18:40–55. PubMed
Fausto N. Liver regeneration. J Hepatol. 2000;32:19–31. PubMed
Yokoyama Y, Nagino M, Nimura Y. Mechanism of impaired hepatic regeneration in cholestatic liver. J Hepatobiliary Pancreat Surg. 2007;14:159–166. PubMed
Cillo U, Fondevila C, Donadon M, Gringeri E, Mocchegiani F, Schlitt HJ, et al. . Surgery for cholangiocarcinoma. Liver Int. 2019;39(suppl 1):143–155. PubMed PMC
Ratti F, Marino R, Olthof PB, Pratschke J, Erdmann JI, Neumann UP, et al. . Predicting futility of upfront surgery in perihilar cholangiocarcinoma: Machine learning analytics model to optimize treatment allocation. Hepatology. 2024;79:341–54. PubMed
Giuliante F, Ardito F, Aldrighetti L, Ferrero A, Pinna AD, De Carlis L, et al. . Liver resection for perihilar cholangiocarcinoma: Impact of biliary drainage failure on postoperative outcome. Results of an Italian multicenter study. Surgery. 2021;170:383–389. PubMed
Farges O, Regimbeau JM, Fuks D, Le Treut YP, Cherqui D, Bachellier P, et al. . Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg. 2013;100:274–283. PubMed
Wiggers JK, Koerkamp BG, Cieslak KP, Doussot A, van Klaveren D, Allen PJ, et al. . Postoperative mortality after liver resection for perihilar cholangiocarcinoma: Development of a risk score and importance of biliary drainage of the future liver remnant. J Am Coll Surg. 2016;223:321–331 e1. PubMed PMC
Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, et al. . Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science. 2006;312:233–236. PubMed
Uriarte I, Fernandez-Barrena MG, Monte MJ, Latasa MU, Chang HCY, Carotti S, et al. . Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut. 2013;62:899–910. PubMed
Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, et al. . A mouse model of hepatocellular carcinoma: Ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol. 2002;160:2295–2307. PubMed PMC
Kong B, Huang J, Zhu Y, Li G, Williams J, Shen S, et al. . Fibroblast growth factor 15 deficiency impairs liver regeneration in mice. Am J Physiol Gastrointest Liver Physiol. 2014;306:G893–G902. PubMed PMC
Alvarez-Sola G, Uriarte I, Latasa MU, Fernandez-Barrena MG, Urtasun R, Elizalde M, et al. . Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: Development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut. 2017;66:1818–1828. PubMed
Kong B, Sun R, Huang M, Chow MD, Zhong XB, Xie W, et al. . A novel fibroblast growth factor 15 dependent- and bile acid independent-promotion of liver regeneration in mice. Hepatology. 2018;68:1961–1976. PubMed PMC
Schaap FG, van der Gaag NA, Gouma DJ, Jansen PLM. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology. 2009;49:1228–1235. PubMed
Li Z, Lin B, Lin G, Wu Y, Jie Y, Li X, et al. . Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis. PLoS One. 2017;12:e0178580. PubMed PMC
Brandl K, Hartmann P, Jih LJ, Pizzo DP, Argemi J, Ventura-Cots M, et al. . Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J Hepatol. 2018;69:396–405. PubMed PMC
Nyholm I, Hukkinen M, Pihlajoki M, Davidson JR, Tyraskis A, Lohi J, et al. . Serum FGF19 predicts outcomes of Kasai portoenterostomy in biliary atresia. Hepatology. 2023;77:1263–1273. PubMed PMC
Koelfat KVK, van Mierlo KMC, Lodewick TM, Bloemen JG, van der Kroft G, Amygdalos I, et al. . Bile salt and FGF19 signaling in the early phase of human liver regeneration. Hepatol Commun. 2021;5:1400–1411. PubMed PMC
Otao R, Beppu T, Isiko T, Mima K, Okabe H, Hayashi H, et al. . External biliary drainage and liver regeneration after major hepatectomy. Br J Surg. 2012;99:1569–1574. PubMed
Hoekstra LT, van Lienden KP, Schaap FG, Chamuleau RAFM, Bennink RJ, van Gulik TM. Can plasma bile salt, triglycerides, and apoA-V levels predict liver regeneration? World J Surg. 2012;36:2901–2908. PubMed
Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, et al. . The Clavien-Dindo classification of surgical complications: Five-year experience. Ann Surg. 2009;250:187–196. PubMed
Rahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, et al. . Posthepatectomy liver failure: A definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149:713–724. PubMed
Modica S, Murzilli S, Moschetta A. Characterizing bile acid and lipid metabolism in the liver and gastrointestinal tract of mice. Curr Protoc Mouse Biol. 2011;1:289–321. PubMed
Lenicek M, Juklova M, Zelenka J, Kovar J, Lukas M, Bortlik M, et al. . Improved HPLC analysis of serum 7alpha-hydroxycholest-4-en-3-one, a marker of bile acid malabsorption. Clin Chem. 2008;54:1087–1088. PubMed
Bednarsch J, Czigany Z, Lurje I, Amygdalos I, Strnad P, Halm P, et al. . Insufficient future liver remnant and preoperative cholangitis predict perioperative outcome in perihilar cholangiocarcinoma. HPB (Oxford). 2021;23:99–108. PubMed
Koelfat KVK, Plummer MP, Schaap FG, Lenicek M, Jansen PLM, Deane AM, et al. . Gallbladder dyskinesia is associated with an impaired postprandial fibroblast growth factor 19 response in critically ill patients. Hepatology. 2019;70:308–318. PubMed
Baumgartner U, Sellinger M, Ruf G, Jehle L, Ihling C, Farthmann EH. Change of zonal bile acid processing after partial hepatectomy in the rat. J Hepatol. 1995;22:474–480. PubMed
Naugler WE. Bile acid flux is necessary for normal liver regeneration. PLoS One. 2014;9:e97426. PubMed PMC
Cai SY, Ouyang X, Chen Y, Soroka CJ, Wang J, Mennone A, et al. . Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight. 2017;2:e90780. PubMed PMC
Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, et al. . A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med. 2014;6:247ra100. PubMed
Harrison SA, Neff G, Guy CD, Bashir MR, Paredes AH, Frias JP, et al. . Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis. Gastroenterology. 2021;160:219–231 e1. PubMed
Hirschfield GM, Chazouilleres O, Drenth JP, Thorburn D, Harroisn SA, Landis CS, et al. . Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol. 2019;70:483–93. PubMed
Sanyal AJ, Ling L, Beuers U, DePaoli AM, Lieu HD, Harrison SA, et al. . Potent suppression of hydrophobic bile acids by aldafermin, an FGF19 analogue, across metabolic and cholestatic liver diseases. JHEP Rep. 2021;3:100255. PubMed PMC
Zollner G, Wagner M, Fickert P, Silbert D, Gumhold J, Zatloukal K, et al. . Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int. 2007;27:920–929. PubMed
Kong B, Wang L, Chiang JYL, Zhang Y, Klaassen CD, Guo GL. Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology. 2012;56:1034–1043. PubMed PMC
Song K-H, Li T, Owsley E, Strom S, Chiang JY. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology (Baltimore, Md). 2009;49:297–305. PubMed PMC
Xu HS, Rosenlof LK, Jones RS. Bile secretion and liver regeneration in partially hepatectomized rats. Ann Surg. 1993;218:176–182. PubMed PMC
Csanaky IL, Aleksunes LM, Tanaka Y, Klaassen CD. Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice. Am J Physiol Gastrointest Liver Physiol. 2009;297:G419–G433. PubMed PMC
Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43:S45–S53. PubMed
Gartung C, Ananthanarayanan M, Rahman M, Schuele S, Nundy S, Soroka C, et al. . Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis. Gastroenterology. 1996;110:199–209. PubMed
Vos TA, Ros JE, Havinga R, Moshage H, Kuipers F, Jansen PL, et al. . Regulation of hepatic transport systems involved in bile secretion during liver regeneration in rats. Hepatology. 1999;29:1833–1839. PubMed
Gerloff T, Geier A, Stieger B, Hagenbuch B, Meier PJ, Matern S, et al. . Differential expression of basolateral and canalicular organic anion transporters during regeneration of rat liver. Gastroenterology. 1999;117:1408–1415. PubMed
Lee JM, Trauner M, Soroka CJ, Stieger B, Meier PJ, Boyer JL. Expression of the bile salt export pump is maintained after chronic cholestasis in the rat. Gastroenterology. 2000;118:163–172. PubMed
Geier A, Zollner G, Dietrich CG, Wagner M, Fickert P, Denk H, et al. . Cytokine-independent repression of rodent Ntcp in obstructive cholestasis. Hepatology. 2005;41:470–477. PubMed
Miura T, Kimura N, Yamada T, Shimizu T, Nanashima N, Yamana D, et al. . Sustained repression and translocation of Ntcp and expression of Mrp4 for cholestasis after rat 90% partial hepatectomy. J Hepatol. 2011;55:407–414. PubMed
Slijepcevic D, Roscam Abbing RLP, Fuchs CD, Haazen LCM, Beuers U, Trauner M, et al. . Na(+) -taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice. Hepatology. 2018;68:1057–1069. PubMed PMC
Zhang M, Wang J, He K, Xia X. Bsep expression in hilar cholangiocarcinoma of rat model. Sci Rep. 2021;11:2861. PubMed PMC
Vartak N, Damle‐Vartak A, Richter B, Dirsch O, Dahmen U, Hammad S, et al. . Cholestasis-induced adaptive remodeling of interlobular bile ducts. Hepatology. 2016;63:951–964. PubMed PMC
Zhang L, Huang X, Meng Z, Dong B, Shiah S, Moore DD, et al. . Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration. Mol Endocrinol. 2009;23:137–145. PubMed PMC
Santamaría E, Rodríguez‐Ortigosa CM, Uriarte I, Latasa MU, Urtasun R, Alvarez‐Sola G, et al. . The epidermal growth factor receptor ligand amphiregulin protects from cholestatic liver injury and regulates bile acids synthesis. Hepatology. 2019;69:1632–1647. PubMed
Berasain C, García-Trevijano ER, Castillo J, Erroba E, Lee DC, Prieto J, et al. . Amphiregulin: An early trigger of liver regeneration in mice. Gastroenterology. 2005;128:424–432. PubMed
Yu C, Wang F, Jin C, Huang X, McKeehan WL. Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids. J Biol Chem. 2005;280:17707–17714. PubMed
Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. . Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2:217–225. PubMed
Zappa M, Dondero F, Sibert A, Vullierme MP, Belghiti J, Vilgrain V. Liver regeneration at day 7 after right hepatectomy: Global and segmental volumetric analysis by using CT. Radiology. 2009;252:426–432. PubMed