FGF19 in Obstructive Cholestasis: "Unveil the Signal"

NCT05718349 | Unknown

• 1 other identifier: EK172/17
• Study Type: observational
• Target: 81
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: Bile salts are potent signalling molecules influencing various metabolic and functional processes. Bile salts exert these functions by activating nuclear (e.g. FXR ) and plasma cell membrane-bound receptors (e.g. TGR5) which are expressed in several tissues (e.g. liver, small intestine, colon, kidney and gallbladder). Bile salts regulate their own biosynthesis by controlling the transcription of the hepatic bile salt synthetic enzyme CYP7A1. Two pathways are involved in the negative feedback control of bile salt synthesis: i) the hepatic FXR-SHP pathway and ii) the ileal FXR-FGF19 pathway. Studies showed that the latter is more prominent in controlling CYP7A1 transcript levels (viz. bile salt synthesis). Thus, bile salts are synthesized in the liver, excreted in bile and expelled by the gallbladder into the proximal intestine (to aid in lipid absorption and digestion) and reabsorbed in the terminal ileum to recycle back to the liver via portal blood. Bile salts reclaimed from the intestinal lumen by the ileocyte, activate FXR. This induces the expression of an enterokine, FGF19, which signals via portal blood to the liver to activate its receptor which initiates downstream signalling to repress bile salt synthesis. The FXR/FGF19 signalling pathway is the subject of the present study. Patients with obstructive cholestasis (=accumulation of bile) caused by malignancies (e.g. pancreatic cancer, cholangiocarcinoma) have a perturbed enterohepatic cycle. Obstructive cholestasis is associated with i) gut barrier dysfunction, ii) endotoxemia, iii) bacterial overgrowth and iv) liver injury. Previous study showed that FGF19 is expressed in the liver of patients with obstructive cholestasis. However, knowledge about the contribution of FGF19 protein by the gut in obstructive cholestasis has thus far been unexplored. Preliminary findings revealed that FGF19 is produced by the portal drained viscera (viz. intestine) of non-cholestatic patients undergoing liver surgery. The inter-organ signalling of FGF19 in an obstructed entero-hepatic cycle has not yet been characterized and likewise the metabolic and other functional effects of inflicted FGF19 signalling during cholestasis have not been clarified. The hypothesis is that the FXR-FGF19 pathway is disturbed in patients with obstructive cholestasis, and this is associated with organ injury and metabolic dysfunction. The investigators postulate that FGF19 is not produced by the terminal ileum under conditions of obstructive cholestatic, but production is shifted to the liver and this affects metabolic processes. The aim of this study is to investigate FGF19 signalling in patients with cholestasis compared to non-cholestatic patients or post-cholestatic patients (drained patients) by calculating fluxes across the portal drained organs. Secondly, the investigators aim to investigate the metabolic and functional consequences (glucose, lipid homeostasis, cholestatic itch, gut barrier function) of a disturbed FXR-FGF19 pathway in humans. This study will provide insights that may lead to potential therapeutic strategies for patients with a disturbed enterohepatic cycle (e.g. cholestatic liver diseases). Study population: Adult (\>18 years old) cholestatic (cholestasis group), drained (restored enterohepatic cycle) and non-cholestatic patients (controls, normal enterohepatic circulation) undergoing pancreaticoduodenectomy (Whipple procedure) for hepatopancreaticobiliary malignancies (e.g. pancreatic cancer, cholangiocarcinoma) or liver resection for hepatic malignancies (e.g. cholangiocarcinoma, colorectal liver metastases) are eligible for this study. Study period: inclusion is planned from 1.12.2017 until 1.12.2024

Conditions

Cholestasis; Icterus; Cholangiocarcinoma; Pancreatic Neoplasms; Liver Metastasis Colon Cancer

Outcome Measures

Primary Outcomes (13)

• plasma FGF19 levels

  A factor which signals to the liver to repress the expression of Cyp7a1 (rate limiting enzyme of bile salt synthesis)

  Intraoperatively

• plasma bile salt levels

  Bile salts are synthesized in the liver, and efficiently returned to the liver via the intestinal lumen and portal blood

  Intraoperatively

• Gene expression levels of genes implicated in bile salt homeostasis and FGF19 signaling

  in liver, proximal jejunum, gallbladder, common bile duct, subcutaneous adipose tissue, omental adipose tissue, visceral adipose tissue, and rectus abdominis muscle

  Intraoperatively

• Biliary FGF19 level

  A factor which signals to the liver to repress the expression of Cyp7a1 (rate limiting enzyme of bile salt synthesis)

  Intraoperatively

• itch intensity

  by means of a Visual Analogue Scale (VAS, a scale from 0 (no itch) to 10 (worst itch possible))

  Preoperatively

• Enterocyte damage

  Plasma IFABP

  Intraoperatively

• Enterocyte function

  Plasma Citrulline

  Intraoperatively

• Transmural intestinal damage

  Plasma SM22

  Intraoperatively

• Endotoxinemia

  Plasma LBP

  Intraoperatively

• Bile salt composition

  In stool, jejunal content, plasma, and urine

  Preoperatively

• Bile salt composition

  In stool, jejunal content, plasma, and urine

  Intraoperatively

• Microbial composition

  In stool and jejunal content

  Preoperatively

• Microbial composition

  In stool and jejunal content

  Intraoperatively

Study Arms (3)

Non-cholestasis

Patients planned for pancreaticoduodenectomy or liver resection (with or without hepaticojejunostomy) who do not have cholestasis preoperatively.

Other: Biospecimen sampling

Drained

Patients planned for pancreaticoduodenectomy or liver resection (with or without hepaticojejunostomy) who had cholestasis and underwent ERCP (endoscopic retrograde choledochopancreatography) with stenting to normalize the enterohepatic circulation.

Other: Biospecimen sampling

Cholestasis

Patients planned for pancreaticoduodenectomy or liver resection (with or without hepaticojejunostomy) who have cholestasis preoperatively and did not undergo drainage.

Other: Biospecimen sampling

Interventions

Biospecimen sampling OTHER

From the patients participating in the study i) blood, ii) tissue from resected material, iii) bile, iv) stool, v) urine, vi) jejunal content and vii) information on the itch severity will be collected.

Cholestasis; Drained; Non-cholestasis

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with obstructive jaundice undergoing pp Whipple or liver resection are eligible for this study. Controls are non-jaundiced and drained patients undergoing pp Whipple or liver resection. The rationale for including patients undergoing pp Whipple or liver resection is that the nature of the surgical procedure in the abdomen allows sampling of blood from the portal drained organs, and tissue sampling. Patients will be recruited at the surgical outpatient clinic of Maastricht University Medical Center (MUMC+) and University Hospital RWTH Aachen (Germany). Patients in the cholestasis group (group III), will be included largely at the University Hospital RWTH Aachen. Ten to twenty percent of the cholestasis group can be included in MUMC+.

You may qualify if:

• Patients undergoing pp Whipple or liver resection
• Age \>18 and \<75 years

You may not qualify if:

• Jejunostomy
• Lactation, pregnancy and planning of pregnancy
• Inflammatory bowel disease
• Alcohol or drug abuse within 1 year
• Inborn errors of bile salt synthesis
• Failure to give informed consent or refusal to store patient data for fifteen years

Sponsors & Collaborators

• Nicole Hildebrand: lead
• RWTH Aachen University: collaborator

Study Sites (1)

RWTH Aachen

Aachen, Germany

RECRUITING

Related Publications (16)

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  PMID: 19273221 BACKGROUND

• Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014 Jan;11(1):55-67. doi: 10.1038/nrgastro.2013.151. Epub 2013 Aug 27.

  PMID: 23982684 BACKGROUND

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• Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N, Di Tullio G, Palasciano G, Moustafa T, Halilbasic E, Trauner M, Moschetta A. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology. 2012 Feb;142(2):355-65.e1-4. doi: 10.1053/j.gastro.2011.10.028. Epub 2011 Nov 2.

  PMID: 22057115 BACKGROUND

• Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000 Sep;6(3):517-26. doi: 10.1016/s1097-2765(00)00051-4.

  PMID: 11030332 BACKGROUND

• Xie MH, Holcomb I, Deuel B, Dowd P, Huang A, Vagts A, Foster J, Liang J, Brush J, Gu Q, Hillan K, Goddard A, Gurney AL. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine. 1999 Oct;11(10):729-35. doi: 10.1006/cyto.1999.0485.

  PMID: 10525310 BACKGROUND

• Hart RA, Woo SL, Newton PO. Ultrastructural morphometry of anterior cruciate and medial collateral ligaments: an experimental study in rabbits. J Orthop Res. 1992 Jan;10(1):96-103. doi: 10.1002/jor.1100100112.

  PMID: 1727939 BACKGROUND

• Parks RW, Clements WD, Smye MG, Pope C, Rowlands BJ, Diamond T. Intestinal barrier dysfunction in clinical and experimental obstructive jaundice and its reversal by internal biliary drainage. Br J Surg. 1996 Oct;83(10):1345-9. doi: 10.1002/bjs.1800831007.

  PMID: 8944448 BACKGROUND

• Wells CL, Jechorek RP, Erlandsen SL. Inhibitory effect of bile on bacterial invasion of enterocytes: possible mechanism for increased translocation associated with obstructive jaundice. Crit Care Med. 1995 Feb;23(2):301-7. doi: 10.1097/00003246-199502000-00016.

  PMID: 7867356 BACKGROUND

• Bloemen JG, Venema K, van de Poll MC, Olde Damink SW, Buurman WA, Dejong CH. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin Nutr. 2009 Dec;28(6):657-61. doi: 10.1016/j.clnu.2009.05.011. Epub 2009 Jun 11.

  PMID: 19523724 BACKGROUND

• Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology. 2009 Apr;49(4):1228-35. doi: 10.1002/hep.22771.

  PMID: 19185005 BACKGROUND

• Zweers SJ, Booij KA, Komuta M, Roskams T, Gouma DJ, Jansen PL, Schaap FG. The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract. Hepatology. 2012 Feb;55(2):575-83. doi: 10.1002/hep.24702. Epub 2011 Dec 19.

  PMID: 21953282 BACKGROUND

• Mraz M, Lacinova Z, Kavalkova P, Haluzikova D, Trachta P, Drapalova J, Hanusova V, Haluzik M. Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-alpha agonist treatment. Physiol Res. 2011;60(4):627-36. doi: 10.33549/physiolres.932099. Epub 2011 May 16.

  PMID: 21574752 BACKGROUND

• Galman C, Angelin B, Rudling M. Pronounced variation in bile acid synthesis in humans is related to gender, hypertriglyceridaemia and circulating levels of fibroblast growth factor 19. J Intern Med. 2011 Dec;270(6):580-8. doi: 10.1111/j.1365-2796.2011.02466.x. Epub 2011 Nov 2.

  PMID: 22003820 BACKGROUND

• Kuipers F, Bloks VW, Groen AK. Beyond intestinal soap--bile acids in metabolic control. Nat Rev Endocrinol. 2014 Aug;10(8):488-98. doi: 10.1038/nrendo.2014.60. Epub 2014 May 13.

  PMID: 24821328 BACKGROUND

• Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, Schaap FG. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010 Mar;298(3):G440-5. doi: 10.1152/ajpgi.00322.2009. Epub 2010 Jan 21.

  PMID: 20093562 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

From the patients participating in the study i) blood, ii) tissue from resected material, iii) bile, iv) stool, v) urine, vi) jejunal content and vii) information on the itch severity will be collected. Since the blood vessels indicated below are easily accessible in patients undergoing pylorus-preserving pancreaticoduodenectomy (pp Whipple) or liver resection, these patients are eligible for the study and will be included.

MeSH Terms

Conditions

Cholestasis; Jaundice; Cholangiocarcinoma; Pancreatic Neoplasms

Condition Hierarchy (Ancestors)

Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Hyperbilirubinemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Manifestations; Signs and Symptoms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• Steven Olde Damink, MD, PhD

  Academisch Ziekenhuis Maastricht

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Steven Olde Damink, MD, PhD

CONTACT

steven.oldedamink@maastrichtuniversity.nl

Jan Bednarsch, MD, PhD

CONTACT

jbednarsch@ukaachen.de

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Coordinating Investigator

Study Record Dates

• First Submitted: January 27, 2023
• First Posted: February 8, 2023
• Study Start: January 1, 2017
• Primary Completion: December 1, 2024
• Study Completion: June 1, 2025
• Last Updated: February 8, 2023

Record last verified: 2023-02

Locations

DE (1)