Intestinal failure to produce FGF19: A culprit in intestinal failure–associated liver disease?
Authors: Karel J. van Erpecum, Frank G. Schaap
Journal: Journal of Hepatology (2015)

Loss of ileum decreases serum fibroblast growth factor 19 in relation to liver inflammation and fibrosis in pediatric onset intestinal failureJournal of HepatologyVol. 62Issue 6PreviewThe pathogenesis of intestinal failure (IF) associated liver disease (IFALD) is uncertain, we therefore investigated the role of FGF19 and pro-inflammatory cytokines has on this disease state. Full-Text PDF Intestinal failure (IF) is a rare condition that results in severe malabsorption and requires parenteral nutrition (PN) to maintain energy, fluid and electrolyte balance. Neonatal causes of IF include extensive intestinal resections resulting in short bowel syndrome, congenital enteropathies affecting mucosal function and severe intestinal motility disorders due to enteric nerve or muscle dysfunction. In the adult population, IF typically develops after major resection of affected intestine in inflammatory bowel disease or intestinal ischemia. PN is central to the management of IF, ideally serving as a nutritional bridge until intestinal autonomy is restored through intestinal adaptation. Notwithstanding its vital therapeutic importance, PN has been associated with hepatobiliary complications in this setting (i.e. IF-associated liver disease, IFALD) since its introduction in the late 1960s. Children on long-term PN are especially affected by IFALD, with prevalence rates ranging from 22% to 50%. Four percent of all children on PN will eventually die or require intestinal or multivisceral transplantation because of IFALD [[1]Lacaille F. Gupte G. Colomb V. D'Antiga L. Hartman C. Hojsak I. et al.Intestinal failure-associated liver disease: a position paper of the ESPGHAN working group of intestinal failure and intestinal transplantation.J Pediatr Gastroenterol Nutr. 2015; 60: 272-283Crossref PubMed Scopus (130) Google Scholar]. In infants, the predominant histological feature of IFALD is cholestasis, which appears to relate to immaturity of the hepatobiliary system and septic complications. In older children and adults, the dominant histological finding is steatosis. Pediatric IFALD can rapidly progress to cirrhosis with all the associated complications. Risk factors for IFALD include prematurity (especially in case of concomitant necrotizing enterocolitis), small bowel bacterial overgrowth, bacterial infections, inability to tolerate any enteral nutrition, and formulation or mode of administration of PN. Bile salts are signaling molecules that activate specific receptors during their enterohepatic circulation (Fig. 1). Disruption of the enterohepatic circulation is a frequent phenomenon in IFALD, as a consequence of hepatocellular cholestasis, absence of enteral feeding-induced gallbladder contraction and intestinal motility, and (partial) loss of the ileum. In this issue, Mutanen et al. explore a consequence of perturbed enterohepatic cycling in IFALD by studying serum levels of the bile salt-induced enterokine FGF19. They report a negative association between FGF19 levels and severity of IFALD, with potential therapeutic implications [[2]Mutanen A. Lohi J. Heikkila P. Jalanko H. Pakarinen M.P. 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: 1391-1397Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. FGF19 is an endocrine-acting member of the family of fibroblast growth factors (FGF). Its intestinal expression is restricted to the ileum, and is induced following reclamation of bile salts from the intestinal lumen. In the enterocyte, absorbed bile salts subsequently activate the farnesoid X receptor (FXR). This ligand-activated transcription factor (abundantly expressed in ileum and liver) controls expression of numerous genes including FGF19 and regulates various processes in the small intestine and liver, with protection of the liver against detrimental effects of bile salt overload [[3]Schaap F.G. Trauner M. Jansen P.L. Bile acid receptors as targets for drug development.Nat Rev Gastroenterol Hepatol. 2014; 11: 55-67Crossref PubMed Scopus (481) Google Scholar]. After secretion into the portal circulation, FGF19 reaches the liver, where it binds to a hepatocytic cell surface receptor (FGF Receptor 4). In the hepatocyte, FGF19 signaling acts in accord with the transcriptional repressor SHP to downregulate expression of a key enzyme related to the conversion of cholesterol into bile salts, thus providing negative feedback control of bile salt synthesis [[3]Schaap F.G. Trauner M. Jansen P.L. Bile acid receptors as targets for drug development.Nat Rev Gastroenterol Hepatol. 2014; 11: 55-67Crossref PubMed Scopus (481) Google Scholar]. FGF19 has also been implicated in the regulation of energy and lipid metabolism, compensatory liver growth and possibly (by counteracting NF-κB signaling) control of inflammation [3Schaap F.G. Trauner M. Jansen P.L. Bile acid receptors as targets for drug development.Nat Rev Gastroenterol Hepatol. 2014; 11: 55-67Crossref PubMed Scopus (481) Google Scholar, 4Drafahl K.A. McAndrew C.W. Meyer A.N. Haas M. Donoghue D.J. The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling.PLoS One. 2010; 5: e14412Crossref PubMed Scopus (48) Google Scholar]. Studies in mice revealed that FGF19 – or constitutive ileal FXR activation – protects against cholestatic liver injury induced by bile duct ligation [[5]Modica S. Petruzzelli M. Bellafante E. Murzilli S. Salvatore L. Celli N. et al.Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis.Gastroenterology. 2012; 142: 355-365Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar]. Given the plethora of effects of the FXR-FGF19 axis on processes disturbed in IFALD, it is conceivable that dysfunction of this axis may contribute to the pathogenesis of IFALD. This notion is supported by observations in piglets receiving total PN, where enteral administration of bile salts prevented intestinal atrophy and cholestatic liver injury [[6]Jain A.K. Stoll B. Burrin D.G. Holst J.J. Moore D.D. Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G218-G224Crossref PubMed Scopus (85) Google Scholar]. To explore potential dysfunction of the FXR-FGF19 axis, Mutanen et al. retrospectively studied 52 pediatric patients with IFALD due to short bowel syndrome (69%) or dysmotility disorders (31%) [[2]Mutanen A. Lohi J. Heikkila P. Jalanko H. Pakarinen M.P. 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: 1391-1397Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. Fifty percent of these patients had residual ileum. Serum FGF19 levels were lower (∼3-fold) in IFALD patients than in age- and sex-matched controls, and were particularly low in cases of ileal resection, portal inflammation or fibrosis. Furthermore, serum levels of inflammatory cytokines, TNFα and IL-6, were elevated in patients with IFALD. At histological examination of liver biopsies (available in 39 patients), fibrosis was present in 62%, steatosis in 46%, portal inflammation in 18% and cholestasis in 13%. Serum FGF19 levels were negatively associated with the grade of portal inflammation and METAVIR fibrosis stage, serum TNFα and IL-6, as well as serum cholesterol precursors. Although levels of a serum marker for bile salt synthesis (e.g. 7α-hydroxy-4-cholesten-3-on) were not determined, these data suggest that bile salt synthesis is elevated in patients with low serum FGF19 and that this is accompanied by compensatory cholesterol neo-synthesis to replenish the bile salt precursor pool. De-repression of bile salt synthesis due to lowered FGF19 levels, combined with inflammation/PN-related lowering of the hepatocytic canalicular bile salt transporter ABC-B11 (i.e. "bile salt export pump") may result in intra-hepatocytic bile salt accumulation and cholestatic liver injury. Although a causal role of FGF19 in the histological abnormalities in IFALD cannot be inferred from the study of Mutanen et al. [[2]Mutanen A. Lohi J. Heikkila P. Jalanko H. Pakarinen M.P. 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: 1391-1397Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar], it is conceivable that partial loss of the ileum, and accordingly impaired activity of the FXR–FGF19 axis, may contribute to progressive liver disease. Future animal experiments in Fgf15- or intestine-specific Fxr knockout mice subject to an IFALD-inducing protocol may shed light on a potential initiating or contributory role of the FXR–FGF19 axis. Such insights may also provide a rationale for pharmacological intervention. The findings of Mutanen et al. come at a time in which FXR is drawing much attention from hepatologists worldwide. For some time, gut microbiota have been appreciated as key determinants of intestinal inflammation and impaired intestinal barrier function, and FXR has recently been implicated in the prevention of intestinal bacterial overgrowth, maintenance of intestinal barrier integrity [[7]Inagaki T. Moschetta A. Lee Y.K. Peng L. Zhao G. Downes M. et al.Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor.Proc Natl Acad Sci U S A. 2006; 103: 3920-3925Crossref PubMed Scopus (836) Google Scholar] and pathogenesis of Crohn's disease [8Vavassori P. Mencarelli A. Renga B. Distrutti E. Fiorucci S. The bile acid receptor FXR is a modulator of intestinal innate immunity.J Immunol. 2009; 183: 6251-6261Crossref PubMed Scopus (418) Google Scholar, 9Nijmeijer R.M. Gadaleta R.M. van Mil S.W. van Bodegraven A.A. Crusius J.B. Dijkstra G. et al.Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease.PLoS One. 2011; 6: e23745Crossref PubMed Scopus (101) Google Scholar, 10Gadaleta R.M. van Erpecum K.J. Oldenburg B. Willemsen E.C. Renooij W. Murzilli S. et al.Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease.Gut. 2011; 60: 463-472Crossref PubMed Scopus (522) Google Scholar]. Accumulating evidence indicates that the gut microbiota and the "gut–liver axis" are also playing a key role in chronic inflammatory disease of the liver [[11]Chassaing B. Etienne-Mesmin L. Gewirtz A.T. Microbiota-liver axis in hepatic disease.Hepatology. 2014; 59: 328-339Crossref PubMed Scopus (254) Google Scholar] (Fig. 1). In mice with global deficiency of Fxr, restored intestinal FXR expression is sufficient to maintain bile salt homeostasis through the FGF15 axis and to prevent hepatic inflammation and progressive liver disease with hepatocellular carcinoma [[12]Degirolamo C. Modica S. Vacca M. Di T.G. Morgano A. D'Orazio A. et al.Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation.Hepatology. 2015; 61: 161-170Crossref PubMed Scopus (90) Google Scholar]. Apart from preventing derangement of bile salt homeostasis, restored intestinal barrier function and anti-inflammatory effects through inhibition of NF-κB are likely to be involved in these beneficial effects [4Drafahl K.A. McAndrew C.W. Meyer A.N. Haas M. Donoghue D.J. The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling.PLoS One. 2010; 5: e14412Crossref PubMed Scopus (48) Google Scholar, 13Wang Y.D. Chen W.D. Wang M. Yu D. Forman B.M. Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response.Hepatology. 2008; 48: 1632-1643Crossref PubMed Scopus (464) Google Scholar]. Potentially relevant for the work of Mutanen et al. [[2]Mutanen A. Lohi J. Heikkila P. Jalanko H. Pakarinen M.P. 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: 1391-1397Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar], both intestinal compromise (mimicked by oral administration of the bowel irritant dextran sodium sulphate) and intravenous PN administration are required to induce cholestatic liver injury in a novel mouse model of IFALD [[14]El Kasmi K.C. Anderson A.L. Devereaux M.W. Vue P.M. Zhang W. Setchell K.D. et al.Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease.Sci Transl Med. 2013; 5: 206ra137Crossref PubMed Scopus (154) Google Scholar]. Key features of this model are increased intestinal permeability, elevation of portal lipopolysaccharide levels, Kupffer cell activation and transcriptional repression of hepatobiliary transporters. Of note, in this model, liver injury could be prevented by fish oil-based PN, and could be provoked by addition of stigmasterol to the fish oil-based PN. Stigmasterol is a plant sterol in soybean oil-based PN that can act as an FXR antagonist [[15]Carter B.A. Taylor O.A. Prendergast D.R. Zimmerman T.L. Von F.R. Moore D.D. et al.Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR.Pediatr Res. 2007; 62: 301-306Crossref PubMed Scopus (229) Google Scholar]. FXR controls a number of processes that are deranged in the multifactorial origin of IFALD. Thus, the presumed impairment of bile salt signaling in IFALD may be prone to stimulation with FXR agonists in patients with residual ileum. In recently published randomized controlled trials, the FXR agonist 6-ethyl-chenodeoxycholic acid (Obeticholic acid®) improved biochemical parameters in primary biliary cirrhosis patients with inadequate response to ursodeoxycholic acid alone [[16]Hirschfield G.M. Mason A. Luketic V. Lindor K. Gordon S. Mayo M. et al.Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid.Gastroenterology. 2015; 148: 751-761Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar], and led to markedly improved liver histology in patients with non-alcoholic steatohepatitis [[17]Neuschwander-Tetri B.A. Loomba R. Sanyal A.J. Lavine J.E. Van Natta M.L. Abdelmalek M.F. et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965Abstract Full Text Full Text PDF PubMed Scopus (1591) Google Scholar]. In fact, the FDA has just granted "Breakthrough Designation" for Obeticholic acid® for the treatment of non-alcoholic steatohepatitis with liver fibrosis. "Breakthrough Designation" is a relatively new scheme that is intended to streamline drug development for highly promising agents and is awarded to a drug in relation to a serious or life-threatening disease based on preliminary clinical evidence which suggests substantial improvement over existing therapies [[18]Sherman R.E. Li J. Shapley S. Robb M. Woodcock J. Expediting drug development–the FDA's new "breakthrough therapy" designation.N Engl J Med. 2013; 369: 1877-1880Crossref PubMed Scopus (108) Google Scholar]. Nevertheless, a word of caution should be given here, in the sense that these studies (inherent to their short-term follow-up design) did not reveal improvement of hard clinical endpoints. Also, there was a deterioration of the serum lipid profile during Obeticholic acid®, in part due to the inhibition of cholesterol conversion into bile salts. Obviously, cardiovascular rather than liver disease is the major cause of morbidity and mortality in non-alcoholic steatohepatitis. Returning to the study of Mutanen et al. [[2]Mutanen A. Lohi J. Heikkila P. Jalanko H. Pakarinen M.P. 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: 1391-1397Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar], the merit of this study is that in a relatively large number of patients with this rare disease, low serum FGF19 are clearly established. The reported negative correlations between serum FGF19 and length of resected ileum as well as severity of the liver disease do not prove causality but could very well be secondary to altered enterohepatic circulation of bile salts. Likewise, it is conceivable that reduced intestinal FXR activation is an important player in IFALD pathogenesis, considering its key role in intestinal permeability. In conclusion, the study of Mutanen et al. [[2]Mutanen A. Lohi J. Heikkila P. Jalanko H. Pakarinen M.P. 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: 1391-1397Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar] should stimulate further research to elucidate the role of the FXR-FGF19 axis in IFALD, before any therapeutic trials with FGF19 can be considered [[19]Luo J. Ko B. Elliott M. Zhou M. Lindhout D.A. Phung V. et al.A nontumorigenic variant of FGF19 treats cholestatic liver diseases.Sci Transl Med. 2014; 6: 247ra100Crossref PubMed Scopus (126) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this editorial.