Karel J. van Erpecum

Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease

Background & aims Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models. Methods Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types. Results INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor α secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD. Conclusions FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD.

Improved Prognosis of Patients With Primary Biliary Cirrhosis That Have a Biochemical Response to Ursodeoxycholic Acid

BACKGROUND & AIMS Ursodeoxycholic acid (UDCA) improves laboratory liver test results in patients with primary biliary cirrhosis (PBC). Few studies have assessed the prognostic significance of biochemical data collected following UDCA treatment. We performed a prospective multicenter study of patients with PBC treated with UDCA to compare prognosis with biochemical response. METHODS PBC was classified as early (pretreatment bilirubin and albumin levels normal), moderately advanced (one level abnormal), or advanced (both levels abnormal). Biochemical response was defined as proposed by Pares (decrease in alkaline phosphatase [ALP] level>40% of baseline level or normal level), Corpechot (ALP level<3-fold the upper limit of normal [ULN], aspartate aminotransferase level<2-fold the ULN, bilirubin level<1-fold the ULN), and our group (Rotterdam; normalization of abnormal bilirubin and/or albumin levels). RESULTS The study included 375 patients, and median follow-up time was 9.7 (range, 1.0-17.3) years. The prognosis for early PBC was comparable with that of the Dutch population and better than predicted by the Mayo risk score. Survival of responders was better than that of nonresponders, according to Corpechot and Rotterdam criteria (P<.001). Prognosis of early PBC was comparable for responders and nonresponders; prognosis of responders was significantly better in those with (moderately) advanced disease. CONCLUSIONS Prognosis for UDCA-treated patients with early PBC is comparable to that of the general population. Survival of those with advanced PBC with biochemical response to UDCA is significantly better than for nonresponders. Thus, UDCA may be of benefit irrespective of the stage of disease. Prognostic information, based on bilirubin and albumin levels, is superior to that provided by ALP levels.

Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

BACKGROUND & AIMS Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons. METHODS Cytosolic free calcium ([Ca(2+)](i)) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca(2+)](i)-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device. RESULTS Transient increases in neuronal [Ca(2+)](i) induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca(2+)](i) agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P < .0001) and cholestatic patients with versus without pruritus (P < .0001). Autotaxin activity correlated with intensity of pruritus (P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or mu-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal. CONCLUSIONS We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.

Early endoscopic retrograde cholangiopancreatography versus conservative management in acute biliary pancreatitis without cholangitis: a meta-analysis of randomized trials

Background:Early endoscopic retrograde cholangiopancreatography (ERCP) should be performed in all patients with acute biliary pancreatitis (ABP) and coexisting acute cholangitis. In patients without cholangitis and predicted mild ABP it is generally accepted that early ERCP should not be performed. Nevertheless, there is a controversy regarding the role of early ERCP in the treatment of patients with predicted severe ABP without cholangitis. We reviewed randomized trials on early ERCP versus conservative management in patients with ABP without acute cholangitis. Methods:Relevant publications in 3 electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) were systematically reviewed and meta-analyzed. Results:Seven randomized trials on ERCP in acute pancreatitis were found, of which 3 including a total of 450 patients (230 in the invasive arm and 220 in the control arm) qualified for a meta-analysis according to predefined criteria. In all patients with ABP (predicted mild and severe), early ERCP was associated with a nonsignificant reduction in overall complications [risk ratio (RR) 0.76; 95% confidence interval (CI) 0.41–1.04; P = 0.38] and a nonsignificant increase in mortality (RR 1.13; 95% CI 0.23–5.63; P = 0.88). Subgroup analysis based on predicted severity did not affect these outcomes (overall complications: predicted mild: RR 0.86; 95% CI 0.62–1.19; P = 0.36; predicted severe: RR 0.82; 95% CI 0.32–2.10; P = 0.68; mortality: predicted mild: RR 1.90; 95% CI 0.25–14.55; P = 0.53; predicted severe: RR 1.28; 95% CI 0.20–8.06; P = 0.80). Conclusion:In this meta-analysis, early ERCP in patients with predicted mild and predicted severe ABP without acute cholangitis did not lead to a significant reduction in the risk of overall complications and mortality.

Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions†‡

Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkins disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values. Conclusion: Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR‐dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis. (HEPATOLOGY 2012)

Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

BACKGROUND & AIMS Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.

Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis

Objectives:To determine the relation between intestinal barrier dysfunction, bacterial translocation, and clinical outcome in patients with predicted severe acute pancreatitis and the influence of probiotics on these processes. Summary of Background data:Randomized, placebo-controlled, multicenter trial on probiotic prophylaxis (Ecologic 641) in patients with predicted severe acute pancreatitis (PROPATRIA). Methods:Excretion of intestinal fatty acid binding protein (IFABP, a parameter for enterocyte damage), recovery of polyethylene glycols (PEGs, a parameter for intestinal permeability), and excretion of nitric oxide (NOx, a parameter for bacterial translocation) were assessed in urine of 141 patients collected 24 to 48 h after start of probiotic or placebo treatment and 7 days thereafter. Results:IFABP concentrations in the first 72 hours were higher in patients who developed bacteremia (P = 0.03), infected necrosis (P = 0.01), and organ failure (P = 0.008). PEG recovery was higher in patients who developed bacteremia (PEG 4000, P = 0.001), organ failure (PEG 4000, P < 0.0001), or died (PEG 4000, P = 0.009). Probiotic prophylaxis was associated with an increase in IFABP (median 362 vs. 199 pg/mL; P = 0.02), most evidently in patients with organ failure (P = 0.001), and did not influence intestinal permeability. Overall, probiotics decreased NOx (P = 0.05) but, in patients with organ failure, increased NOx (P = 0.001). Conclusions:Bacteremia, infected necrosis, organ failure, and mortality were all associated with intestinal barrier dysfunction early in the course of acute pancreatitis. Overall, prophylaxis with this specific combination of probiotic strains reduced bacterial translocation, but was associated with increased bacterial translocation and enterocyte damage in patients with organ failure.

Nasobiliary drainage induces long‐lasting remission in benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by episodic cholestasis and pruritus without anatomical obstruction. Effective medical treatment is not available. We report complete and long‐lasting disappearance of pruritus and normalization of serum bile salt concentrations in cholestatic BRIC patients within 24 hours after endoscopic nasobiliary drainage (NBD). Relative amounts of phospholipids and bile salts in bile collected during NBD appeared to be normal, but phospholipids other than phosphatidylcholine (especially sphingomyelin) were increased. In conclusion, we propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic BRIC patients. (HEPATOLOGY 2006;43:51–53.)

Small Gallstones Are Associated with Increased Risk of Acute Pancreatitis: Potential Benefits of Prophylactic Cholecystectomy?

OBJECTIVES:Pancreatitis is a severe complication of gallstone disease with considerable mortality. Small gallstones may increase the risk of pancreatitis. Our aims were to evaluate potential association of small stones with pancreatitis and potential beneficial effects of prophylactic cholecystectomy.METHODS:Stone characteristics were determined in patients with biliary pancreatitis (115), obstructive jaundice due to gallstones (103), acute cholecystitis (79), or uncomplicated gallstone disease (231). Sizes and numbers of gallbladder and bile duct stones were determined by ultrasonography and endoscopic retrograde cholangiopancreatography, respectively. Effects of prophylactic cholecystectomy were assessed by decision analyses with a Markov model and Monte Carlo simulations.RESULTS:Patients with pancreatitis or obstructive jaundice had more and smaller gallbladder stones than those with acute cholecystitis or uncomplicated disease (diameters of smallest stones: 3 ± 1, 4 ± 1, 8 ± 1, and 9 ± 1 mm, respectively, p < 0.01). Bile duct stones were smaller in case of pancreatitis than in obstructive jaundice (diameters of smallest stones: 4 ± 1 vs 8 ± 1, p < 0.01). Multivariate analysis identified old age and small stones as independent risk factors for pancreatitis. Decision analysis in a representative group of patients with small (≤5 mm) gallstones (5,000 patients, 67% females, 45 yr old, 10-yr follow-up) indicates that life-years may be gained or lost by cholecystectomy, depending on incidence and mortality of pancreatitis.CONCLUSIONS:Small gallstones are associated with pancreatitis. Prophylactic cholecystectomy may lead to gain or loss of life-years in patients with small stones, depending on incidence and mortality of pancreatitis.

Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease

Background: Primary sclerosing cholangitis (PSC) is strongly associated with inflammatory bowel disease (IBD). The aim of this study was to assess the IBD phenotype associated with PSC in a large well‐phenotyped population‐based PSC cohort using endoscopic and histopathologic criteria. Methods: PSC cases were identified and ascertained, fulfilling well‐established criteria, in 39 hospitals in a geographically defined region of The Netherlands. IBD location was recorded according to the Montreal Classification. As this classification does not consider segmental inflammation, backwash ileitis, or rectal sparing, an additional subgroup analysis was performed in 80 cases and 80 age‐ and sex‐matched IBD controls, reviewing all endoscopy and pathology reports filed between 2000 and 2010. Results: In all, 380 (66%) of a total of 579 PSC patients had coexistent IBD, mainly ulcerative colitis (UC) (75%). Overall, 207 (83%) of the PSC‐UC patients had a pancolitis, 32 (13%) a left‐sided colitis, and 9 (4%) a proctitis only. Seventy (95%) PSC‐Crohns disease (CD) patients had an (ileo)colitis and four (5%) ileitis only. In the subgroup analysis 53 (66%) PSC‐UC patients were identified, 24 (30%) PSC‐CD patients, and three (4%) PSC‐IBD‐U patients. Fifty (94%) PSC‐UC patients had a pancolitis, compared with 32 (62%) matched UC patients (P < 0.001). Left‐sided colitis was seen in 16 (31%) UC controls and in one PSC‐UC patient (P < 0.001). Backwash ileitis and rectal sparing were rare findings (<10%) in the cohorts under study. Conclusions: IBD in PSC patients represents a distinct phenotype in that pancolitis is observed in 94% of PSC‐UC and colitis in 96% of PSC‐CD patients. Backwash ileitis and rectal sparing were rare findings in the PSC‐UC patients. (Inflamm Bowel Dis 2012;)