Dine Koriche

Pre-operative management is associated with low rate of post-operative morbidity in penetrating Crohn?s disease

Aliment Pharmacol Ther 2010; 32: 459–465

Relevance of the ISGLS definition of posthepatectomy liver failure in early prediction of poor outcome after liver resection: study on 680 hepatectomies.

Objective:To assess the relevance of the International Study Group of Liver Surgery (ISGLS) definition of posthepatectomy liver failure compared with 2 well-established criteria, 50–50 and PeakBili >7, as early predictors of posthepatectomy outcome. Background:There is limited data on the postoperative use of ISGLS definition of posthepatectomy liver failure as early predictor of outcome. Methods:Between 2007 and 2012, a total of 680 hepatectomies were analyzed from a prospective database. The value of each definition for prediction of 3-month major complications (Clavien III–V) and mortality was assessed either within 10 days of surgery or on postoperative day 5. Results:Three-month major morbidity and mortality rates were 16.5% and 4.4%, respectively. Within 10 days, 79 patients fulfilled ISGLS definition compared with 24 for 50–50 and 44 for PeakBili >7 criteria. Sensitivities of ISGLS definition and 50–50 and PeakBili >7 criteria for prediction of major morbidity and mortality were 35.8, 17.4, 24.8% and 56.7, 36.7, 56.7%, respectively. Patients with no positive score had a risk of death or major complication below 5% and 15%, respectively. In patients with a positive score, the ISGLS definition was the least relevant to predict major complications and mortality (positive predictive values of 49.4% and 21.8% vs 79.2% and 47.8% for 50–50 and 61.4% and 40.5% for PeakBili >7 criteria). The relative risk of death was 6.9 (95% confidence interval, 3.1–15.4) if the ISGLS definition was evaluated on postoperative day 5 versus 21.1 (95% confidence interval, 7.7–57.7) for 50–50 and 21.7 (95% confidence interval, 7.4–63.3) for PeakBili >7 criteria. Conclusions:ISGLS definition was less discriminatory than 50–50 and PeakBili >7 criteria in identifying patients at risk of posthepatectomy major complications or death.

Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

The glucagon-like peptide 2 (GLP-2) is an intestinotrophic hormone with growth promoting and anti-inflammatory actions. However, the full biological functions of GLP-2 and the localization of its receptor (GLP-2R) remain controversial. Among cell lines tested, the expression of GLP-2R transcript was detected in human colonic myofibroblasts (CCD-18Co) and in primary culture of rat enteric nervous system but not in intestinal epithelial cell lines, lymphocytes, monocytes, or endothelial cells. Surprisingly, GLP-2R was expressed in murine (GLUTag), but not human (NCI-H716) enteroendocrine cells. The screening of GLP-2R mRNA in mice organs revealed an increasing gradient of GLP-2R toward the distal gut. An unexpected expression was detected in the mesenteric fat, mesenteric lymph nodes, bladder, spleen, and liver, particularly in hepatocytes. In two mice models of trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis, the colonic expression of GLP-2R mRNA was decreased by 60% compared with control mice. Also, GLP-2R mRNA was significantly downregulated in intestinal tissues of inflammatory bowel disease patients. Therapeutically, GLP-2 showed a weak restorative effect on intestinal inflammation during TNBS-induced colitis as assessed by macroscopic score and inflammatory markers. Finally, GLP-2 treatment accelerated mouse liver regeneration following partial hepatectomy as assessed by histological and molecular analyses. In conclusion, the limited therapeutic effect of GLP-2 on colonic inflammation dampens its utility in the management of severe inflammatory intestinal disorders. However, the role of GLP-2 in liver regeneration is a novelty that might introduce GLP-2 into the management of liver diseases and emphasizes on the importance of elucidating other extraintestinal functions of GLP-2.

Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis

Background and aims Immune tolerance breakdown during UC involves the peroxisome proliferator-activated receptor-γ (PPARγ), a key factor in mucosal homoeostasis and the therapeutic target of 5-aminosalycilates, which expression is impaired during UC. Here we assess the impact of glucocorticoids (GCs) on PPARγ expression, focusing especially on extra-adrenal cortisol production by colonic epithelial cells (CECs). Methods Activation of PPARγ in the colon was evaluated using transgenic mice for the luciferase gene under PPAR control (peroxisome proliferator response element-luciferase mice). Protein and mRNA expression of PPARγ were evaluated with colon fragments and purified CEC from mice. Cortisol production and steroidogenic factor expression were quantified in human CEC of patients with UC and those of controls. Gene expression knockdown by short hairpin RNA in Caco-2 cells was used for functional studies. Results GCs were able to raise luciferase activity in peroxisome proliferator response element-luciferase mice. In the mice colons and Caco-2 cells, PPARγ expression was increased either with GCs or with an inducer of steroidogenesis and then decreased after treatment with a steroidogenesis inhibitor. Cortisol production and steroidogenic factor expression, such as liver receptor homologue-1 (LRH-1), were decreased in CEC isolated from patients with UC, directly correlating with PPARγ impairment. Experiments on Caco-2 cells lacking LRH-1 expression confirmed that LRH-1 controls PPARγ expression by regulating GC synthesis in CEC. Conclusions These results demonstrate cortisol control of PPARγ expression in CEC, highlighting cortisol production deficiency in colonocytes as a key molecular event in the pathophysiology of UC.

Previous Exposure to Multiple Anti-TNF Is Associated with Decreased Efficiency in Preventing Postoperative Crohn’s Disease Recurrence

Background and Aims Infliximab and adalimumab are increasingly used to prevent postoperative recurrence in Crohns disease patients. The impact of previous exposure to one or more anti-tumour necrosis factor [TNF] agents before surgery on the efficacy of anti-TNF therapy on postoperative recurrence is unknown. Methods We performed a retrospective analysis of Crohns disease patients who underwent surgical bowel resection with anastomosis and prophylactic treatment with anti-TNF therapy between January 2005 and June 2013. Results A total of 57 consecutive Crohns disease patients with bowel resection and anastomosis followed by prophylactic treatment with anti-TNF were included; 21 [37%] and 24 [42%] patients had a previous exposure to one and more than one anti-TNF agents, respectively; 39 patients [68%] had a surveillance colonoscopy. Cumulative rates of postoperative endoscopic recurrence at 2 years were 45.5% [26.6-69.6%] in patients exposed to two or more anti-TNFα as compared with 29.1% [11.5-48.1%] in patients exposed to one or to zero anti-TNFα before surgery [p = 0.07]. Cumulative rates of clinical recurrence at 1 year were 21.6% [9.6-44.4%] in patients exposed to two or more anti-TNFα as compared with 6.9% [1.8-25.1%] in patients exposed to zero or one anti-TNFα before surgery [p = 0.02]. Multivariable analysis identified smoking and previous exposure to two or more anti-TNFα as risk factors for Crohns disease clinical or endoscopic postoperative recurrence (hazard ratio [HR] = 3.17; 95% confidence interval [CI]: 1.3-7.8, p = 0.01 and HR = 4.2; 95% CI: 1.8-10.2, p = 0.001, respectively). Conclusions Previous exposure to two or more anti-TNF agents was associated with a higher risk of postoperative recurrence in Crohns disease patients.