Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.

BACKGROUND: The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) ("fibrotic NASH") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. AIM: To develop a new blood test specifically dedicated for this new diagnostic target of interest. METHODS: Eight Hundred and forty-six biopsy-proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. RESULTS: The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK-3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut-offs were calculated. In the validation set, MACK-3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut-offs (36.0% of the patients), MACK-3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well-classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. CONCLUSION: The new blood test MACK-3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved.

ER stress induces NLRP3 inflammasome activation and hepatocyte death.

The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1ß secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1ß secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

Treatment of hepatocellular carcinomas by thermal ablation and hepatic transarterial chemoembolization.

Local tumor recurrence after thermal ablation of hepatocellular carcinoma (HCC) can impact on overall survival and are very closely linked to partial treatment of the primary lesion or to potential microvascular invasion or satellite micronodules located close to the main lesion. The diagnosis of these liver metastases close to the primary lesion on CT and MRI is difficult and their incidence, number and spread throughout the liver correlates with diameter of primary tumor. Tumor diameter is currently the key factor to predict whether or not thermal ablation of HCC will be complete or not. It has now been shown for monopolar radiofrequency ablation that this therapy alone is sufficient to effectively treat single HCCs<3cm in diameter provided that liver micrometastases are not present. If the HCC is>3cm in size, multifocal or in the case of tumor recurrence, overall survival and recurrence-free survival results are better if monopolar radiofrequency ablation is combined with hepatic trans-arterial chemoembolization. The timing of this combination of treatments probably influences its effectiveness on tumor and tolerability and remains to be assessed.

Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation.

OBJECTIVE: To determine the role of colonic barrier defects and low-grade inflammation in irritable bowel syndrome (IBS)-like symptoms in quiescent inflammatory bowel disease (IBD). DESIGN: Caecal biopsies were collected from 51 IBS, 49 quiescent IBD (31 Crohn's disease (CD) and 18 ulcerative colitis (UC)) patients and 27 controls. IBS was assessed using the Rome III criteria and the IBS severity score. Epithelial barrier integrity was evaluated by determining the paracellular permeability of biopsies mounted in Ussing chambers and the mRNA expression of tight junction proteins (ZO-1, α-catenin and occludin). Low-grade inflammation was evaluated by counting cells, including intraepithelial lymphocytes (IELs), eosinophils and mast cells, and by determining the mRNA and protein expression of tumour necrosis factor (TNF)-α in biopsies and culture supernatants. RESULTS: IBS-like symptoms were present in 35.4 and 38% of CD and UC patients, respectively. Paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms (p<0.01, respectively) or controls (p<0.01, respectively). Significantly lower expression of ZO-1 and α-catenin was detected in IBS and quiescent IBD with IBS-like symptoms. IELs and TNF-α were significantly increased in quiescent IBD with IBS-like symptoms, but not in IBS. CONCLUSIONS: In quiescent IBD, IBS-like symptoms related to persistent subclinical inflammation associated with increased colonic paracellular permeability. A persistent increase in TNF-α in colonic mucosa may contribute to the epithelial barrier defects associated with abdominal pain in quiescent IBD, but not in IBS. Optimisation of anti-inflammatory therapy may be considered in quiescent IBD with IBS-like symptoms.

Evolution of low-grade systemic inflammation, insulin resistance, anthropometrics, resting energy expenditure and metabolic syndrome after bariatric surgery: a comparative study between gastric bypass and sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) for morbid obesity is gaining in popularity as it offers several advantages over laparoscopic Roux-en-Y gastric bypass (LRYGBP), but comparative data between these two procedures have rarely been reported. METHODS: This case control study compared the incidence of low-grade systemic inflammation, insulin resistance, anthropometrics, resting energy expenditure and metabolic syndrome in 30 patients undergoing LRYGBP and 30 patients undergoing LSG, matched for age, sex, body mass index (BMI), and glycosylated hemoglobin (HbA1c). RESULTS: At 1-year after surgery, the percent of excess weight loss was 67.8 ± 20.9 for LRYGBP and 61.6 ± 19.4 for LSG. Patients undergoing LRYGBP showed significantly lower plasma levels of C-reactive protein (3.3 ± 2.7 mg/dL vs. 5.3 ± 3.9 mg/dL; P < 0.05), waist circumference (97.4 ± 16.0 vs. 105.5 ± 14.7 cm; P < 0.05), total cholesterol (4.6 ± 1.0 vs. 5.7 ± 0.9 mmol/L; P < 0.01) and LDL cholesterol (2.6 ± 0.8 vs. 3.6 ± 0.8 mmol/L; P < 0.01). Insulin resistance (HOMA index 1.6 ± 1.0 after LRYGBP vs. 2.3 ± 2.4 after LSG), resting energy expenditure (1666.7 ± 320.5 after LRYGBP vs. 1600.4 ± 427.3 Kcal after LSG) and remission of metabolic syndrome (92.9% after LRYGBP vs. 80% after LSG) were not different between the two groups. CONCLUSION: In this study, patients undergoing LRYGBP demonstrated significantly improved lipid profiles, decreased systemic low-grade inflammation compared with those undergoing LSG at 1-year follow-up.

First case report of an acute genotype 3 hepatitis E infected pregnant woman living in South-Eastern France.

In European countries, epidemiology of hepatitis E virus (HEV) infection is not well known. Although, seroprevalence of HEV Immunoglobulin G reached a few percent in European women, no acute hepatitis E during pregnancy has been described so far. Here, we report a case of an autochthonous HEV genotype 3 infection in a 41-years-old pregnant woman living in a non-endemic country. The acute hepatitis had a spontaneous good outcome for the mother and the child. In non-endemic areas where Hepatitis E infections are emerging, unexplained cytolysis, whatever its level, in a pregnant woman could be investigated for HEV, using biological molecular and serology tools.

Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells.

OBJECTIVES: Recent evidence suggests a role for increased colonic permeability and mucosal mast cell (MC) mediators on symptoms related to the irritable bowel syndrome (IBS). Whether allergic factors (AFs) are involved in the pathophysiology of IBS is unclear. We addressed the question of the possible influence of an allergic background on IBS symptoms. METHODS: We assessed paracellular permeability, mucosal MCs counts, and spontaneous release of tryptase of colonic biopsy specimens in 34 IBS patients and 15 healthy subjects. The severity of IBS was assessed through self-reported questionnaires. All individuals were tested for the presence of AF, including self-perception of adverse reaction to food, personal and familial history of atopic disease, elevated total or specific immunoglobulin E against food/inhalant antigens, blood eosinophilia, and skin tests. RESULTS: IBS patients had significant enhanced colonic permeability, higher number of MCs, and spontaneous release of tryptase than healthy subjects. The severity of IBS was significantly correlated with colonic permeability (r=0.48, P=0.004), MCs counts (r=0.36, P=0.03), and tryptase (r=0.48, P=0.01). In 13 IBS patients (38.2%) having at least three AFs, symptoms scores, colonic permeability, MCs counts, and tryptase release by colonic biopsies were significantly higher than in those with less than three AFs. IBS patients with at least three AFs were more prone to diarrhea or alternating symptoms. None AF was found to be predictive of IBS severity. CONCLUSIONS: In IBS patients, the presence of an allergic background correlates with a more severe disease and diarrhea predominance, possibly by enhancing mucosal MC activation and paracellular permeability.

Plasma carnitine is associated with fatigue in chronic hepatitis C but not in the irritable bowel syndrome.

BACKGROUND: Fatigue is an important determinant of altered quality of life in patients affected by chronic hepatitis C or the irritable bowel syndrome (IBS). AIM: In this study, we aimed at determining the contributory role of plasma levels of leptin and carnitine on fatigue in chronic hepatitis C and IBS. METHODS: We enrolled 81 patients with chronic hepatitis C, 42 with IBS and 44 healthy subjects. Fatigue was evaluated using the Fatigue Impact Scale questionnaire. Body composition was assessed through impedance analysis. Plasma carnitine and leptin were measured. RESULTS: Fatigue scores were significantly more elevated in patients with chronic hepatitis C and IBS than in healthy subjects. Patients with chronic hepatitis C but not IBS, had significant lower plasma levels of total and free carnitine adjusted for fat mass compared with healthy subjects. In patients with chronic hepatitis C and not with IBS, fatigue scores were negatively correlated with plasma levels of carnitine. Levels of free carnitine were significantly and independently associated with the severity of fatigue in patients with chronic hepatitis C [OR=2.019, P=0.02, CI 95% (1.01-1.23)]. CONCLUSIONS: In patients with chronic hepatitis C, the severity of fatigue is associated with a low level of carnitine, suggesting that an oral supplementation may be effective to relieve fatigue in chronic hepatitis C. The underlying mechanism of fatigue in IBS does not seem to involve carnitine.

[Splenic artery aneurysm: diagnosis and endovascular therapy]. / Anévrisme de l'artère splénique: diagnostic et thérapeutique endovasculaire.

Splenic artery aneurysms are now diagnosed more frequently thanks to the increase and improvement in different imaging techniques. In case of rupture they are potentially life threatening and thus in certain cases may require appropriate preventive treatment. This treatment should be offered to patients with suspected pseudoaneurysms, with an aneurysm larger than 20mm in diameter, or which is progressing. The development of interventional endovascular radiology has provided new therapeutic options for the management of aneurysms, by excluding the sac from the arterial circulation with coil embolisation or with a covered stent. The success rate of these treatments is between 75 and 100% with significantly less morbidity and mortality than with surgical techniques.

A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients.

BACKGROUND: Non-invasive approaches are useful to differentiate simple steatosis from non-alcoholic steatohepatitis (NASH) in obese and morbidly obese patients. AIM: To develop a new scoring system to diagnose definitive NASH. METHODS: Preoperative clinical and biological data including serum caspase 3-generated cytokeratin-18 fragments (CK18) and surgical liver biopsies were obtained from 464 morbidly obese patients who had undergone bariatric surgery. The cohort was divided into two groups: training group (n = 310) and validation group (n = 154). Definitive NASH was defined according to Kleiner's classification with a Non-alcoholic fatty liver disease Activity Score (NAS) ≥5. RESULTS: Alanine aminotransferase (ALT), CK18 fragments and the presence of metabolic syndrome were independent predictors for discriminating patients with NAS ≥5 in the training group. These three parameters were used to carry out a scoring system for the prediction of NAS ≥5. Whereas serum CK18 fragment alone had an area under the receiver operating characteristic (AUROC) curve = 0.74, AUROC curves of the scoring system were 0.88 and 0.83 in the training group and the validation group, respectively. CONCLUSION: A simple and non-invasive composite model (the Nice Model) including metabolic syndrome, ALT and CK18 fragments is able to predict accurately a non-alcoholic fatty liver disease activity score ≥5 in morbidly obese subjects.

Predictive factors of bleeding related to post-banding ulcer following endoscopic variceal ligation in cirrhotic patients: a case-control study.

BACKGROUND: Life-threatening bleeding caused by early spontaneous slippage of rubber bands has been described after variceal ligation in cirrhotic patients. AIM: To determine the predictive factors of this complication in cirrhotic patients. METHODS: Among 605 patients, 21 patients (mean age 56.6 +/- 13.5 years) developed 23 spontaneous band slippages with bleeding on post banding ulcer, as confirmed by endoscopy. Cirrhosis was alcoholic in 13 patients (62%), post viral hepatitis in three (14%) and from other causes in five (24%). A case-control study was performed comparing 17 from these patients who presented the complication after a first ligation with 84 of the 584 controls who underwent first endoscopic variceal ligation without bleeding complication. RESULTS: Bleeding occurred 13.5 days +/- 7.3 (2-29) following ligation. Eleven patients died following the bleeding complication (52%). Using a multivariate analysis, previous upper variceal digestive bleeding [OR 12.07, 95%CI (2.3-63.43)], peptic oesophagitis [OR 8.9, 95%CI (1.65-47.8)], high platelet ratio index (APRI) score [OR 1.54, 95%CI (1.11-2.16)] and low prothrombin index [OR 0.54, 95% CI (0.31-0.94)] were independent predictive factors of bleeding. CONCLUSIONS: Bleeding related to post-banding ulcer is a rare, but severe complication. The proposed predictive factors should be looked for and minimized before variceal ligation.