[Treatments of non-alcoholic steatohepatitis]. / Traitements de la stéatohépatite non-alcoolique.

Non-alcoholic fatty liver diseases are highly prevalent in Western countries and associated with insulin resitance and metabolic syndrome. Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and hepatocellular ballooning, and may be associated with liver fibrosis leading to cirrhosis and its complications as hepatocarcinoma. The presence of obesity, type 2 diabetes mellitus or increased liver enzymes in patients with metabolic syndrome should prompt non-invasive screening (liver ultrasound, serum markers and/or transient elastography) to predict steatosis, NASH and fibrosis. Structured programmes aimed at lifestyle changes towards healthy diet and habitual physical activity are essential in patients with NASH. Currently, no drug is recognized definitively as efficient therapy in NASH and can be firmly recommended. Several emerging therapies targeting metabolic pathways, inflammation, fibrosis and apoptosis are evaluating in clinical phase II and III studies.

L'hépatopathie dysmétabolique (NAFLD pour nonalcoholic fatty liver disease) est épidémique dans nos sociétés occidentales et étroitement liée à l'insulinorésistance et au syndrome métabolique. La stéatohépatite non alcoolique (NASH) est caractérisée par une inflammation lobulaire et un ballonisation hépatocytaire, parfois associée à de la fibrose conduisant à la cirrhose et ses complications comme le carcinome hépatocellulaire. La présence d'une obésité, d'un diabète de type 2 ou d'altération des tests hépatiques chez un patient ayant un syndrome métabolique devrait justifier un dépistage non invasif de la NAFLD (échographie hépatique, marqueurs sériques, élastographie pulsée) pour mettre en évidence la forme progressive de la maladie. Des programmes structurés visant à des modifications de style de vie (régime adéquat et activité physique quotidienne) restent les pierres angulaires du traitement des patients ayant une NASH. Actuellement, aucun médicament n'a démontré une efficacité définitive dans la NASH. Donc, aucun traitement spécifique ne peut formellement être recommandé. De nombreuses molécules ciblant des voies métaboliques, l'inflammation, la fibrose et l'apoptose sont en cours d'évaluation dans de grandes études cliniques de phase II et III.

Hepatic expression of CCL2 in alcoholic liver disease is associated with disease severity and neutrophil infiltrates.

Serum levels and liver expression of CCL2 are increased in patients with alcoholic hepatitis (AH). In an experimental model of alcoholic liver disease (ALD), CCL2 was implicated in proinflammatory cytokines activation and hepatic lipid metabolism, but its role in human disease is currently unknown. In a large cohort of ALD patients, we analysed plasma levels and liver expression of CCL2 and their association with liver disease severity and histological lesions. We also studied the relationship between -2518 A > G CCL2 and CCR2 190 A/G polymorphisms and severity of ALD. We show that CCL2 plasma levels are increased in ALD patients compared with healthy subjects. AH patients had significantly higher plasma levels and hepatic expression of CCL2 than patients without AH. Plasma levels and hepatic expression of CCL2 were associated with disease severity. CCL2 liver expression was correlated with neutrophil infiltrate and interleukin (IL)-8 expression, but not with steatosis. Moreover, there were more G-allele carriers of -2518 A > G CCL2 polymorphism in severe AH patients than in other ALD patients. Our results demonstrate that CCL2 is increased in ALD, particularly in severe forms, and suggest a role for CCL2 in the pathogenesis of ALD via neutrophil recruitment.

[Management of alcoholic hepatitis]. / Prise en charge de l'hépatite alcoolique aiguë.

Alcoholic hepatitis is a severe form of alcoholic liver disease. Diagnosis is based on the association of new onset of jaundice and a compatible liver biopsy. Alcoholic hepatitis is severe when the Maddrey is up to 32 and, in this case, is associated with a mortality of 40-50% at 2 months. Corticosteroids improve survival of patients suffering from severe alcoholic hepatitis. The decrease of total bilirubin at day 7 of treatment and the Lille score are markers of response to corticosteroids. The absence of response is associated with a dramatic outcome (mortality rate of 75% at 6 months). Liver transplantation could be an alternative in a strictly selected group of non-responders.

[Multidisciplinary management of hepatocellular carcinoma in cirrhotic patients]. / Traitement du carcinome hépato-cellulaire chez le patient cirrhotique: la nécessité d'une approche pluridisciplinaire.

The treatment of hepatocellular carcinoma (HCC) in cirrhotic patients is challenging: the incidence is increasing, the cirrhosis dramatically limits the tolerance to treatment possibilities, there are many therapeutic modalities but resources are limited, namely in the context of organ shortage for transplantation. Liver transplantation (LT) is the optimal treatment as it combines the largest tumor resection possible and the correction of the underlying liver disease. Due to organ shortage however, LT is reserved for early-stages HCC. Surgical resection and radiofrequency destruction represent potentially curative options in highly selected patients. Arterial embolizations, chemo- or radio-embolizations, allow local tumor control but are not curative. These techniques could be performed before surgical resection or LT, to downstage the tumor and/or to control tumor progression while waiting for a graft. Finally, sorafenib is the only systemic treatment which has shown a survival benefit in advanced HCC. The benefit of combination of sorafenib and surgical treatments remains undetermined. The challenge in the management of HCC in cirrhotic patients is to integrate both individual (age, comorbidities, cirrhosis stage, tumor stage, specific contraindications to LT, etc.) and collective variables (expected waiting time before LT) to determine the best therapeutic option for each patient. In this process, multidisciplinarity is a key for success.

Liver transplantation during the COVID-19 epidemic : recommendations from the Belgian Liver Intestine Transplant Committee (BeLIAC).

Since January 2020, the Novel Coronavirus Disease 2019 (COVID-19) pandemic has dramatically impacted the world. In March 2020, the COVID-19 epidemic reached Belgium creating uncertainty towards all aspects of life. There has been an impressive capacity and solidarity of all healthcare professionals to acutely reconvert facilities to treat these patients. In the context of liver transplantation (LTx), concerns are raised about organ donation shortage and safety, the ethics of using limited healthcare resources for LTx, selection criteria for LTx during the epidemic and the risk of de novo COVID-19 infection on the waiting list and after LTx. BeLIAC makes several recommendations to try to mitigate the deleterious effect that this epidemic has/will have on donation and LTx, taking into account the available resources, and trying to maximize patients and healthcare professionals' safety.

Management of liver failure in general intensive care unit.

OBJECTIVE: To produce French guidelines on Management of Liver failure in general Intensive Care Unit (ICU). DESIGN: A consensus committee of 23 experts from the French Society of Anesthesiology and Critical Care Medicine (Société française d'anesthésie et de réanimation, SFAR) and the French Association for the Study of the Liver (Association française pour l'étude du foie, AFEF) was convened. A formal conflict-of-interest (COI) policy was developed at the start of the process and enforced throughout. The entire guideline process was conducted independently of any industrial funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide their assessment of the quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. Some recommendations were ungraded. METHODS: Two fields were defined: acute liver failure (ALF) and cirrhotic patients in general ICU. The panel focused on three questions with respect to ALF: (1) Which etiological examinations should be performed to reduce morbidity and mortality? (2) Which specific treatments should be initiated rapidly to reduce morbidity and mortality? (3) Which symptomatic treatment should be initiated rapidly to reduce morbidity and mortality? Seven questions concerning cirrhotic patients were addressed: (1) Which criteria should be used to guide ICU admission of cirrhotic patients in order to improve their prognosis? (2) Which specific management of kidney injury should be implemented to reduce morbidity and mortality in cirrhotic ICU patients? (3) Which specific measures to manage sepsis in order to reduce morbidity and mortality in cirrhotic ICU patients? (4) In which circumstances, human serum albumin should be administered to reduce morbidity and mortality in cirrhotic ICU patients? (5) How should digestive haemorrhage be treated in order to reduce morbidity and mortality in cirrhotic ICU patients? (6) How should haemostasis be managed in order to reduce morbidity and mortality in cirrhotic ICU patients? And (7) When should advice be obtained from an expert centre in order to reduce morbidity and mortality in cirrhotic ICU patients? Population, intervention, comparison and outcome (PICO) issues were reviewed and updated as required, and evidence profiles were generated. An analysis of the literature and recommendations was then performed in accordance with the GRADE® methodology. RESULTS: The SFAR/AFEF Guidelines panel produced 18 statements on liver failure in general ICU. After two rounds of debate and various amendments, a strong agreement was reached on 100% of the recommendations: six had a high level of evidence (Grade 1 ±), seven had a low level of evidence (Grade 2 ±) and six were expert judgments. Finally, no recommendation was provided with respect to one question. CONCLUSIONS: Substantial agreement exists among experts regarding numerous strong recommendations on the optimum care of patients with liver failure in general ICU.

An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease.

In chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130-Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130-Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease.

Liver transplantation in cases of portal vein thrombosis in the recipient: a case report and review of the various options.

Several surgical techniques have been developed to allow liver transplantation in cases of complete portal vein thrombosis in the recipient. Despite this, these transplantations remain associated with a significant complication rate. We report herein a case of liver transplantation in a patient with complete portal vein thrombosis, underlying the potential pitfalls and the risk of intestinal sutures in case of hepaticojejunostomy. We discuss the technical options and their relative indications in such cases.

Sepsis and cirrhosis: many similarities.

Sepsis and cirrhosis are both characterised by a hyperdynamic state associated with a low systemic vascular resistance, and the release of many mediators. The haemodynamic characteristics are so similar that sepsis is difficult to recognise in cirrhotic patients. Nevertheless, the occurrence of sepsis in cirrhotic patients is associated with high mortality rates. The resemblance of the two conditions may be in part related to the common translocation of bacterial products in cirrhosis. This article reviews the similarities and differences between sepsis and cirrhosis and defines the basis for the treatment of severe sepsis in cirrhotic patients.

Profile of soluble cytokine receptors in Crohn's disease.

INTRODUCTION: Soluble cytokine receptors (sCRs) modulate the in vivo activity of cytokines. Deficient sCR production could participate in the pathogenesis and course of Crohn's disease (CD). The aim of the study was to examine the profile of sCRs in CD patients and their modulation by infliximab and corticosteroids. METHODS: We prospectively examined active CD patients (aCD) treated with either infliximab (n = 21) or corticosteroids (n = 9), CD patients in clinical remission (rCD, n = 20), ulcerative colitis patients (UC, n = 24), and healthy subjects (HS, n = 15). Cultures of colonic biopsies were also examined from CD inflamed (n = 8), CD non-inflamed (n = 7), and healthy mucosa (n = 8). Levels of tumour necrosis factor alpha (TNF-alpha), soluble TNF receptor I (sTNFRI), soluble TNF receptor II (sTNFRII), interleukin 1beta (IL-1beta), soluble IL-1 receptor I (sIL-1RI), soluble IL-1 receptor II (sIL-1RII), IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 were measured using ELISA. RESULTS: Higher levels of sTNFRI (p<0.05, p<0.01), sTNFRII (p<0.01, p<0.01), sIL-1RI (p<0.05, NS), IL-6 (p<0.01, p<0.01), and sIL-6R (p<0.05, NS) were observed in aCD compared with rCD and HS. Interestingly, sIL-1RII (p<0.05, p<0.01) and sgp130 (p<0.01, p<0.01) were profoundly decreased in aCD compared with rCD and HS, and were negatively correlated with CRP. Deficient production of sIL-1RII was specific to CD (not observed in ulcerative colitis), and was further confirmed at the mucosal level. Infliximab decreased sTNFRII at one and four weeks (p<0.05) and enhanced sIL-6R levels at one week (p<0.05). Corticosteroids increased sIL-1RII levels at one week (p<0.05). CONCLUSION: CD is associated with dysregulated production of sCRs. Deficiency in sIL-1RII and sgp130 may be essential to CD pathogenesis. Their replacement through the use of fusion proteins could represent future alternative therapeutic strategies for CD.

Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: Elicitation of an innate immune response to bacterial products is mediated through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and the NODs. The recently characterised Asp299Gly polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with impaired LPS signalling and increased susceptibility to Gram negative infections. We sought to determine whether this polymorphism was associated with Crohn's disease (CD) and/or ulcerative colitis (UC). METHODS: Allele frequencies of the TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140 controls. A transmission disequilibrium test (TDT) was then performed on 318 inflammatory bowel disease (IBD) trios. RESULTS: The allele frequency of the TLR4 Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds ratio (OR) 2.31 (95% confidence interval (CI) 1.28-4.17), p = 0.004; and cohort 2: 12% v 5%, OR 2.45 (95% CI 1.24-4.81), p = 0.007) and UC patients (10% v 5%, OR 2.05 (95% CI 1.07-3.93), p = 0.027) compared with the control population. A TDT on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly polymorphism from heterozygous parents to affected children (T/U: 68/34, p = 0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and NOD2 variants separately. CONCLUSION: We have reported on a novel association of the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further supports the genetic influence of PRRs in triggering IBD.