Eliminating Hepatitis C Virus From a Prevalent Kidney Transplant Recipient Population: A Single-Center Study in Belgium in the Direct-Acting Antivirals Era

Background: Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection. Although previous studies have reported positive results with DAAs after kidney transplantation (KT), their impact on the prevalence of HCV viremia (HCVv) in prevalent kidney transplant recipients (KTRs) remains ill defined. Methods: We retrospectively reviewed the HCV status of all patients followed at Cliniques Universitaires Saint-Luc, Brussels, Belgium, outpatient KT clinic between January 2014 and December 2018. We collected the clinical features of KTRs treated with DAAs during this period and calculated the annual prevalence of HCVv over this period. Results: Out of 1451 KTRs, 22 (1.52%) had HCVv in 2014 to 2018. From 2014 to 2018, the annual prevalence of HCVv dropped from 1.97% to 0.43%, (P < .001). Fourteen KTRs were treated with DAAs a median of 197 months (range: 5-374) after KT, mostly (79%) in 2017 after reimbursement restrictions of DAAs for KTRs in Belgium were removed. DAA treatment was safe with a sustained virological response rate at 12 weeks after treatment (SVR12) of 93%. Two patients died 14 months (lymphoma, despite SVR12) and 7 months (hepatocarcinoma, no SVR12) after DAAs initiation, respectively. Among HCVv KTRs not treated with DAAs (n = 8), 2 lost their graft, 5 died, and 1 is initiating therapy. The current prevalence of HCVv in the cohort is 0.08%, with a single patient currently on treatment. Conclusion: Treatment with DAAs led to a dramatic decrease of HCVv prevalence in this KTR cohort. DAA use was safe and effective. Elimination of HCV is possible at KT clinics

Macrophages infiltration and extracellular matrix remodeling in liver fibrosis and hepatocellular carcinoma

Today, as a consequence of perpetual medical progresses, health care professionals have to deal not only with the worldwide increasing number of elderly people but also with a still increasing rate of neoplastic disease such as hepatocellular carcinoma (HCC). Data in the literature suggest aging as a risk factor for the development of liver fibrosis as complication of chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (HCV) infection. Few animal studies also report a higher susceptibility of aged rodents to develop liver fibrosis but mechanisms remain debated. To date, the treatment of the underlying cause of the liver disease is the sole available strategy to prevent or reduce liver fibrosis, while the search for direct anti-fibrotic treatment is ongoing. In this context, it appears necessary to better understand the mechanisms underlying the impact of aging on fibrosis to envisage tailoring therapy to the elderly population. In our work, we evaluated whether and how aging modulates the fibrotic response in a mouse model. Liver fibrosis was induced by carbon tetrachloride (CCl4) injections in 7 weeks- and 15 months-old mice (young and old, respectively). Old mice developed more severe fibrosis compared to young ones. Expression of pro-fibrogenic genes was equally induced in the two age-groups but enhanced fibrolysis in young mice was demonstrated by a significantly higher Mmp13 induction and collagenase activity. While fibrosis resolution occurred after cessation of injury in young mice, no significant fibrosis attenuation was observed in old mice. Although recruitment of monocytes-derived macrophages was similar in young and old livers, young macrophages had globally a remodeling phenotype but old ones, a pro-fibrogenic phenotype. Moreover, we observed a higher proportion of thick fibers and enhanced expression of enzymes involved in collagen maturation in old mice. Our data suggest that impaired fibrolysis of a matrix less prone to remodeling associated with a pro-inflammatory phenotype of infiltrated macrophages contribute to a more severe fibrosis in old mice. Ninety percent of HCC develop in a chronically damaged liver. Interactions between non-tumor stromal components, especially macrophages, and cancer cells are still incompletely understood. Thus, in the second part of this doctoral thesis, we investigated whether a chronically injured liver represents a favorable environment for the seeding and growth of HCC cells, and we evaluated the potential roles of macrophages infiltrated within the tumor. HCC cells were injected into the liver in healthy mice (healthy liver group [HL]) and in mice chronically treated with CCl4 for 7 weeks (CCl4 7w group). Livers were examined 2 weeks post-injection for the presence of tumor. Fifty-three percent of mice developed neoplastic lesion in the HL group whereas a tumor lesion was found in all livers in the CCl4 7w group. Macrophages infiltrated more deeply the tumors of the CCl4 7w group. Evaluation of factors involved in the recruitment of macrophages and of markers of their polarization state was in favor of prominent infiltration of pro-tumor monocyte-derived macrophages inside the tumors developing in a chronically injured liver. MMP-2 and -9 production, attributed to pro-tumor macrophages, was significantly higher in the tumors of the CCl4 7w group. In our model, chronic liver damage promotes cancer development. Our results suggest that an injured background favors the infiltration of pro-tumor monocyte-derived macrophages that secrete MMP-2 and MMP-9, promoting tumor progression. Globally, our data emphasize the major roles of macrophages in the pathogenesis of liver fibrosis and HCC, suggesting that macrophages specific targeting may be an attractive strategy to treat liver diseases.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

combined hepatocellular-cholangiocarcinoma : epidemiological, radiological and survival data from a monocenter retrospective study

Introduction : Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy with a poor prognosis and very few available data in terms of pathophysiology, risk factors, imaging features and no current consensus in terms of treatment recommendations. Therefore, our aims were to assess the risk factors, imaging-pathology correlation and survival of cHCC-CCA compared to other malignant liver tumours (hepatocarcinoma (HCC) and cholangiocarcinoma (CCA)). Methods : All patients with histologically-confrmed or with imaging-based suspicion of cHCC-CCA (classifed Li-Rads M) treated between 2016 and 2021 in the Cliniques Saint-Luc were screened in a retrospective single-center study. Other histological subtypes of liver tumor in the absence of radiological suspicion of mixed tumor by magnetic resonance imaging (MRI) were excluded. Patients with other histological subtypes or non histologically assessed were included in the non-HCC-CCA group. MRI data of transplanted patients were not recorded considering the artifacts due to waiting treatments. Treatment modalities were defned as HCC regimen if included anti-VEGF drugs or as CCA regimen if included a chemotherapy combining Gemcitabine and a platinum salt. All data were recorded based on medical records. Results : Among 761 screened patients, 57 patients (7.5%) were included among which 26 patients with histologically confrmed cHCCCCA (cHCC-CCA group - 45.6%), 18 patients with HCC ( HCC group - 31.6%), 9 patients with CCA (CCA group - 15.8%) and 4 patients with benign tumor (7%). 735 patients (92.5%) were included in the non-HCC-CCA group. In terms of imaging diagnostic accury in the HCC-CCA group (N=26), 17 patients had a positive MRI for HCC-CCA (65.4%) and 9 had a negative MRI (34.6%). In the non-HCC-CCA group (N = 735), 31 patients had a positive MRI (4.2 %) and 704 had a negative MRI (95.8 %) (Sensitivity = 0.65; Specifcity = 0.96; positive predictive value = 0.35 (PPV); negative predictive value = 0.99 (NPV); p<0.0001). In terms of median survival, no signifcant differences were observed between histological subgroups (cHCC-CCA : 44.77 months; CCA : undefned; HCC : 37.61 – p=0.81). No signifcant differences were also observed in the cHCC-CCA group depending on treatment modality (liver directed therapy : 44.8 months; systemic treatment : 26.86 – p=0.14). Take home messages : ● Liver MRI has an excellent NPV for the diagnosis of cHCCCCA. ● Median survival does not differ according to histological subtype. ● Median survival does not differ in the cHCC-CCA group according to treatment modalit

Animal Models for Fibrotic Liver Diseases: What We Have, What We Need, and What Is under Development.

Liver fibrosis is part of the wound-healing response to liver damage of various origins and represents a major health problem. Although our understanding of the pathogenesis of liver fibrosis has grown considerably over the last 20 years, effective antifibrotic therapies are still lacking. The use of animal models is crucial for determining mechanisms underlying initiation, progression, and resolution of fibrosis and for developing novel therapies. To date, no animal model can recapitulate all the hepatic and extra-hepatic features of liver disease. In this review, we will discuss the current rodent models of liver injuries. We will then focus on the available ways to target specifically particular compounds of fibrogenesis and on the new models of liver diseases like the humanized liver mouse model

A rare cause of high liver stiffness

A 71-year-old man with a past medical history of arterial hypertension was referred to our outpatient clinic for a suspected liver disease, based on biochemical and radiological findings. He was poorly symptomatic with discrete weight loss due to reduced appetite. Physical examination revealed a good general condition, hepatosplenomegaly, overweight (BMI 27) and enhanced waist circumference. Biochemical examination showed pancytopenia (hemoglobin 11,4 g/dL [13.3-16.7 g/dL], white cells count 3870/μL [4-10x103/μL], platelets count 38000/μL[150-350x103/μL]) and cholestasis (gGT 147 U/L [<60U/L], alkaline phosphatase 152 U/L [40-130 U/L], total bilirubin 2.1 mg/dL [<1.2mg/dL]). ALT and AST levels were normal. [...

Innovations 2022 en hépato-gastroentérologie

L’année 2022 a été riche en enseignements et en recommandations en hépatologie. En effet, des études animales et humaines ont montré que la stéatose hépatique était étroitement liée à l’insulinorésistance, justifiant non-seulement de rechercher un diabète chez un patient présentant une stéatose hépatique mais également d’évaluer la sévérité de l’éventuelle atteinte hépatique des patients diabétiques. Par ailleurs, de nouvelles recommandations (Baveno VII) ont été publiées en 2022 et proposent des valeurs seuils d’élastométrie hépatique pour le dépistage de l’hypertension portale cliniquement significative en cas d’hépatopathie chronique avancée compensée et son traitement par βbloquant non cardio-sélectif afin de prévenir le premier épisode de décompensation cirrhotique. Enfin, l’American Association for the Study of Liver Diseases a publié en janvier 2022 un guide sur la prise en charge palliative des patients atteints de cirrhose décompensée chez qui une transplantation hépatique n’est pas indiquée. Dans le domaine des maladies inflammatoires du tube digestif, deux nouveaux médicaments sont venus renforcer le traitement de la rectocolite en Belgique en 2022 : le filgotinib et l'ozanimod. De plus, la première étude randomisée contrôlée de comBIOthérapie a été réalisée : l’étude « VEGA ». Cette étude est la première randomisée qui s’intéresse à l’association de biologiques dans le domaine des maladies inflammatoires digestives. A contrario, l’étude « SPARE » s’est intéressée à une stratégie de décroissance des traitements plus particulièrement chez les patients atteints de maladie de Crohn. Enfin, un groupe d’experts belges s’est réuni à de nombreuses reprises au cours des années 2021 et 2022 afin d’établir les recommandations belges de prise en charge du syndrome de l’intestin irritable. Le produit de ce travail exhaustif a été publié en avril 2022

Stéatose métabolique, carcinome hépatocellulaire, prurit cholestatique, encéphalopathie et maladies inflammatoires intestinales: quelles nouveautés en 2020?

Voici quelques nouveautés importantes dans le domaine de l’hépato-gastroentérologie au cours de l’année 2020… Un consensus d’experts a décidé d’une dénomination plus claire pour la maladie stéatosique « non-alcoolique », désormais appelée « métabolique » et définie par des critères positifs. En cas de stéatohépatite fibrosante, le lanifibranor, un agoniste triple des trois isoformes du récepteur activé par les proliférateurs de peroxysomes (PPARα,δ,γ) a montré une nette supériorité par rapport au placebo pour la guérison de la maladie, la régression de la fibrose et l’amélioration du profil métabolique. Pour les patients souffrant d’un carcinome hépatocellulaire à un stade avancé, l’approche combinée par atezolizumab (anti-PD-L1) et bevacizumab (anti-VEGF)améliore grandement le pronostic, et est incontestablement la réference en première ligne. En cas de prurit cholestatique, les fibrates sont bénéfiques sur les symptômes. La rifaximine, un antibiotique à large spectre, faiblement absorbé, efficace pour la prévention secondaire de l’encéphalopathie hépatique est désormais remboursée en association avec le lactulose. Pour les maladies inflammatoires intestinales, l’ustekinumab (anti-IL12-IL23) est maintenant remboursé dans la rectocolite et l’infliximab (anti-TNF) ainsi que le vedolizumab (anti-intégrine) peuvent être administrés par voie sous-cutanée. Enfin, les patients présentant une maladie inflammatoire intestinale n’ont pas de risque accru d’infection à coronavirus ni de développement de COVID-19 sévère. Malgré leur traitement immunosuppresseur, ces patients peuvent (et doivent même…) bénéficier du vaccin actuellement disponible

Hépatologie, endoscopie et proctologie: quelques faits marquants en 2021

L’année 2021 a comporté plusieurs mises au point et avancées en hépato-gastro-entérologie, notamment à destination du médecin traitant généraliste. Des moyens non-invasifs simples sont à sa disposition et validés par la société scientifique européenne de l’étude du foie pour rechercher la présence d’une fibrose hépatique chez les individus à risque (syndrome métabolique ou alcool). Les critères de remboursement de certaines médications contre le virus de l’hépatite B ont été revus. Ils ne comportent plus la réalisation d’une biopsie hépatique systématique et ciblent plus de patients à risque. Concernant la maladie stéatosique métabolique, plusieurs études scientifiques ont été réalisées avec différents types de régimes alimentaires permettant une régression de la maladie. Leurs avantages et inconvénients potentiels sont décrits. Ces régimes peuvent donc être proposés par le médecin traitant. Un domaine de l’endoscopie moins connu est également présenté avec l’utilisation de l’entéroscopie spiralée motorisée qui fait son apparition aux Cliniques universitaires Saint-Luc et qui permettra d’améliorer l’exploration et la prise en charge des maladies de l’intestin grêle. Enfin, les praticiens sont souvent confrontés à la maladie hémorroïdaire. Des recommandations de sa prise en charge ont été rédigées et publiées par un groupe de proctologues experts belges

Immunotherapy and Gene Therapy: New Challenges in the Diagnosis and Management of Drug-Induced Liver Injury

International audienceIn the last 5 years, the landscape of oncologic treatment has been deeply modified with the development and use of immune checkpoint inhibitors (ICIs) that exert their antitumoral effect by reverting the exhausted phenotype of tumor-infiltrating lymphocytes. This innovative therapeutic strategy has widely changed the prognosis of some advanced neoplastic diseases such as melanoma and lung cancer, providing durable remission for a significant number of patients. Unfortunately, immune-related adverse events (irAEs), especially ICI-induced hepatitis, may be very severe in some cases, impairing the prognosis of the patient. Guidelines available today on the diagnosis and management of ICI-induced hepatitis are mainly based on expert opinions and case series. This lack of large data is explained not only by the low incidence of hepatic adverse events but also by their clinical heterogeneity and variable severity. In this article, we will review the clinical, biological, and histological characteristics of ICI-induced liver injury. We will discuss the current knowledge on their pathological mechanisms and their therapeutic strategy based on immunosuppressive treatment for more severe cases. Regarding severity assessment, we will discuss the gap between the oncologist and the hepatologist’s point of view, highlighting the need for multidisciplinary management. While initially developed for notably less frequent diseases than neoplastic ones, gene therapy is going to be a revolution for the treatment of diseases not responding to pharmacological therapy. Limited but growing data describe liver injury after the administration of such therapy whose exact physiopathology remains unknown. In this article, we will discuss the available data supporting the role of gene therapies in the onset of drug-induced liver injury and related mechanisms. We will describe the clinical context, the biological and histological features, and the management currently proposed