Targeting Kupffer cells in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Why and how?

Mechanisms for non-alcoholic steatohepatitis(NASH)development are under investigation in an era of increased prevalence of obesity and metabolic syndrome. Previous findings have pointed to the role of adipose tissue, adipose tissue macrophages and their secretory products in the development of a chronic inflammatory status inducing insulin resistance and a higher risk of liver steatosis called non-alcoholic fatty liver disease. The activation of resident macrophages [Kupffer cells(KC)] and the recruitment of blood derived monocytes/macrophages into the diseased liver have now been identified as key elements for disease initiation and progression. Those cells could be activated through gut flora modifications and an altered gut barrier function but also through the internalization of toxic lipid compounds in adjacent hepatocytes or in KC themselves. Due to the role of activated KC in insulin resistance, fibrosis development and inflammation amplification, they became a target in clinical trials. A shift towards an anti-inflammatory KC phenotype through peroxisome proliferator activator-receptorδ agonists, an inhibition of macrophage recruitment through anti-C-C chemokine receptor 2 action and a specific blocking of internalization of toxic lipoxidation or glycation compounds into KC by galectin-3 receptor inhibitors are now under investigation in human NASH.

Improving the prognosis before and after liver transplantation:Is muscle a game changer?

Liver transplantation(LT)is currently the only curative treatment option for selected patients with end stage liver disease or hepatocellular carcinoma.Improving waiting list-mortality,post-transplant morbidity and mortality and refining the selection of the patients remain our current central objectives.In this field,different concepts dealing with nutrition and the muscle such as sarcopenia,malnutrition,frailty or myosteatosis have emerged as possible game changers.For more than a decade,many prospective studies have demonstrated that sarcopenia and frailty are major predictive factors of mortality in the waiting list but also after LT.Malnutrition is also a well-known risk factor for morbidity and mortality.Muscle composition is a newer concept giving insight on muscle quality which has also been shown to be linked to poorer outcomes.Each of these terms has a precise definition as well as pathophysiological mechanisms.The bidirectional liver-muscle axis makes sense in this situation.Defining the best,easy to use in clinical practice tools to assess muscle quality,quantity,and function in this specific population and developing quality prospective studies to identify interventional strategies that could improve these parameters as well as evaluate the effect on mortality are among the important challenges of today.

Anti-hepatitis C virus drugs and kidney

Hepatitis C virus(HCV) mainly targets the liver but can also induce extrahepatic manifestations. The kidney may be impacted via an immune mediated mechanism or a cytopathic effect. HCV patients are clearly at a greater risk of chronic kidney disease(CKD) than uninfected patients are, and the presence of CKD increases mortality. Interferon-based therapies and ribavirin are difficult to manage and are poorly effective in endstage renal disease and hemodialysis. These patients should be given priority treatment with new direct anti-viral agents(DAAs) while avoiding peginterferon and ribavirin. The first results were convincing. To aid in the correct use of these drugs in patients with renal insufficiency, their pharmacokinetic properties and potential renal toxicity must be known. The renal toxicity of these new drugs was not a safety signal in clinical trials, and the drugs are generally efficient in these frail populations. These drugs are usually well tolerated, but recent cohort studies have demonstrated that these new regimens may be associated with renal side effects, especially when using sofosbuvir combinations. HCV, renal diseases and comorbidities are intimately linked. The close monitoring of renal function is required, particularly for at-risk patients(transplanted, HIV-coinfected, CKD, hypertensive or diabetic patients). New DAA regimens, which will soon be approved, will probably change the landscape.

Reactivation of Tuberculosis during Dual Therapy with Pegylated Interferon and Ribavirin for Chronic Hepatitis C about a Case

The infection by the virus of the hepatitis C can be associated with other infectious diseases, including the viral and bacterial infections of which the tuberculosis. The infection to Mycobacterium tuberculosis can remain latent during several years and show itself during a state of immunesuppression. The role of the antiviral treatment in the reactivation of the tuberculosis is debated. We bring back an observation of tubercular reactivation during dual therapy with pegylated interferon and ribavirin for a viral chronic hepatitis C. A virologique answer slow was obtained in the 40th week, as well as the reactivation of the tuberculosis. The tuberculosis was of ganglionic localization at our patient. The antituberculous treatment was established while maintaining the treatment. The evolution of the tuberculosis under treatment was favorable but for the VHC, we noted a virologique answer with premature relapse.

Patient Experience at Endoscopy Centers in Three West African Countries during the COVID-19 Pandemic

Corona virus infection and the risk of contagiousness to medical personnel or patients during endoscopy necessitated further measures in the endoscopy rooms. The objective of this study was to assess the experience of patients in endoscopy rooms during the COVID-19 epidemic in West Africa. Patients and Methods: This was a multicenter cross-sectional study that took place over a period of 3 months (June to August 2020) in endoscopy centers in Burkina Faso, Benin and Niger. An online questionnaire was sent to patients who had performed upper digestive endoscopies, in 8 digestive endoscopy centers including private, public and religious structures. Depending on the choice of patients, questionnaires were either sent electronically or completed in the endoscopy room with the help of field investigators. The choice of centers was random from the list of centers and descriptive analyses were carried out. Results: A total of 294 patients responded to the online questionnaire. There were 37 lower and 257 upper gastrointestinal endoscopies. The female sex represented 52.1%. The wait times for obtaining an endoscopy appointment were considered satisfactory by 281 patients 95.6%. In the endoscopy departments, 112 patients, or 38.1%, were questioned about the risk factors for contamination of SARS-CoV-2. Among the risk factors found, 6 patients (2.0%) would have traveled abroad in the 2 weeks preceding the examination, 4 patients 1.4% had already been in contact with a subject at risk. The most frequent symptoms were chest pain (80 cases;27.2%), flu-like syndrome (29 cases;9.9%), cough (40 cases;13.6%), fever (46 cases;15.6%). In contrast, ageusia (7 cases;2.4%) and anosmia (5 cases;1.7%) were only found in very few patients. Twenty-two patients (7.5%) felt highly exposed to COVID-19 during the endoscopy examination and 144 patients (48.9%) rated the examination as satisfactory. Conclusion: Gastrointestinal symptoms initially described as rare are being reported with increasing frequency in studies and may motivate the request for endoscopy examinations. However, the risk associated with infection with SARS-CoV-2 does not seem to have been sufficiently taken into account in endoscopy centers in the 3 countries.

Incomplete Situs Inversus Revealed by Acute Pain of the Right Hypochondrium

Situs inversus is an abnormal placement of the thoracic and/or abdominal organs that are inverted right/left from normal. It is a rare congenital malformation often discovered in childhood. In adults, it can lead to misdiagnosis. Clinical case: A 35-year-old female patient, seen in a hepatogastroenterology consultation for acute spontaneous pain in the right hypochondrium. She had no particular clinical history. A diagnosis of hepatopathy was suspected. Abdominal and pelvic CT scans showed the left liver, stomach and spleen in the right hypochondrium, but with the heart in place, suggesting incomplete situs inversus. The evolution in our patient was spontaneously resolved with analgesics and antispasmodics, which leads us to believe that the volvulus was probably partial and without other complications. Conclusion: In developing countries, antenatal diagnosis of situs inversus is rare and is usually made during a pathology that leads the patient to a medical consultation. CT is one of the key paraclinical examinations for its diagnosis as genetic tests are not widely available.

Hepatitis B Virus in Cirrhosis and Primary Livers Cancers

Introduction: Hepatitis B virus (HBV) infection is a public health problem in sub-Saharan Africa, due to its frequency and progression to complications such as cirrhosis and/or hepatocellular carcinoma (HCC). Objective: To help improve the management of cirrhosis and hepatocellular carcinoma. Patients and Methods: This was a 34-month cross-sectional study conducted in the Hepato-Gastroenterology Department of the CHU de l’Amitié Sino-centra-fricaine in Bangui. It included patients of both sexes aged 18 years or older with a diagnosis of HBV-related cirrhosis and/or HCC. Results: During the study period, 1344 patients were admitted to hospital, 681 of them for chronic liver disease (51%). Among patients admitted for chronic liver disease, in particular cirrhosis and/or HCC, HBV was implicated in 288 cases (42.30%), of whom 170 (24.96%) met our inclusion criteria. These included 123 men (72.35%) and 47 women (27.65%). The sex ratio was 2.61. The mean age of our patients was 40 years (±11 years) with extremes of 18 and 76 years. Cirrhosis was observed in 101 cases (59.41%), HCC on cirrhosis in 59 cases (34.70%) and HCC in 10 cases (5.89%). Cirrhosis was classified as Child-Pugh B in 62 cases and C in 20 cases. HCC on cirrhosis was classified according to BCLC stage C in 7 cases and stage D in 52 cases. Conclusion: HBV is the leading cause of cirrhosis and HCC in the Central African Republic. Chronic liver disease is diagnosed at the advanced stage of the disease. Hence the importance of early detection, prevention through vaccination at birth, and management of infected patients.

Anal Pathologies: What Management at the Reference Health Center of Bamako’s Commune V?

Anal pathologies are conditions affecting the anal margin and the anal canal. The aim of our study was to update data on anal diseases. Non-specific, it can reveal an emergency, a serious illness, a chronic disease or a benign condition. It was a prospective, descriptive and analytical study from April 2022 to March 2023, carried out in the hepato-gastroenterology unit of the Centre de Santé de Référence de la commune V du District de Bamako in Mali. Out of seven hundred and forty-nine (749) patients seen in consultation, 98 had anal pathology, i.e. a prevalence of 13.08%. The mean age was 40 ± 15.15 years and the sex ratio was 1.5. Hemorrhoidal disease and anal fissure were the most frequent pathologies in 66.4% and 24.4% of cases respectively. Medical treatment was initiated in 91.9% of patients with hemorrhoidal disease and 91.7% with anal fissure. Anal pathologies are common in young male patients. In our context, they are dominated by benign conditions.

Alfapump®implantable device in management of refractory ascites:An update

Refractory ascites(RA)is a frequent and life-threatening complication of cirrhosis.In selected patients with RA,transjugular intrahepatic portosystemic shunt(TIPS)placement and liver transplantation(LT)are currently considered the best therapeutic alternatives to repeated large volume paracentesis.In patients with a contraindication to TIPS or LT,the alfapump®system(Sequana Medical,Ghent,Belgium)has been developed to reduce the need for iterative paracentesis,and consequently to improve the quality of life and nutritional status.We report here recent data on technical progress made since the first implantation,the efficacy and tolerance of the device,the position of the pump in the therapeutic arsenal for refractory ascites,and the grey areas that remain to be clarified regarding the optimal selection of patients who are potential candidates for this treatment.

Involvement of CRF2 signaling in enterocyte differentiation

To determine the role of corticotropin releasing factor receptor (CRF2) in epithelial permeability and enterocyte cell differentiation.METHODSFor this purpose, we used rat Sprague Dawley and various colon carcinoma cell lines (SW620, HCT8R, HT-29 and Caco-2 cell lines). Expression of CRF2 protein was analyzed by fluorescent immunolabeling in normal rat colon and then by western blot in dissociated colonic epithelial cells and in the lysates of colon carcinoma cell lines or during the early differentiation of HT-29 cells (ten first days). To assess the impact of CRF2 signaling on colonic cell differentiation, HT-29 and Caco-2 cells were exposed to Urocortin 3 recombinant proteins (Ucn3, 100 nmol/L). In some experiments, cells were pre-exposed to the astressin 2b (A2b) a CRF2 antagonist in order to inhibit the action of Ucn3. Intestinal cell differentiation was first analyzed by functional assays: the trans-cellular permeability and the para-cellular permeability were determined by Dextran-FITC intake and measure of the transepithelial electrical resistance respectively. Morphological modifications associated to epithelial dysfunction were analyzed by confocal microscopy after fluorescent labeling of actin (phaloidin-TRITC) and intercellular adhesion proteins such as E-cadherin, p120ctn, occludin and ZO-1. The establishment of mature adherens junctions (AJ) was monitored by following the distribution of AJ proteins in lipid raft fractions, after separation of cell lysates on sucrose gradients. Finally, the mRNA and the protein expression levels of characteristic markers of intestinal epithelial cell (IEC) differentiation such as the transcriptional factor krüppel-like factor 4 (KLF4) or the dipeptidyl peptidase IV (DPPIV) were performed by RT-PCR and western blot respectively. The specific activities of DPPIV and alkaline phosphatase (AP) enzymes were determined by a colorimetric method.RESULTSCRF2 protein is preferentially expressed in undifferentiated epithelial cells from the crypts of colon and in human colon carcinoma cell lines. Furthermore, CRF2 expression is down regulated according to the kinetic of HT-29 cell differentiation. By performing functional assays, we found that Ucn3-induced CRF2 signaling alters both para- and trans-cellular permeability of differentiated HT-29 and Caco-2 cells. These effects are partly mediated by Ucn3-induced morphological changes associated with the disruption of mature AJ in HT-29 cells and tight junctions (TJ) in Caco-2 cells. Ucn3-mediated activation of CRF2 decreases mRNA and protein expression levels of KLF4 a transcription factor involved in IEC differentiation. This signaling is correlated to a down-regulation of key IEC markers such as DPPIV and AP, at both transcriptional and post-transcriptional levels.CONCLUSIONOur findings suggest that CRF2 signaling could modulate IEC differentiation. These mechanisms could be relevant to the stress induced epithelial alterations found in inflammatory bowel diseases.

Duodenal Metastases of Malignant Melanoma: One Case Report

The duodenal metastases of a malignant melanoma are rare. We report a case at a 86-year-old, hypertense patient, without tumoral history, who was hospitalized in our department for a change of the general state and an anaemia ferriprive without found home (foyer) of display. In the clinical examination, we had found anemia syndrome, nodules under cutaneous about 2 cm in diameter at the level of the thorax, of the belly, the members and of the lower lip partners in a painless left adenopathy axillary about 3 cm in diameter and an absence of méléna in the rectal touch. The gastroscopy had highlighted polypoides ulcéro-bourgeonnantes hurts with a blackish pigmentation by places at the level of the bulb and of the second duodenum. In the histology of biopsie fragments, we noted a fuso-cellular proliferation and epithelioid with deposits of melanin. The positivity of antibodies anti-protein S100 and anti HMB45 in the immunohistochemical study allowed confirming the diagnosis. The gastroduodenal hurts, persons suffering from a liver complaint and lungworts in the scanner testify of a terminal metastatic scattering. The death arose two months later, in a picture of circulatory collapse further to a high digestive bleeding of big abundance.

Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis:an international registry study

Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may be useful in diagnosing NASH,but results across studies have been inconsistent.We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.Methods:Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease(NAFLD),and in all patients,circulating CK-18 M30 levels were measured.Individuals with a NAFLD activity score(NAS)≥5 with a score of≥1 for each of steatosis,ballooning,and lobular inflammation were diagnosed as having definite NASH;individuals with a NAS≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver(NAFL).Results:A total of 2571 participants were screened,and 1008(153 with NAFL and 855 with NASH)were finally enrolled.Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL(mean difference 177 U/L;standardized mean difference[SMD]:0.87[0.69–1.04]).There was an interaction between CK-18 M30 levels and serum alanine aminotransferase,body mass index(BMI),and hypertension(P<0.001,P=0.026 and P=0.049,respectively).CK-18 M30 levels were positively associated with histological NAS in most centers.The area under the receiver operating characteristics(AUROC)for NASH was 0.750(95%confidence intervals:0.714–0.787),and CK-18 M30 at Youden’s index maximum was 275.7 U/L.Both sensitivity(55%[52%–59%])and positive predictive value(59%)were not ideal.Conclusion:This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.

A Cross-sectional Real-life Study of the Prevalence,Severity,and Determinants of Metabolic Dysfunction-associated Fatty Liver Disease in Type 2 Diabetes Patients

Background and Aims:Most data on liver assessment in type 2 diabetes mellitus(T2DM)patients are from retrospective cohorts with selection bias.We aimed at appraising the feasibility,results,and benefits of an outpatient systematic noninvasive screening for metabolic dysfunction-associated fatty liver disease(MAFLD)severity and determinants in T2DM patients.Methods:We conducted a 50-week crosssectional study enrolling adult T2DM outpatients from a diabetes clinic.An algorithm based on guidelines was applied using simple bioclinical scores and,if applicable,ultrasound and/or elastometry.Results:Two hundred and thirteen patients were included.Mean age and body mass index were 62 years and 31 kg/m^(2) and 29% of patients had abnormal transaminase levels.The acceptance rate of additional liver examinations was 92%.The prevalence of MAFLD,advanced fibrosis and cirrhosis was 87%,11%,and 4%,respectively.More than half of the cases of advanced fibrosis had not been suspected and were detected by this screening.MAFLD was associated with poor glycemic control,elevated transaminases,low HDL-C and the absence of peripheral arterial disease.Advanced fibrosis was linked to high waist circumference and excessive alcohol consumption,which should be interpreted with caution owing to the small number of patients reporting excessive consumption.Conclusions:Simple bioclinical tools allowed routine triage of T2DM patients for MAFLD severity,with high adherence of high-risk patients to subsequent noninvasive exams.

Hepatitis C treatment in patients with substance use disorder:the faster the better

Hepatitis C virus(HCV)infection is a major cause of liver disease and hepatocellular carcinoma worldwide(1).HCV is a blood-borne infection and prevalence is particularly high in patients with a history of injective drug use or unsafe health care or sexual practices.Substance use disorder(SUD),and especially opioid misuse is a growing problem worldwide(2).This is particularly relevant in the United States(US)where opioid misuse has raised sharply in the last years(3,4),termed also opioid epidemic.SUD is associated with an increase incidence of HCV infections and reinfections and associated liver disease(2,4).Moreover,alcohol use disorder is frequent in patients with SUD(5),representing another major risk factor for chronic liver disease in this population.Patients with SUD often experience poor access to health care resulting in higher mortality(5,6).Finally,SUD is associated with psychiatric conditions and social problems such as housing instability,unemployment,and reduced access to medical care(7)which could result in a reduced access and compliance to HCV treatment.

Cabozantinib and the moving field of systemic treatments in advanced hepatocellular carcinoma

Most of patients with hepatocellular carcinoma(HCC),are diagnosed at an advanced-stage explaining the poor prognosis of this cancer with a median survival without treatment around 8 months(1-3).Currently,two systemic multi-kinase inhibitors with anti-proliferative and antiangiogenic effects are available as first line treatments in advanced HCC.The first one,Sorafenib,was the only available systemic treatment available during one decade and was associated with an improvement of overall survival of around 3 months compared to placebo(4,5).The second one,lenvatinib,showed a similar median overall survival compared to Sorafenib in a non-inferiority phase-3 trial(6).No second line was available during several years due to toxicity or absence of efficacy of the different drugs tested in multicentric phase 3 randomized controlled trials.

Hepatocellular carcinoma with portal invasion,still a place for liver surgery in the era of immunotherapy?

Hepatocellular carcinoma(HCC)is a leading cause of cancer death worldwide and is associated with a 5-year overall survival(OS)of 10-15%all stages combined.However,5-year OS reaches 50-70%when patients are in an early stage and can access curative treatments such as liver transplantation,liver resection(LR)or ablation.Currently,LR is reserved to very selected patients with adequate performance status,preserved liver function,to be matched with grade of portal hypertension(PHT),sufficient volume of the future liver remnant and acceptable tumor burden(1,2).Worldwide,the definitions of“tumor burden”and vascular invasion vary as illustrated in Tables 1,2,and the impact of portal vein tumoral thrombosis(PVTT)on the choice for HCC treatment is not consensual(1,2).