Hepatic steatosis, metabolic dysfunction and risk of mortality: findings from a multinational prospective cohort study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are implicated in the aetiology of non-communicable diseases. Our study aimed to evaluate associations between NAFLD and MetS with overall and cause-specific mortality. METHODS: We used dietary, lifestyle, anthropometric and metabolic biomarker data from a random subsample of 15,784 EPIC cohort participants. NAFLD was assessed using the fatty liver index (FLI) and MetS using the revised definition. Indices for metabolic dysfunction-associated fatty liver disease (MAFLD) were calculated. The individual associations of these indices with overall and cause-specific mortality were assessed using multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs). As a subobjective, risk associations with adaptations of new classifications of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic and alcohol-related liver disease (MetALD) were also assessed. RESULTS: Among the 15,784 sub-cohort participants, a total of 1997 deaths occurred (835 due to cancer, 520 to CVD, 642 to other causes) over a median 15.6 (IQR, 12.3-17.1) years of follow-up. Compared to an FLI < 30, FLI ≥ 60 was associated with increased risks of overall mortality (HR = 1.44, 95%CI = 1.27-1.63), and deaths from cancer (HR = 1.32, 95%CI = 1.09-1.60), CVD (HR = 2.06, 95% CI = 1.61-2.63) or other causes (HR = 1.21, 95%CI = 0.97-1.51). Mortality risk associations were also elevated for individuals with MAFLD compared to those without. Individuals with MetS were at increased risk of all mortality endpoints, except cancer-specific mortality. MASLD and MetALD were associated with higher risk of overall mortality. CONCLUSIONS: Our findings based on a prospective cohort suggest that individuals with hepatic steatosis or metabolic dysfunction have a higher overall and cause-specific mortality risk.

Impact of sleeve gastrectomy on renal function in patients with morbid obesity: a 1-year prospective cohort study.

PURPOSE: Obesity is an independent risk factor for renal injury. A more favorable metabolic environment following weight loss may theoretically lead to improved renal function. We aimed to evaluate the evolution of renal function one year after sleeve gastrectomy in a large prospective cohort of patients with morbid obesity and assess the influence of fat-free mass (FFM) changes. METHODS: We prospectively included obese patients admitted for sleeve gastrectomy between February 2014 and November 2016. We also included a historical observational cohort of patients undergoing sleeve gastrectomy between January 2013 and January 2014 who had FFM evaluation. Patients were systematically evaluated 1 year after surgery. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The FFM was estimated by analyzing computerized tomography (CT) scan sections from CT systematically performed 2 days and 1 year after sleeve gastrectomy to detect surgery complications. RESULTS: Five hundred sixty-three patients fulfilled the inclusion criteria. The mean age was 41.2 ± 0.5 years. The mean body mass index was 43.5 ± 0.3 kg/m2 and 20.4, 30.5, and 30.7% of the included patients had type 2 diabetes, hypertension, and dyslipidemia, respectively. One hundred fifteen patients were excluded and four hundred forty-eight patients were finally included in the analysis. The eGFR was significantly higher 1 year after sleeve gastrectomy than before surgery (87.8 ± 0.9 versus 86.1 ± 0.9, p < 0.01). There was no difference in terms of post-surgery FFM loss between patients with an improved eGFR and those without (6.7 ± 0.3 kg versus 6.8 ± 0.5 kg, p = 0.9). Furthermore, post-surgery changes in the eGFR did not correlate with the amount of FFM loss (r = 0.1, p = 0.18). CONCLUSION: Renal function assessed by eGFR is significantly improved at 1-year post-sleeve gastrectomy, independent of changes in skeletal muscle mass.

Modulation of the Bile Acid Enterohepatic Cycle by Intestinal Microbiota Alleviates Alcohol Liver Disease.

Reshaping the intestinal microbiota by the ingestion of fiber, such as pectin, improves alcohol-induced liver lesions in mice by modulating bacterial metabolites, including indoles, as well as bile acids (BAs). In this context, we aimed to elucidate how oral supplementation of pectin affects BA metabolism in alcohol-challenged mice receiving feces from patients with alcoholic hepatitis. Pectin reduced alcohol liver disease. This beneficial effect correlated with lower BA levels in the plasma and liver but higher levels in the caecum, suggesting that pectin stimulated BA excretion. Pectin modified the overall BA composition, favoring an augmentation in the proportion of hydrophilic forms in the liver, plasma, and gut. This effect was linked to an imbalance between hydrophobic and hydrophilic (less toxic) BAs in the gut. Pectin induced the enrichment of intestinal bacteria harboring genes that encode BA-metabolizing enzymes. The modulation of BA content by pectin inhibited farnesoid X receptor signaling in the ileum and the subsequent upregulation of Cyp7a1 in the liver. Despite an increase in BA synthesis, pectin reduced BA serum levels by promoting their intestinal excretion. In conclusion, pectin alleviates alcohol liver disease by modifying the BA cycle through effects on the intestinal microbiota and enhanced BA excretion.

ABO blood group does not influence Child-Pugh A cirrhosis outcome: An observational study from CIRRAL and ANRS CO12 CIRVIR cohorts.

BACKGROUND AND AIMS: Non-O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non-O group on the outcome of Child-Pugh A cirrhotic patients. METHODS: We used two prospective cohorts of Child-Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 µmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation¼ or « the occurrence of one or more parameters ¼ among: prothrombin time (PT) <45%, albumin <28 g/L, Child-Pugh worsening (B or C vs A or B, C vs B), hepatorenal syndrome, and hepato-pulmonary syndrome, (2) other events such as non-malignant portal vein thrombosis (nmPVT), and (3) overall survival. RESULTS: Patients (n = 1789; 59.9% Non-O group; 40.1% group O) were followed during a median of 65.4 months. At 3 years cumulated incidence of Decompensation was 8.3% in Non-O group and 7.2% in group O (P = .27). Cumulated incidence of Disease Progression was 20.7% in Non-O group and 18.9% in group O (P = .26). Cumulated incidence of nmPVT was 2.7% in Non-O group and 2.8% in group O (P = .05). At 3 years overall survival was 92.4% in Non-O group and 93.4% in group O (P = 1). CONCLUSION: Non-O group does not influence disease outcome in Child-Pugh A cirrhotic patients. Clinicals trial number NCT03342170.

Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling  = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

Current strategies to induce liver remnant hypertrophy before major liver resection.

Hepatic resection is the gold standard for patients affected by primary or metastatic liver tumors but is hampered by the risk of post-hepatectomy liver failure. Despite recent improvements, liver surgery still requires excellent clinical judgement in selecting patients for surgery and, above all, efficient pre-operative strategies to provide adequate future liver remnant. The aim of this article is to review the literature on the rational, the preliminary assessment, the advantages as well as the limits of each existing technique for preparing the liver for major hepatectomy.

Gut Microbiota Reshaped by Pectin Treatment Improves Liver Steatosis in Obese Mice.

Pectin, a soluble fiber, improves non-alcoholic fatty-liver disease (NAFLD), but its mechanisms are unclear. We aimed to investigate the role of pectin-induced changes in intestinal microbiota (IM) in NAFLD. We recovered the IM from mice fed a high-fat diet, treated or not with pectin, to perform a fecal microbiota transfer (FMT). Mice fed a high-fat diet, which induces NAFLD, were treated with pectin or received a fecal microbiota transfer (FMT) from mice treated with pectin before (preventive FMT) or after (curative FMT) being fed a high-fat diet. Pectin prevented the development of NAFLD, induced browning of adipose tissue, and modified the IM without increasing the abundance of proteobacteria. Preventive FMT also induced browning of white adipose tissue but did not improve liver steatosis, in contrast to curative FMT, which induced an improvement in steatosis. This was associated with an increase in the concentration of short-chain fatty acids (SCFAs), in contrast to preventive FMT, which induced an increase in the concentration of branched SCFAs. Overall, we show that the effect of pectin may be partially mediated by gut bacteria.

Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: a prospective case-control study.

Background: The microbiota interacts with the brain through the gut-brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment. Methods: In this case-control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry. Results: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment. Limitations: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results. Conclusion: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode.

[Management of toxicities of BRAF inhibitors and MEK inhibitors in advanced melanoma]. / Gestion des toxicités des inhibiteurs BRAF et MEK dans le mélanome métastatique.

Major therapeutic advances have been made recently in the treatment of metastatic melanoma, due to the development of targeted therapies, namely BRAF and MEK inhibitors, in patients with BRAF V600 mutation. Combinations of vemurafenib+cobimetinib, dabrafenib+trametinib, et encorafenib+binimetinib, evaluated in coBRIM, COMBI-d/COMBI-v and COLUMBUS trials respectively have been approved in this indication. Toxicities induced by combination therapies are different from those reported with monotherapies, in terms of frequency and intensity. Physicians who treat melanoma patients thus face news issues relating to prevention, detection and treatment of these adverse events. This paper summarizes tolerance data from the three pivotal trials (coBRIM, COMBI-v and COLUMBUS) and issues recommendations for the specific management of main toxicities, based on experts' opinion. We discuss dermatological, ophthalmological, cardiovascular, digestive, musculoskeletal, renal and general toxicities and propose a timetable for examinations to be performed before and during treatment.

Bile acid-receptor TGR5 deficiency worsens liver injury in alcohol-fed mice by inducing intestinal microbiota dysbiosis.

BACKGROUND & AIMS: Bile-acid metabolism and the intestinal microbiota are impaired in alcohol-related liver disease. Activation of the bile-acid receptor TGR5 (or GPBAR1) controls both biliary homeostasis and inflammatory processes. We examined the role of TGR5 in alcohol-induced liver injury in mice. METHODS: We used TGR5-deficient (TGR5-KO) and wild-type (WT) female mice, fed alcohol or not, to study the involvement of liver macrophages, the intestinal microbiota (16S sequencing), and bile-acid profiles (high-performance liquid chromatography coupled to tandem mass spectrometry). Hepatic triglyceride accumulation and inflammatory processes were assessed in parallel. RESULTS: TGR5 deficiency worsened liver injury, as shown by greater steatosis and inflammation than in WT mice. Isolation of liver macrophages from WT and TGR5-KO alcohol-fed mice showed that TGR5 deficiency did not increase the pro-inflammatory phenotype of liver macrophages but increased their recruitment to the liver. TGR5 deficiency induced dysbiosis, independently of alcohol intake, and transplantation of the TGR5-KO intestinal microbiota to WT mice was sufficient to worsen alcohol-induced liver inflammation. Secondary bile-acid levels were markedly lower in alcohol-fed TGR5-KO than normally fed WT and TGR5-KO mice. Consistent with these results, predictive analysis showed the abundance of bacterial genes involved in bile-acid transformation to be lower in alcohol-fed TGR5-KO than WT mice. This altered bile-acid profile may explain, in particular, why bile-acid synthesis was not repressed and inflammatory processes were exacerbated. CONCLUSIONS: A lack of TGR5 was associated with worsening of alcohol-induced liver injury, a phenotype mainly related to intestinal microbiota dysbiosis and an altered bile-acid profile, following the consumption of alcohol. LAY SUMMARY: Excessive chronic alcohol intake can induce liver disease. Bile acids are molecules produced by the liver and can modulate disease severity. We addressed the specific role of TGR5, a bile-acid receptor. We found that TGR5 deficiency worsened alcohol-induced liver injury and induced both intestinal microbiota dysbiosis and bile-acid pool remodelling. Our data suggest that both the intestinal microbiota and TGR5 may be targeted in the context of human alcohol-induced liver injury.

Specific microbiome profile in Takayasu's arteritis and giant cell arteritis.

Recent studies have provided evidence of a close link between specific microbiota and inflammatory disorders. While the vessel wall microbiota has been recently described in large vessel vasculitis (LVV) and controls, the blood microbiome in these diseases has not been previously reported (LVV). We aimed to analyse the blood microbiome profile of LVV patients (Takayasu's arteritis [TAK], giant cell arteritis [GCA]) and healthy blood donors (HD). We studied the blood samples of 13 patients with TAK (20 samples), 9 patients with GCA (11 samples) and 15 HD patients. We assessed the blood microbiome profile by sequencing the 16S rDNA blood bacterial DNA. We used linear discriminant analysis (LDA) coupled with linear discriminant effect size measurement (LEfSe) to investigate the differences in the blood microbiome profile between TAK and GCA patients. An increase in the levels of Clostridia, Cytophagia and Deltaproteobacteria and a decrease in Bacilli at the class level were found in TAK patients compared with HD patients (LDA > 2, p < 0.05). Active TAK patients had significantly lower levels of Staphylococcus compared with inactive TAK patients. Samples of GCA patients had an increased abundance of Rhodococcus and an unidentified member of the Cytophagaceae family. Microbiota of TAK compared with GCA patients was found to show higher levels of Candidatus Aquiluna and Cloacibacterium (LDA > 2; p < 0.05). Differences highlighted in the blood microbiome were also associated with a shift of bacterial predicted metabolic functions in TAK in comparison with HD. Similar results were also found in patients with active versus inactive TAK. In conclusion, patients with TAK were found to present a specific blood microbiome profile in comparison with healthy donors and GCA subjects. Significant changes in the blood microbiome profiles of TAK patients were associated with specific metabolic functions.

Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: an individual patient data meta-analysis.

BACKGROUND: Diagnostic tools for liver disease can now include estimation of the grade of hepatic steatosis (S0 to S3). Controlled attenuation parameter (CAP) is a non-invasive method for assessing hepatic steatosis that has become available for patients who are obese (FibroScan XL probe), but a consensus has not yet been reached regarding cutoffs and its diagnostic performance. We aimed to assess diagnostic properties and identify relevant covariates with use of an individual patient data meta-analysis. METHODS: We did an individual patient data meta-analysis, in which we searched PubMed and Web of Science for studies published from database inception until April 30, 2019. Studies reporting original biopsy-controlled data of CAP for non-invasive grading of steatosis were eligible. Probe recommendation was based on automated selection, manual assessment of skin-to-liver-capsule distance, and a body-mass index (BMI) criterion. Receiver operating characteristic methods and mixed models were used to assess diagnostic properties and covariates. Patients with non-alcoholic fatty liver disease (NAFLD) were analysed separately because they are the predominant patient group when using the XL probe. This study is registered with PROSPERO, CRD42018099284. FINDINGS: 16 studies reported histology-controlled CAP including the XL probe, and individual data from 13 papers and 2346 patients were included. Patients with a mean age of 46·5 years (SD 14·5) were recruited from 20 centres in nine countries. 2283 patients had data for BMI; 673 (29%) were normal weight (BMI <25 kg/m2), 530 (23%) were overweight (BMI ≥25 to <30 kg/m2), and 1080 (47%) were obese (BMI ≥30 kg/m2). 1277 (54%) patients had NAFLD, 474 (20%) had viral hepatitis, 285 (12%) had alcohol-associated liver disease, and 310 (13%) had other liver disease aetiologies. The XL probe was recommended in 1050 patients, 930 (89%) of whom had NAFLD; among the patients with NAFLD, the areas under the curve were 0·819 (95% CI 0·769-0·869) for S0 versus S1 to S3 and 0·754 (0·720-0·787) for S0 to S1 versus S2 to S3. CAP values were independently affected by aetiology, diabetes, BMI, aspartate aminotransferase, and sex. Optimal cutoffs differed substantially across aetiologies. Risk of bias according to QUADAS-2 was low. INTERPRETATION: CAP cutoffs varied according to cause, and can effectively recognise significant steatosis in patients with viral hepatitis. CAP cannot grade steatosis in patients with NAFLD adequately, but its value in a NAFLD screening setting needs to be studied, ideally with methods beyond the traditional histological reference standard. FUNDING: The German Federal Ministry of Education and Research and Echosens.

Computed Tomography Assessment of Fat Distribution and Staple-Line Leak Risk After Sleeve Gastrectomy.

PURPOSE: Sleeve gastrectomy (SG) has become the most frequent bariatric procedure and staple-line leak represents its most feared complication. Visceral obesity, a core component of the metabolic syndrome, has been associated with worst postoperative outcomes after various abdominal surgical procedures, and can be estimated by computed tomography (CT). The aim of this study was to assess the impact of radiologically determined visceral obesity in the risk of staple-line leak after SG. MATERIAL AND METHODS: A retrospective analysis of a prospective database was performed in consecutive patients undergoing SG. Several anthropometric variables were measured on a preoperative CT scan. Multivariate analysis was performed to determine preoperative risk factors for staple-line leak. RESULTS: During the study period, 377 patients were included in the analysis. The median BMI was 39.7 kg/m2 (36.5-43.5) and 8 patients (2.1%) presented a gastric leak. After multivariate analysis, visceral obesity defined by visceral fat area (VFA)/body surface area (BSA) ≥ 85 cm2/m2 was the only independent predictive factor for gastric leak (OR = 5312). CONCLUSION: CT scan-assessed visceral obesity defined by a VFA/BSA ratio ≥ 85 cm2/m2 is associated with an increased risk of gastric leak after SG. Preoperatively radiological examination in patients suspected of visceral obesity would be useful to optimize preoperative management.

Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study.

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

Laparoscopic Greater Curvature Plication for the Treatment of Obesity: a Systematic Review.

BACKGROUND: During the last decade, laparoscopic greater curvature plication (LGCP) has been used as a bariatric procedure for the treatment of obesity, regarded as less invasive and less expensive than other surgical bariatric procedures. We aimed to systematically review the literature and highlight recent clinical data regarding outcomes of LGCP in the treatment of obesity. METHODS: A comprehensive research of Pubmed database on LGCP was performed. The search was conducted on the first of May 2020 and was not limited to any date range. Outcomes of interest were surgical technique, postoperative complications, weight loss outcomes, comorbidities improvement or resolution, and revisional surgeries after technical failure or weight regain. RESULTS: Fifty-three articles were eligible for inclusion, with 3103 patients undergoing LGCP (mean age: 13.8-55 years). Mean preoperative body mass index (BMI) ranged from 31.2 to 47.8 kg/m2. Mean operative time ranged from 48 to 193 min. Length of hospital stay ranged from 0.75 to 7.2 days. Most studies provided postoperative follow-up up to 12 months. Mean percentage of excess weight loss (%EWL) ranged from 30.2 to 71.1% and 35 to 77.1% at 6 and 12 months post-LGCP, respectively. Only one study followed patients for more than 10 years and mean %EWL at 1, 5, and 10 years was 67%, 55%, and 42%, respectively. CONCLUSION: LGCP seems to be an acceptable surgical procedure for the treatment of obesity, especially in centers having a low medical budget. However, most existing comparative studies report superiority of LSG regarding weight loss.

Multikinase inhibitor-induced liver injury in patients with cancer: A review for clinicians.

BACKGROUND: Multikinase inhibitors (MKI) are targeted molecular agents that have revolutionized cancer management. However, there is a paucity of data concerning MKI-related liver injury risk and clinical guidelines for the management of liver toxicity in patients receiving MKI for cancer are scarce. DESIGN: We conducted a PubMed search of articles in English published from January 2000 to December 2018 related to hepatotoxicity of the 29 FDA-approved MKIs at doses used in clinical practice. The search terms were the international non-proprietary name of each agent cross-referenced with «hepatotoxicity¼, «hepatitis¼, «hepatic adverse event¼, or «liver failure¼, and «phase II clinical trial¼, «phase III clinical trial¼, or «case report¼. RESULTS: Following this search, 140 relevant studies and 99 case reports were considered. Although asymptomatic elevation of aminotransferase levels has been frequently observed in MKI clinical trials, clinically significant hepatotoxicity is a rare event. In most cases, the interval between treatment initiation and the onset of liver injury is between one week and two months. Liver toxicity is often hepatocellular and less frequently mixed. Life-threatening MKI-induced hepatic injury has been described, involving fulminant liver failure or death. Starting from existing data, a description of MKI-related liver events, grading of hepatotoxicity risk, and recommendations for management are also given for various MKI molecules. CONCLUSION: All MKIs can potentially cause liver injury, which is sometimes irreversible. As there is still no strategy available to prevent MKI-related hepatotoxicity, early detection remains crucial. The surveillance of liver function during treatment may help in the early detection of hepatotoxicity. Furthermore, the exclusion of potential causes of hepatic injury is essential to avoid unnecessary MKI withdrawal.

Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury.

OBJECTIVE: Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions. DESIGN: We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice. RESULTS: Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists. CONCLUSIONS: Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target.

Laparoscopic sleeve gastrectomy for the treatment of idiopathic intracranial hypertension in patients with severe obesity.

BACKGROUND: Severe obesity is a major risk factor for idiopathic intracranial hypertension (IIH). Data on the role of bariatric surgery for the treatment of this condition are scarce. OBJECTIVE: To evaluate the effectiveness of laparoscopic sleeve gastrectomy (LSG) on treating IIH in severely obese patients. SETTING: Two university bariatric surgery centers. METHODS: Prospectively collected data from consecutive patients undergoing LSG were retrospectively analyzed. Patients with IIH and referred by neuroophthalmologists for bariatric surgery were included in the analysis. RESULTS: Fifteen female patients with IIH underwent LSG (median age: 31 yr). Median preoperative body mass index was 42.1 kg/m2. Preoperatively, 14 patients (93.3%) had chronic headaches, 8 (53.3%) pulsatile tinnitus, and 1 (6.6%) epistaxis episodes. Ophthalmologic assessment showed bilateral papilledema in all patients, of whom 13 had visual symptoms. Median initial cerebrospinal fluid opening pressure was 31 cmH2 O (range: 25-50 cmH2 O); 4 patients required repeated decompressing lumbar punctures (1 ventriculoperitoneal shunt). LSG was successfully performed in all patients. No patients were lost to follow-up. Mean excess weight loss was and 87.4% and 88.1% 1 and 2 years after LSG, respectively. Headaches totally resolved in 13 patients (93.3%) and improved in 1 (P < .001). Pulsatile tinnitus (P = .013), epistaxis, visual symptoms (P < .001), and papilledema (P < .001) significantly resolved. Medication was stopped in 14 patients (93.3%). Two years after LSG, IIH outcomes for 7 patients reaching this time point remained unchanged. CONCLUSION: This study suggests that LSG is effective for severely obese patients with IIH, resulting in complete remission or significant improvement of their symptoms as well as medication discontinuation.

Laparoscopic sleeve gastrectomy for morbid obesity in renal transplantation candidates: a matched case-control study.

Obesity has become an important issue in patients with end-stage renal disease (ESRD). Since it is considered a relative contraindication for renal transplantation, bariatric surgery has been advocated to treat morbid obesity in transplant candidates, and laparoscopic sleeve gastrectomy (LSG) is the most reported procedure. However, comparative data regarding outcomes of LSG in patients with or without ESRD are scarce. Consecutive patients with ESRD (n = 29) undergoing LSG were compared with matched patients with normal renal function undergoing LSG in a 1:3 ratio using propensity score adjustment. Data were collected from a prospective database. Eligibility for transplantation was also studied. A lower weight loss (20 kg (16-30)) was observed in patients with ESRD within the first year as compared to matched patients (28 kg (21-34)) (P < 0.05). After a median follow-up of 30 (19-50) months in the ESRD group, contraindication due to morbid obesity was lifted in 20 patients. Twelve patients underwent transplantation. In patients with ESRD potentially eligible for transplantation, LSG allows similar weight loss in comparison with matched patients with normal renal function, enabling lifting contraindication for transplantation due to morbid obesity in the majority of patients within the first postoperative year.

A Model to Identify Heavy Drinkers at High Risk for Liver Disease Progression.

BACKGROUND & AIMS: Alcohol-related liver disease (ALD) causes chronic liver disease. We investigated how information on patients' drinking history and amount, stage of liver disease, and demographic feature can be used to determine risk of disease progression. METHODS: We collected data from 2334 heavy drinkers (50 g/day or more) with persistently abnormal results from liver tests who had been admitted to a hepato-gastroenterology unit in France from January 1982 through December 1997; patients with a recorded duration of alcohol abuse were assigned to the development cohort (n=1599; 75% men) or the validation cohort (n=735; 75% men), based on presence of a liver biopsy. We collected data from both cohorts on patient history and disease stage at the time of hospitalization. For the development cohort, severity of the disease was scored by the METAVIR (due to the availability of liver histology reports); in the validation cohort only the presence of liver complications was assessed. We developed a model of ALD progression and occurrence of liver complications (hepatocellular carcinoma and/or liver decompensation) in association with exposure to alcohol, age at the onset of heavy drinking, amount of alcohol intake, sex and body mass index. The model was fitted to the development cohort and then evaluated in the validation cohort. We then tested the ability of the model to predict disease progression for any patient profile (baseline evaluation). Patients with a 5-y weighted risk of liver complications greater than 5% were considered at high risk for disease progression. RESULTS: Model results are given for the following patient profiles: men and women, 40 y old, who started drinking at an age of 25 y, drank 150 g/day, and had a body mass index of 22 kg/m2 according to the disease severity at baseline evaluation. For men with baseline F0-F2 fibrosis, the model estimated the probabilities of normal liver, steatosis, or steatohepatitis at baseline to be 31.8%, 61.5% and 6.7%, respectively. The 5-y weighted risk of liver complications was 1.9%, ranging from 0.2% for men with normal liver at baseline evaluation to 10.3% for patients with steatohepatitis at baseline. For women with baseline F0-F2 fibrosis, probabilities of normal liver, steatosis, or steatohepatitis at baseline were 25.1%, 66.5% and 8.4%, respectively; the 5-y weighted risk of liver complications was 3.2%, ranging from 0.5% for women with normal liver at baseline to 14.7% for patients with steatohepatitis at baseline. Based on the model, men with F3-F4 fibrosis at baseline have a 24.5% 5-y weighted risk of complications (ranging from 20.2% to 34.5%) and women have a 30.1% 5-y weighted risk of complications (ranging from 24.7% to 41.0%). CONCLUSIONS: We developed a Markov model that integrates data on level and duration of alcohol use to identify patients at high risk of liver disease progression. This model might be used to adapt patient care pathways.