Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target.

OBJECTIVE: We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. DESIGN: Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. RESULTS: The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. CONCLUSIONS: These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. TRIAL REGISTRATION NUMBER: NCT02390232.

Acute kidney injury in patients with cirrhosis: Prospective longitudinal study in 405 patients.

BACKGROUND: Acute kidney injury (AKI) is common in patients with cirrhosis. In 2015, the International Club of Ascites (ICA) proposed new definitions of AKI in order to improve the prediction of outcomes. Our aim was to assess the prevalence and prognostic value of ICA 2015 - AKI criteria in hospitalised patients with cirrhosis. METHODS: We prospectively collected data from 405 consecutive cirrhotic patients admitted to the hospital between November 2016 and November 2017. AKI was diagnosed at inclusion according to ICA 2015 criteria, and was assessed to predict 30-day and 90-day in-hospital mortality. RESULTS: AKI was diagnosed in 78 (19.3%) patients. AKI was independently associated with 90-day death (HR 7.61; 95% CI 4.75-12.19; p < 0.001). In hospital, 30-day and 90-day survival was lower in the group of patients with AKI compared to the group with no AKI (72% vs. 98%, p < 0.001; 64% vs. 96%, p < 0.001; and 49% vs. 81%, p < 0.001, respectively). Patients with stage 1a AKI had a lower 30-day and 90-day survival compared to the group of patients who did not develop AKI (71% vs. 96%, p < 0.001, and 71% vs. 91%, p < 0.01, respectively) and better survival than patients with more severe AKI (71% vs. 40%, p < 0.01). CONCLUSIONS: AKI was independently associated with mortality in patients with cirrhosis, even at the very early 1a stage. Response to treatment improved survival, and was inversely proportional to the stage of AKI, which suggests that treatment should be started at the earliest stage of AKI.

Non-invasive diagnosis and follow-up of non-alcoholic fatty liver disease.

NAFLD is a frequent disease that affects 25% of the worldwide population. There is no specific diagnostic test for NAFLD, and the diagnosis mainly relies on the elimination of the other causes of chronic liver diseases with liver biopsy kept for unsure diagnoses. Non-invasive tests are now available to assess NAFLD severity and therefore to help physicians decide on the patient management and follow-up. These non-invasive tests can also be used to define pathways that organize referrals from primary care and diabetology clinics to the liver specialist, with the ambition to improve the screening of asymptomatic patients with NAFLD and advanced liver disease. NAFLD being the liver expression of the metabolic syndrome, physicians need also take care to screen for diabetes and to evaluate the cardiovascular risk in those patients. These recommendations from the French Association for the Study of the Liver (AFEF) aim at providing guidance on the following questions: how to diagnose NAFLD; how non-invasive tests should be used to assess NAFLD severity; how to follow patients with NAFLD; when to perform liver biopsy in NAFLD; and how to decide referral to the liver specialist for a patient with NAFLD.

A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH.

BACKGROUND: Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. METHODS: In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis. RESULTS: A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo. CONCLUSIONS: In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.).

Management of diabetes mellitus in patients with cirrhosis: An overview and joint statement.

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity in patients with cirrhosis that is projected to rise in prevalence due to the worldwide burden of obesity, insulin-resistance and non-alcoholic fatty liver disease. The management of T2DM in patients with cirrhosis is complex given the requirement for accurate adaptation according to the level of liver function impairment, with lack of summary of the little evidence available in the literature. Here, we summarise the data available with respect to the epidemiology and the impact of T2DM in patients with cirrhosis, as well as those on the management of T2DM in these patients. We provide guidance for the diagnosis of T2DM and the monitoring of glycaemic control in patients with cirrhosis, and for the management of nutrition and pharmacological treatments in relation to the level of liver dysfunction.

Noninvasive Diagnosis of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease.

INTRODUCTION: We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice. METHODS: This is an international cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10 kPa, and no previous decompensation. Portal hypertension was defined by an HVPG >5 mm Hg. A positive predictive value ≥90% was considered to validate LSM cutoffs for CSPH (HVPG ≥10 mm Hg), whereas a negative predictive value ≥90% ruled out CSPH. RESULTS: A total of 836 patients with hepatitis C (n = 358), nonalcoholic steatohepatitis (NASH, n = 248), alcohol use (n = 203), and hepatitis B (n = 27) were evaluated. Portal hypertension prevalence was >90% in all cACLD etiologies, except for patients with NASH (60.9%), being even lower in obese patients with NASH (53.3%); these lower prevalences of portal hypertension in patients with NASH were maintained across different strata of LSM values. LSM ≥25 kPa was the best cutoff to rule in CSPH in alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, and nonobese patients with NASH, whereas in obese NASH patients, the positive predictive value was only 62.8%. A new model for patients with NASH (ANTICIPATE-NASH model) to predict CSPH considering body mass index, LSM, and platelet count was developed, and a nomogram was constructed. LSM ≤15 kPa plus platelets ≥150 × 10/L ruled out CSPH in most etiologies. DISCUSSION: Patients with cACLD of NASH etiology, especially obese patients with NASH, present lower prevalences of portal hypertension compared with other cACLD etiologies. LSM ≥25 kPa is sufficient to rule in CSPH in most etiologies, including nonobese patients with NASH, but not in obese patients with NASH.

Large-scale screening of lipase acid deficiency in at risk population.

BACKGROUND: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD). METHODS: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots. RESULTS: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel. CONCLUSION: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations.

Non-alcoholic fatty liver disease and heart failure with preserved ejection fraction: from pathophysiology to practical issues.

The prevalence of non-alcoholic fatty liver disease (NAFLD) in heart failure (HF) preserved left ventricular ejection fraction (HFpEF) patients could reach 50%. Therefore, NAFLD is considered an emerging risk factor. In 20% of NAFLD patients, the condition progresses to non-alcoholic steatohepatitis (NASH), the aggressive form of NAFLD characterized by the development of fibrosis in the liver, leading to cirrhosis. The purpose of this review is to provide an overview of the relationships between NAFLD and HFpEF and to discuss its impact in clinical setting. Based on international reports published during the past decade, there is growing evidence that NAFLD is associated with an increased incidence of cardiovascular diseases, including impaired cardiac structure and function, arterial hypertension, endothelial dysfunction, and early carotid atherosclerosis. NAFLD and HFpEF share common risk factors, co-morbidities, and cardiac outcomes, in favour of a pathophysiological continuum. Currently, NAFLD and NASH are principally managed with non-specific therapies targeting insulin resistance like sodium-glucose co-transporter-2 inhibitors and liraglutide, which can effectively treat hepatic and cardiac issues. Studies including HFpEF patients are ongoing. Several specific NAFLD-oriented therapies are currently being developed either alone or as combinations. NAFLD diagnosis is based on a chronic elevation of liver enzymes in a context of metabolic syndrome and insulin resistance, with fibrosis scores being available for clinical practice. In conclusion, identifying HF patients at risk of NAFLD is a critically important issue. As soon as NAFLD is confirmed and its severity determined, patients should be proposed a management focused on symptoms and co-morbidities.

Lessons from "real life experience" of rifaximin use in the management of recurrent hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy (HE) is a major complication of cirrhosis with independent prognostic significance. The current management of HE is mainly based on lactulose. Rifaximin has been shown to decrease the risk of HE recurrence in patients with episodic forms. HE can also be persistent. However, there is no drug support recommendation for rifaximin use in this setting. AIM: To assess the effectiveness of rifaximin in the management of recurrent episodes of HE and recurrent acute exacerbations on persistent HE, in "real life conditions". METHODS: In this retrospective study, using a within-subjects design, we collected data of patients treated with rifaximin for HE in two liver diseases centers, during the six-month period before and during the six-month period after the initiation of rifaximin. The primary effectiveness endpoint was the total number of HE events involving hospitalization. RESULTS: Rifaximin was introduced for prevention of recurrent HE episodes in 29 out of 62 patients with normal mental status between episodes and for prevention of recurrent acute exacerbations on persistent HE in 33 out of 62 patients. In the "prevention of recurrent HE episodes" group, fewer HE events (0.79 vs 1.78; P = 0.013) were reported during the period of time when rifaximin was used. In the "prevention of recurrent acute exacerbations on persistent HE" group, there was no significant difference in the number of HE-events (1.48 vs 1.77; P = 0.582). CONCLUSION: In this real-life experience, the effectiveness of rifaximin was confirmed in the prevention of HE episodes recurrence but was not proved in the prevention of acute exacerbations recurrence on persistent HE.

Direct comparison of the specialised blood fibrosis tests FibroMeterV2G and Enhanced Liver Fibrosis score in patients with non-alcoholic fatty liver disease from tertiary care centres.

BACKGROUND: The Enhanced Liver Fibrosis score (ELF) and the FibroMeterV2G are two specialized blood fibrosis tests which include direct markers of liver fibrosis. They have been shown to be more accurate than the simple blood fibrosis tests FIB4 and the non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS). AIMS: To directly compare the accuracies of ELF and FibroMeterV2G for the non-invasive diagnosis of liver fibrosis in NAFLD. METHODS: Four hundred and seventeen patients with biopsy-proven NAFLD were enrolled from two tertiary care centres. Four blood fibrosis tests were calculated: ELF, FibroMeterV2G , NFS, and FIB4. Advanced fibrosis F3/4 on liver biopsy (NASH CRN scoring) was the primary endpoint. RESULTS: Areas under the receiver operating characteristic (AUROC) curve for advanced fibrosis were not significantly different between the direct markers of liver fibrosis (hyaluronate, PIIINP, TIMP-1, alpha2-macroglobulin) and the simple blood fibrosis tests NFS and FIB4. ELF (0.793 ± 0.022) and FibroMeterV2G (0.804 ± 0.021) had significantly higher AUROC than NFS (0.722 ± 0.025, P < .010) and FIB4 (0.739 ± 0.024, P < .020). AUROC for advanced fibrosis and Obuchowski index were not significantly different between ELF and FibroMeterV2G . Algorithms using first ELF or FibroMeterV2G and then liver biopsy in case of undetermined diagnosis provided high diagnostic accuracy for advanced fibrosis: 90% sensitivity, 90% specificity, 93% negative predictive value, 85% positive predictive value, and 90% correct classification. In these algorithms, the rate of liver biopsy was 45.3% with ELF versus 39.3% with FibroMeterV2G (P = .065). CONCLUSIONS: ELF and FibroMeterV2G have equal accuracy and perform better than the simple FIB4 and NFS tests for the non-invasive diagnosis of advanced liver fibrosis in patients with NAFLD from tertiary care centres.

A Prospective Study Identifying Predictive Factors of Cardiac Decompensation After Transjugular Intrahepatic Portosystemic Shunt: The Toulouse Algorithm.

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is now a standard for the treatment of portal hypertension-related complications. After the TIPS procedure, incidence and risk factors of cardiac decompensation are poorly known. The main objectives were to measure the incidence of the onset of cardiac decompensation after TIPS and identify the predictive factors. APPROACH AND RESULTS: All patients with cirrhosis treated with TIPS between May 2011 and June 2016 were considered for inclusion. They received a cardiac assessment by standard biological parameters, transthoracic echocardiography, and right heart catheterization. Patients were followed for 1 year after TIPS insertion. The main endpoint was the incidence of cardiac decompensation requiring hospitalization. One hundred seventy-four patients were treated by TIPS during the period. One hundred patients who underwent a complete cardiac evaluation were included. A cardiac decompensation occurred in 20% of the patients. The parameters associated with the occurrence of severe cardiac decompensation were a prolonged QT interval corrected (462 vs. 443 ms; P = 0.05), an elevated pre-TIPS brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) level, an elevated E/A ratio (1.5 vs. 1.0; P = 0.001) and E/e' ratio (11 vs. 7; P < 0.001), and a left atrial dilatation (40 vs. 29 mL/m2 ; P = 0.011). The presence of aortic stenosis was also associated with cardiac decompensation. A level of BNP <40 pg/mL and NT-proBNP <125 pg/mL allowed identifying patients without risk of cardiac decompensation. Additionally, absence of diastolic dysfunction criteria at echocardiography ruled out the risk of further cardiac decompensation. CONCLUSIONS: Hospitalization for cardiac decompensation is observed in 20% of patients in the year after TIPS insertion. Combining BNP or NT-proBNP levels and echocardiographic parameters should help improve patient selection.

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice.

Hepatocyte estrogen receptor α (ERα) was recently recognized as a relevant molecular target for nonalcoholic fatty liver disease (NAFLD) prevention. The present study defined to what extent hepatocyte ERα could be involved in preserving metabolic homeostasis in response to a full (17ß-estradiol [E2]) or selective (selective estrogen receptor modulator [SERM]) activation. Ovariectomized mice harboring a hepatocyte-specific ERα deletion (LERKO mice) and their wild-type (WT) littermates were fed a high-fat diet (HFD) and concomitantly treated with E2, tamoxifen (TAM; the most used SERM), or vehicle. As expected, both E2 and TAM prevented all HFD-induced metabolic disorders in WT mice, and their protective effects against steatosis were abolished in LERKO mice. However, while E2 still prevented obesity and glucose intolerance in LERKO mice, hepatocyte ERα deletion also abrogated TAM-mediated control of food intake as well as its beneficial actions on adiposity, insulin sensitivity, and glucose homeostasis, suggesting a whole-body protective role for liver-derived circulating factors. Moreover, unlike E2, TAM induced a rise in plasma concentration of the anorectic hepatokine growth differentiation factor 15 (Gdf15) through a transcriptional mechanism dependent on hepatocyte ERα activation. Accordingly, ERα was associated with specific binding sites in the Gdf15 regulatory region in hepatocytes from TAM-treated mice but not under E2 treatment due to specific epigenetic modifications. Finally, all the protective effects of TAM were abolished in HFD-fed GDF15-knockout mice. Conclusion: We identified the selective modulation of hepatocyte ERα as a pharmacologic strategy to induce sufficient anorectic hepatokine Gdf15 to prevent experimental obesity, type 2 diabetes, and NAFLD.

New sequential combinations of non-invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD.

BACKGROUND & AIMS: Advanced liver fibrosis is an important diagnostic target in non-alcoholic fatty liver disease (NAFLD) as it defines the subgroup of patients with impaired prognosis. The non-invasive diagnosis of advanced fibrosis is currently limited by the suboptimal positive predictive value and the grey zone (representing indeterminate diagnosis) of fibrosis tests. Here, we aimed to determine the best combination of non-invasive tests for the diagnosis of advanced fibrosis in NAFLD. METHODS: A total of 938 patients with biopsy-proven NAFLD were randomized 2:1 into derivation and validation sets. All patients underwent liver stiffness measurement with vibration controlled transient elastography (VCTE) and blood fibrosis tests (NAFLD fibrosis score, Fibrosis-4 [FIB4], Fibrotest, Hepascore, FibroMeter). FibroMeterVCTE, which combines VCTE results and FibroMeter markers in a single test, was also calculated in all patients. RESULTS: For the diagnosis of advanced fibrosis, VCTE was significantly more accurate than the blood tests (area under the receiver operating characteristic curve [AUROC]: 0.840 ±â€¯0.013, p ≤0.005). FibroMeter was the most accurate blood test (AUROC: 0.793 ±â€¯0.015, p ≤0.017). The combinatory test FibroMeterVCTE outperformed VCTE and blood tests (AUROC: 0.866 ±â€¯0.012, p ≤0.005). The sequential combination of FIB4 then FibroMeterVCTE (FIB4-FMVCTE algorithm) or VCTE then FibroMeterVCTE (VCTE-FMVCTE algorithm) provided an excellent diagnostic accuracy of 90% for advanced fibrosis, with liver biopsy only required to confirm the diagnosis in 20% of cases. The FIB4-FMVCTE and VCTE-FMVCTE algorithms were significantly more accurate than the pragmatic algorithms currently proposed. CONCLUSION: The sequential combination of fibrosis tests in the FIB4-FMVCTE and VCTE-FMVCTE algorithms provides a highly accurate solution for the diagnosis of advanced fibrosis in NAFLD. These algorithms should now be validated for the diagnosis of advanced liver fibrosis in diabetology or primary care settings. LAY SUMMARY: The evaluation of liver fibrosis is mandatory in non-alcoholic fatty liver disease (NAFLD), as advanced fibrosis identifies the subgroup of patients with impaired prognosis. FibroMeterVCTE is a new fibrosis test combining blood markers and the result of vibration controlled transient elastography (VCTE) into a single diagnostic test. Our results show that FibroMeterVCTE outperforms other blood fibrosis tests and VCTE alone for the diagnosis of advanced fibrosis in a large multi-centric cohort of 938 patients with biopsy-proven NAFLD. Sequential algorithms using a simple blood test or VCTE as a first-line procedure, then FibroMeterVCTE as a second-line test accurately classified 90% of patients.

Estrogen receptor subcellular localization and cardiometabolism.

BACKGROUND: In addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective effects. These beneficial actions are mainly mediated by estrogen receptor alpha (ERα), which is widely expressed in metabolic and vascular tissues. As a member of the nuclear receptor superfamily, ERα was primarily considered as a transcription factor that controls gene expression through the activation of its two activation functions (ERαAF-1 and ERαAF-2). However, besides these nuclear actions, a pool of ERα is localized in the vicinity of the plasma membrane, where it mediates rapid signaling effects called membrane-initiated steroid signals (MISS) that have been well described in vitro, especially in endothelial cells. SCOPE OF THE REVIEW: This review aims to summarize our current knowledge of the mechanisms of nuclear vs membrane ERα activation that contribute to the cardiometabolic protection conferred by estrogens. Indeed, new transgenic mouse models (affecting either DNA binding, activation functions or membrane localization), together with the use of novel pharmacological tools that electively activate membrane ERα effects recently allowed to begin to unravel the different modes of ERα signaling in vivo. CONCLUSION: Altogether, available data demonstrate the prominent role of ERα nuclear effects, and, more specifically, of ERαAF-2, in the preventive effects of estrogens against obesity, diabetes, and atheroma. However, membrane ERα signaling selectively mediates some of the estrogen endothelial/vascular effects (NO release, reendothelialization) and could also contribute to the regulation of energy balance, insulin sensitivity, and glucose metabolism. Such a dissection of ERα biological functions related to its subcellular localization will help to understand the mechanism of action of "old" ER modulators and to design new ones with an optimized benefit/risk profile.

Towards optimization of estrogen receptor modulation in medicine.

Women now spend more than one-third of their lives in the postmenopausal years, and the decline of endogenous estrogen production during menopause is accompanied by a series of functional disorders that affect the quality of life. These symptoms could be alleviated or even totally suppressed by menopausal hormone therapy (MHT), initially based on natural estrogens extracted from the urine of pregnant mares (mainly in the USA, using the oral route) and later from the synthesis of the natural estrogen, 17ß-estradiol (mainly in Europe, in particular using the transdermal route). Estrogen receptor (ER) α is the main receptor mediating the physiological effects of estrogens. ERα belongs to the nuclear receptor superfamily and activates gene transcription in a time and tissue-specific manner through two distinct activation functions (AF), AF1 and AF2. In addition to these classical genomic actions, ERα also mediates membrane initiated signaling enabling rapid actions of estrogen, potentially along or in interaction with other receptors. Here, we provide a brief historical overview of MHT, and we then highlight recent advances in the characterization of new treatments based on the association of estrogens with selective estrogen receptor modulators (SERMs) or on the modulation of nuclear or membrane ERα.

Grazoprevir plus elbasvir in HCV genotype-1 or -4 infected patients with stage 4/5 severe chronic kidney disease is safe and effective.

Patients with advanced chronic kidney disease who receive direct-acting antiviral drugs require special consideration regarding comorbid conditions. Here we assessed the efficacy and safety of grazoprevir plus elbasvir in 93 patients infected with HCV genotype 1 or 4 and with advanced chronic kidney disease in a non-randomized, multicenter, nationwide observational survey. Twenty patients with HCV genotype 1a, 51 patients with 1b, four unclassified genotype 1, 17 with genotype 4 and one with genotype 6 received grazoprevir plus elbasvir (100/50 mg) once daily. All patients had severe chronic kidney disease with 70 patients stage G5, including patients on hemodialysis (74.2%), and 23 were stage G4 chronic kidney disease. Severe liver disease (Metavir F3/F4) was found in 33 patients. A sustained virologic response 12 weeks after the end of therapy was achieved in 87 of 90 patients. Two patients had a virologic breakthrough and one had a relapse after treatment withdrawal. Most patients received many concomitant medications (mean 7.7) related to comorbid conditions. Serious adverse events occurred in six patients, including three deaths while on grazoprevir plus elbasvir, not related to this therapy. Thus, once-daily grazoprevir plus elbasvir was highly effective with a low rate of adverse events in this advanced chronic kidney disease difficult-to-treat population with an HCV genotype 1 or 4 infection.

Bleeding risk of variceal band ligation in extrahepatic portal vein obstruction is not increased by oral anticoagulation.

BACKGROUND AND OBJECTIVES: Noncirrhotic nontumoral extrahepatic portal vein obstruction (EHPVO) is the second leading cause of portal hypertension (PHT) and is mainly related to prothrombotic disorders. Patients with EHPVO often require prolonged oral anticoagulation therapy (OAT) together with variceal band ligation (VBL) to prevent thrombosis recurrence and PHT-related bleeding, respectively. The benefit-risk balance of VBL in this context remains unknown. We aimed to assess upper gastrointestinal bleeding (UGB) risk and variceal eradication efficacy in EHPVO patients undergoing a VBL program without stopping OAT. PATIENTS AND METHODS: All patients with EHPVO treated (group A) or not (group B) with OAT and undergoing the VBL program were included between 2001 and 2010 in two tertiary French liver centers. We compared the incidence, source, and severity of UGB and variceal eradication efficacy. All EHPVO patients were then matched 1 : 1 with compensated cirrhotic patients with PHT not receiving OAT (group C) to compare UGB incidence and VBL efficacy. RESULTS: Forty-three EHPVO patients (30 with and 13 without OAT) and 43 cirrhotic patients were included for a total of 471 VBL sessions. The incidence of UGB was similar between group A (nine episodes/121 sessions) and group B (6/130), and tended to be higher in EHPVO patients (group A and B) than in cirrhotic patients (2/220). There was no difference between groups when considering bleeding source or severity and variceal eradication efficacy (84%). CONCLUSION: VBL can be performed safely and efficiently without stopping anticoagulation therapy in EHPVO patients.

The antagonist properties of Bazedoxifene after acute treatment are shifted to stimulatory action after chronic exposure in the liver but not in the uterus.

A promising alternative to conventional hormone therapy for postmenopausal symptoms is treatment combining Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), and conjugated equine estrogen (CE). This combination is also known as a tissue-selective estrogen complex (TSEC). Understanding the tissue-specific actions of SERMs and the TSEC remains a major challenge to try to predict their clinical effects. The aim of this study was to compare acute versus chronic treatment with BZA, CE or CE + BZA in two major targets of estrogens, the uterus and the liver. In these two tissues, acute treatment with CE, but not with BZA, induced similar gene expression change than the most important endogenous estrogen, 17-ß estradiol (E2). Acute induction of gene expression by E2 or by CE was antagonized by the addition of BZA. Concomitantly, BZA alone or in combination with E2 or CE induced a partial degradation of ERα protein after acute exposure. In uterus, chronic treatment of BZA alone had no impact on tissue weight gain or on epithelial cell proliferation, and also antagonized CE-effect in uterus, thereby mimicking the acute effect. By contrast, in the liver, chronic BZA and CE + BZA elicited agonistic transcriptional effects similar to those of CE alone. In addition, at variance to BZA acute effect, no change in ERα protein abundance was observed after chronic treatment in this tissue. These experimental in vivo data highlight a new aspect of the time-dependent tissue-specific action of BZA or TSEC, i.e. they can act acutely as antagonists but become agonists after chronic treatment. This shift was observed in liver tissue, but not in proliferative sex target such as the uterus.