Multimodal treatment confers best overall survival results in patients with huge hepatocellular carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Huge (>10 cm) hepatocellular carcinoma is burdened by elevated mortality due to its peculiar characteristics and delayed diagnosis. Liver resection is considered the gold standard although survival is poor. Recently, some different strategies have been evaluated to improve results in tumor recurrence and survival. The aim of this research is to identify which strategy offers the best results in terms of overall survival for resectable huge hepatocellular carcinoma. METHODS: A systematic review and network meta-analysis of 13 studies was conducted from PubMed, Embase, Scopus, Cochrane Library, and Web of Science databases including research comparing two or more treatments to manage huge hepatocellular carcinoma. Results were synthesized through forest plots and risk of bias assessed with the CINeMA framework as recommended. RESULTS: The association of liver resection and transcatheter arterial chemoembolization confers a significant improvement in survival compared to liver resection alone (HR: 0.55) while transcatheter arterial chemoembolization, radioembolization, and ethanol ablation alone were associated to decreased overall survival. Within-study bias, indirectness and incoherence were the domains mainly affected by concerns in risk of bias analysis. CONCLUSION: Multimodal treatment including liver resection and transcatheter arterial chemoembolization increases survival in patients with resectable huge hepatocellular carcinoma.

Enhanced liver fibrosis score is stable after withdrawal in patients with heavy alcohol consumption: A pilot study.

BACKGROUND: Enhanced liver fibrosis (ELF) score is an accurate, noninvasive test for assessing the severity of liver fibrosis in chronic liver disease, including alcohol-related liver disease. However, whether the ELF score changes during alcohol withdrawal is unknown. This pilot study assessed changes in the ELF score during withdrawal in patients with a history of excessive alcohol intake. METHODS: In this prospective study, ELF was performed on day 0 (D0, at the beginning of hospitalization), at day 7 (D7, on discharge from hospital), and at follow-up visits on days 30 (D30) and 90 (D90). Transient elastography (TE) was also assessed on days 4 (D4) and D30. RESULTS: The study included 35 patients (71% male) with a mean alcohol intake of 139 g/day. On D30 and D90, 8 and 13 patients had resumed alcohol consumption (mean intake of 90 and 80 g/day, respectively). In patients who remained abstinent, the mean ELF score was 8.93 on D0, 9.14 on D30 (p = 0.32), and 9.27 on D90 (p = 0.14). In patients who resumed alcohol, mean ELF score was 9.7 on D0, 10.05 on D30 (p = 0.09), and 9.71 on D90 (p = 0.12). ELF score was comparable over the first months after withdrawal, although there was a slight increase in the first week (mean ELF score increased from 9.24 on D0 to 9.74 on D7, p < 0.001). Mean TE value was 7.9 kPa on D4 and 8.1 kPa on D30 (p = 0.84) in patients who resumed alcohol consumption, and 8.3 and 7.5 kPa (p = 0.03) on D4 and D30, respectively, in abstinent patients. CONCLUSION: The ELF score is stable during the first months after withdrawal and thus appears to be a useful tool to assess liver fibrosis or cirrhosis in this setting. Nevertheless, because in the first week there is a transient increase in ELF score, caution in interpretation is warranted.

Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.

BACKGROUND: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.

Roles of innate lymphoid cells in metabolic and alcohol-associated liver diseases.

Innate lymphoid cells (ILCs) have been identified as potent regulators of inflammation, cell death and wound healing, which are the main biological processes involved in the progression of chronic liver disease. Obesity and chronic alcohol consumption are the leading contributors to chronic liver diseases in developed countries, due to inappropriate lifestyles. In particular, inflammation is a key factor in these liver abnormalities and promotes the development of more severe lesions such as fibrosis, cirrhosis and hepatocellular carcinoma. Opposite roles of ILC subsets have been described in the development of chronic liver disease, depending on the stage and aetiology of the disease. The heterogeneous family of ILCs encompasses cytotoxic natural killer cells, the cytokine-producing type 1, 2 and 3 ILCs and lymphoid tissue inducer cells. Dysfunction of these immune cells provokes uncontrolled inflammation and tissue damage, which are the basis for tumour development. In this review, we provide an overview of the recent and putative roles of ILC subsets in obesity and alcohol-associated liver diseases, which are currently the major contributors to end-stage liver complications such as fibrosis/cirrhosis and hepatocellular carcinoma.

Remission of nonalcoholic steatohepatitis after bariatric surgery: a single referral center cohort study.

BACKGROUND: Obesity is associated with nonalcoholic steatohepatitis (NASH), which leads to an increased rate of primary liver cancers, cirrhosis, and decreased life expectancy. Metabolic/bariatric surgery (MBS) determines long-term weight loss and the resolution of obesity-related medical problems. OBJECTIVE: The aim of this study was to evaluate the impact of MBS on liver histologic features in individuals with obesity. SETTING: Tertiary referral university hospital. METHODS: We retrospectively analyzed data on 37 patients undergoing MBS from a prospectively held database. All patients had a liver biopsy at the time of MBS and a second liver biopsy in case of further surgery or for NASH follow-up. Eighteen patients had NASH on the first liver biopsy. The primary endpoint was the resolution of steatohepatitis without worsening of fibrosis on the second liver biopsy. Secondary endpoints were the evolution of liver steatosis, hepatocyte ballooning, nonalcoholic fatty liver disease activity score, and biochemical parameters from the time of the first to the second liver biopsy. RESULTS: Fifteen (83.3%) patients had significant resolution of steatohepatitis (P < .001) without fibrosis worsening. There was a statistically significant improvement of all blood tests except for low-density lipoprotein, alkaline phosphatases, and bilirubinemia. The Homeostatic Model Assessment (HOMA) index was significantly improved after MBS (P < .001), and circulating insulin and leptin concentrations were significantly reduced. Mean weight loss was 47 kg, with a 16.6 kg/m2 body mass index reduction and a % of total weight loss (%TWL) of 40.3 ±14% from the moment of MBS to the last follow-up. CONCLUSION: MBS is effective in determining NASH regression without fibrosis worsening and in reducing HOMA index and leptin and insulin concentrations.

Osteopontin-driven T-cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD.

OBJECTIVE: This study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T-cell regulation in initiation of obesity-driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic-associated fatty liver disease (MAFLD) development. METHODS: SPP1 and T-cell marker expression was evaluated in AT and liver according to type 2 diabetes and MAFLD in human individuals with obesity. The role of SPP1 on T cells was evaluated in Spp1-knockout mice challenged with a high-fat diet. RESULTS: In humans with obesity, elevated SPP1 expression in AT was parallel to T-cell marker expression (CD4, CD8A) and IR. Weight loss reversed AT inflammation with decreased SPP1 and CD8A expression. In liver, elevated SPP1 expression correlated with MAFLD severity and hepatic T-cell markers. In mice, although Spp1 deficiency did not impact obesity, it did improve AT IR associated with prevention of proinflammatory T-cell accumulation at the expense of regulatory T cells. Spp1 deficiency also decreased ex vivo helper T cell, subtype 1 (Th1) polarization of AT CD4+ and CD8+ T cells. In addition, Spp1 deficiency significantly reduced obesity-associated liver steatosis and inflammation. CONCLUSIONS: Current findings highlight a critical role of SPP1 in the initiation of obesity-driven chronic inflammation by regulating accumulation and/or polarization of T cells. Early targeting of SPP1 could be beneficial for IR and MAFLD treatment.

Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma: Real-life Data on Liver Disease, Treatment and Prognosis.

Background and Aims: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have common features and differences. This real-life study investigated their characteristics, treatment modalities, and prognoses. Methods: This retrospective comparative study was performed in 1,075 patients seen at one tertiary center between January 2008 and December 2020. Overall survival (OS) was estimated by the Kaplan-Meier method. Subclassification of iCCAs after histological and radiological review, and molecular profiling was performed. Results: HCCs patients were more likely to have early-stage disease than iCCA patients. iCCA patients were more likely to be female, especially those patients without cirrhosis (43% vs. 17%). Cirrhosis was prominent among HCC patients (89% vs. 34%), but no difference in underlying liver disease among cirrhotic patients was found. OS of HCC patients was 18.4 (95% CI: 6.4, 48.3) months, that of iCCA patients was 7.0 (95% CI: 3.4, 20.1) months. OS of Barcelona Clinic Liver Cancer C HCC patients was 7.8 (95% CI: 4.3, 14.2) months, that of advanced/metastatic iCCA patients was 8.5 (95% CI: 5.7, 12.3) months. In patients treated with sorafenib, OS was longer in HCC patients who received subsequent tyrosine kinase inhibitor therapies. No significant OS difference was found between iCCA patients with and without cirrhosis or according to histological subtype. A targetable molecular alteration was detected in 50% of the iCCA patients. Conclusions: In this French series, cirrhosis was common in iCCA, which showed etiological factors comparable to those of HCC, implying a distinct oncogenic pathway. Both entities had a dismal prognosis at advanced stages. However, systemic therapies sequencing in HCC and molecular profiling in iCCA offer new insights.

Unresectable hepatocellular carcinoma at dawn of immunotherapy era: real-world data from the French prospective CHIEF cohort.

BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma epidemiological data are limited in France. The Epidemio Liver Immunotherapy Tecentriq outcome research (ELITor) retrospective study, based on real-world data from the Carcinome HépatocellulaIrE en France (CHIEF) French cohort of hepatocellular carcinoma patients, aimed to get insight into the treatment patterns, the sociodemographic, clinical, biological, and etiological characteristics, and the quality of life of patients with unresectable hepatocellular carcinoma. METHODS AND RESULTS: Between 1 September 2019 and 4 December 2020, 367 patients from the CHIEF cohort received at least one locoregional (52.8%) chemoembolization or radioembolization or systemic treatment (88.3%) and were selected for ELITor. Most patients had a Barcelona Clinic Liver Cancer (BCLC) C (93.2%) hepatocellular carcinoma stage and were affected by cirrhosis (67.7%). Alcohol was confirmed as the main etiology both as a single etiology (29.1%) and in association with other risk factors (26.9%), mainly metabolic disorders (16.2%).Tyrosine-kinase inhibitors, mainly sorafenib, were the most administered systemic treatments in first line. Patients who received at least one combination of atezolizumab and bevacizumab during the study period ( N  = 53) had a better performance status and less portal hypertension frequency than the overall population and more hepatitis B virus infection and fewer metabolic disorders as single etiology. Overall, the global health score before treatment (62.3 ±â€…21.9) was in line with that of reference cancer patients and worsened in 51.9% of the cases after first-line palliative-intent treatment. CONCLUSION: This study provided real-life data on advanced hepatocellular carcinoma characteristics and treatment patterns and described the first patients to receive the atezolizumab-bevacizumab combination before it became the new standard of care for advanced hepatocellular carcinoma.

Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial.

Importance: The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear. Objective: To determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone. Design, Setting, and Participants: Multicenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease [MELD] score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019. Intervention: Patients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147). Main Outcome and Measures: The primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days. Results: Among 292 randomized patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group [P = .33]; between-group difference, -4.7% [95% CI, -14.0% to 4.7%]; hazard ratio, 0.77 [95% CI, 0.45-1.31]). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, -11.8% [95% CI, -23.0% to -0.7%]; subhazard ratio, 0.62; [95% CI, 0.41-0.91]; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group). Conclusion and Relevance: In patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis. Trial Registration: ClinicalTrials.gov Identifier: NCT02281929.

Early intrahepatic recurrence of HBV infection in liver transplant recipients despite antiviral prophylaxis.

Background & Aims: Prophylaxis with nucleos(t)ide analogues (NUCs) and hepatitis B immunoglobulin (HBIG) has decreased the rate of HBV recurrence after orthotopic liver transplantation (OLT), but the duration of this prophylaxis remains debated. Our aim was to investigate the recurrence of both intrahepatic and serum HBV markers after OLT in patients receiving long-term NUC and HBIG prophylaxis. Methods: A total of 31 HBV-positive patients benefiting from OLT were prospectively enrolled in five French centres between 2012 and 2015. Tissue samples from the native liver, liver reperfusion biopsy, and 12-month post-OLT (M12) biopsy were collected. Intrahepatic HBV markers were quantified using Droplet Digital PCR. Serum hepatitis B core-related antigen (HBcrAg) and HBsAg were quantified using the Lumipulse platform. Results: Among the 31 patients, 26 were HBeAg negative and 28 had undetectable serum HBV DNA at OLT. All patients received HBIG and NUC after OLT, and serum HBV DNA was undetectable at M12. Of the 27 available native livers, 26 had detectable total HBV DNA (median, 0.045 copies/cell), 21 were positive for cccDNA (0.001 copies/cell), and 19 were positive for 3.5-kb HBV RNA (0.0004 copies/cell). Among the 14 sequential reperfusion and M12 biopsies, seven were positive for HBV markers on the reperfusion sampling, and six of them were also positive at M12. Of the 27 patients with available serum samples at M12, eight were positive for HBcrAg and five were positive for HBsAg by ultrasensitive quantification, although they were negative by conventional techniques. Overall, among the 17 patients having a matched biopsy and serum sample at M12, only one had undetectable HBV markers in both the liver and serum. Conclusions: Our results demonstrate a very early detection of viral genome in the graft and intrahepatic viral recurrence despite NUC and HBIG prophylaxis. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT02602847). Impact and Implications: In this work, we show that, despite the recommended prophylaxis based on NUC and HBIG, HBV can infect the new liver very rapidly after transplantation. Twelve months after transplantation, the majority of patients had at least one HBV marker detected in either serum or the liver. Therefore, our results demonstrate early intrahepatic viral recurrence despite NUC and HBIG therapy and underline the importance of an optimal patient compliance to the antiviral prophylaxis to prevent viral rebound.

Prevalence of small intestinal bacterial overgrowth in irritable bowel syndrome (IBS): Correlating H2 or CH4 production with severity of IBS.

Background and Aim: The prevalence and the role of small intestinal bacterial overgrowth (SIBO) in irritable bowel syndrome (IBS) remain unclear, as the literature provides heterogeneous information on the subject. The aim of this study was to determine the prevalence of SIBO in IBS and to assess the correlation between methane and hydrogen levels measured during breath tests and the severity of IBS. Method: Two-hundred and forty-seven patients with IBS were prospectively included. A glucose breath test (GBT) measured H2 and CH4 production to diagnose SIBO. A test was positive when H2 values exceeded 12 ppm in the first 90 min and/or when a CH4 value exceeded 10 ppm at any time. IBS severity (IBS-SSS), quality of life (GIQLI), and anxiety and depression (HAD) were assessed to investigate the correlation with H2 and CH4 production. Results: The prevalence of SIBO in IBS was 36.4% (9.7% with H2, 26.7% with CH4). CH4 levels were significantly higher in the predominantly constipated patients (P = 0.00), while H2 levels were significantly higher within the diarrheal phenotype (P = 0.01). IBS severity was not correlated with either H2 levels (r = 0.02; P = 0.84) or CH4 levels (r = 0.05; P = 0.64). H2 production was inversely correlated with the quality of life (r = -0.24; P = 0.03) and significantly correlated with the HAD scale (r = 0.22; P = 0.03). The pain and discomfort experienced during GBT was not correlated with methane levels (r = -0.09, P = 0.40), hydrogen levels (r = -0.01, P = 0.93), or sum of both (r = 0.06, P = 0.58), but significantly associated with IBS severity (r = 0.50, P <0.00). Conclusion: SIBO has a high prevalence in IBS but does not increase its severity. Individual susceptibility to pain may have a greater influence on the severity of IBS.

Radiomics, a Promising New Discipline: Example of Hepatocellular Carcinoma.

Radiomics is a discipline that involves studying medical images through their digital data. Using "artificial intelligence" algorithms, radiomics utilizes quantitative and high-throughput analysis of an image's textural richness to obtain relevant information for clinicians, from diagnosis assistance to therapeutic guidance. Exploitation of these data could allow for a more detailed characterization of each phenotype, for each patient, making radiomics a new biomarker of interest, highly promising in the era of precision medicine. Moreover, radiomics is non-invasive, cost-effective, and easily reproducible in time. In the field of oncology, it performs an analysis of the entire tumor, which is impossible with a single biopsy but is essential for understanding the tumor's heterogeneity and is known to be closely related to prognosis. However, current results are sometimes less accurate than expected and often require the addition of non-radiomics data to create a performing model. To highlight the strengths and weaknesses of this new technology, we take the example of hepatocellular carcinoma and show how radiomics could facilitate its diagnosis in difficult cases, predict certain histological features, and estimate treatment response, whether medical or surgical.

Therapeutic Physical Exercise Programs in the Context of NASH Cirrhosis and Liver Transplantation: A Systematic Review.

In recent years, various physical exercise interventions have been developed with a view to reducing comorbidity and morbidity rates among patients with chronic diseases. Regular physical exercise has been shown to reduce hypertension and mortality in patients with type 2 diabetes. Diabetes and obesity are often associated with the development of nonalcoholic fatty liver disease, which can lead to liver fibrosis and then (in some cases) nonalcoholic steatohepatitis cirrhosis. We searched the literature for publications on personalized physical exercise programs in cirrhotic patients before and after liver transplantation. Eleven studies in cirrhotic patients and one study in liver transplant recipients were included in the systematic review, the results of which were reported in compliance with the preferred reporting items for systematic reviews and meta-analyses guidelines. The personalized physical exercise programs lasted for 6 to 16 weeks. Our review evidenced improvements in peak oxygen consumption and six-minute walk test performance and a reduction in the hepatic venous pressure gradient. In cirrhotic patients, personalized physical exercise programs improve quality of life, are not associated with adverse effects, and (for transplant recipients) might reduce the 90-day hospital readmission rate. However, none of the literature data evidenced reductions in the mortality rates before and after transplantation. Further prospective studies are needed to evaluate the benefit of long-term physical exercise programs in cirrhotic patients before and after liver transplantation.

Mid-Infrared Spectroscopy as a New Tool for Ruling Out Spontaneous Bacterial Peritonitis: A Proof-of-Concept Study.

BACKGROUND AND AIMS: A highly sensitive and specific point-of-care method for diagnosing spontaneous bacterial peritonitis (SBP) is currently lacking. The objective of the present study is to evaluate the diagnostic value of a rapid, easy-to-use, mid-infrared fiber evanescent wave spectroscopy (MIR-FEWS) method for ruling out SBP. PATIENTS AND METHODS: Cirrhotic patients (n = 256) at five centers in France were included for suspected SBP or for the scheduled evacuation of ascites fluid. The mid-infrared spectrum of 7 µL of an ascites fluid sample was recorded using a MIR-FEWS system. To define a model for the diagnosis of SBP, the patients were divided into a calibration group (n = 170) and a validation group (n = 86). RESULTS: Most of the patients were male (71%). The mean age was 60.25 years. Alcohol-related liver disease was the most common cause of cirrhosis. SBP was observed in 18% of the patients. For the diagnosis of SBP in the calibration and validation groups, respectively, the model gave areas under the receiver operating characteristic curves of 0.87 and 0.89, sensitivities of 90% and 87%, specificities of 78% and 80%, positive predictive values of 48% and 50%, negative predictive values of 97% and 96%, positive likelihood ratio of 4.09 and 4.35, negative likelihood ratio of 0.13 and 0.16, Youden index of 0.68 and 0.67, and correct classification rates of 80% and 81%. CONCLUSION: The results of this proof-of-concept study show that MIR-FEWS is a highly sensitive diagnostic method for ruling out SBP. The method warrants further investigation.

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.

Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching.

BACKGROUND: Starting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available. AIM: To evaluate the progression-free survival (PFS) of patients treated with REG or CBZ, we investigated the disease control rate (DCR), overall survival (OS), and safety of both drugs. To identify the variables associated with disease progression over time. METHODS: A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers (Avignon, Marseille, and Nice) between January 2017 and March 2021 using propensity score matching. PFS and OS were assessed using the Kaplan-Meier method. Multivariate analysis (MA) of progression risk factors over time was performed in matched-pair groups. RESULTS: Fifty-eight patients 68 (62-74) years old with HCC, Barcelona clinic liver cancer (BCLC) B/C (86%), Child-Pugh (CP)-A/B (24%) received REG for 3.4 (1.4-10.5) mo as second-line therapy. Twenty-eight patients 68 (60-73) years, BCLC B/C (75%), CP-A/B (25%) received CBZ for 3.7 (1.8-4.9) mo after first-line treatment with sorafenib [3 (2-4) (CBZ) vs 4 (2.9-11.8) mo (REG), P = 0.0226]. Twenty percent of patients received third-line therapy. After matching, PFS and DCR were not significantly different after a median follow-up of 6.2 (2.7-11.7) mo (REG) vs 5.2 (4-7.2) mo (CBZ), P = 0.6925. There was no difference in grade 3/4 toxicities, dose reductions, or interruptions. The OS of CP-A patients was 8.3 (5.2-24.8) vs 4.9 (1.6-11.7) mo (CP-B), P = 0.0468. The MA of risk factors for progression over time identified C-reactive protein (CRP) > 10 mg/L, neutrophil-to-lymphocyte ratio (NLR) > 3, and aspartate aminotransferase (AST) > 45 IU as predictive factors. CONCLUSION: This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC. Elevated levels of inflammatory markers (CRP and NLR) and AST were associated with non-control of TKIs over time. A 2-mo online progression risk calculation is proposed.

Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation.

Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT. We also assessed the expression of four key regulators of PPi in liver tissues and established correlations between AC, and scores of liver fibrosis and liver failure in these patients. LT candidates with various liver diseases were included. AC scores were assessed in coronary arteries, abdominal aorta, and aortic valves. Liver fibrosis was evaluated on liver biopsies and from non-invasive tests (FIB-4 and APRI scores). Liver functions were assessed by measuring serum albumin, ALBI, MELD, and Pugh−Child scores. An enzymatic assay was used to dose [PPi]pl. A group of patients without liver alterations from a previous cohort provided a control group. Gene expression assays were performed with mRNA extracted from liver biopsies and compared between LT recipients and the control individuals. [PPi]pl negatively correlated with APRI (r = −0.57, p = 0.001, n = 29) and FIB-4 (r = −0.47, p = 0.006, n = 29) but not with interstitial fibrosis index from liver biopsies (r = 0.07, p = 0.40, n = 16). Serum albumin positively correlated with [PPi]pl (r = 0.71; p < 0.0001, n = 20). ALBI, MELD, and Pugh−Child scores correlated negatively with [PPi]pl (r = −0.60, p = 0.0005; r = −0.56, p = 0.002; r = −0.41, p = 0.02, respectively, with n = 20). Liver fibrosis assessed on liver biopsies by FIB-4 and by APRI positively correlated with coronary AC (r = 0.51, p = 0.02, n = 16; r = 0.58, p = 0.009, n = 20; r = 0.41, p = 0.04, n = 20, respectively) and with abdominal aorta AC (r = 0.50, p = 0.02, n = 16; r = 0.67, p = 0.002, n = 20; r = 0.61, p = 0.04, n = 20, respectively). FIB-4 also positively correlated with aortic valve calcification (r = 0.40, p = 0.046, n = 20). The key regulator genes of PPi production in liver were lower in patients undergoing liver transplantation as compared to controls. Three months after surgery, serum albumin levels were restored to physiological levels (40 [37−44] vs. 35 [30−40], p = 0.009) and [PPi]pl was normalized (1.40 [1.07−1.86] vs. 0.68 [0.53−0.80] µmol/L, p = 0.0005, n = 12). Liver failure and/or fibrosis correlated with AC in several arterial beds and were associated with low plasma PPi and dysregulation of key proteins involved in PPi homeostasis. Liver transplantation normalized these parameters.

Management of alcohol-related liver disease: the French Association for the Study of the Liver and the French Alcohol Society clinical guidelines.

Excessive alcohol consumption is the leading cause of liver diseases in Western countries, especially in France. Alcohol-related liver disease (ARLD) is an extremely broad context and there remains much to accomplish in terms of identifying patients, improving prognosis and treatment, and standardising practices. The French Association for the Study of the Liver wished to organise guidelines together with the French Alcohol Society in order to summarise the best evidence available about several key clinical points in ARLD. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe how patients with ARLD should be managed nowadays and discuss the main unsettled issues in the field.

Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis.

BACKGROUND & AIMS: Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions; however, whether MAM dysfunction plays a causal role in hepatic insulin resistance and steatosis is not clear. Thus, we aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment. METHODS: We analyzed hepatic ER-mitochondria interactions and calcium exchange in a time-dependent and reversible manner in mice with diet-induced obesity. Additionally, we used recombinant adenovirus to express a specific organelle spacer or linker in mouse livers, to determine the causal impact of MAM dysfunction on hepatic metabolic alterations. RESULTS: Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in mice with diet-induced obesity. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks' overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type 2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index. CONCLUSIONS: ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could help to restore metabolic homeostasis. LAY SUMMARY: The literature suggests that interactions between the endoplasmic reticulum and mitochondria could play a role in hepatic insulin resistance and steatosis during chronic obesity. In the present study, we reappraised the time-dependent regulation of hepatic endoplasmic reticulum-mitochondria interactions and calcium exchange, investigating reversibility and causality, in mice with diet-induced obesity. We also assessed the relevance of our findings to humans. We show that organelle miscommunication is an early causal trigger of hepatic insulin resistance and steatosis that can be improved by nutritional strategies.