Comparison Between Radial and Femoral Artery Access for Transarterial Chemoembolisation in Patients With Hepatocellular Carcinoma.

PURPOSE: The purpose of this study was to compare the technical success rate, the selectivity of transarterial chemoembolisation (TACE), the complication rate, the radiation dose given to the patients and the hospitalization stay between TACE performed using femoral artery approach (FAA) and TACE performed using radial artery approach (RAA) in patients with hepatocellular carcinoma (HCC). METHODS: Between June 2020 and April 2022, 49 patients with HCC who underwent 116 TACEs (75 using FAA and 41 using RAA) were included. Differences in technical success rate, selectivity of micro-catheterization, radiation dose given to the patients, fluoroscopy time, hospitalization stay duration, and complication rate were compared between FAA and RAA using Fisher exact or Student t tests. RESULTS: No differences in technical success rates were found between RAA (93%; 39/41 TACEs) and FAA (100%; 75/75 TACEs) (P = .12). There were no differences between the two groups in terms of selectivity of catheterization, radiation dose, fluoroscopy time and hospitalization stay duration. Five patients had Grade 2 complications (hematoma) after FAA vs. one patient with one Grade 1 complication (radial artery occlusion) after RAA (5/75 [7%] vs. 1/41 [2%], respectively; P = .42). No major arterial access site complications occurred with FAA or RAA. CONCLUSIONS: This study confirms that RAA is a safe approach that does not compromise the technical efficacy and the selectivity of TACE compared to FAA in patients with HCC.

Burden of liver disease progression in hospitalized patients with type 2 diabetes mellitus.

BACKGROUND & AIMS: There are uncertainties regarding the burden of liver disease in patients with type 2 diabetes (T2D). Thus, we aimed to quantify the burden of liver disease, identify risk factors, and estimate attributable risks in patients with T2D. METHODS: We measured adjusted hazard ratios of liver disease progression to hepatocellular carcinoma and/or decompensated cirrhosis in a 2010-2020 retrospective, bicentric, longitudinal, cohort of 52,066 hospitalized patients with T2D. RESULTS: Mean age was 64±14 years and 58% were men. Alcohol use disorders accounted for 57% of liver-related complications and were associated with all liver-related risk factors. Non-metabolic liver-related risk factors accounted for 37% of the liver burden. T2D control was not associated with liver disease progression. The incidence (95% CI) of liver-related complications and of competing mortality were 3.9 (3.5-4.3) and 27.8 (26.7-28.9) per 1,000 person-years at risk, respectively. The cumulative incidence of liver disease progression exceeded the cumulative incidence of competing mortality only in the presence of well-identified risk factors of liver disease progression, including alcohol use. The incidence of hepatocellular carcinoma was 0.3 (95% CI 0.1-0.5) per 1,000 person-years in patients with obesity and it increased with age. The adjusted hazard ratios of liver disease progression were 55.7 (40.5-76.6), 3.5 (2.3-5.2), 8.9 (6.9-11.5), and 1.5 (1.1-2.1), for alcohol-related liver disease, alcohol use disorders without alcohol-related liver disease, non-metabolic liver-related risk factors, and obesity, respectively. The attributable fractions of alcohol use disorders, non-metabolic liver-related risk factors, and obesity to the liver burden were 55%, 14%, and 7%, respectively. CONCLUSIONS: In this analysis of data from 2 hospital-based cohorts of patients with T2D, alcohol use disorders, rather than obesity, contributed to most of the liver burden. These results suggest that patients with T2D should be advised to drink minimal amounts of alcohol. LAY SUMMARY: There is uncertainty on the burden of liver-related complications in patients with type 2 diabetes. We studied the risks of liver cancer and complications of liver disease in over 50,000 patients with type 2 diabetes. We found that alcohol was the main factor associated with complications of liver disease. This finding has major implications on the alcohol advice given to patients with type 2 diabetes.

Micro-elimination of hepatitis C virus.

BACKGROUND & AIMS: HCV affects about 71 million people worldwide with 1.75 million new infections a year, mainly associated with healthcare, blood transfusion before screening of donors and drug use. Hepatitis C is a systemic disease with hepatic and extrahepatic manifestations resulting in increased morbidity and mortality in HCV-infected patients compared to cured or uninfected individuals. RESULTS: The goal of eliminating hepatitis C by 2030 is based on the following three main actions: strengthening and increasing outreach screening; increasing access to treatment; and improving prevention. Although the tools and the targets of HCV elimination have now been well established, micro-elimination, a cure in high-risk populations, is possible, but has not been achieved. These populations are mainly migrants, prisoners, drug users, HIV co-infected patients and psychiatric patients. New tools must be developed to achieve micro-elimination, in particular, rapid diagnostic orientation tests for better screening, delocalization of healthcare services to improve access to care, and training physicians to raise awareness of the disease, increase understanding of its pathogenesis and provide information on the availability of safe and effective treatment to cure chronic infection and reverse hepatic and extrahepatic manifestations. CONCLUSION: Thus, while the goal of complete elimination of hepatitis C virus was feasible in Western countries, it was more difficult in high-prevalence countries where improvement in the detection of chronic infection (with rapid serological and virological diagnostic tests), outsourcing of diagnostic and therapeutic care and access to direct oral antivirals are urgently needed.

Treatment of hepatitis C: the use of the new pangenotypic direct-acting antivirals in "special populations".

BACKGROUND & AIMS: The recommended combination of pangenotypic direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) associates the co-formulation of 2 or 3 second-generation DAAs. In the so-called "special populations" defined as patients with chronic kidney disease (CKD), HCV/HIV co-infection, HCV/HBV co-infection and an unsuccessful previous DAA regimen, these combinations have a high antiviral potency (sustained virologic response (SVR) > 95%), fair tolerance and a reduced pill burden. METHODS: We have taken into account the scientific evidence on the treatment of "special populations", in particular from the RUBY 1-2 trials, EXPEDITION 2-4 study, C-WORTHY trial, ASTRAL 5, POLARIS 1-4 studies, MAGELLAN 1 and REVENGE study. RESULTS: CKD and HCV/HIV co-infection are not predictors of a non-viral response. The glecaprevir/pibentrasvir (Maviret) combination appears to be the first-line therapy for CKD patients while the sofosbuvir/vlpatasvir/voxaliprevir (Sovesi) combination is the first-line option for DAAs failures. Both are effective in patients with HIV-or HBV-HCV co-infection and should be chosen according to the potential drug-drug interaction profile. CONCLUSIONS: The notion of "special populations" is no longer pertinent with pangenotypic DAAs combinations. International guidelines recommend treating all infected patients and the next challenge is not the therapeutic choice, but to improve the limitations for screening and access to care in HCV infection.

MELDNa score is associated with psychopathology and reduced quality of life in cirrhotic patients with a liver transplant perspective.

Psychopathological symptoms and reduced health related quality of life (HRQoL) are frequent in cirrhotics, but no data on their association with cirrhosis prognosis assessed by the MELDNa score are available. Prospective data on the long-term effect of deceased donor liver transplantation (LT) on psychopathological symptoms are needed. Before entering the LT waiting list, 44 consecutive LT cirrhotic candidates without a major psychiatric disorder underwent a psychopathological assessment, including Symptom Checklist-90-revised (SCL-90-R) and Defense Style Questionnaire (DSQ). HRQoL was measured by Short Form 36 Health Survey (SF-36). Abnormal performance at each questionnaire was defined by using 44 age, gender, BMI and education-matched healthy subjects. Separate binary logistic regression models were used to test the association of the Child-Pugh, MELD and MELDNa scores with abnormal performance at each questionnaire. Fourteen patients repeated the battery tests 3 years after LT. Before LT, increasing MELDNa was the only prognostic score independently associated with an abnormal SCL-90-R global psychopathological score index (OR: 1.207; 95% CI: 1.026-1.420; P = 0.02) and the best independent predictor of reduced HRQoL. After LT, compared to status prior to LT, performance at SF-36 general health perception scale ameliorated (P = 0.02), performance at SCL-90-R somatization scale (P = 0.001) and global psychopathological score index (P < 0.001) worsened and the negative correlation between the psychopathological global score index and HRQoL disappeared. The severity of cirrhosis in LT candidates should be monitored by the MELDNa score to better establish the right psychological counselling. Psychopathology, and in particular somatization, worsens after LT and should be carefully investigated.

Hepatic encephalopathy expands the predictivity of model for end-stage liver disease in liver transplant setting: Evidence by means of 2 independent cohorts.

Despite its documented prognostic relevance, hepatic encephalopathy (HE) is not considered in liver transplantation (LT) due to its possible poor objectivity. To override this problem, we aimed to analyze if an objective diagnosis of HE may confer additional mortality risk beyond MELD. Study and validation cohorts of patients with cirrhosis were considered in Italy and Canada, respectively. Patients were considered to be HE+ if an episode of overt HE was documented in a hospitalization. Of the 486 patients enrolled in Italy, 184 (38%) were HE+. During the 6-month follow-up, 77 patients died and 50 underwent transplantation. The 6-month mortality of HE+ versus HE- patients was significantly higher (P < 0.001). Model for End-Stage Liver Disease (MELD; subdistribution hazard ratio [sHR], 1.2; 95% confidence interval [CI], 1.1-1.2; P < 0.001), HE+ (sHR, 3.6; 95% CI, 1.8-7.1; P < 0.001), and sodium (sHR, 0.9; 95% CI, 0.8-0.9; P < 0.001) were independent predictors of 6-month mortality. In HE+ patients, short-term mortality increased across the entire MELD spectrum (range, 6-40). The results were unchanged by including or excluding patients with hepatocellular carcinoma or stratifying patients according to HE characteristics. The higher 6-month mortality of HE+ versus HE- patients was confirmed also in the Canadian cohort (P < 0.001; n = 300, 33% HE+; 33 died, 104 transplanted). A similar and statistically significant C-index increase derived by the incorporation of HE in MELD was observed both in the Italian (from 0.67 to 0.75) and Canadian (from 0.69 to 0.74) cohorts. A score based on MELD plus 7 points (95% CI, 4-10) for HE+ patients optimally predicted 6-month mortality in the 2 cohorts. According to the net reclassification index, by not considering HE, 29% of overall patients were misclassified by MELD score. In conclusion, the incorporation of HE in MELD score might improve the listing and allocation policy in LT. Liver Transplantation 22 1333-1342 2016 AASLD.

Recipient perioperative cholesterolaemia and graft cholesterol metabolism gene expression predict liver transplant outcome.

BACKGROUND & AIMS: We analysed for the first time whether recipient perioperative serum total cholesterol (sTC) concentration is associated with liver transplantation outcome. METHODS: We studied noncholestatic cirrhotics submitted to primary deceased-donor liver transplantation in a prospective group (n=140) from Rome and in a validation retrospective cohort (n=157) from Udine, Italy. Pre-ischaemia and post-reperfusion cholesterol metabolism gene mRNA was measured by RT-PCR in 74 grafts of the study group. RESULTS: At Cox regression analysis, independently from confounders including recipient MELD score, the recipient pre-operative sTC pooled quintiles 2-5, compared with the lowest quintile showed HR (95% CI) and significances for overall graft loss (GL) of 0.215 (0.104-0.444) P<0.001 in the study group and 0.319 (0.167-0.610) P=0.001 in the validation cohort. Analysing sTC as a continuous variable, the risk of overall GL for every 10-mg/dl decrease in pre-operative sTC increased by 13% and by 9% in the study group and in the validation cohort respectively. In the study group, independent associations at multivariate analyses were: (a) high graft pre-ischaemia expression of INSIG-1, which indicates hepatocellular cholesterol depletion, with post-reperfusion graft necrosis; (b) GL with inadequate graft post-reperfusion response to cholesterol depletion, shown by a failure to reduce the PCSK9 to LDLR expression ratio; (c) GL with a relative increase of sTC on post-operative day-7, selectively because of the LDL fraction, which indirectly suggests poor cholesterol uptake from blood. CONCLUSIONS: Low recipient pre-transplant sTC concentration, its post-operative day-7 increase and a genetically determined low graft cholesterol availability predict poor liver transplant outcome.

Corrigendum to "O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis" [JHEP Reports 6 [2024] 100878].

[This corrects the article DOI: 10.1016/j.jhepr.2023.100878.].

O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis.

Background & Aims: O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. Methods: To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGTLKO) were generated and challenged with different carbohydrate- and lipid-containing diets. Results: Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. Conclusions: These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis. Impact and Implications: Our study shows that hepatocyte-specific deletion of O-GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O-GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet (i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies.

Hepatitis C virus cure from direct-acting antivirals and mortality: Are people with and without a history of injection drug use in the same boat? (ANRS CO22 Hepather cohort).

INTRODUCTION: The risk of mortality in people with a history of injection drug use (PHID) is high, as is the prevalence of hepatitis C virus (HCV) infection. Although direct-acting antivirals (DAA) are effective in this population in terms of sustained virological response, it is not known whether PHID benefit as much as people with no history of injection drug use from DAA-related HCV cure in terms of reduced all-cause mortality. METHODS: Using Cox proportional hazards models based on the ANRS CO22 Hepather cohort data (n = 9735), we identified factors associated with all-cause mortality among HCV-infected people. We tested for interaction effects between drug injection status, HCV cure and other explanatory variables. RESULTS: DAA-related HCV cure was associated with a 66% (adjusted hazard ratio [95% confidence interval]: 0.34 [0.29-0.39]) lower risk of all-cause mortality, irrespective of drug injection status. Detrimental effects of unhealthy alcohol use on mortality were identified in PHID only. DISCUSSION AND CONCLUSIONS: DAA-related HCV cure led to comparable benefits in terms of reduced mortality in PHID and people with no history of injection drug use. Policies and strategies to enhance DAA uptake among PHID are needed to lower mortality in this population. Clinical trial registration details: ClinicalTrials.gov: NCT01953458.

New insights into the inter-organ crosstalk mediated by ChREBP.

Carbohydrate response element binding protein (ChREBP) is a glucose responsive transcription factor recognized by its critical role in the transcriptional control of glycolysis and de novo lipogenesis. Substantial advances in the field have revealed novel ChREBP functions. Indeed, due to its actions in different tissues, ChREBP modulates the inter-organ communication through secretion of peptides and lipid factors, ensuring metabolic homeostasis. Dysregulation of these orchestrated interactions is associated with development of metabolic diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Here, we recapitulate the current knowledge about ChREBP-mediated inter-organ crosstalk through secreted factors and its physiological implications. As the liver is considered a crucial endocrine organ, we will focus in this review on the role of ChREBP-regulated hepatokines. Lastly, we will discuss the involvement of ChREBP in the progression of metabolic pathologies, as well as how the impairment of ChREBP-dependent signaling factors contributes to the onset of such diseases.

The role of ChREBP in carbohydrate sensing and NAFLD development.

Excessive sugar consumption and defective glucose sensing by hepatocytes contribute to the development of metabolic diseases including type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). Hepatic metabolism of carbohydrates into lipids is largely dependent on the carbohydrate-responsive element binding protein (ChREBP), a transcription factor that senses intracellular carbohydrates and activates many different target genes, through the activation of de novo lipogenesis (DNL). This process is crucial for the storage of energy as triglycerides in hepatocytes. Furthermore, ChREBP and its downstream targets represent promising targets for the development of therapies for the treatment of NAFLD and T2DM. Although lipogenic inhibitors (for example, inhibitors of fatty acid synthase, acetyl-CoA carboxylase or ATP citrate lyase) are currently under investigation, targeting lipogenesis remains a topic of discussion for NAFLD treatment. In this Review, we discuss mechanisms that regulate ChREBP activity in a tissue-specific manner and their respective roles in controlling DNL and beyond. We also provide in-depth discussion of the roles of ChREBP in the onset and progression of NAFLD and consider emerging targets for NAFLD therapeutics.

Histological Characteristics and Management of Hepatitis on Immune Checkpoint Inhibitors: A Retrospective Descriptive Study.

BACKGROUND AND AIMS: the side effects of immune checkpoint inhibitors (ICI) pose a problem for the clinical management of cancer patients. There is a lack of knowledge of the value of liver biopsy in patients with ICI-related drug-induced liver injury (ICI-DILI). The aim of this study was to explore the impact of liver biopsy on clinical management and response to corticosteroids, according to histological findings. METHODS: We conducted a retrospective, single-center study to evaluate the biochemical, histological and clinical data of 35 patients with ICI-DILI between 2015 and 2021 in a university hospital in France. RESULTS: Of the 35 patients with ICI-DILI (median [interquartile range] age 62 [48-73] years, 40% males) studied, 20 underwent a liver biopsy. There was no difference in the management of ICI-DILI according to liver biopsy in terms of ICI withdrawal, reduction or rechallenge. According to the histological profile, patients with toxic and granulomatous profiles had a better response to corticosteroids, while patients with cholangitic lesions had the worst response. CONCLUSION: In ICI-DILI, liver biopsy must not delay patient care but may be useful in identifying patients with a cholangitic profile who have a poorer response to corticosteroids.

Burden of grade 3 or 4 liver injury associated with immune checkpoint inhibitors.

Background & Aims: There is concern about the burden of liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs). Methods: In a retrospective cohort study, we evaluated the likelihood of grade 3/4 liver injury, of grade 3/4 cholestatic liver injury, and of liver failure, as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5, following treatment with ICIs. We compared these occurrences with a group of cancer patients who were propensity-matched and treated with conventional chemotherapy. For all ICI patients experiencing grade 3/4 liver injury, we conducted a causality assessment using the RUCAM method and examined patient outcomes. Results: Among 952 patients (median [IQR] age 66 [57-73] years, 64% males) who were treated with ICI between January 1, 2015, and December 31, 2019, a total of 86 (9%) progressed to grade 3/4 liver injury, and liver failure was not observed. Anti-PD-(L)1/anti-CTLA-4 antibodies combinations (adjusted hazard ratio 3.36 [95% CI: 1.67-6.79]; p <0.001), and chronic hepatitis B (adjusted hazard ratio 5.48 [95% CI: 1.62-18.5]; p = 0.006], were independent risk factors. Liver injury was attributed to ICI treatment in 19 (2.0%) patients. Patients with ICI toxicity typically presented with granulomatous hepatitis or cholangiocyte inflammation. ICI withdrawal was associated with cancer progression and mortality. Re-introduction of ICI was not associated with recurrent grade 3/4 liver injury. Compared with matched patients treated with conventional, non-ICI-based chemotherapy, anti-PD-(L)1/anti-CTLA-4 combinations (p <0.001) and anti-PD-(L)1 monotherapies (p = 0.053) increased the risk of grade 3/4 liver injury and of grade 3/4 cholestatic liver injury, respectively. Conclusions: An increased risk of grade 3/4 liver injury under anti-PD-(L)1/anti-CTLA-4 antibodies was observed, whereas no substantial increase in the likelihood of liver failure occurred even after treatment reintroduction. Impact and implications: There is concern about liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs). We investigated the burden of grade 3/4 liver injury after treatment with ICIs in a multicentric cohort of patients with cancer. Overall, a 9% incidence of grade 3/4 liver injury was detected after ICIs, and direct ICI hepatotoxicity was demonstrated in 2% of patients. Anti-PD-(L)1/Anti-CTLA-4 antibody combinations, and chronic HBV infection were independent risk factors. ICI withdrawal for grade 3/4 liver injury was associated with cancer progression. Re-introduction of ICI treatment was not associated with recurrent grade 3/4 liver injury.

New targets for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease worldwide. It is characterised by steatosis, liver inflammation, hepatocellular injury and progressive fibrosis. Several preclinical models (dietary and genetic animal models) of NAFLD have deepened our understanding of its aetiology and pathophysiology. Despite the progress made, there are currently no effective treatments for NAFLD. In this review, we will provide an update on the known molecular pathways involved in the pathophysiology of NAFLD and on ongoing studies of new therapeutic targets.

Treatment of hepatitis C virus infection.

Hepatitis C virus infection affects 71 million people worldwide. It is at the origin of a multi-organ disease associating hepatic manifestations, cryoglobulinemic vasculitis and general manifestations linked to chronic inflammation (diabetes, cardio-, reno- or cerebrovascular manifestations, extra-hepatic cancers including non-Hodgkin's lymphoma). The significant morbidity and mortality linked to the hepatitis C virus therefore justify its screening and access to treatments which have increased considerably over the past two decades. Understanding the replicative cycle of the hepatitis C virus has enabled the development of direct HCV-specific antivirals targeting viral proteins (NS3/4A protease, NS5B polymerase and the multifunctional NS5A replication complex). The combination of two to three specific inhibitors often co-formulated in a capsule, without pegylated interferon and most often without ribavirin, allows high antiviral efficacy (more than 97% cure) for a treatment duration of 8-12 weeks with satisfactory tolerance. HCV infection is the only chronic viral infection that can be cured and the hepatic or extrahepatic manifestations are mainly reversible. This underlines the importance of strengthening screening and access to care policies in order to achieve the elimination of viral infection C in the short term, in 2030, as expected from the program of the World Health Organization. If this elimination is possible in some countries (Iceland, France, Germany …), it seems compromised in others where prevention (USA), screening and/or access to care are still insufficient (Sub-Saharan Africa, Russia…).

[Epidemiology of non-alcoholic steatohepatitis. Extent/burden of the problem and its impact on public health]. / Épidémiologie de la stéato-hépatite non alcoolique. Étendue du problème et son impact sur la santé publique.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, the most common cause of chronic liver function augmentation and it will be the most common indication for liver transplantation in 2020. The prevalence of NAFLD has increased over time in line with the increase of obesity and type 2 diabetes. There is a discrepancy between the studies concerning the prevalence of NAFLD because of the different diagnostic methods used (ultrasound or magnetic resonance, fibroscan, controlled attenuation parameter (CAP), histology). Because of its high prevalence the impact of NAFLD in public health is real. Therapeutic advances must be made to better understand the natural history of NAFLD and improve the management of this emerging liver disease.