Publications by authors named "Jean-François Dufour"

246 Publications

PPAR-Targeted Therapies in the Treatment of Non-Alcoholic Fatty Liver Disease in Diabetic Patients.

Int J Mol Sci 2022 Apr 13;23(8). Epub 2022 Apr 13.

Centre des Maladies Digestives, 1003 Lausanne, Switzerland.

Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cause a significant burden worldwide and therapeutic strategies are needed. This review provides an overview of the evidence on PPAR-targeted treatment of NAFLD and NASH in individuals with type 2 diabetes mellitus. We considered current evidence from clinical trials and observational studies as well as the impact of treatment on comorbid metabolic conditions such as obesity, dyslipidemia, and cardiovascular disease. Future areas of research, such as possible sexually dimorphic effects of PPAR-targeted therapies, are briefly reviewed.
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http://dx.doi.org/10.3390/ijms23084305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028563PMC
April 2022

The NAFLD-MAFLD debate: Is there a Consensus-on-Consensus methodology?

Liver Int 2022 04 24;42(4):742-748. Epub 2022 Feb 24.

Division of Gastroenterology and Hepatology, Loma Linda University, Loma Linda, California, USA.

Polarizing opinions have recently arisen in hepatology on the name and redefinition of fatty liver disease associated with metabolic dysfunction. In spite of growing and robust evidence of the superior utility of the term metabolic (dysfunction) associated fatty liver disease (MAFLD) definition for clinical and academic practice, controversy abounds. It should therefore come, as no surprise that the most common arguments used in contrarian op-eds is that there are no consensus on any name change. In this context, we suggest that discourse on an accurate understanding of what scientific consensus means, the various methods of achieving consensus, as well as other alternative models for reaching agreement is pivotal for the field. In this opinion piece, we provide an overview of these aspects as it applies to the case of fatty liver disease. We provide evidence that consensus on a change from non-alcoholic fatty liver disease (NAFLD) to MAFLD has already been achieved. We believe that the time has come for redirecting stakeholder focus and energy on capitalizing on the momentum generated by the debate to improve the lives of people at its centre, our patients.
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http://dx.doi.org/10.1111/liv.15197DOI Listing
April 2022

Prognostic Factors and Treatment Efficacy in Spinal Cord Sarcoidosis: An Observational Cohort With Long-term Follow-up.

Neurology 2022 04 10;98(14):e1479-e1488. Epub 2022 Feb 10.

From the Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation (A.G., R.M.) and Service de Neuro-Oncologie (B.J.), Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon, Bron; Service de Biostatistique-Bioinformatique (A.G.), Département de Médecine Interne et Immunologie Clinique, Hôpital Édouard Herriot (C.-A.D.), and Département de Médecine Interne, Hôpital de la Croix Rousse (P.S.), Hospices Civils de Lyon; Université Lyon 1 (A.G., B.J., R.M.), Université de Lyon, Villeurbanne; Pitié-Salpêtrière University Hospital (A.-C.D., C.C.-A., D.S.), Sorbonne Universités; Department of Internal Medicine and Clinical Immunology (A.-C.D., C.C.-A., D.S.), AP-HP; Centre de Référence des Maladies Auto-Immunes Systémiques Rares (A.-C.D., C.C.-A., D.S.), Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose Inflammatoire, Paris; Département de Médecine Interne et Maladies Systémiques (C.A., A.T., B.B.) and Département de Neurologie (T.M.), CHU Dijon; Département de Médecine Interne (E.B.), CH Saint Luc Saint Joseph, Lyon; Département de Médecine Interne (T.D.), CH Montluçon; Département de Médecine Interne (J.F.D.), Centre Hospitalier Fleyriat, Bourg-en-Bresse; Département de Médecine Interne, CHU Estaing (G.L.G., M.R.), and Service de Médecine Interne, Hôpital Gabriel Montpied (M.A.), CHU de Clermont-Ferrand; Département de Neurologie (J.-P.C., J.-C.G.A.), Hôpital Nord, CHU de Saint-Etienne; and Research on Healthcare Performance (RESHAPE) (P.S.), INSERM U1290, Université Claude Bernard Lyon 1, France.

Background And Objectives: Spinal cord sarcoidosis is a rare manifestation of sarcoidosis with a consequent risk of neurologic sequelae for the patient. We investigated prognostic factors and efficacy of immunosuppressive treatments in a longitudinal cohort.

Methods: We retrospectively studied patients with spinal cord sarcoidosis followed between 1995 and 2021 in 7 centers in France. Patients with definite, probable, or possible spinal cord sarcoidosis according to the Neurosarcoidosis Consortium Consensus Group criteria and with spinal cord involvement confirmed by MRI were included. We analyzed relapse or progression rate with a Poisson model, initial Rankin score with a linear model, and change in the Rankin score during follow-up with a logistic model.

Results: A total of 97 patients were followed for a median of 7.8 years. Overall mean relapse or progression rate was 0.17 per person-year and decreased over time. At last visit, 46 (47.4%) patients had a loss of autonomy (Rankin score ≥2). The main prognostic factors significantly associated with relapse or progression rate were gadolinium enhancement (relative rate [95% CI] 0.61 [0.4, 0.95]) or meningeal involvement (relative rate [95% CI] 2.05 [1.31, 3.19]) on spinal cord MRI and cell count (relative rate [95% CI] per 1 log increase 1.16 [1.01, 1.33]) on CSF analysis. Relapse or progression rate was not significantly associated with initial Rankin score or Expanded Disability Status Scale. Tumor necrosis factor-α (TNF-α) antagonists significantly decreased relapse or progression rate compared with corticosteroids alone (relative rate [95% CI] 0.33 [0.11, 0.98]). Azathioprine was significantly less effective than methotrexate on relapse or progression rate (relative rate [95% CI] 2.83 [1.04, 7.75]) and change in Rankin score (mean difference [95% CI] 0.65 [0.23, 1.08]).

Discussion: Regarding the relapse or progression rate, meningeal localization of sarcoidosis was associated with a worse prognosis, TNF-α antagonists resulted in a significant decrease compared to corticosteroids alone, and methotrexate was more effective than azathioprine.

Classification Of Evidence: This study provides Class IV evidence that in individuals with spinal cord neurosarcoidosis, TNF-α antagonists were associated with decreased relapse or progression rate compared to corticosteroids alone, but other therapies showed no significant benefit.
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http://dx.doi.org/10.1212/WNL.0000000000200020DOI Listing
April 2022

Combined treatments in hepatocellular carcinoma: Time to put them in the guidelines?

World J Gastrointest Oncol 2021 Dec;13(12):1896-1918

Department for BioMedical Research, Hepatology, University of Bern, Bern 3008, Switzerland.

The time for battling cancer has never been more suitable than nowadays and fortunately against hepatocellular carcinoma (HCC) we do have a far-reaching arsenal. Moreover, because liver cancer comprises a plethora of stages-from very early to advanced disease and with many treatment options-from surgery to immunotherapy trials-it leaves the clinician a wide range of options. The scope of our review is to throw light on combination treatments that seem to be beyond guidelines and to highlight these using evidence-based analysis of the most frequently used combination therapies, discussing their advantages and flaws in comparison to the current standard of care. One particular combination therapy seems to be in the forefront: Transarterial chemoembolization plus ablation for medium-size non-resectable HCC (3-5 cm), which is currently at the frontier between Barcelona Clinic Liver Cancer classification A and B. Not only does it improve the outcome in contrast to each individual therapy, but it also seems to have similar results to surgery. Also, the abundance of immune checkpoint inhibitors that have appeared lately in clinical trials are bringing promising results against HCC. Although the path of combination therapies in HCC is still filled with uncertainty and caveats, in the following years the hepatology and oncology fields could witness an HCC guideline revolution.
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http://dx.doi.org/10.4251/wjgo.v13.i12.1896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713312PMC
December 2021

The MELD upgrade exception: a successful strategy to optimize access to liver transplantation for patients with high waiting list mortality.

HPB (Oxford) 2021 Dec 21. Epub 2021 Dec 21.

Department of Visceral Surgery and Medicine, Berne University Hospital, University of Berne, Berne, Switzerland Freiburgstrasse 18, 3010 Bern, Switzerland. Electronic address:

Background: MELD exceptions are designed to equipoise liver transplant waiting list survival. We aimed to analyze the impact of the MELD Upgrade rule and all other MELD exceptions on the liver transplant waiting list outcomes during 2012-2017 in Switzerland.

Methods: We conducted a nationwide cohort study including all adult patients registered on the Swiss liver transplant waiting list between 2012 and 2017. Waiting list mortality and access to transplantation were analyzed, considering MELD exceptions as time-dependent covariates.

Results: 730 patients were included. Patients with MELD Upgrade exceptions had a higher risk of dying while on the waiting list (OR 2.13; CI 95% 1.30-3.47) and also an increased likelihood of receiving a liver transplantation, when compared to patients without MELD exceptions. Patients with any type of MELD exceptions were more likely to be transplanted when compared to patients without MELD exceptions. The proportion of patients with MELD exceptions increased from 2012 to 2017 (44% vs 88%). Allocation MELD at the time of transplantation showed an annual increase (23 ± 8 points vs 32 ± 5 points, p < 0.001).

Conclusion: Only patients with MELD Upgrade exceptions had the expected combination of higher waiting list mortality and quicker access to liver transplantation.
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http://dx.doi.org/10.1016/j.hpb.2021.12.009DOI Listing
December 2021

Humoral response to SARS-CoV-2 infection among liver transplant recipients.

Gut 2022 04 5;71(4):746-756. Epub 2022 Jan 5.

Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

Objective: Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody response to SARS-CoV-2 in liver transplant (LT) recipients after COVID-19.

Design: Prospective multicentre case-control study, analysing antibodies against the nucleocapsid protein, spike (S) protein of SARS-CoV-2 and their neutralising activity in LT recipients with confirmed SARS-CoV-2 infection (COVID-19-LT) compared with immunocompetent patients (COVID-19-immunocompetent) and LT recipients without COVID-19 symptoms (non-COVID-19-LT).

Results: Overall, 35 LT recipients were included in the COVID-19-LT cohort. 35 and 70 subjects fulfilling the matching criteria were assigned to the COVID-19-immunocompetent and non-COVID-19-LT cohorts, respectively. We showed that LT recipients, despite immunosuppression and less symptoms, mounted a detectable antinucleocapsid antibody titre in 80% of the cases, although significantly lower compared with the COVID-19-immunocompetent cohort (3.73 vs 7.36 index level, p<0.001). When analysing anti-S antibody response, no difference in positivity rate was found between the COVID-19-LT and COVID-19-immunocompetent cohorts (97.1% vs 100%, p=0.314). Functional antibody testing showed neutralising activity in 82.9% of LT recipients (vs 100% in COVID-19-immunocompetent cohort, p=0.024).

Conclusions: Our findings suggest that the humoral response of LT recipients is only slightly lower than expected, compared with COVID-19 immunocompetent controls. Testing for anti-S antibodies alone can lead to an overestimation of the neutralising ability in LT recipients. Altogether, routine antibody testing against separate SARS-CoV-2 antigens and functional testing show that the far majority of LT patients are capable of mounting an adequate antibody response with neutralising ability.
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http://dx.doi.org/10.1136/gutjnl-2021-326609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753112PMC
April 2022

Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease.

J Hepatol 2022 May 21;76(5):1001-1012. Epub 2021 Dec 21.

Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood.

Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1 and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank.

Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients.

Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD.

Lay Summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice.
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http://dx.doi.org/10.1016/j.jhep.2021.12.012DOI Listing
May 2022

Immune thrombocytopenia with clinical significance in systemic lupus erythematosus: a retrospective cohort study of 90 patients.

Rheumatology (Oxford) 2021 Dec 16. Epub 2021 Dec 16.

Department of Internal Medicine, Hospices Civils de Lyon, France.

Objectives: To describe the characteristics, treatment, and outcome of patients with immune thrombocytopenia with clinical significance (ITPCS) associated with systemic lupus erythematosus (SLE).

Methods: This retrospective multicentre study included SLE patients who experienced ≥1 ITPCS (defined as ITP with attributable bleeding disorders and/or a platelet count <30 x109/L). Other causes of secondary thrombocytopenia were excluded. Major bleeding event (MBG) was defined as Khellaf score>8 and/or WHO score>2.

Results: A total of 90 patients were included, the median (range) follow-up duration was 80 (6-446) months. ITP was diagnosed before SLE in 25 patients. They presented high rate of autoimmune haemolytic anaemia (15%), antiphospholipid antibody (62%), and antiphospholipid syndrome (19%). The 25 (28%) patients who experienced MBG had significantly more bleedings at ITP diagnosis and higher bleeding scores, and serositis and thrombosis during follow-up. They required significantly more treatment lines, transfusions, and hospitalizations. The 11 (12%) patients who experienced no bleeding event presented a significantly more restricted SLE phenotype (cutaneous and/or articular). Patients received a mean (range) of 4.2 (1-11) treatment lines. Corticosteroids and hydroxychloroquine allowed ITPCS overall response in one third of patients. The median relapse-free survival of rituximab (n = 34), azathioprine (n = 19), mycophenolate mofetil (n = 8), thrombopoietin-receptor agonists (n = 16), and splenectomy (n = 19) were 53, 31.5, 61, 24.5, and 78 months, respectively. Four patients experienced thrombotic events after splenectomy and one occurred under thrombopoietin-receptor agonist treatment.

Conclusion: SLE-ITCS patients displayed a high rate of haematological abnormalities and MBG patients exhibited higher morbidity. Management of thrombocytopenia was highly heterogeneous and many options seem viable.
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http://dx.doi.org/10.1093/rheumatology/keab925DOI Listing
December 2021

NTCP: a pharmacological target for multiple liver conditions.

Gut 2021 Dec 2. Epub 2021 Dec 2.

Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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http://dx.doi.org/10.1136/gutjnl-2021-325917DOI Listing
December 2021

HCV disease burden and population segments in Switzerland.

Liver Int 2022 02 10;42(2):330-339. Epub 2021 Dec 10.

CDA Foundation, Lafayette, Colorado, USA.

Background: Switzerland has made strides towards hepatitis C virus elimination, but as of 2019, elimination was not guaranteed. However, political interest in viral hepatitis has been increasing. We sought to develop a better understanding of Switzerland's progress towards HCV elimination and the profile of remaining HCV-RNA-positive patients.

Methods: A previously described Markov model was updated with recent diagnosis and treatment data and run to generate new forecasts for HCV disease burden. Two scenarios were developed to evaluate HCV morbidity and mortality under the status quo and a scenario that achieves the Swiss Hepatitis Strategy Elimination targets. Next, an analysis was conducted to identify population segments bearing a high burden of disease, where future elimination efforts could be directed.

Results: At the beginning of 2020, an estimated 32 100 viremic infections remained in Switzerland (0.37% viremic prevalence). Adult (≥18 years of age) permanent residents born abroad represented the largest subpopulation, accounting for 56% of HCV infections. Thirteen countries accounted for ≥60% of viremic infections amongst permanent residents born abroad, with most people currently residing in Zurich, Vaud, Geneva, Bern, Aargau and Ticino. Amongst Swiss-born HCV-RNA-positive persons, two-thirds had a history of IDU, corresponding to 33% of total infections.

Conclusions: In Switzerland, extra efforts for diagnosis and linkage to care are warranted in foreign-born populations and people with a history of drug use. Population-level measures (eg increasing the number of providers, increase screening) can identify patients who may have otherwise fallen through the gaps or avoided care because of stigma.
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http://dx.doi.org/10.1111/liv.15111DOI Listing
February 2022

Inflammatory activity affects the accuracy of liver stiffness measurement by transient elastography but not by two-dimensional shear wave elastography in non-alcoholic fatty liver disease.

Liver Int 2022 01 3;42(1):102-111. Epub 2021 Dec 3.

Department of Visceral Surgery and Medicine, Inselspital- Bern University Hospital, University of Bern, Bern, Switzerland.

Background: In patients with non-alcoholic fatty liver disease (NAFLD), the impact of the severity of steatosis and inflammatory activity on the accuracy of liver stiffness measurement (LSM) by transient elastography (TE) and by two-dimensional shear wave elastography (2D-SWE) in staging liver fibrosis is still debated and scarce. We aimed to focus on this aspect.

Methods: We prospectively studied 104 patients requiring biopsy for the assessment of NAFLD. We used ordinary least squares regression to test for differences in the association between fibrosis and LSM by TE and 2D-SWE when other factors (steatosis and inflammatory activity) are considered.

Results: Among 104 patients, 102 had reliable LSM by TE, and 88 had valid LSM by 2D-SWE. The association between fibrosis based on histology and LSM was significantly stronger when 2D-SWE assessed LSM compared to TE (Spearman's correlation coefficient of .71; P < .001 vs .51, P < .001; Z = 2.21, P = .027). Inflammatory activity was an independent predictor of LSM by TE but not of LSM by 2D-SWE. After controlling for fibrosis, age, sex and body mass index, the inflammatory activity and the interaction between inflammatory activity and fibrosis independently explained 11% and 13% of variance in LSM by TE respectively. Steatosis did not affect the association of fibrosis and LSM by either method.

Conclusion: Inflammatory activity on histology significantly affects LSM by TE, but not LSM by 2D-SWE in NAFLD. LSM by 2D-SWE reflects liver fibrosis more accurately than LSM by TE. Furthermore, the severity of steatosis on histology did not influence the association of LSM and fibrosis by either elastography method.
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http://dx.doi.org/10.1111/liv.15116DOI Listing
January 2022

Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study.

J Hepatol 2022 03 15;76(3):536-548. Epub 2021 Nov 15.

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié - Salpêtrière, Institute for Cardiometabolism and Nutrition, INSERM UMRS 1138 CRC, Paris, France. Electronic address:

Background & Aims: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study.

Methods: Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study.

Results: Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable.

Conclusions: Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. CLINICALTRIALS.

Gov Number: NCT02548351 LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy.
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http://dx.doi.org/10.1016/j.jhep.2021.10.029DOI Listing
March 2022

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

J Hepatol 2022 02 12;76(2):353-363. Epub 2021 Oct 12.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Background & Aims: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need.

Methods: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204).

Results: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response.

Conclusions: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation.

Lay Summary: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.
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http://dx.doi.org/10.1016/j.jhep.2021.09.035DOI Listing
February 2022

Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis.

Cancers (Basel) 2021 Oct 4;13(19). Epub 2021 Oct 4.

Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.

The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development-contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as , subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC.
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http://dx.doi.org/10.3390/cancers13194983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508272PMC
October 2021

Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests.

Nat Rev Gastroenterol Hepatol 2021 12 10;18(12):835-856. Epub 2021 Sep 10.

School of Medical Sciences, Örebro University, Örebro, Sweden.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.
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http://dx.doi.org/10.1038/s41575-021-00502-9DOI Listing
December 2021

COVID-19 in Liver Transplant Recipients: A Systematic Review.

J Clin Med 2021 Sep 5;10(17). Epub 2021 Sep 5.

University Clinic for Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.

Liver transplant (LT) recipients are considered a vulnerable population amidst the COVID-19 pandemic. To date, available data have been heterogeneous and scarce. Therefore, we conducted a systematic literature review identifying English-language articles published in PubMed between November 2019 and 30 May 2021. We aimed to explore three areas: (1) outcome and clinical course; (2) immunological response after COVID-19 in LT recipients; and (3) vaccination response. After systematic selection, 35, 4, and 5 articles, respectively, were considered suitable for each area of analysis. Despite the heterogeneity of the reports included in this study, we found that gastrointestinal symptoms were common in LT recipients. The outcome of the LT population was not per se worse compared to the general population, although careful management of immunosuppressive therapy is required. While a complete therapy discontinuation is not encouraged, caution needs to be taken with use of mycophenolate mofetil (MMF), favoring tacrolimus (TAC) use. Although data conflicted about acquired immunity after SARS-CoV-2 infection, vaccine immunogenicity appeared to be low, suggesting that the level of surveillance should be kept high in this population.
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http://dx.doi.org/10.3390/jcm10174015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432463PMC
September 2021

Cabozantinib in Advanced Hepatocellular Carcinoma: Efficacy and Safety Data from an International Multicenter Real-Life Cohort.

Liver Cancer 2021 Jul 1;10(4):360-369. Epub 2021 Jun 1.

Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt, Germany.

Background And Aims: The multikinase inhibitor cabozantinib has been approved for hepatocellular carcinoma (HCC) previously treated with sorafenib. We report safety and efficacy data of an international, multicenter, real-life cohort of patients with advanced HCC treated with cabozantinib.

Methods: Patients with HCC who were treated with cabozantinib were retrospectively identified across 11 centers in Austria, Switzerland, and Germany. Patients' characteristics, adverse events, duration of treatment and overall survival (OS) data were analyzed until April 1, 2020.

Results: Eighty-eight patients from 11 centers were included. The predominant underlying liver diseases were NAFLD/NASH in 26 (30%) and hepatitis C infection in 21 (24%) patients. Seventy-eight patients (89%) were classified as Barcelona clinic liver cancer (BCLC) stage C. Sixty patients (68%) were Child-Pugh A, whereas 22 (25%) were Child-Pugh B, respectively. Cabozantinib was used as systemic second- and third-line or later treatment in 41 (47%) and 46 (52%) patients, respectively. The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) patients, respectively. Fifty-two patients (59%) died during follow-up. The median OS from start of cabozantinib treatment was 7.0 months in the entire cohort and 9.7 months in Child-Pugh A patients, while Child-Pugh B patients had a median OS of 3.4 months, respectively. Thirty-seven (42%) patients fulfilled the CELESTIAL inclusion and exclusion criteria, showing a median OS of 11.1 months. Most common adverse events were fatigue (15.6%) and diarrhea (15.6%).

Conclusion: Cabozantinib treatment was effective, safe, and feasible in patients with advanced HCC in patients with compensated cirrhosis. Patients in the real-life setting had more advanced liver disease - in which 25% of patients were Child-Pugh B. However, OS in patients with Child-Pugh A cirrhosis was similar to that reported in the phase 3 trial (CELESTIAL).
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http://dx.doi.org/10.1159/000515490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339523PMC
July 2021

Effects of Home Care on patients with hepatocellular carcinoma treated with sorafenib.

JGH Open 2021 Aug 6;5(8):864-870. Epub 2021 Jul 6.

Hepatology, Department of Clinical Research University of Bern Bern Switzerland.

Background And Aim: Treatment with sorafenib causes diverse side effects, which limits adherence. This work assesses whether Home Care, a psychosocial nursing intervention, prolongs the duration of treatment in patients with advanced hepatocellular carcinoma (HCC) and if it influences health-related quality of life (HRQL).

Methods And Results: This is a cohort study using data from patients receiving sorafenib in the prospective Bern HCC Cohort at the University Hospital. Duration of treatment, overall survival, and HRQL using the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire were compared in the two groups. A total of 173 patients were eligible for the analysis. Among them, 141 were in the Home Care program, and 32 were not. Patients with Home Care had a significantly longer duration of treatment (265 days 152 days,  = 0.003) and a better functional well-being (17.7 12.5,  = 0.015).

Conclusion: Psychosocial interventions such as Home Care are a valid method in improving adherence to sorafenib and can therefore be recommended.
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http://dx.doi.org/10.1002/jgh3.12533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341184PMC
August 2021

Prevention of NAFLD-associated HCC: Role of lifestyle and chemoprevention.

J Hepatol 2021 11 31;75(5):1217-1227. Epub 2021 Jul 31.

University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.

In many countries worldwide, the burden of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. Preventive strategies are needed to counteract this trend. In this review, we provide an overview of the evidence on preventive strategies in NAFLD-associated HCC. We consider the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, antidiabetic treatments and statins is summarised. The role of adjuvant therapies for tertiary prevention of HCC is briefly reviewed.
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http://dx.doi.org/10.1016/j.jhep.2021.07.025DOI Listing
November 2021

Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.

J Hepatol 2021 10 13;75(4):865-878. Epub 2021 May 13.

Sema4, Stamford, Connecticut, USA; Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, USA.

Background And Aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies.

Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays.

Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved.

Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature.

Lay Summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.
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http://dx.doi.org/10.1016/j.jhep.2021.04.049DOI Listing
October 2021

Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns.

Gut Microbes 2021 Jan-Dec;13(1):1-20

Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università Della Svizzera Italiana, Lugano, Switzerland.

Intestinal microbiota regulates multiple host metabolic and immunological processes. Consequently, any difference in its qualitative and quantitative composition is susceptible to exert significant effects, in particular along the gut-liver axis. Indeed, recent findings suggest that such changes modulate the severity and the evolution of a wide spectrum of hepatobiliary disorders. However, the mechanisms linking intestinal microbiota and the pathogenesis of liver disease remain largely unknown. In this work, we investigated how a distinct composition of the intestinal microbiota, in comparison with germ-free conditions, may lead to different outcomes in an experimental model of acute cholestasis. Acute cholestasis was induced in germ-free (GF) and altered Schaedler's flora (ASF) colonized mice by common bile duct ligation (BDL). Studies were performed 5 days after BDL and hepatic histology, gene expression, inflammation, lipids metabolism, and mitochondrial functioning were evaluated in normal and cholestatic mice. Differences in plasma concentration of bile acids (BA) were evaluated by UHPLC-HRMS. The absence of intestinal microbiota was associated with significant aggravation of hepatic bile infarcts after BDL. At baseline, we found the absence of gut microbiota induced altered expression of genes involved in the metabolism of fatty and amino acids. In contrast, acute cholestasis induced altered expression of genes associated with extracellular matrix, cell cycle, autophagy, activation of MAPK, inflammation, metabolism of lipids, and mitochondrial functioning pathways. Ductular reactions, cell proliferation, deposition of collagen 1 and autophagy were increased in the presence of microbiota after BDL whereas GF mice were more susceptible to hepatic inflammation as evidenced by increased gene expression levels of osteopontin, interleukin (IL)-1β and activation of the ERK/MAPK pathway as compared to ASF colonized mice. Additonally, we found that the presence of microbiota provided partial protection to the mitochondrial functioning and impairment in the fatty acid metabolism after BDL. The concentration of the majority of BA markedly increased after BDL in both groups without remarkable differences according to the hygiene status of the mice. In conclusion, acute cholestasis induced more severe liver injury in GF mice compared to mice with limited intestinal bacterial colonization. This protective effect was associated with different hepatic gene expression profiles mostly related to tissue repair, metabolic and immune functions. Our findings suggest that microbial-induced differences may impact the course of cholestasis and modulate liver injury, offering a background for novel therapies based on the modulation of the intestinal microbiota.
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http://dx.doi.org/10.1080/19490976.2021.1911534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049203PMC
January 2022

A Role in the Genetic Predisposition to NAFLD-HCC?

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Translational and Clinical Research Institute, Faculty of Medical Sciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver ( rs738409; rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes ( rs2596542; rs187115; rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. and SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. rs7421861 was independently associated with NAFLD-HCC development, while rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis.
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http://dx.doi.org/10.3390/cancers13061412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003582PMC
March 2021

Auto-aggressive CXCR6 CD8 T cells cause liver immune pathology in NASH.

Nature 2021 04 24;592(7854):444-449. Epub 2021 Mar 24.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer. The accumulation of metabolites leads to cell stress and inflammation in the liver, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6 CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6 CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6 CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.
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http://dx.doi.org/10.1038/s41586-021-03233-8DOI Listing
April 2021

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Nature 2021 04 24;592(7854):450-456. Epub 2021 Mar 24.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need. Here we report the progressive accumulation of exhausted, unconventionally activated CD8PD1 T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8PD1 T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8PD1CXCR6, TOX, and TNF T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 T cells or TNF neutralization, suggesting that CD8 T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8PD1 T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
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http://dx.doi.org/10.1038/s41586-021-03362-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046670PMC
April 2021

Calcium transfer between endoplasmic reticulum and mitochondria in liver diseases.

FEBS Lett 2021 05 4;595(10):1411-1421. Epub 2021 Apr 4.

Hepatology, Department for BioMedical Research, University of Bern, Switzerland.

Calcium (Ca ) is a second messenger essential for cellular homeostasis. Inside the cell, Ca is compartmentalized and exchanged among organelles in response to both external and internal stimuli. Mitochondria-associated membranes (MAMs) provide a platform for proteins and channels involved in Ca transfer between the endoplasmic reticulum (ER) and mitochondria. Deregulated Ca signaling and proteins regulating ER-mitochondria interactions have been linked to liver diseases and intensively investigated in recent years. In this review, we summarize the role of MAM-resident proteins in Ca transfer and their association with different liver diseases.
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http://dx.doi.org/10.1002/1873-3468.14078DOI Listing
May 2021

Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.

Gut 2022 03 19;71(3):593-604. Epub 2021 Mar 19.

Liver and Transplant Unit, Policlinico Tor Vergata, Rome, Italy.

Objective: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration.

Design: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.

Results: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I=74.6%) and 5.7 (2.5 to 15.3, I=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1).

Conclusion: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.
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http://dx.doi.org/10.1136/gutjnl-2020-323663DOI Listing
March 2022
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