Immune Monitoring-Guided Versus Fixed Duration of Antiviral Prophylaxis Against Cytomegalovirus in Solid-Organ Transplant Recipients: A Multicenter, Randomized Clinical Trial.

BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. METHODS: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection. CLINICAL TRIALS REGISTRATION: NCT02538172.

Hepatic safety and efficacy of immunomodulatory drugs used in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: There is little data on the hepatic efficacy and safety of immunomodulatory drugs used in patients with autoimmune hepatitis (AIH), despite their established use in dermatology, rheumatology and inflammatory bowel diseases (IBD). Our aim was to collect real-life data on the experience of expert centres in treating AIH patients with these drugs, considered unconventional for AIH management. METHODS: Online survey among hepatology centres being part of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). RESULTS: 25 AIH patients have been reported. Ten were female, median age at diagnosis was 28 years; median follow-up was 17 months. All had initially received AIH-standard treatment. AIH-unconventional treatment was initiated for concomitant autoimmune diseases in 15 cases: nine for IBD (five vedolizumab and four ustekinumab), and one each for following diseases: autoinflammatory syndrome (tocilizumab), chronic urticaria (omalizumab), rheumatoid arthritis (abatacept), psoriasis (guselkumab), psoriatric arthritis (secukinumab, followed by ustekinumab) and alopecia (ruxolitinib). Three patients were treated with immunomodulatory drugs for side effects of previous treatments, including two patients with IBD treated with vedolizumab and ustekinumab, respectively, and one treated with belimumab. At the end of follow-up, 13 patients were in complete biochemical response, the patient on omalizumab had a relapse, and four patients with concomitant IBD had insufficient response. Seven patients were treated for lack of biochemical remission, of whom six with belimumab, all initially reaching complete biochemical response, but five relapsing during follow-up; and one with secukinumab, having concomitant rheumatoid arthritis and ankylosing spondylitis, reaching complete biochemical response. Only the patient on abatacept received unconventional treatment as monotherapy. Side effects were reported in two patients on belimumab: one recurrent soft tissue infections, one fatigue and arthralgia. CONCLUSION: Among 25 AIH patients who were treated with immunomodulatory drugs for different reasons, the majority had a fovorable course, relapse was frequent in difficult-to-treat patients who received belimumab, and four with concomitant IBD had insufficient response.

Hepatitis C Virus Infection Upregulates Plasma Phosphosphingolipids and Endocannabinoids and Downregulates Lysophosphoinositols.

A mass spectrometry-based lipidomic investigation of 30 patients with chronic hepatitis C virus (HCV) infection and 30 age- and sex-matched healthy blood donor controls was undertaken. The clustering and complete separation of these two groups was found by both unsupervised and supervised multivariate data analyses. Three patients who had spontaneously cleared the virus and three who were successfully treated with direct-acting antiviral drugs remained within the HCV-positive metabotype, suggesting that the metabolic effects of HCV may be longer-lived. We identified 21 metabolites that were upregulated in plasma and 34 that were downregulated (p < 1 × 10-16 to 0.0002). Eleven members of the endocannabinoidome were elevated, including anandamide and eight fatty acid amides (FAAs). These likely activated the cannabinoid receptor GPR55, which is a pivotal host factor for HCV replication. FAAH1, which catabolizes FAAs, reduced mRNA expression. Four phosphosphingolipids, d16:1, d18:1, d19:1 sphingosine 1-phosphate, and d18:0 sphinganine 1-phosphate, were increased, together with the mRNA expression for their synthetic enzyme SPHK1. Among the most profoundly downregulated plasma lipids were several lysophosphatidylinositols (LPIs) from 3- to 3000-fold. LPIs are required for the synthesis of phosphatidylinositol 4-phosphate (PI4P) pools that are required for HCV replication, and LPIs can also activate the GPR55 receptor. Our plasma lipidomic findings shed new light on the pathobiology of HCV infection and show that a subset of bioactive lipids that may contribute to liver pathology is altered by HCV infection.

Belimumab treatment in autoimmune hepatitis and primary biliary cholangitis - a case series.

Background: The majority of patients with autoimmune hepatitis (AIH) achieve complete remission with established treatment regiments. In patients with intolerance or insufficient response to these drugs, the remaining options are limited and novel treatment approaches necessary. In primary biliary cholangitis (PBC), ursodeoxycholic acid (UDCA) and fibrates have improved prognosis dramatically, but there remains a proportion of patients with refractory disease.In patients with refractory AIH and/or PBC, we used a novel treatment strategy with the anti-B cell activating factor, belimumab. The first three patients had concomitant Sjögren's disease. The connecting element between all three diseases is B cell activation, including elevated levels of the B cell activating factor (BAFF). Furthermore, belimumab has been shown to be beneficial in Sjögren's disease. Aims and methods: To retrospectively investigate treatment response in six patients with AIH or PBC with or without concomitant Sjögren's disease treated with the anti-BAFF therapy belimumab at the University Hospital in Bern, Switzerland. Results: In all three patients with AIH, belimumab improved disease control and helped by-pass or reduce problematic side effects from corticosteroids and calcineurin inhibitors. In PBC patients (n = 3), there was no clear improvement of liver function tests, despite reduction or normalization of IgM. All patients with concomitant Sjögren's disease (n = 3) had an improvement of sicca symptoms and two out of three patients experienced an initially marked reduction in fatigue, which lessened over time. Conclusions: Belimumab may be a promising treatment option for patients with AIH and further investigations are needed. In PBC however, response was not convincing. The effects on sicca symptoms and fatigue were encouraging.

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination.

Background & Aims: Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features. Methods: Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited; 35 females; median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines. Results: Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases; seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed. Conclusion: Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition. Impact and implications: Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition.

Mycophenolate mofetil as second line treatment in autoimmune hepatitis - A retrospective single center analysis.

Background: Most patients with autoimmune hepatitis respond to standard treatment with steroids and azathioprine. While the disease is usually fatal if untreated, patients who respond well to therapy have an excellent prognosis. Nevertheless, second-line treatment is necessary in approximately 20% of patients, due to either intolerance or insufficient response to first line treatment.While data for mycophenolate mofetil (MMF) in patients intolerant to azathioprine is encouraging, MMF seems of less benefit in patients with insufficient response to first line treatment, but analyzed data on this issue is limited. Aim: To evaluate the efficacy and safety of MMF as a second-line therapy in patients with AIH. Methods: Retrospective analysis of a monocentric database of AIH patients who received medical care from 2000 to 2022. Clinical, immunological and biochemical parameters were assessed at different time points including last follow-up. Results: Overall, 144 patients with AIH were identified. Fifty out of 144 (35%) AIH patients received MMF. Forty (80%) received MMF due to first line treatment intolerance, while ten (20%) due to insufficient response to first line treatment.Remission with MMF monotherapy was 81.5% in the intolerance group versus 30% in the insufficient response group. Patients switched to MMF because of an insufficient response, more often needed additional prednisolone doses higher than 5 mg/day, a switch to third-line treatment or combination regiments, to achieve disease control. Conclusions: Patients treated with MMF because of intolerance to first line treatment show a good disease control under MMF in the majority of cases. Efficacy is considerably lower in the patients switched to MMF because of an insufficient response to first line treatment.

Rational development and application of biomarkers in the field of autoimmunity: A conceptual framework guiding clinicians and researchers.

Clear guidance is needed in the development and implementation of laboratory biomarkers in medicine. So far, no standardized phased approach is established that would pilot researchers and clinicians in this process. This leads to often incompletely validated biomarkers, which can bear the consequence of wrong applications, misinterpretation and inadequate management in the clinical context. In this conceptual article, we describe a stepwise approach to develop and comprehensively validate laboratory biomarkers. We will delineate basic steps including technical performance, pre-analytical issues, and biological variation, as well as advanced aspects of biomarker utility comprising interpretability, diagnostic and prognostic accuracy, and health-care outcomes. These aspects will be illustrated by using well-known examples from the field of immunology. The application of this conceptual framework will guide researchers in conducting meaningful projects to develop and evaluate biomarkers for the use in clinical practice. Furthermore, clinicians will be able to adequately interpret pre-clinical and clinical diagnostic literature and rationally apply biomarkers in clinical practice. Improvement in the implementation and application of biomarkers might relevantly change the management and outcomes of our patients for the better.

HCV disease burden and population segments in Switzerland.

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.

Accelerated Course of Alveolar Echinococcosis After Treatment With Steroids in a Patient With Autoimmune Encephalitis.

Human alveolar echinococcosis (AE) is a zoonotic infection caused by the fox tapeworm Echinococcus â€‹â€‹â€‹â€‹â€‹â€‹multilocularis. We report the case of a patient who developed an accelerated course of AE with diffuse liver involvement after high-dose steroid treatment for autoimmune encephalitis. Immunosuppressive therapies present us with new challenges regarding the management of AE. With this article, we would like to draw attention to the importance of a screening program for AE before planned immunosuppressive therapy.

Pilot Sub-Study of the Effect of Hepatitis C Cure by Glecaprevir/Pibrentasvir on the Gut Microbiome of Patients with Chronic Hepatitis C Genotypes 1 to 6 in the Mythen Study.

In this small pilot sub-study, longitudinal gut microbiota composition changes, after successful treatment of hepatitis C virus (HCV) with the co-formulated glecaprevir/pibrentasvir (GLE/PIB), were analyzed before treatment (baseline) and 12 weeks post-treatment. Participating patients provided a fresh stool sample the week before their study visit, from which microbial DNA was extracted and sequenced for the 16S rRNA region in an Illumina MiSeq2 platform. Microbial and statistical analyses were conducted to determine the alpha-diversity (number of different taxa within a sample) and beta-diversity (number of overlapping taxa between samples). Stool samples from 58 patients were eligible for analysis. There were 27 patients with HCV genotype 1, 10 with genotype 2, 16 with genotype 3, and 5 with genotype 4. No statistically significant differences in gut microbiota diversity, species richness, or microbial community pattern were found at baseline and at post-treatment Week 12. Lack of statistically significant differences remained consistent in further analysis by demographic and baseline disease characteristics. Surprisingly, no statistically significant changes in alpha- and beta-diversity were seen in the microbiota after GLE/PIB treatment, though there was a trend toward less richness over time. Further investigation is needed into this unexpected outcome to better understand the role of HCV treatment and the gut microbiota.

Autoimmune hepatitis triggered by SARS-CoV-2 vaccination.

The development of autoimmune diseases has been reported after SARS-CoV-2 infection. Vaccination against SARS-CoV-2 could also trigger auto-immunity, as it has been described with other vaccines. An aberrant immune response induced by molecular mimicry and bystander activation, especially in predisposed individuals, is a potential mechanism. We report the case of a 76-year-old woman with Hashimoto thyroiditis and prior COVID-19 infection who developed severe autoimmune hepatitis (with typical features including strongly positive anti-smooth muscle antibody and markedly elevated immunoglobulins G, as well as typical histological findings) following SARS-CoV-2 vaccination (mRNA-1273 SARS-CoV-2 vaccine, Moderna®). The link between SARS-CoV-2 vaccination and the development of autoimmune diseases needs to be further investigated. Although a causality relationship cannot be proven, caution may be warranted when vaccinating individuals with known autoimmune diseases.

Real-World Outcomes in Historically Underserved Patients with Chronic Hepatitis C Infection Treated with Glecaprevir/Pibrentasvir.

INTRODUCTION: Glecaprevir/pibrentasvir is approved for treating chronic hepatitis C virus (HCV) genotypes (GT) 1-6. We evaluated real-world effectiveness, safety, and patient-reported outcomes of glecaprevir/pibrentasvir in underserved patient populations, focusing on persons who use drugs infected with HCV. METHODS: Data were pooled from nine countries (13 November 2017-31 January 2020). Patients had HCV GT1-6, with or without compensated cirrhosis, with or without prior HCV treatment and received glecaprevir/pibrentasvir consistent with local label at their physician's discretion. Patients with prior direct-acting antiviral exposure were excluded from efficacy and quality-of-life analyses. The percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12) was assessed. Mean changes from baseline to SVR12 visit in 36-Item Short-Form Health Survey mental and physical component summary scores were reported. Safety was assessed in patients receiving at least one dose of glecaprevir/pibrentasvir. RESULTS: Of 2036 patients, 1701 (83.5%) received 8-week glecaprevir/pibrentasvir. In 1684 patients with sufficient follow-up, SVR12 rates were 98.0% (1651/1684) overall, 98.1% (1432/1459) in 8-week treated patients, 97.0% (519/535) in persons who use drugs, and greater than 95% across subgroups. Mean changes from baseline in mental and physical component summary scores were 3.7 and 2.4, respectively. One glecaprevir/pibrentasvir-related serious adverse event was reported; six glecaprevir/pibrentasvir-related adverse events led to discontinuation. CONCLUSIONS: Glecaprevir/pibrentasvir was highly effective, well tolerated, and improved quality of life in HCV-infected persons who use drugs and other underserved patients. TRIAL REGISTRATION: These multinational post-marketing observational studies are registered with ClinicalTrials.gov, number NCT03303599.

Real-world effectiveness and safety of glecaprevir/pibrentasvir therapy in patients with chronic hepatitis C virus infection in Switzerland.

AIM OF THE STUDY: In the era of pangenotypic treatment regimens against hepatitis C virus (HCV) infection, data from postmarketing observational studies are crucial to better understand the treatment patterns used in specific countries and treatment outcomes under real-life conditions. We report data from Switzerland from an ongoing, multinational postmarketing observational study on the pangenotypic treatment regimen of glecaprevir (GLE; NS3/4A protease inhibitor) and pibrentasvir (PIB; NS5A inhibitor), coformulated as GLE/PIB. METHODS: Adults infected with chronic HCV genotypes 1–6 were eligible to participate in the postmarketing observational study if they started GLE/PIB at the treating physician’s discretion. The primary objective was to evaluate the effectiveness of GLE/PIB based on sustained virological response 12 weeks after completion of treatment (SVR12); secondary outcomes included patient-reported outcomes (Fatigue Severity Scale, Work Productivity and Activity Impairment Questionnaire, Pictorial Representation of Illness and Self Measure tool) and safety data. RESULTS: In Switzerland, 109 patients were enrolled, and 107 patients received ≥1 dose GLE/PIB (94.4% non-cirrhotic; 43.9%/14.0%/29.0%/13.1% GT1/GT2/GT3/GT4; 89.7% treatment-naïve; 91.6% assigned to an 8-week GLE/PIB regimen). Overall, 95 of 98 patients with sufficient follow-up data (96.9%) achieved SVR12 (95% confidence interval [CI] 91.4% to 99.0%), and 91.6% in the safety population (including six non-virological failures). The three treatment failures were due to relapse. All three failures were GT3, without cirrhosis and treatment naïve. Patient-reported outcomes improved as well. GLE/PIB was well tolerated with no serious adverse events and no adverse events leading to discontinuation or interruption of GLE/PIB treatment. CONCLUSION: These real-world effectiveness and safety data of GLE/PIB in patients from Switzerland were consistent with those seen in the multinational registration trials. (Trial registration number: Clinicaltrials.gov: NCT03303599.).

Adult form of Langerhans cell histiocytosis with pulmonary and hepatic involvement mimicking malignancy in a patient with chronic hepatitis C infection.

Langerhans cell histiocytosis (LCH) is a myeloid neoplasm with inflammatory properties. There are few published reports of adult LCH with liver involvement, which is still poorly understood, but shows high morbidity and mortality. We report a case of a 37-year-old woman suffering from hepatitis C showing a LCH affecting the lung as well as the liver. Consistent with histology, we found an early stage of a proliferative/granulomatous phase of hepatobiliary LCH, whereas pulmonary findings showed a nodular stage of adult pulmonary LCH. Although hepatocellular carcinoma is a common malignancy in patients suffering from hepatitis C, it is crucial to keep in mind differential diagnosis for newly appearing liver lesions.

A prospective, multicenter, post-marketing observational study to measure the quality of life of HCV genotype 1 infected, treatment naïve patients suffering from fatigue and receiving 3D regimen: The HEMATITE study.

AIM: Fatigue is the most commonly reported symptom of Hepatitis C Virus (HCV) infected patients and severely impacts their quality of life. The aim of this study was to measure the impact of 3D regimen treatment on the fatigue, daytime physical activity and sleep efficiency of HCV infected patients with fatigue. METHODS: HEMATITE was an observational, prospective, open-label, single-arm, Swiss multi-centric study in mono-infected HCV genotype 1 patients. The 28 week observation period comprised of 4 weeks preparation, 12 weeks treatment and 12 weeks follow-up. Fatigue was assessed using the fatigue severity scale (FSS) questionnaire. Patients with FSS ≥ 4 (clinically significant fatigue) were included. The activity tracker, ActiGraph GT9X Link®, was used to measure daytime physical activity and sleep efficiency. Outcome analysis was performed on a scaled down intention to treat (sdITT) population, which excluded patients with insufficient tracker data at all study visits and a modified ITT (mITT) population, which consisted of patients with complete tracker data at all study visits. RESULTS: Forty of 41 patients in the ITT population had a sustained virologic response 12 weeks post-treatment (SVR12). Mean baseline FSS score was 6.0 for the sdITT population and 5.9 for the mITT population and decreased from baseline to 12 weeks post-treatment by 2.6 (95% confidence interval [CI]: 2.1, 3.1) for the sdITT (n = 37) population and 2.8 (95% CI: 2.2, 3.4) for the mITT (n = 24) population. Mean daytime physical activity or sleep efficiency did not change considerably over the course of the study. CONCLUSION: Measurement by the activity tracker of mean day time physical activity did not show a considerable change from baseline to SVR12 upon treatment with 3D regimen. Nevertheless, a reduction of fatigue as assessed with the validated fatigue severity scale (FSS) was observed, suggesting a causative role of HCV in this extrahepatic manifestation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03002818.

All-Cause Mortality and Causes of Death in the Swiss Hepatitis C Cohort Study (SCCS).

BACKGROUND: With direct-acting antiviral agents (DAAs), mortality rates and causes of death among persons with hepatitis C virus (HCV) infection may change over time. However, the emergence of such trends may be delayed by the slow progression of chronic hepatitis C. To date, detailed analyses of cause-specific mortality among HCV-infected persons over time remain limited. METHODS: We evaluated changes in causes of death among Swiss Hepatitis C Cohort Study (SCCS) participants from 2008 to 2016. We analyzed risk factors for all-cause and cause-specific mortality, accounting for changes in treatment, fibrosis stage, and use of injectable drugs over time. Mortality ascertainment was completed by linking lost-to-follow-up participants to the Swiss Federal Statistical Office death registry. RESULTS: We included 4700 SCCS participants, of whom 478 died between 2008 and 2016. The proportion of unknown causes of death decreased substantially after linkage, from 42% to 10%. Leading causes of death were liver failure (crude death rate 4.4/1000 person-years), liver cancer (3.4/1000 person-years), and nonliver cancer (2.8/1000 person-years), with an increasing proportion of cancer-related deaths over time. Cause-specific analysis showed that persons with sustained virologic response were less at risk for liver-related mortality than those never treated or treated unsuccessfully. CONCLUSIONS: Although the expected decrease in mortality is not yet observable, causes of death among HCV-infected persons have evolved over time. With the wider use of DAAs, liver-related mortality is expected to decline in the future. Continued monitoring of cause-specific mortality will remain important to assess the long-term effect of DAAs and design effective interventions.

Controlled attenuation parameter reflects steatosis in compensated advanced chronic liver disease.

BACKGROUND & AIMS: Controlled attenuation parameter (CAP) for steatosis assessment has not been validated in compensated advanced chronic liver disease compensated advanced chronic liver disease (cACLD). We primarily aimed at assessing the accuracy of CAP for the diagnosis and quantification of steatosis in cACLD. Secondary aim: to assess the validity of non-invasive criteria for cACLD according to liver stiffness measurement (LSM). METHODS: This is a single-centre retrospective study including patients with cACLD defined as LSM ≥10 kPa, CAP measurement and liver biopsy (reference standard for steatosis and fibrosis) observed in 06/2015-06/2017. Steatosis was graded as S0 (<5%), S1 (5%-32%), S2 (33%-66%) and S3 (>66%). The diagnostic performance of CAP for any grade of steatosis and for high-grade steatosis (≥S2) was studied. RESULTS: Among 461 consecutive patients, 111 with LSM-based diagnosis of cACLD were included (63% male, median age 55 years, median body mass index 28.1 Kg/m2 , aetiology: 32% non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, 32% alcohol or viral + metabolic syndrome, 15% viral, 6% autoimmune, 4% alcohol, 11% others). Median LSM and CAP were 16.1 kPa and 277 dB/m respectively. On liver biopsy, steatosis was found in 88/111 patients (79%); 44 patients (43 with metabolic syndrome) had high-grade steatosis. CAP was accurate in identifying any grade of steatosis (area under the receiving operating characteristic curves 0.847; 95% CI 0.767-0.926, P < .0001), and ≥S2 steatosis (0.860; 95% CI 0.788-0.932, P < .0001). CAP performed similarly in patients with CAP- interquartile range (IQR) ≥ or <40 dB/m. CONCLUSIONS: Steatosis is frequent in patients with cACLD and metabolic syndrome. CAP diagnostic accuracy for any steatosis and high-grade steatosis is good in this population. A CAP-IQR ≥40 dB/m does not impair CAP diagnostic accuracy in cACLD.

Identification of an Endoglin Variant Associated With HCV-Related Liver Fibrosis Progression by Next-Generation Sequencing.

Despite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-ß pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39-6.69). Our results suggest that endoglin, a key player in TGF-ß signaling, is involved in HCV-related liver fibrogenesis.

A closer look at the spectrum of drug-induced liver injury in sub-Saharan Africa.

Introduction: Drug-induced liver injury (DILI) has become the most frequent cause of acute liver failure in high-income countries. However, little is known about the determinants of DILI in sub-Saharan Africa (SSA), where the prescription of antimicrobials and the use of potentially hepatotoxic traditional medicine are common. Areas covered: Based on an extensive literature search, we summarize current data available on the epidemiology and risk factors of DILI in SSA. We discuss the most likely causes of DILI in the region, including antimicrobial therapies and traditional medicine. We also highlight research gaps as well as barriers to diagnosis and management of the condition, and explore ways to address these important challenges. Expert opinion: DILI is underestimated in SSA and several factors challenge its early diagnosis, including lack of information on the causes of DILI in the region, sub-optimal knowledge about the condition among clinicians, and structural difficulties faced by health care systems. In order to better prevent the occurrence of DILI and its complications, it is crucial to enhance awareness among health care providers and patients, adapt drug prescription habits and regulations, and improve current knowledge on the main risk factors for DILI, including host genetic and environmental determinants.