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BACKGROUND & AIMS: In patients with compensated alcohol-related cirrhosis, reliable prognostic biomarkers are lacking. Keratin-18 and hepatocyte-derived large extracellular vesicle (lEV) concentrations reflect disease activity, but their ability to predict liver-related events is unknown. METHODS: We measured plasma keratin-18 and hepatocyte lEV concentrations in 500 patients with Child-Pugh class A alcohol-related cirrhosis. The ability of these hepatocyte-derived biomarkers, alone or combined with model for end-stage liver disease (MELD) and FibroTest scores, to predict liver-related events at 2 years was analyzed, taking into account the alcohol consumption at inclusion and during follow-up. RESULTS: Keratin-18 and hepatocyte lEV concentrations increased with alcohol consumption. In patients without active alcohol consumption at enrollment (n = 419), keratin-18 concentration predicted liver-related events at 2 years, independently of FibroTest and MELD. Patients with both keratin-18 concentrations >285 U/L and FibroTest >0.74 had a 24% cumulative incidence of liver-related events at 2 years, vs. 5% to 14% in other groups of patients. Similar results were obtained when combining keratin-18 concentrations >285 U/L with MELD >10. In patients with active alcohol consumption at enrollment (n = 81), hepatocyte lEVs predicted liver-related events at 2 years, independently of FibroTest and MELD. Patients with both hepatocyte lEV concentrations >50 U/L and FibroTest >0.74 had a 62% cumulative incidence of liver-related events at 2 years, vs. 8% to 13% in other groups of patients. Combining hepatocyte lEV concentrations >50 U/L with MELD >10 had a lower discriminative ability. Similar results were obtained when using decompensation of cirrhosis, defined according to Baveno VII criteria, as an endpoint. CONCLUSION: In patients with Child-Pugh class A alcohol-related cirrhosis, combining hepatocyte-derived biomarkers with FibroTest or MELD scores identifies patients at high risk of liver-related events, and could be used for risk stratification and patient selection in clinical trials. IMPACT AND IMPLICATIONS: In patients with compensated alcohol-related cirrhosis, reliable predictors of outcome are lacking. In patients with Child-Pugh class A alcohol-related cirrhosis, combining hepatocyte-derived biomarkers (keratin-18 and hepatocyte-large extracellular vesicles) with FibroTest or MELD scores identifies those at high risk of liver-related events at 2 years. The identified patients at high risk of liver-related events are the target-of-choice population for intensive surveillance (e.g., referral to tertiary care centers; intensive control of risk factors) and inclusion in clinical trials.
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Enfermedad Hepática en Estado Terminal , Queratina-18 , Humanos , Índice de Severidad de la Enfermedad , Cirrosis Hepática Alcohólica , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Biomarcadores , Hepatocitos , PronósticoRESUMEN
BACKGROUND & AIMS: Histological classifications used to diagnose/stage non-alcoholic fatty liver disease (NAFLD) are based on morphology, with undetermined clinical correlates and relevance. We assessed the clinical relevance of the fatty liver inhibition of progression (FLIP) algorithm and the steatosis, activity, and fibrosis (SAF) scoring system. METHODS: One hundred and forty consecutive patients with suspected NAFLD and a separate validation cohort of 78 patients enrolled in a therapeutic trial, all with central reading of liver biopsy, were included. FLIP and SAF were used to categorize patients with non-alcoholic steatohepatitis (NASH), non-NASH NAFLD (NAFL), or non-NAFLD. The SAF activity score assessed hepatocyte ballooning and lobular inflammation; a histologically severe disease was defined as a SAF activity score of ≥3 and/or bridging fibrosis or cirrhosis. Clinical, biochemical, and metabolic data were analyzed in relation to histology. RESULTS: Patients with NASH according to the FLIP algorithm had a clinical profile distinct from those with NAFL, with a higher prevalence of metabolic risk factors (increased body mass index [BMI], central obesity, serum glucose, and glycated hemoglobin), more severe insulin resistance (fasting insulin and homeostasis model assessment for insulin resistance [HOMA-IR] values), and higher levels of aminotransferases. Similar findings were documented for patients with severe disease vs. those without. Positive linear trends existed between NASH or severe disease and increasing BMI and HOMA-IR. There was a strong association between liver fibrosis and NASH or SAF-defined scores of activity. Patients with either significant or bridging fibrosis overwhelmingly had NASH, and bridging fibrosis most often coexisted with severe activity. CONCLUSIONS: The FLIP algorithm/SAF score, although based on purely morphological grounds, are clinically relevant, as they identify patients with distinct clinical and biological profiles of disease severity. Disease activity in NAFLD is associated with fibrosis severity. LAY SUMMARY: The examination of liver tissue under the microscope (histology) serves to define the type and severity of non-alcoholic fatty liver disease morphologically, and is also used to determine improvement in therapeutic or natural history clinical trials. The FLIP algorithm/SAF classification is a new histological classification well validated on morphological but not clinical grounds. Here, we demonstrate that different disease categories defined by the FLIP/SAF classification correspond to entities of different clinical and biological severity. We also show a strong association between the activity of steatohepatitis (defined histologically) and the amount of fibrotic scar.
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Algoritmos , Cirrosis Hepática/epidemiología , Enfermedad del Hígado Graso no Alcohólico/clasificación , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Obesidad Abdominal/epidemiología , Proyectos de Investigación , Índice de Severidad de la Enfermedad , Adulto , Biopsia , Glucemia , Índice de Masa Corporal , Estudios de Cohortes , Comorbilidad , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/patología , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: HDV infection causes severe chronic liver disease in individuals infected with HBV. However, the factors associated with poor prognosis are largely unknown. Thus, we aimed to identify prognostic factors in patients with HDV infection. METHODS: The French National Reference Centre for HDV performed a nationwide retrospective study on 1,112 HDV-infected patients, collecting epidemiological, clinical, virological and histological data from the initial referral to the last recorded follow-up. RESULTS: The median age of our cohort was 36.5 (29.9-43.2) years and 68.6% of our cohort were male. Most patients whose birthplace was known were immigrants from sub-Saharan Africa (52.5%), southern and eastern Europe (21.3%), northern Africa and the Middle East (6.2%), Asia (5.9%) and South America (0.3%). Only 150 patients (13.8%) were French native. HDV load was positive in 659 of 748 tested patients (88.1%). HDV-1 was predominant (75.9%), followed by sub-Saharan genotypes: HDV-5 (17.6%), HDV-7 (2.9%), HDV-6 (1.8%) and HDV-8 (1.6%). At referral, 312 patients (28.2%) had cirrhosis, half having experienced at least 1 episode of hepatic decompensation. Cirrhosis was significantly less frequent in African than in European patients regardless of HDV genotype. At the end of follow-up (median 3.0 [0.8-7.2] years), 48.8% of the patients had developed cirrhosis, 24.2% had ≥1 episode(s) of decompensation and 9.2% had hepatocellular carcinoma. European HDV-1 and African HDV-5 patients were more at risk of developing cirrhosis. Persistent replicative HDV infection was associated with decompensation, hepatocellular carcinoma and death. African patients displayed better response to interferon therapy than non-African patients (46.4% vs. 29.1%, p <0.001). HDV viral load at baseline was significantly lower in responders than in non-responders. CONCLUSION: Place of birth, HDV genotype and persistent viremia constitute the main determinants of liver involvement and response to treatment in chronic HDV-infected patients. LAY SUMMARY: Chronic liver infection by hepatitis delta virus (HDV) is the most severe form of chronic viral hepatitis. Despite the fact that at least 15-20 million people are chronically infected by HDV worldwide, factors determining the severity of liver involvement are largely unknown. By investigating a large cohort of 1,112 HDV-infected patients followed-up in France, but coming from different areas of the world, we were able to determine that HDV genotype, place of birth (reflecting both viral and host-related factors) and persistent viremia constitute the main determinants of liver involvement and response to treatment.
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Carcinoma Hepatocelular , Hepatitis D Crónica , Virus de la Hepatitis Delta , Cirrosis Hepática , Neoplasias Hepáticas , Viremia , Adulto , Carcinoma Hepatocelular/etnología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Femenino , Francia/epidemiología , Hepatitis D Crónica/complicaciones , Hepatitis D Crónica/diagnóstico , Hepatitis D Crónica/epidemiología , Hepatitis D Crónica/terapia , Virus de la Hepatitis Delta/genética , Virus de la Hepatitis Delta/aislamiento & purificación , Virus de la Hepatitis Delta/patogenicidad , Humanos , Interferones/uso terapéutico , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etnología , Cirrosis Hepática/etiología , Neoplasias Hepáticas/etnología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Masculino , Características de la Residencia/estadística & datos numéricos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Carga Viral/métodos , Carga Viral/estadística & datos numéricos , Viremia/diagnóstico , Viremia/etnologíaRESUMEN
Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S-transferase α, alpha-fetoprotein, arginase-1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin-5, macrophage colony-stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell-derived chemotaxin-2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR-122, and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End-Stage Liver Disease was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR-122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.
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Biomarcadores/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Adulto , Estudios de Casos y Controles , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
BACKGROUND & AIMS: In small-size and short-term studies of hepatitis C virus-associated cryoglobulinemia vasculitis (HCV-CryoVas), patients had a higher rate of response and tolerance to direct-acting antiviral (DAA) agents than interferon-containing regimens. We collected follow-up data from a clinical trial to determine the long-term effectiveness and tolerance of all-oral, interferon-free DAA regimens in patients with CryoVas. METHODS: We collected follow-up data from a prospective international multicenter cohort study of 148 patients with symptomatic HCV-CryoVas (53.7% with cirrhosis and 49.3% naive to treatment with DAAs). All patients received DAA (sofosbuvir plus daclatasvir, n = 53; sofosbuvir plus ribavirin, n = 51; sofosbuvir plus ledipasvir, n = 23; or sofosbuvir plus simeprevir, n = 18), for 12 or 24 weeks, from 2014 through 2017; the median follow-up time was 15.3 months. A complete clinical response was defined as improvement of all organs involved at baseline and the absence of clinical relapse; a partial response was defined as improvement in some but not all organs involved at baseline. The primary end point was clinical response of CryoVas symptoms at week 12 after stopping DAA therapy. RESULTS: A complete response was reported for 106 patients (72.6%), a partial response for 33 patients (22.6%), and no response for 7 patients (4.8%). Cryoglobulins were no longer detected in blood samples from 53.1% of patients, and 97.2% of the patients had a sustained virologic response to therapy. Premature DAA withdrawal was reported for 4.1% of patients. Factors associated with no or partial response to therapy included a severe form of CryoVas (odds ratio, 0.33; 95% CI, 0.12-0.91; P = .03) and peripheral neuropathy (odds ratio, 0.31; 95% CI, 0.11-0.84; P = .02). After a median follow-up time of 15.3 months, 4 patients (2.8%) died. The CryoVas manifestation of purpura was cleared from 97.2% of patients, renal involvement from 91.5% of patients, arthralgia from 85.7% of patients, neuropathy from 77.1% of patients, and cryoglobulinemia from 52.2%. CONCLUSIONS: In a long-term follow-up analysis of data from a clinical trial, we found that more than 95% of patients with HCV-CryoVas have a full or partial response of symptoms to different DAA treatment regimens. Fewer than 5% of patients stop therapy prematurely and less than 3% die. A severe form of CryoVas and peripheral neuropathy were associated with a lack of response of HCV-CryoVas to DAA therapy.
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Antivirales/uso terapéutico , Crioglobulinemia/complicaciones , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Vasculitis/patología , Anciano , Antivirales/efectos adversos , Ensayos Clínicos como Asunto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Resultado del TratamientoAsunto(s)
Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , Hígado/patología , Biomarcadores , Biopsia , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
BACKGROUND & AIMS: Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity. METHODS: We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay. RESULTS: Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions of IgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P < .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P < .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P = .03), and positive correlations with numbers of Tfh cells (P = .03) and serum levels of cryoglobulin (P = .01). DAA therapy increased patients' numbers of T-regulatory cells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively). CONCLUSIONS: In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.
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Antivirales/uso terapéutico , Subgrupos de Linfocitos B/efectos de los fármacos , Crioglobulinemia/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Virus de Hepatitis/efectos de los fármacos , Imidazoles/uso terapéutico , Tolerancia Inmunológica/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Ribavirina/uso terapéutico , Simeprevir/uso terapéutico , Sofosbuvir/uso terapéutico , Subgrupos de Linfocitos T/efectos de los fármacos , Vasculitis/tratamiento farmacológico , Anciano , Antivirales/efectos adversos , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/virología , Biomarcadores/sangre , Carbamatos , Estudios de Casos y Controles , Crioglobulinemia/diagnóstico , Crioglobulinemia/inmunología , Crioglobulinemia/virología , Citocinas/sangre , Quimioterapia Combinada , Femenino , Hepatitis C/complicaciones , Hepatitis C/diagnóstico , Hepatitis C/inmunología , Virus de Hepatitis/inmunología , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Prospectivos , Pirrolidinas , Ribavirina/efectos adversos , Simeprevir/efectos adversos , Sofosbuvir/efectos adversos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/virología , Factores de Tiempo , Resultado del Tratamiento , Valina/análogos & derivados , Vasculitis/diagnóstico , Vasculitis/inmunología , Vasculitis/virología , Carga ViralRESUMEN
Circulating mixed cryoglobulins are detected in 40%-60% of patients with hepatitis C virus (HCV) infection, and overt cryoglobulinemia vasculitis (CryoVas) develops in approximately 15% of patients. Remission of vasculitis has been associated with viral clearance, but few studies have reported the effectiveness of direct-acting antiviral drugs in these patients. We performed an open-label, prospective, multicenter study of the effectiveness and tolerance of an all-oral, interferon- and ribavirin-free regimen of sofosbuvir plus daclatasvir in patients with HCV-associated CryoVas. Forty-one consecutive patients with active HCV-associated CryoVas (median age, 56 y; 53.6% women) were recruited from hospitals in Paris, France, from 2014 through 2016. They received sofosbuvir (400 mg/day) plus daclatasvir (60 mg/day) for 12 weeks (n = 32) or 24 weeks (n = 9), and were evaluated every 4 weeks until week 24 and at week 36. Blood samples were analyzed for complete blood count, serum chemistry profile, level of alanine aminotransferase, rheumatoid factor activity, C4 fraction of complement, and cryoglobulin; peripheral blood mononuclear cells were isolated for flow cytometry analysis. Thirty-seven patients (90.2%) had a complete clinical response (defined by improvement of all the affected organs involved at baseline and no clinical relapse) after a median time of 12 weeks of therapy; all had a sustained virologic response (no detectable serum HCV RNA 12 weeks after the end of antiviral therapy). Patients' mean cryoglobulin level decreased from 0.56 ± 0.18 at baseline to 0.21 ± 0.14 g/L at week 36, and no cryoglobulin was detected in 50% of patients at this time point. After antiviral therapy, patients had increased numbers of T-regulatory cells, IgM+CD21-/low-memory B cells, CD4+CXCR5+ interleukin 21+ cells, and T-helper 17 cells, compared with before therapy. After a median follow-up period of 26 months (interquartile range, 20-30 mo), no patients had a serious adverse event or relapse of vasculitis.
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Antivirales/uso terapéutico , Crioglobulinemia/tratamiento farmacológico , Crioglobulinas/metabolismo , Hepatitis C/tratamiento farmacológico , Imidazoles/uso terapéutico , Sofosbuvir/uso terapéutico , Vasculitis/tratamiento farmacológico , Antivirales/efectos adversos , Linfocitos B/química , Linfocitos T CD4-Positivos/química , Carbamatos , Crioglobulinemia/sangre , Crioglobulinemia/virología , Quimioterapia Combinada , Femenino , Hepatitis C/sangre , Hepatitis C/complicaciones , Humanos , Imidazoles/efectos adversos , Inmunoglobulina M/análisis , Interleucinas/análisis , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirrolidinas , Receptores CXCR5/análisis , Receptores de Complemento 3d/análisis , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Linfocitos T Reguladores , Células Th17 , Valina/análogos & derivados , Vasculitis/sangre , Vasculitis/virologíaRESUMEN
There is growing evidence that human genetic variants contribute to liver fibrosis in subjects with hepatitis C virus (HCV) monoinfection, but this aspect has been little investigated in patients coinfected with HCV and human immunodeficiency virus (HIV). We performed the first genome-wide association study of liver fibrosis progression in patients coinfected with HCV and HIV, using the well-characterized French National Agency for Research on AIDS and Viral Hepatitis CO13 HEPAVIH cohort. Liver fibrosis was assessed by elastography (FibroScan), providing a quantitative fibrosis score. After quality control, a genome-wide association study was conducted on 289 Caucasian patients, for a total of 8,426,597 genotyped (Illumina Omni2.5 BeadChip) or reliably imputed single-nucleotide polymorphisms. Single-nucleotide polymorphisms with P values <10-6 were investigated in two independent replication cohorts of European patients infected with HCV alone. Two signals of genome-wide significance (P < 5 × 10-8 ) were obtained. The first, on chromosome 3p25 and corresponding to rs61183828 (P = 3.8 × 10-9 ), was replicated in the two independent cohorts of patients with HCV monoinfection. The cluster of single-nucleotide polymorphisms in linkage disequilibrium with rs61183828 was located close to two genes involved in mechanisms affecting both cell signaling and cell structure (CAV3) or HCV replication (RAD18). The second signal, obtained with rs11790131 (P = 9.3 × 10-9 ) on chromosome region 9p22, was not replicated. CONCLUSION: This genome-wide association study identified a new locus associated with liver fibrosis severity in patients with HIV/HCV coinfection, on chromosome 3p25, a finding that was replicated in patients with HCV monoinfection; these results provide new relevant hypotheses for the pathogenesis of liver fibrosis in patients with HIV/HCV coinfection that may help define new targets for drug development or new prognostic tests, to improve patient care. (Hepatology 2016;64:1462-1472).
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Sitios Genéticos , Infecciones por VIH/complicaciones , Hepatitis C Crónica/complicaciones , Cirrosis Hepática/genética , Cirrosis Hepática/virología , Coinfección , Progresión de la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND & AIMS: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. METHODS: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. RESULTS: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. CONCLUSIONS: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.
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Antígenos CD/sangre , Cadherinas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Proteínas de Unión a Ácidos Grasos/sangre , Acetaminofén/administración & dosificación , Adulto , Alanina Transaminasa/sangre , Biomarcadores/sangre , Femenino , Infecciones por VIH , Heparina/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Proteómica , Factores de Riesgo , Tuberculosis , Adulto JovenRESUMEN
OBJECTIVES: Hepatobiliary complications are a leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Knowledge of the underlying pathological aspects and optimal clinical management is, however, sorely lacking. METHODS: We provide a summary of the lectures given by international speakers at the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) monothematic conference on cystic fibrosis-related liver disease (CFLD) held in Paris in January 2016, to discuss the status of our current knowledge of liver disease in CF patients, to define the critical areas that need to be addressed, and to resolve actions to elucidate relevant mechanisms of disease to optimise future therapeutic options. CONCLUSIONS: The need for a universal consensus on the definition of CFLD to clarify disease stage and to identify relevant biomarkers to assess disease severity was highlighted. A deeper understanding of the pathophysiology and prognostic factors for the long-term evolution of CFLD is fundamental to move forward and has a strong bearing on identifying potential treatments. Novel experimental models and new treatment options under investigation are discussed and offer hope for the near future of CFLD.
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Fibrosis Quística/complicaciones , Hepatopatías/etiología , Biomarcadores/metabolismo , Fibrosis Quística/diagnóstico , Fibrosis Quística/metabolismo , Fibrosis Quística/terapia , Fármacos Gastrointestinales/uso terapéutico , Humanos , Hepatopatías/diagnóstico , Hepatopatías/metabolismo , Hepatopatías/terapia , Trasplante de Hígado , Trasplante de Páncreas , PronósticoRESUMEN
Because of global epidemics of obesity and type 2 diabetes, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing both in Europe and the United States, becoming one of the most frequent causes of chronic liver disease and predictably, one of the leading causes of liver transplantation both for end-stage liver disease and hepatocellular carcinoma. For most transplant teams around the world this will raise many challenges in terms of pre- and post-transplant management. Here we review the multifaceted impact of NAFLD on liver transplantation and will discuss: (1) NAFLD as a frequent cause of cryptogenic cirrhosis, end-stage chronic liver disease, and hepatocellular carcinoma; (2) prevalence of NAFLD as an indication for liver transplantation both in Europe and the United States; (3) the impact of NAFLD on the donor pool; (4) the access of NAFLD patients to liver transplantation and their management on the waiting list in regard to metabolic, renal and vascular comorbidities; (5) the prevalence and consequences of post-transplant metabolic syndrome, recurrent and de novo NAFLD; (6) the alternative management and therapeutic options to improve the long-term outcomes with particular emphasis on the correction and control of metabolic comorbidities.
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Enfermedad del Hígado Graso no Alcohólico , Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Europa (Continente) , Humanos , Neoplasias Hepáticas , Trasplante de Hígado , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: Whether steatosis is incidentally or causally associated with carotid atherosclerosis is debated, and long-term follow-up data are missing. This study aims to examine the impact of steatosis on the presence and progression of carotid intima-media thickness (C-IMT) and carotid plaques (CP) in a large cohort with longitudinal follow-up. METHODS: A retrospective single-center study between 1995 and 2012. Transversal cohort: patients with ⩾2 cardiovascular risk factors without previous cardiovascular events. Longitudinal cohort: patients with two consecutive C-IMT measurements more than 2years apart. Steatosis was defined by a surrogate marker, the fatty liver index (FLI). CP and C-IMT were assessed by carotid ultrasound. RESULTS: In the transversal cohort (n=5671) both C-IMT and the Framingham risk score (FRS) increased across FLI quartiles (0.58±0.12, 0.61±0.14, 0.63±0.14, 0.64±0.14mm, and 5±5%, 9±7%, 12±8%, 15±9%, p<0.001 for both). Steatosis predicted C-IMT better than diabetes or dyslipidemia. Steatosis independently predicted C-IMT (p=0.002) and FRS (p<0.001) after adjustment for metabolic syndrome and cardiovascular risk factors. In the longitudinal cohort (n=1872, mean follow-up 8±4years), steatosis occurred in 12% and CP in 23% of patients. C-IMT increased in patients with steatosis occurrence (from 0.60±0.13mm to 0.66±0.14mm, p=0.001) whereas it did not change in those that stayed free of steatosis. Steatosis at baseline predicted CP occurrence (OR=1.63, 95% CI 1.10-2.41, p=0.014), independent of age, sex, type-2 diabetes, tobacco use, hsCRP, hypertension and C-IMT. CONCLUSIONS: In patients with metabolic syndrome at risk for cardiovascular events, steatosis contributes to early atherosclerosis and progression thereof, independent of traditional cardiovascular risk factors.
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Hígado Graso , Enfermedades Cardiovasculares , Enfermedades de las Arterias Carótidas , Grosor Intima-Media Carotídeo , Humanos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Hepatitis C virus (HCV) is the aetiological agent for most cases of cryoglobulinaemia vasculitis. Interferon-containing regimens are associated with important side effects and may exacerbate the vasculitis. OBJECTIVE: To evaluate safety and efficacy of an oral interferon-free regimen, sofosbuvir plus ribavirin, in HCV-cryoglobulinaemia vasculitis. PATIENTS AND METHODS: We enrolled 24 consecutive patients (median age of 56.5â years and 46% of women) with HCV-cryoglobulinaemia vasculitis. Sofosbuvir (400â mg/day) was associated with ribavirin (200-1400â mg/day), for 24â weeks. The primary efficacy end point was a complete clinical response of the vasculitis at the end of treatment (week 24). RESULTS: Main features of HCV-cryoglobulinaemia vasculitis included purpura and peripheral neuropathy (67%), arthralgia (58%), glomerulonephritis (21%) and skin ulcers (12%). Twenty-one patients (87.5%) were complete clinical response at week 24. Complete clinical response was achieved in six (25%) patients at week 4, four (16.6%) at week 8, seven (29.2%) at week 12, three (12.5%) at week 16 and one (4.2%) at week 20. The cryoglobulin level decreased from 0.35 (0.16-0.83) at baseline to 0.15 (0.05-0.45) g/L at week 24. The C4 serum level increased from 0.10 (0.07-0.19) to 0.17 (0.09-0.23) g/L at week 24. Seventy-four per cent of patients had a sustained virological response at week 12 post treatment. The most common side effects were fatigue, insomnia and anaemia. Two serious adverse events were observed. CONCLUSIONS: Sofosbuvir plus ribavirin combination was associated with a high rate of complete clinical response and a low rate of serious adverse events in HCV-cryoglobulinaemia vasculitis.
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Antivirales/administración & dosificación , Crioglobulinemia/tratamiento farmacológico , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Vasculitis/tratamiento farmacológico , Crioglobulinemia/virología , Quimioterapia Combinada , Femenino , Hepacivirus , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Vasculitis/virologíaRESUMEN
BACKGROUND & AIMS: All trials on severe alcoholic hepatitis (AH) have included patients with "pure" AH, i.e., without concomitant gastrointestinal bleeding (GIB). Severe AH is often suspected in cirrhotic patients with GIB. We aimed at (1) assessing the prevalence of AH in patients with GIB and Maddrey discriminant function (DF) ⩾32; (2) comparing the outcome in AH patients with or without GIB (AH-GIB+, AH-GIB-); and (3) assessing the performance of the Lille model for survival in AH-GIB+ patients. METHODS: We retrospectively included all patients with alcoholic cirrhosis admitted between January 2005 and March 2011 with the following: (1) jaundice <3 months; (2) DF ⩾32 at admission; (3) bilirubin level >50 µmol/L; and (4) active drinking. Exclusion criteria were advanced hepatocellular carcinoma, other etiology of cirrhosis, severe comorbidities and DF <32 after stabilization. In our centre, we systematically plan a liver biopsy for these patients. Patients with severe AH received prednisolone. RESULTS: We screened 161 patients (86 GIB+, 75 GIB-), and analyzed data for 58 and 47 patients in each group, respectively. The 2 groups did not differ in prevalence of AH (77.3% vs. 81%), demographic data, MELD/Child-Pugh score, or DF. The 2 groups were similar in 6-month probability of survival (73.9 ± 6.0% vs. 69.9 ± 7%, p=0.49). The probability of developing infection was lower for AH-GIB+ patients (24.1% vs. 44.7%, p=0.04). The AUC for the Lille model in predicting 6-month survival was 0.71 ± 0.06 for all patients and 0.74 ± 0.06 for AH-GIB+ patients (p>0.05). CONCLUSIONS: Prevalence of AH is 80% for patients with cirrhosis and GIB, recent jaundice and DF ⩾32. Infection was lower for AH-GIB+ patients, which suggests a beneficial role of antibiotic prophylaxis treatment. Survival among subjects with GIB was the same as among subjects without GIB.
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Hemorragia Gastrointestinal , Hepatitis Alcohólica , Cirrosis Hepática , Prednisolona/uso terapéutico , Adulto , Antiinflamatorios/uso terapéutico , Biopsia , Femenino , Francia/epidemiología , Hemorragia Gastrointestinal/epidemiología , Hemorragia Gastrointestinal/etiología , Hepatitis Alcohólica/complicaciones , Hepatitis Alcohólica/diagnóstico , Hepatitis Alcohólica/epidemiología , Hepatitis Alcohólica/terapia , Hospitalización/estadística & datos numéricos , Humanos , Hígado/patología , Cirrosis Hepática/epidemiología , Cirrosis Hepática/etiología , Pruebas de Función Hepática/métodos , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
BACKGROUND & AIMS: Chronic liver diseases are highly prevalent and require an accurate evaluation of liver fibrosis to determine patient management. Over the last decade, great effort has been made to develop non-invasive liver fibrosis tests. The ensuing increase of literature is, however, impaired by extensive heterogeneity in the quality of published reports. The Standards for Reporting of Diagnostic Accuracy Studies (STARD), first published in 2003, were developed to improve the quality of research reports on diagnostic studies. We aimed to evaluate STARD statements in the setting of diagnostic studies on non-invasive liver fibrosis tests, and to propose an extended version developed specifically for those studies. METHODS: Eight French experts evaluated STARD statement adequacy in 10 studies on non-invasive liver fibrosis tests and then developed an extended version with a glossary. The new checklist and glossary were independently evaluated by seven international experts. RESULTS: Fourteen of the 25 STARD items were considered only partially adequate for the evaluation of diagnostic studies on non-invasive liver fibrosis tests. Inter-expert agreement was at least very good for 8 STARD items (32%), moderate for 9 (36%), and poor or very poor for 8 (32%). The experts' proposals were developed into the new Liver-FibroSTARD standards including a checklist with 62 items/sub-items and a corresponding comprehensive glossary. New proposals were inserted in the 25 STARD items as a complementary module. Independent evaluation of the Liver-FibroSTARD checklist showed at least very good inter-expert agreement for 39 items/sub-items (63%), moderate agreement for 11 (18%), and poor or very poor agreement for only 12 (19%). CONCLUSIONS: As a supplement of the STARD statements, the Liver-FibroSTARD checklist and its glossary are new tools specifically designed for the evaluation of diagnostic studies about non-invasive liver fibrosis tests.
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Exactitud de los Datos , Precisión de la Medición Dimensional , Cirrosis Hepática/diagnóstico , Pruebas de Función Hepática/normas , Informe de Investigación/normas , Protocolos Clínicos , Manejo de la Enfermedad , Francia , Humanos , Mejoramiento de la Calidad , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND & AIMS: Transient elastometry is a noninvasive procedure used to measure fibrosis when patients are diagnosed with liver disease; it might be used to monitor changes over time. We investigated whether there are short-term variations in stiffness measurements that are not attributable to changes in fibrosis by studying patients with stable liver disease. METHODS: We performed a retrospective analysis of 531 paired liver stiffness measurements made by Fibroscan when the study began (LSM1) and at follow-up (LSM2), more than 1 day and less than 1 year apart, from 432 stable (for body mass index, waist circumference, and alcohol consumption), untreated, immunocompetent patients with chronic liver disease (from January 2006 through March 2009). Variations between the first and follow-up measurements were expressed as absolute (LSM2-LSM1, kPa) or relative ([LSM2-LSM1]/LSM1*100) or as changes in fibrosis stage. RESULTS: There was >20% variation in 49.7%, >30% in 34.3%, and >50% in 12.2% of paired measurements; this variation was constant across the spectrum of LSM1 values. The variations produced a 1-fibrosis stage difference in 31.5% of pairs and a ≥ 2-stage difference in 9.8% of pairs. Patients with LSM1 >7 kPa had increased probability of having a different stage of fibrosis at LSM2, compared with patients with LSM1 <7 kPa. Factors associated with variation included measurements made by 2 different operators or at least 1 non-senior operator, ratios of interquartile range:median values, significant fibrosis (≥ 7 kPa) at LSM1, baseline body mass index, or a 2-fold difference in level of alanine aminotransferase between measurements. When the analyses were restricted to measurements made by the same operator, the variation was slightly reduced; fibrosis stage differed between measurements for only 34.3% of cases. CONCLUSIONS: Operator-related and patient-related factors produce significant variations in liver stiffness measurements made by transient elastometry, limiting its use in monitoring patients. These variations are unrelated to disease progression. The lowest levels of variation occur in measurements made in patients with no or early-stage fibrosis or by a single experienced operator.
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Diagnóstico por Imagen de Elasticidad/métodos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , Adulto , Anciano , Enfermedad Crónica , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Many patients with alcohol-associated cirrhosis also have diabetes, obesity, or insulin resistance-mediated steatosis, but little is known about how these disorders affect the severity of liver disease. We analyzed the prevalence and prognostic implications of metabolic risk factors (MRFs) such as overweight, diabetes, dyslipidemia, and hypertension in patients with alcohol-associated cirrhosis awaiting liver transplants. METHODS: We performed a retrospective study of 110 patients with alcohol-associated cirrhosis (77% male; mean age, 55 y; 71% with >6 mo of abstinence) who received liver transplants at a single center in Paris, France, from 2000 through 2013. We collected data on previous exposure to MRFs, steatosis (>10% in the explant), and histologically confirmed hepatocellular carcinoma (HCC). RESULTS: HCC was detected in explants from 29 patients (26%). Steatosis was detected in explants from 47 patients (70% were abstinent for ≥6 mo); 50% had a history of overweight or type 2 diabetes. Fifty-two patients (47%) had a history of MRFs and therefore were at risk for nonalcoholic fatty liver disease. A higher proportion of patients with MRF had HCC than those without MRF (46% vs 9%; P < .001). A previous history of overweight or type 2 diabetes significantly increased the risk for HCC (odds ratio, 6.23; 95% confidence interval [CI], 2.47-15.76, and odds ratio, 4.63; 95% CI, 1.87-11.47, respectively; P < .001). MRF, but not steatosis, was associated with the development of HCC (odds ratio, 11.76; 95% CI, 2.60-53; P = .001) independent of age, sex, amount of alcohol intake, or severity of liver disease. CONCLUSIONS: Patients with alcohol-associated cirrhosis who received transplants frequently also had nonalcoholic fatty liver disease. MRFs, particularly overweight, obesity, and type 2 diabetes, significantly increase the risk of HCC.
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Carcinoma Hepatocelular/epidemiología , Cirrosis Hepática Alcohólica/complicaciones , Neoplasias Hepáticas/epidemiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Hígado Graso/complicaciones , Hígado Graso/epidemiología , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/epidemiología , Paris , Prevalencia , Estudios Retrospectivos , Medición de RiesgoRESUMEN
BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.
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Antivirales/uso terapéutico , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Prolina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/efectos adversos , Estudios de Cohortes , Comorbilidad , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/virología , Humanos , Interferón-alfa/uso terapéutico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oligopéptidos/efectos adversos , Polietilenglicoles/uso terapéutico , Prolina/efectos adversos , Prolina/uso terapéutico , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: The first aim was to extend the validation of FibroTest® (FT) and transient elastography (TE) as markers of occurrence of cirrhosis without complications (F4.1), oesophageal varices (F4.2), and severe complications (F4.3) in patients with chronic hepatitis B (CHB). The second aim was to validate a previous definition of an inactive carrier based on normal FT and ActiTest® (normal-FT-AT). The third aim was to assess the long-term dynamics of fibrosis in patients with sustained virological response. METHODS: The 10-year updated individual data of 1434 patients were pooled from two prospective cohorts. RESULTS: Of the 1312 patients without a history of complications, varices had occurred after 10 years in 14 patients (F4.2, incidence of 1.7%, 95% CI [0.6-2.8]), and severe complications in 25 (F4.3 3.7% [1.8-5.7]), including hepatocellular carcinoma (HCC) in 21 (3.7% [1.5-5.8]). Using Cox-multivariate analysis adjusted for treatment, viral load, HBeAg status and ALT, FT, and TE were predictive of liver complications (n=37; AUROC=0.83 [0.71-0.90]; p<0.0001) and (n=8/844; AUROC=0.82 [0.72-0.89]; p<0.0001) respectively. Normal FT-AT better identified patients with lower fibrosis progression than the ALT-based standard: 3/163 (1.8%) vs. 16/181 (8.8%; p=0.004) in the Paris cohort, and 5/195 (2.6%) vs. 15/228 (6.6%; p=0.05) in the Bordeaux cohort. Of the 582 responders, 23 had complications (incidence 6.2% [3.2-9.1]) including 19 HCC (5.8% [2.6-9.0]) and 10 with varices (2.6% [0.8-4.4]). Of the 138 responders with advanced fibrosis, only 31% (15-47%) had fibrosis regression. CONCLUSIONS: FibroTest® and TE identified three categories of cirrhosis with increasing morbidity. Normal FibroTest® and ActiTest® were better able to identify inactive hepatitis B carriers than the standard definition. Despite virological response, the overall incidence of cirrhosis increased, with a remaining 5.8% risk of HCC.