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BACKGROUND: Acquired hepatocerebral degeneration (AHD) is a neurologic complication of severe chronic liver disease (CLD) with portosystemic shunts. The proposed etiology is manganese accumulation in the brain tissue, especially in the basal ganglia. Combination of clinical manifestation, mostly extrapyramidal movement disorders, and hyperintensities on T1-weighted brain magnetic resonance imaging (MRI) is diagnostic. Although liver transplantation controversial, it is suggested for AHD. OBJECTIVES: To depict clinical and neuroimaging characteristics and response to treatments in patients diagnosed with AHD at Sheba Medical Center. METHODS: Review of patients with AHD diagnosis at the Liver Diseases Center at Sheba Medical Center between 2012 and 2017, data of clinical and neuroimaging, follow-up, and response to treatments, including liver transplantation were recorded. RESULTS: Five patients with diagnosis of AHD were identified, median age at diagnosis 55 years (range 45-64 years). Four patients had cirrhosis at the time of AHD diagnosis. The main risk factor for AHD was the presence of portosystemic shunts. The most prevalent clinical manifestations were movement disorders, specifically a combination of extrapyramidal and cerebellar signs including instability, rigidity, tremor, bradykinesia, and cognitive impairment. Brain MRI revealed hyperintensities on T1-weighted images in the basal ganglia in all patients. Administration of antiparkinsonian drugs showed clinical improvement, whereas liver transplantation performed in two patients was not associated to neurological improvement. CONCLUSIONS: AHD is related to portosystemic shunts. The combination of Parkinsonism and cerebellar signs and MRI pallidal lesions should alert physicians to the diagnosis. The role of liver transplantation in AHD is still controversial.
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Degeneración Hepatolenticular , Trasplante de Hígado , Humanos , Persona de Mediana Edad , Degeneración Hepatolenticular/complicaciones , Degeneración Hepatolenticular/diagnóstico , Cirrosis Hepática/diagnóstico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Factores de Riesgo , Imagen por Resonancia Magnética/métodosRESUMEN
UNLABELLED: The present review includes translational and clinical research that characterize non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Clinical and experimental evidence led to the recognition of the key toxic role played by lipotoxicity in the pathogenesis of NAFLD. The current understanding of lipotoxicity suggests that organ injury is initiated by the generation of oxidative metabolites and the translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. The injury progresses through impairment of tissue regeneration and extracellular matrix turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, predominantly stellate cells, macrophages and parenchymal cells. In response to inflammation, cytokines activate many signaling cascades that regulate fibrogenesis. This examination brings together research focusing on the underlying mechanisms of injury. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, and fibrogenesis in the liver. We searched electronic databases (Medline, Embase) for this review. This integrative work investigates different aspects of liver damage and possible repair. We aim to (1) determine the immuno-pathology of liver damage due to steatosis, (2) suggest diagnostic markers of NASH, (3) examine the role of behaviour in the development of NASH, and (4) develop common tools to study steatosis-induced effects in clinical studies. Special accent is put on co-morbidities with renal and neuropsychological disorders. Moreover, we review the evidence in literature on the role of moderate alcohol consumption in individuals that present NAFLD/NASH. KEY WORDS: behavior, diet, imaging, non-alcoholic fatty liver, nonalcoholic steatohepatitis, laboratory markers.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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Enfermedad del Hígado Graso no Alcohólico/metabolismo , Investigación Biomédica Traslacional , Protocolos Clínicos , Citocinas/metabolismo , Humanos , Inflamación/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical research, translational research, pathogenesis and therapies. A special accent is placed on alcohol misuse, as alcohol is a legally commercialized and taxable product. Drinking alcohol, particularly from a young age, is a major health problem. Alcoholism is known to contribute to morbidity and mortality. A systematic literature search was performed in order to obtain updated data (2008-2015). The review is focused on genetic polymorphisms of alcohol metabolizing enzymes and the role of cytochrome p450 2E1 and iron in ALD. Alcohol-mediated hepatocarcinogenesis is also discussed in the presence or absence of co-morbidities such as viral hepatitis C as well as therapeutic the role of innate immunity in ALD-HCV. Moreover, emphasis was placed on alcohol and drug interactions, as well as liver transplantation for end-stage ALD. Finally, the time came to eradicate alcohol-induced liver and intestinal damage by using betaine.
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Hepatopatías Alcohólicas , Citocromo P-450 CYP2E1/genética , Humanos , Polimorfismo Genético , Investigación Biomédica TraslacionalRESUMEN
BACKGROUND/PURPOSE: Hepatitis C (HCV) is a major cause of morbidity and mortality in haemophilia patients who received clotting factor concentrates before the availability of virus-inactivated factors in the mid-1980s. Recently, it has been suggested that anti-HCV treated patients, particularly those achieving a sustained virological response (SVR) have an improved outcome. We sought to examine the survival of treated and untreated HCV-infected haemophilia patients. MATERIAL AND METHODS: We studied overall and liver-related survival of patients with haemophilia and other congenital bleeding disorders between 2000 and 2010. The outcome was compared in 3 sub-groups: HCV mono-infected (N = 127), HCV/HIV co-infected (N = 28), and patients with either HCV-antibodies negative or persistent HCV RNA-negative (referred to as non-infected) (N = 45). Sixty-two (40%) (HCV and HCV/HIV) patients underwent anti-HCV treatment with an SVR rate of 40.3%. RESULTS: Overall and liver-related 10-year survival were: 82.1 and 89.3%, 95.3 and 99.2 and 100% for HCV/HIV co-infected, HCV mono-infected and non-infected haemophilia patients, respectively (p = 0.015 and 0.023 for comparisons of HCV/HIV vs. HCV; p = 0.003 for comparison of HCV/HIV and non-infected). One HCV mono-infected and 3 co-infected patients died of end-stage liver disease (2 underwent liver transplantation). There was no survival benefit from anti-HCV treatment or from attaining of an SVR. Only clinically suspected cirrhosis remained as an independent predictor of survival. CONCLUSION: The prognosis of haemophilia patients who acquired HCV/HIV co-infection is worse than that of HCV mono-infected or non-infected or haemophiliacs. This is mainly due to liver-related mortality. Anti-HCV treatment or SVR had no observable impact on survival rate.
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Antivirales/uso terapéutico , Hemofilia A/complicaciones , Hepatitis C Crónica/mortalidad , Cirrosis Hepática/etiología , ARN Viral/sangre , Adolescente , Adulto , Anciano , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Estudios de Cohortes , Coinfección , Progresión de la Enfermedad , Femenino , Infecciones por VIH/complicaciones , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Interferones/uso terapéutico , Masculino , Persona de Mediana Edad , Polietilenglicoles , Pronóstico , Estudios Retrospectivos , Ribavirina/uso terapéutico , Tasa de Supervivencia , Carga Viral , Adulto JovenRESUMEN
Several studies show that gut microbiotas in patients with nonalcoholic fatty liver disease (NAFLD) differ from those in a healthy population, suggesting that this alteration plays a role in NAFLD pathogenesis. We investigated whether prebiotic administration affects liver fat content and/or liver-related and metabolic parameters. Patients with NAFLD and metabolic syndrome (age: 50 ± 11; 79% men) were randomized to receive either 16 g/day of prebiotic (ITFs-inulin-type fructans) (n = 8) or placebo (maltodextrin) (n = 11) for 12 weeks. Patients were instructed to maintain a stable weight throughout the study. Liver fat content (measured by H1MRS), fecal microbiota, and metabolic, inflammatory, and liver parameters were determined before and after intervention. Fecal samples from patients who received the prebiotic had an increased content of Bifidobacterium (p = 0.025), which was not observed with the placebo. However, the baseline and end-of-study liver fat contents did not change significantly in the prebiotic and placebo groups, neither did the liver function tests' metabolic and inflammatory mediators, including fibroblast growth factor-19 and lipopolysaccharide-binding protein. Body weight remained stable in both groups. These findings suggest that prebiotic treatment without weight reduction is insufficient to improve NAFLD.
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Heces , Microbioma Gastrointestinal , Hígado , Enfermedad del Hígado Graso no Alcohólico , Prebióticos , Humanos , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Enfermedad del Hígado Graso no Alcohólico/terapia , Enfermedad del Hígado Graso no Alcohólico/microbiología , Prebióticos/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Proyectos Piloto , Adulto , Hígado/metabolismo , Heces/microbiología , Bifidobacterium , Método Doble Ciego , Síndrome Metabólico/dietoterapia , Síndrome Metabólico/terapiaRESUMEN
PURPOSE: To elucidate the relative role of the immune system and intestinal epithelium in the ethiopatogenesis of Celiac disease (CD). METHODS: A patient with childhood CD who underwent allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukemia was followed for 5 years after resumption of gluten containing diet. Immunological memory to gliadin epitopes was assessed in the index patient and in 5 newly diagnosed CD patients by standard serology testing and by CFSE-based proliferation assays of peripheral blood CD4+ cells and of intestinal LPL towards gliadin-TTG antigens. Intestinal lymphocytes' origin was determined by combined immuno-histochemistry and fluorescent in-situ hybridiazation (FISH). RESULTS: Over 5 years of follow-up after receiving BMT from a HLA-matched woman and cessation of gluten-free diet, the patient has remained well, with negative periodic antibodies assays and unremarkable serial duodenal biopsies. In vitro proliferation assays showed lack of a memory response of the patient's peripheral blood and lamina propria CD4+ T-cells towards TTG, gliadin or TTG-treated gliadin, whereas memory responses were evident in the newly diagnosed CD patients. Immuno-FISH of post-BMT duodenal mucosa showed that the chromosomal phenotype of all the epithelial cells was XY. In contrast, CD45+ lymphocytic lineage cells were all donor-derived XX cells, presumably originating in the transplanted bone marrow and re-populating the intestinal wall. CONCLUSIONS: CD resolution following allogeneic BMT is associated with absent gliadin-specific memory response, and with a dichotomous lymphocyte-epithelial chimeric intestine. These observations suggest that the pathogenesis of CD is critically dependent upon the immune system rather than the epithelial compartment.
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Linfocitos T CD4-Positivos/inmunología , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/terapia , Gliadina/inmunología , Memoria Inmunológica/inmunología , Donantes de Tejidos , Adulto , Aloinjertos , Linfocitos T CD4-Positivos/trasplante , Enfermedad Celíaca/patología , Separación Celular , Femenino , Estudios de Seguimiento , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Masculino , Trasplante Homólogo , Resultado del TratamientoRESUMEN
BACKGROUND: Crohn's disease (CD) is frequently associated with weight loss and malnutrition. However, as the prevalence of obesity increases worldwide, it may become a clinical problem even in CD. AIM: To assess the prevalence of severe/morbid obesity in CD patients and to compare their disease characteristics to nonobese CD patients. METHODS: A retrospective analysis of a computerized CD patient database was performed to identify severely/morbidly obese patients (BMI >35). Prevalence was compared to data of the general population. Severely/morbidly obese CD patients were then compared to randomly selected nonobese CD patients (BMI <30) in a 1:3 ratio. RESULTS: Thirteen severely/morbidly obese patients out of 560 CD patients were found (2.3%), which is significantly lower than the prevalence in the general population (5.6%, p = 0.001). When compared to 39 nonobese CD patients, colonic disease was significantly more common among severely/morbidly obese CD patients (odds ratio: 6, 95% CI: 1.35-26.3, p = 0.02), while there was no difference in other disease parameters. Interestingly, 4 morbidly obese CD patients had undergone laparoscopic sleeve gastrectomy for treatment of morbid obesity with a favorable surgical course. CONCLUSION: CD in severely/morbidly obese patients is more often colonic, but otherwise no different than CD in nonobese patients. Sleeve gastrectomy is a viable therapeutic option for morbidly obese CD patients.
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Enfermedad de Crohn/epidemiología , Obesidad Mórbida/epidemiología , Adulto , Cirugía Bariátrica , Estudios de Casos y Controles , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/cirugía , Femenino , Humanos , Israel/epidemiología , Masculino , Persona de Mediana Edad , Obesidad Mórbida/complicaciones , Obesidad Mórbida/cirugía , Prevalencia , Estudios Retrospectivos , Adulto JovenRESUMEN
ËCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.
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Quimiocina CCL24 , Colangitis Esclerosante , Colestasis , Animales , Humanos , Ratones , Colangitis Esclerosante/complicaciones , Fibrosis , Inflamación , HígadoRESUMEN
A 52-year-old woman with a BMI of 31.2 kg/m2 was treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide as part of her weight-reduction program. Following this, she developed an idiosyncratic drug-related liver injury (IDILI). Advances in noninvasive techniques enabled this diagnosis to be established. By employing easily quantifiable methods based on serum biomarkers, we could explore a wide variety of endpoints in assessing personalized DILI. In addition, we can test endpoints that are associated with the drug's mechanism of action. Personalized medicine and therapeutic pharmacovigilance of incretin-based hypoglycemic agents are needed to ensure the safety of patients.
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BACKGROUND: About 10-30% of gastrointestinal stromal tumors prove to be malignant. Nevertheless, the natural history of gastric gastrointestinal stromal tumors has not been fully elucidated. AIMS: To determine the long-term clinical outcome of nonresected gastric gastrointestinal stromal tumors. METHODS: Clinical follow-up of patients with endosonographic characteristics compatible with gastric gastrointestinal stromal tumors was conducted based on Israeli population registry. Lesions with features suggesting malignancy were usually referred to surgery. Follow-up endoscopic ultrasound examinations of nonoperated patients were reviewed. RESULTS: Seventy-one patients with presumable gastric gastrointestinal stromal tumors were followed. Seventeen patients underwent operation; median tumor size was 43 mm (range 29-70 mm). Within a median of 43 months (range 2-131 months) ten patients died of causes unrelated to gastrointestinal stromal tumor. Forty-four patients with endosonographic diagnosis of gastric gastrointestinal stromal tumors were followed expectantly for a median of 12 years (range 5-15 years). All these patients are alive and without complications associated with gastrointestinal stromal tumor. Follow-up endoscopic ultrasound examinations demonstrated no change in tumor size in six, decrease (by 1-5 mm) in six, and increase (by 2-21 mm) in eight. CONCLUSIONS: Therapeutic decisions guiding surgical interventions may be based on clinical presentation, comorbidity, and endosonographic characteristics. Nonoperated patients may be safely followed conservatively.
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Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/cirugía , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Endoscopía Gastrointestinal , Endosonografía , Femenino , Estudios de Seguimiento , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/terapia , Humanos , Israel/epidemiología , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Fatty liver may be the result of several factors. The two main contributors are nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). SUMMARY: NAFLD is the hepatic manifestation of the metabolic syndrome (MetS) and is the major cause of chronic liver disease worldwide as a result of the obesity epidemic. ALD is also a common cause of chronic liver disease. Obesity is a major contributory factor to MetS and is also common in individuals who consume large amounts of alcohol. There is a similar hepatic pathology and both can result in severe fibrosis, cirrhosis, and its complications including hepatocellular carcinoma. This review discusses the etiology, pathogenesis, and genetics of both NAFLD and ALD and their interaction. It is necessary to understand this better in order to prevent and treat these important causes of liver disease worldwide. KEY MESSAGE: Obesity, MetS, and alcohol consumption are linked to the development and progression of fatty liver disease. The coexistence of these factors in many patients requires a reassessment of many aspects of treatment of fatty liver disease.
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The presence of pathogen-specific antibodies in an individual's blood-sample is used as an indication of previous exposure and infection to that specific pathogen (e.g., virus or bacterium). Measurement of the diagnostic antibodies is routinely achieved using solid phase immuno-assays such as ELISA tests and western blots. Here, we describe a sero-diagnostic approach based on phage-display of epitope arrays we term "Domain-Scan". We harness Next-generation sequencing (NGS) to measure the serum binding to dozens of epitopes derived from HIV-1 and HCV simultaneously. The distinction of healthy individuals from those infected with either HIV-1 or HCV, is modeled as a machine-learning classification problem, in which each determinant ("domain") is considered as a feature, and its NGS read-out provides values that correspond to the level of determinant-specific antibodies in the sample. We show that following training of a machine-learning model on labeled examples, we can very accurately classify unlabeled samples and pinpoint the domains that contribute most to the classification. Our experimental/computational Domain-Scan approach is general and can be adapted to other pathogens as long as sufficient training samples are provided.
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Enfermedades Transmisibles/diagnóstico , Anticuerpos Anti-VIH/sangre , Proteína p24 del Núcleo del VIH/inmunología , Proteínas gp160 de Envoltorio del VIH/inmunología , Infecciones por VIH/diagnóstico , Anticuerpos contra la Hepatitis C/sangre , Antígenos de la Hepatitis C/inmunología , Hepatitis C/diagnóstico , Aprendizaje Automático , Biblioteca de Péptidos , Pruebas Serológicas/métodos , Serodiagnóstico del SIDA/métodos , Secuencia de Aminoácidos , Reacciones Antígeno-Anticuerpo , Secuencia de Bases , Código de Barras del ADN Taxonómico , ADN Recombinante/inmunología , Epítopos/genética , Epítopos/inmunología , Vectores Genéticos , Proteína p24 del Núcleo del VIH/genética , Antígenos de la Hepatitis C/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Oligonucleótidos/genética , Oligonucleótidos/inmunología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Reacción en Cadena de la Polimerasa/métodosRESUMEN
BACKGROUND & AIMS: C-C motif chemokine ligand 24 (CCL24) is a chemokine that regulates inflammatory and fibrotic activities through its receptor, C-C motif chemokine receptor (CCR3). The aim of the study was to evaluate the involvement of the CCL24-CCR3 axis in liver fibrosis and inflammation and to assess the potential of its blockade, by a monoclonal anti-CCL24 antibody, as a therapeutic strategy for non-alcoholic steatohepatitis (NASH) and liver fibrosis. METHODS: Expression of CCL24 and CCR3 was evaluated in liver biopsies and blood samples. CCL24 involvement in NAFLD/NASH pathogenesis was assessed in Ccl24 knockout mouse using the methionine-choline deficient (MCD) diet experimental model. Antifibrotic and anti-inflammatory effects of CM-101 were tested in the MCD and STAM mouse models and in the thioacetamide (TAA) model in rats. Liver enzymes, liver morphology, histology and collagen deposition, as well as fibrosis- and inflammation-related protein expression were assessed. Activation of hepatic stellate cells (HSCs) was evaluated in the human LX2 cell line. RESULTS: Patients with NASH and advanced NAFLD exhibited significant expression of both CCL24 and CCR3 in liver and blood samples. In the experimental MCD-diet model, Ccl24 knockout mice showed an attenuated liver damage response compared to wild-type mice, exhibiting reduced histological NAFLD activity scores and fibrosis, as well as lower levels of liver enzymes. Blocking CCL24 using CM-101 robustly reduced liver damage in 3 experimental animal models (MCD, STAM and TAA), as demonstrated by attenuation of liver fibrosis and NAFLD activity score. Furthermore, blocking CCL24 by CM-101 significantly inhibited CCL24-induced HSC motility, α-SMA expression and pro-collagen I secretion. CONCLUSION: Our results reveal that blocking CCL24 significantly attenuates liver fibrosis and inflammation and may have a potential therapeutic effect in patients with NASH and/or liver fibrosis. LAY SUMMARY: CCL24 is a chemokine that regulates inflammation and fibrosis. It was found to be significantly expressed in patients with non-alcoholic steatohepatitis, in whom it regulates profibrotic processes in the liver. Herein, we show that blockade of CCL24 using a monoclonal antibody robustly attenuated liver fibrosis and inflammation in animal models, thus suggesting a potential therapeutic role for an anti-CCL24 agent.
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Pancreatic cancer (PC) is a leading cause of cancer-related death in developed countries, and since most patients have incurable disease at the time of diagnosis, developing a screening method for early detection is of high priority. Due to its metabolic importance, alterations in pancreatic functions may affect the composition of the gut microbiota, potentially yielding biomarkers for PC. However, the usefulness of these biomarkers may be limited if they are specific for advanced stages of disease, which may involve comorbidities such as biliary obstruction or diabetes. In this study we analyzed the fecal microbiota of 30 patients with pancreatic adenocarcinoma, 6 patients with pre-cancerous lesions, 13 healthy subjects and 16 with non-alcoholic fatty liver disease, using amplicon sequencing of the bacterial 16S rRNA gene. Fourteen bacterial features discriminated between PC and controls, and several were shared with findings from a recent Chinese cohort. A Random Forest model based on the microbiota classified PC and control samples with an AUC of 82.5%. However, inter-subject variability was high, and only a small part of the PC-associated microbial signals were also observed in patients with pre-cancerous pancreatic lesions, implying that microbiome-based early detection of such lesions will be challenging.
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Adenocarcinoma/microbiología , Bacterias/clasificación , Heces/microbiología , Enfermedad del Hígado Graso no Alcohólico/microbiología , Neoplasias Pancreáticas/microbiología , Adulto , Anciano , Área Bajo la Curva , Bacterias/genética , Bacterias/aislamiento & purificación , Estudios de Casos y Controles , Femenino , Microbioma Gastrointestinal , Humanos , Masculino , Persona de Mediana Edad , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel. METHODS: Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes. RESULTS: The majority (71.4%, 35/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6/49) carried GT1a and 14.3% GT3a/b (7), GT4a (1) and GT1b/GT3a. RAS were identified in 85.7% (42/49) of failures, of which 90.5% (38/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A/E/Q/G/N/V (32.6%, 16/49) identified in NS3, and 93H/N (61.2%, 30/49), 31I/M/V (34.7%, 17/49) and 30R/H/K (12.2%, 6/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37/45) than in NS3 (35.7%, 10/28; P<0.01). While RAS were identified in all GT1a, GT3b and GT4a failures (100%, 10/10), only 71.8% (28/39) of GT1b or GT3a failures had RAS (P=0.09). In four cases, NGS identified additional clinically relevant RAS and in one patient, NGS deciphered coexistence of GT3a and GT1b infections. CONCLUSIONS: Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.
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Antivirales/farmacología , Farmacorresistencia Viral , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C/epidemiología , Hepatitis C/virología , Antivirales/uso terapéutico , Quimioterapia Combinada , Femenino , Genotipo , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Israel/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Retratamiento , Análisis de Secuencia de ADN , Insuficiencia del Tratamiento , Proteínas no Estructurales Virales/genéticaRESUMEN
BACKGROUND: Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions. METHODS: In a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure. RESULTS: GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations. CONCLUSIONS: NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.
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Antivirales/uso terapéutico , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Proteínas no Estructurales Virales , Adulto , Anciano , Sustitución de Aminoácidos , Quimioterapia Combinada , Femenino , Hepacivirus/clasificación , Humanos , Masculino , Persona de Mediana Edad , Mutación , Insuficiencia del Tratamiento , Resultado del Tratamiento , Proteínas no Estructurales Virales/genéticaRESUMEN
BACKGROUND AND AIMS: Recent studies have demonstrated that the efficacy of interferon-free direct-acting antiviral agents (DAAs) in patients over 70 is similar to that of younger age groups. Evidence continues to mount that life expectancy (LE) increases with successful treatment of hepatitis C (HCV) patients with advanced fibrosis. The evidence in older people is more limited. Our aim was to estimate the life year (LY) and quality-adjusted life year (QALY) gained by treatment of naïve patients with HCV as a function of patient's age and fibrosis stage. METHODS: We constructed a Markov model of HCV progression toward advanced liver disease. The primary outcome was LY and QALY saved. The model and the sustained virological response of HCV infected subjects treated with a fixed-dose combination of the NS5B polymerase inhibitor Sofosbuvir and the NS5A replication complex inhibitor Ledipasvir were based on the published literature and expert opinion. RESULTS: Generally, both the number of LY gained and QALY gained gradually decreased with advancing age but the rate of decline was slower with more advanced fibrosis stage. For patients with fibrosis stage F1, F2 and F3, LY gained dropped below six months if treated by the age of 55, 65 or 70 years, respectively, while for a patient with fibrosis stage F4, the gain was one LY if treated by the age of 75. The QALY gained for treated over untreated elderly were reasonably high even for those treated at early fibrosis stage. CONCLUSIONS: There is a significant life expectancy benefit to HCV treatment in patients up to age 75 with advanced-stage fibrosis.
Asunto(s)
Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Técnicas de Apoyo para la Decisión , Progresión de la Enfermedad , Femenino , Fluorenos/uso terapéutico , Hepatitis C Crónica/patología , Humanos , Esperanza de Vida , Masculino , Cadenas de Markov , Persona de Mediana Edad , Años de Vida Ajustados por Calidad de Vida , Sofosbuvir , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapéuticoRESUMEN
In conclusion, in the course of patients with advanced liver disease there are several indications for institution of intravenous albumin. These include: a) enhancement of diuretic effect on mobilization of ascites fluid, b) prevention of post-paracentesis circulatory dysfunction after total/large volume paracentesis, c) prevention of hepatorenal syndrome in patients affected with SBP, and d) administration of albumin in combination with vasoconstrictor drugs as the only effective therapy for hepatorenal syndrome. Albumin is relatively inexpensive and can be given in an outpatient setting.
Asunto(s)
Hipoalbuminemia/tratamiento farmacológico , Hipoalbuminemia/etiología , Cirrosis Hepática/complicaciones , Albúmina Sérica/administración & dosificación , Albúmina Sérica/uso terapéutico , Ascitis , Diuréticos/uso terapéutico , Costos de los Medicamentos , Humanos , Peritonitis/complicaciones , Albúmina Sérica/economíaRESUMEN
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor that contributes to the pathogenesis of ALD is lipopolysaccharide (LPS), which plays a central role in the induction of steatosis, inflammation, and fibrosis in the liver. LPS derived from the intestinal microbiota enters the portal circulation, and is recognized by macrophages (Kupffer cells) and hepatocytes. In individuals with ALD, excessive levels of LPS in the liver affect immune, parenchymal, and non-immune cells, which in turn release various inflammatory cytokines and recruit neutrophils and other inflammatory cells. In this review, we elucidate the mechanisms by which alcohol contributes to the activation of Kupffer cells and the inflammatory cascade. The role of the stellate cells in fibrogenesis is also discussed.