ABSTRACT
Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.
ABSTRACT
Introducción: la colangitis biliar primaria (CBP) es una enfermedad rara, de la que existe información limitada en España sobre su epidemiología y manejo en la práctica clínica habitual. Objetivos: conocer la epidemiología, flujo del paciente, diagnóstico, seguimiento y tratamiento de la CBP en España. Métodos: revisión de la literatura y estudio siguiendo la metodología Delphi con participación de 28 especialistas en dos rondas de consulta y un taller de validación de resultados presencial. Resultados: existen, aproximadamente, 9.400 pacientes con CBP en España, con una incidencia anual de entre 0,51 y 3,86 casos/100.000 habitantes, aunque el margen de error se presupone alto dada la escasez de estudios. El intervalo entre sospecha y confirmación diagnóstica puede ser de varios meses, realizándola mayoritariamente un gastroenterólogo o hepatólogo. El papel de la biopsia hepática en el diagnóstico y seguimiento es heterogéneo. El 95% de los pacientes son tratados con ácido ursodesoxicólico (AUDC) y la respuesta se monitoriza mayoritariamente utilizando el criterio de Barcelona. El seguimiento es semestral, con un uso heterogéneo de las diferentes técnicas disponibles. No existen recomendaciones ni fármacos comercializados en segunda línea en caso de no respuesta, respuesta insuficiente o intolerancia al tratamiento con AUDC. Conclusiones: aunque es posible estimar la epidemiología a partir de la opinión de expertos, se necesitan registros nacionales que aporten información precisa y actualizada sobre la epidemiología, el estadio y la respuesta al tratamiento de los pacientes con CBP, así como tratamientos nuevos para ciertos grupos de pacientes
Introduction: primary biliary cholangitis (PBC) is a rare disease with limited data regarding its epidemiology and standard clinical management in Spain. Objective: to gain insight into the epidemiology, patient flow, diagnosis, follow-up and treatment of PBC in Spain. Methods: a review of the literature and Delphi study involving 28 specialists in two rounds of consultations and an in-person results validation workshop. Results: there are approximately 9,400 patients with PBC in Spain, with an annual incidence of 0.51-3.86 cases/100,000 population. Albeit, a high error margin may be presumed due to the scarcity of relevant studies on this subject. Several months may elapse from suspicion to a confirmed diagnosis, usually by a gastroenterologist or hepatologist. The role of the liver biopsy for diagnosis and follow-up is heterogeneous. Overall, 95% of patients are treated with ursodeoxycholic acid (UDCA) and response is primarily monitored using the Barcelona criteria. Follow-up is performed every six months, with a heterogeneous use of the various available techniques. No recommendations or second-line commercial drugs are available in the case of no response, inadequate response or intolerance to UDCA. Conclusions: while epidemiology may be estimated based on expert opinions, national registries are needed to provide accurate, up-to-date information on epidemiological parameters, disease stage and response to treatment in patients with PBC. Furthermore, novel therapies are required for selected patient groups
Subject(s)
Humans , Cholangitis/epidemiology , Asymptomatic Diseases/epidemiology , Spain/epidemiology , Cholangitis/diagnosis , Cholangitis/therapy , Practice Patterns, Physicians' , Time-to-Treatment/statistics & numerical dataABSTRACT
INTRODUCTION: primary biliary cholangitis (PBC) is a rare disease with limited data regarding its epidemiology and standard clinical management in Spain. OBJECTIVE: to gain insight into the epidemiology, patient flow, diagnosis, follow-up and treatment of PBC in Spain. METHODS: a review of the literature and Delphi study involving 28 specialists in two rounds of consultations and an in-person results validation workshop. RESULTS: there are approximately 9,400 patients with PBC in Spain, with an annual incidence of 0.51-3.86 cases/100,000 population. Albeit, a high error margin may be presumed due to the scarcity of relevant studies on this subject. Several months may elapse from suspicion to a confirmed diagnosis, usually by a gastroenterologist or hepatologist. The role of the liver biopsy for diagnosis and follow-up is heterogeneous. Overall, 95% of patients are treated with ursodeoxycholic acid (UDCA) and response is primarily monitored using the Barcelona criteria. Follow-up is performed every six months, with a heterogeneous use of the various available techniques. No recommendations or second-line commercial drugs are available in the case of no response, inadequate response or intolerance to UDCA. CONCLUSIONS: while epidemiology may be estimated based on expert opinions, national registries are needed to provide accurate, up-to-date information on epidemiological parameters, disease stage and response to treatment in patients with PBC. Furthermore, novel therapies are required for selected patient groups.
Subject(s)
Liver Cirrhosis, Biliary , Delphi Technique , Follow-Up Studies , Humans , Liver Cirrhosis, Biliary/diagnosis , Liver Cirrhosis, Biliary/epidemiology , Liver Cirrhosis, Biliary/therapy , Spain/epidemiologyABSTRACT
There is a need, in NAFLD management, to develop non-invasive methods to detect steatohepatitis (NASH) and to predict advanced fibrosis stages. We evaluated a tool based on optical analysis of liver magnetic resonance images (MRI) as biomarkers for NASH and fibrosis detection by investigating patients with biopsy-proven NAFLD who underwent magnetic resonance (MR) protocols using 1.5T General Electric (GE) or Philips devices. Two imaging biomarkers (NASHMRI and FibroMRI) were developed, standardised and validated using area under the receiver operating characteristic curve (AUROC) analysis. The results indicated NASHMRI diagnostic accuracy for steatohepatitis detection was 0.83 (95% CI: 0.73-0.93) and FibroMRI diagnostic accuracy for significant fibrosis determination was 0.85 (95% CI: 0.77-0.94). These findings were independent of the MR system used. We conclude that optical analysis of MRI has high potential to define non-invasive imaging biomarkers for the detection of steatohepatitis (NASHMRI) and the prediction of significant fibrosis (FibroMRI) in NAFLD patients.
