Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD.

OBJECTIVE: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. METHODS: We studied the phenotype of wild-type and Sucnr1-/- mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. RESULTS: Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. CONCLUSIONS: We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.

Hepatitis crónica por virus C: pacientes con enfermedad leve / Chronic hepatitis C: patients with mild disease

La infección crónica por el virus de la hepatitis C cursa habitualmente de forma asintomática. El grado de lesión hepática observado en estos pacientes en el momento de su diagnóstico es variable, y la mayoría de ellos presenta una enfermedad leve desde el punto de vista histopatológico. Se han descrito una serie de factores que se correlacionan con la progresión de la fibrosis en los pacientes con fibrosis leve: la edad en el momento del diagnóstico, la duración de la infección, el sexo masculino, la coinfección con el virus de la inmunodeficiencia humana, los niveles de transaminasas durante el seguimiento, el consumo de alcohol, factores metabólicos como la diabetes y el sobrepeso, la actividad necroinflamatoria en la biopsia inicial y el grado de esteatosis. En los pacientes con genotipo 1, el tratamiento con interferón pegilado y ribavirina ha sido el tratamiento estándar de los pacientes con infección por virus de la hepatitis C. Sin embargo, la asociación con inhibidores de la proteasa de primera generación, boceprevir o telaprevir, aumenta de forma notable la tasa de respuesta. En el caso de los pacientes con fibrosis moderada cabe destacar, además de su eficacia, la buena tolerancia. Actualmente, el tratamiento con biterapia debe reservarse para aquellos pacientes con buenos predictivos basales de respuesta y/o contraindicación para el tratamiento con telaprevir o boceprevir. En los pacientes con genotipos diferentes al 1, el tratamiento estándar sigue siendo la combinación de interferón pegilado y ribavirina, si bien el desarrollo de nuevos antivirales de acción directa como el sofosbuvir y el simeprevir cambiarán las estrategias en estos pacientes. La decisión de esperar a los nuevos tratamientos es compleja por cuanto desconocemos la fecha en la que estarán disponibles; asimismo, debemos tener en cuenta que el precio elevado limitará las posibilidades de su uso

Chronic hepatitis C virus infection is usually asymptomatic. The severity of the hepatic lesion in these patients at diagnosis varies and, from the histopathologic point of view, most have mild disease. A series of factors have been described that correlate with the progression of fibrosis in patients with mild fibrosis: age at diagnosis, the duration of the infection, male sex, HIV coinfection, transaminase levels during follow-up, alcohol consumption, metabolic factors such as diabetes and overweight, necroinflammatory activity in the initial biopsy, and the degree of steatosis. In patients with genotype 1 hepatitis C infection, the standard treatment has been pegylated interferon and ribavirin. However, response rates are markedly increased by concomitant use of first-generation protease inhibitors, boceprevir or telaprevir. In patients with moderate fibrosis, these drugs are well tolerated, in addition to being effective. Currently, dual therapy should be reserved for patients with good baseline predictive factors of response and/or contraindications for treatment with telaprevir or boceprevir. In patients with genotypes other than genotype 1, the standard treatment continues to be the combination of pegylated interferon and ribavirin, although the development of new direct-acting antiviral agents such as sofosbuvir and simeprevir will change the strategies used in these patients. The decision to wait for the new treatments is complex because their release date is unknown; likewise, their high cost will limit the possibilities for their use

[Chronic hepatitis C: patients with mild disease]. / Hepatitis crónica por virus C: pacientes con enfermedad leve.

Chronic hepatitis C virus infection is usually asymptomatic. The severity of the hepatic lesion in these patients at diagnosis varies and, from the histopathologic point of view, most have mild disease. A series of factors have been described that correlate with the progression of fibrosis in patients with mild fibrosis: age at diagnosis, the duration of the infection, male sex, HIV coinfection, transaminase levels during follow-up, alcohol consumption, metabolic factors such as diabetes and overweight, necroinflammatory activity in the initial biopsy, and the degree of steatosis. In patients with genotype 1 hepatitis C infection, the standard treatment has been pegylated interferon and ribavirin. However, response rates are markedly increased by concomitant use of first-generation protease inhibitors, boceprevir or telaprevir. In patients with moderate fibrosis, these drugs are well tolerated, in addition to being effective. Currently, dual therapy should be reserved for patients with good baseline predictive factors of response and/or contraindications for treatment with telaprevir or boceprevir. In patients with genotypes other than genotype 1, the standard treatment continues to be the combination of pegylated interferon and ribavirin, although the development of new direct-acting antiviral agents such as sofosbuvir and simeprevir will change the strategies used in these patients. The decision to wait for the new treatments is complex because their release date is unknown; likewise, their high cost will limit the possibilities for their use.

[Induction therapy with interferon alfa-2a in compensated hepatitis C virus-related cirrhosis. Randomized, multicenter study]. / Terapia de inducción con interferón alfa-2a en la cirrosis por el virus de la hepatitis C compensada. Estudio multicéntrico aleatorizado.

BACKGROUND: Although standard dose interferon (IFN) is successful in only 5% of patients with compensated hepatitis C virus (HCV)-related cirrhosis, it has been suggested that this therapy might decrease the risk of complications or the incidence of hepatocellular carcinoma. Based on HCV kinetics, daily IFN may improve response rates. PATIENTS AND METHOD: Forty cirrhotic patients were randomised to receive (Group I: 19) or not (Group II: 21) treatment with IFN (4.5 MU/daily for 24 weeks, followed by 4.5 MU/48 hours for a further 24 weeks period, only if ALT was within normal values). RESULTS: Dose reduction and discontinuation for adverse events was required in 11 (58%) and 6 (31.5%) cases, respectively. End-of-treatment response was not observed in any of the 21 controls but in 4 of the 19 (21%) treated patients (p = 0.04); a sustained response was achieved in only 2 treated patients (10.5%). The 3-year probability of developing any of the following: ascites, hepatocellular carcinoma, transplantation or death was lower in Group I than in Group II (6% vs 27%; p = 0.05). CONCLUSION: Although induction IFN therapy is associated with common side effects and poor sustained response in compensated HCV-related cirrhosis, it might improve the outcome of patients at the medium-term.

Terapia de inducción con interferón alfa-2a en la cirrosis por el virus de la hepatitis C compensada. Estudio multicéntrico aleatorizado / Induction therapy with interferon alfa-2a in compensated hepatitis C virus-related cirrhosis. Randomized, multicenter study

FUNDAMENTO: Aunque el tratamiento con interferón (IFN) a las dosis estándar sólo consigue una respuesta persistente en el 5 por ciento de los pacientes con cirrosis debida al virus de la hepatitis C (CVHC), se ha planteado que podría disminuir el riesgo de complicaciones y la incidencia de hepatocarcinoma. Teniendo en cuenta los estudios cinéticos del virus de la hepatitis C (VHC), la terapia de inducción con IFN podría aumentar las tasas de respuesta al tratamiento. PACIENTES Y MÉTODO: Cuarenta pacientes con CVHC compensada fueron distribuidos al azar para recibir (grupo I = 19) o no (grupo II = 21) tratamiento con IFN (4,5 MU/día durante 6 meses, seguidos de 4,5 MU/días alternos durante 6 meses más, sólo si la ALT se había normalizado). RESULTADOS: El tratamiento con IFN hubo de reducirse o interrumpirse por efectos adversos en 11 (58 por ciento) y seis (31,5 por ciento) casos, respectivamente. La respuesta al final del tratamiento se observó en 4 pacientes del grupo I (21 por ciento), que fue persistente en dos (10,5 por ciento), y en ninguno del grupo II (p = 0,04 y NS, respectivamente). La probabilidad global de presentar ascitis, hepatocarcinoma y/o muerte o trasplante hepático fue menor en el grupo I que en el II (el 6 frente al 27 por ciento a los tres años; p = 0,05). CONCLUSIONES: Aunque la terapia de inducción con IFN en la CVHC compensada se asocia a frecuentes efectos adversos e induce una respuesta persistente en una proporción baja de pacientes, podría mejorar el pronóstico a medio plazo de los pacientes. (AU)