The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans.

Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined

Sofosbuvir-based therapy cures hepatitis C virus infection after prior treatment failures in a patient with concurrent lymphoma

We report on the first well-tolerated and successful use of sofosbuvir-based therapy in a patient in whom chronic infection with hepatitis C had preceded the development of B-cell non-Hodgkin's lymphoma. The patient had previously failed numerous attempts to clear the hepatitis C virus with traditional antiviral schedules. We demonstrate that sofosbuvir-based therapy resulted in cure of hepatitis C in a patient who had relapsed during combination therapy with an NS5A inhibitor, an NS3 protease inhibitor and ribavirin, as well as treatment failures to multiple courses of interferon-based therapy. This report also suggests that eradication of hepatitis C virus may result in the short-term prevention of B-cell non-Hodgkin's lymphoma relapse. The findings from our case require further validation in future cohorts of patients

Fatty liver is associated with an increased risk of diabetes and cardiovascular disease-Evidence from three different disease models: NAFLD, HCV and HIV

Fatty liver, which frequently coexists with necroinflammatory and fibrotic changes, may occur in the setting of nonalcoholic fatty liver disease (NAFLD) and chronic infections due to either hepatitis C virus (HCV) or human immunodeficiency virus (HIV). These three pathologic conditions are associated with an increased prevalence and incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). In this multidisciplinary clinical review, we aim to discuss the ever-expanding wealth of clinical and epidemiological evidence supporting a key role of fatty liver in the development of T2D and CVD in patients with NAFLD and in those with HCV or HIV infections. For each of these three common diseases, the epidemiological features, pathophysiologic mechanisms and clinical implications of the presence of fatty liver in predicting the risk of incident T2D and CVD are examined in depth. Collectively, the data discussed in this updated review, which follows an innovative comparative approach, further reinforce the conclusion that the presence of fatty/inflamed/fibrotic liver might be a shared important determinant for the development of T2D and CVD in patients with NAFLD, HCV or HIV. This review may also open new avenues in the clinical and research arenas and paves the way for the planning of future, well-designed prospective and intervention studies

Nonalcoholic fatty liver disease and aging: epidemiology to management

Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients

Do Nonalcoholic Fatty Liver Disease and Fetuin-A Play Different Roles in Symptomatic Coronary Artery Disease and Peripheral Arterial Disease?

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with both atherosclerotic cardiovascular disease (CVD) and Fetuin-A. However, the association of Fetuin-A with atherosclerosis is more controversial. We hypothesized that the pathogenic interplay of NAFLD, Fetuin-A and atherosclerosis varies based on arterial site. Accordingly, we aimed to assess NAFLD prevalence, Fetuin-A values and their relationship with symptomatic atherosclerosis occurring in different localizations: coronary artery disease (CAD) vs. peripheral arterial disease (PAD)

Relationship of Serum Fetuin-A Levels with Coronary Atherosclerotic Burden and NAFLD in Patients Undergoing Elective Coronary Angiography

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Caracterización de los engordes a corral de ganado bovino en el Alto Valle de Río Negro y Neuquén

Los engordes a corral en la zona del Alto Valle del Río Negro y Neuquén, son un sector productivo relativamente “nuevo” que no está totalmente establecido y se desconoce su grado de inserción en una cadena estructurada local que garantice la provisión de insumos y necesidades de innovación tecnológica. Esta actividad se ha expandido en los últimos 10 años para abastecer el consumo local de carne, a partir de la expansión de la zona libre de vacunación contra la fiebre aftosa hacia el norte desde el río Negro hasta el río Colorado. Este desarrollo podría deberse también al crecimiento de la población de las localidades del área metropolitana influenciadas por el desarrollo de la zona petrolera “Vaca Muerta” y al crecimiento de las exportaciones de carne que retrajeron la oferta y el ingreso de carnes de otras zonas de producción. Los establecimientos encuestados proveen más de 15.000 animales para faena por año. Son productores de tipo empresarial, propietarios de tierras bajo riego, que diversificaron otras actividades productivas agrarias y extra-agrarias. La escala de producción es variable desde los 500 a los 5000 animales terminados por año. Presentan heterogeneidad en el nivel de integración en la cadena comercial, según la producción propia de forrajes conservados, la duración de los engordes y la procedencia de los animales. La provisión de terneros se realiza desde las vastas zonas de cría bovina de ambas provincias, Neuquén y Río Negro y el grano de maíz es importado desde otras provincias, dada la nula o escasa producción local condicionada por diversos factores, entre ellos la baja disponibilidad de maquinaria para la cosecha en la región. Es un sector que demanda innovación tecnológica y aspira a tener más animales en los engordes, situación que está muy vinculada a los precios de los alimentos, los terneros y el animal terminado. Se destaca el alto nivel de mecanización, la utilización de MEJs (macho entero joven) en los engordes, la adopción del cultivo de maíz para el ensilado de planta entera y la producción propia de rollos de alfalfa.EEA Alto ValleFil: Jockers, Esteban Ricardo. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; ArgentinaFil: Villarreal, Patricia Liliana. Instituto Nacional Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Alto Valle; ArgentinaFil: Medina, Víctor Hugo. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; ArgentinaFil: Ignacio, Dante. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; ArgentinaFil: Bergamo, Nadia. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; ArgentinaFil: Paredes, Tamara. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; ArgentinaFil: Cascardo, Pablo. Programa Ganadero Bovino de la provincia de Río Negro; ArgentinaFil: Villarroel, Luis. Centro PyMe Adeneu; ArgentinaFil: Romagnoli, Sergio Osvaldo. Instituto Nacional Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Alto Valle. Agencia de Extensión Rural Cipolletti; ArgentinaFil: Malcotti, Valeria. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; ArgentinaFil: Hafford, Mariana. Centro PyMe Adeneu; Argentin

Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

Background: Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design: Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results: HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted \u3b4 and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted \u3bb, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions: Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis

NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals’ ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered

The independent predictors of non-alcoholic steatohepatitis and its individual histological features.: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment

Aim: The diagnosis of non-alcoholic steatohepatitis (NASH) is based on the individual histological features: steatosis, lobular inflammation and ballooning. Non-alcoholic fatty liver disease (NAFLD) activity score (NAS ≥ 5) is used in clinical trials. Fibrosis dictates long-term NAFLD prognosis. Recently, more-than-mild portal inflammation has raised interest as a marker of NAFLD severity. We assessed the independent predictors of: (I) individual histological lesions of NASH; (II) diagnosis of NASH; (III) significant (stage ≥2) and advanced (stage ≥3) fibrosis; and (IV) more-than-mild portal inflammation. Methods: Data from 118 consecutive biopsy-proven NAFLD patients observed at our institution were retrospectively analyzed. Results: At stepwise multivariate logistic regression analyses, independent predictors were as follows. For the individual histological features of NASH: insulin resistance (IR), assessed with Homeostasis Model Assessment-IR (HOMA-IR), serum uric acid (SUA) and serum total cholesterol (TCH) for moderate-to-severe steatosis; waist circumference (waist), HOMA-IR and TCH for lobular inflammation; waist, HOMA-IR, metabolic syndrome (MS), serum alanine aminotransferase (ALT), SUA and TCH for ballooning. For NASH diagnosis: waist, HOMA-IR, MS, ALT, SUA and TCH (Brunt et al.'s classification); ALT, SUA and TCH for NAS ≥ 5. For significant and advanced fibrosis, respectively: waist, MS and ALT; age, platelets, HOMA-IR, diabetes and TCH. For more-than-mild portal inflammation: serum aspartate aminotransferase (AST), serum iron, NAS ≥ 5 and significant liver fibrosis. Conclusion: HOMA-IR, SUA, MS, ALT and TCH are independent predictors of NASH and its individual histological lesions, notably including fibrosis. Based on our findings, these factors should be considered major pathogenic drivers of NASH and, by inference, potential targets for treatment