Diagnosis and Characterization of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) can develop cirrhosis and even hepatocellular carcinoma, resulting in a high liver-related morbidity and mortality, being important to know those risk factors for disease progression, among which the presence of diabetes stands out. In addition, it is a disease with multisystemic behavior, becoming an independent risk factor for cardiovascular disease and extrahepatic tumors. Hence, early diagnosis and multidisciplinary management of NAFLD are really important. In this chapter, we will expose the different diagnostic and follow-up tools available for this disease, and with them we will make an algorithm according to the recommendations and the current evidence

The Crosstalk between Hypoxia and Innate Immunity in the Development of Obesity-Related Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) has become a major health issue in western countries in parallel with the dramatic increase in the prevalence of obesity and all obesity related conditions, including respiratory diseases as obstructive sleep apneahypopnea syndrome (OSAHS). Interestingly, the severity of the liver damage in obesity-relatedNAFLD has been associatedwith the concomitant presence of OSAHS. In the presence of obesity, the proinflammatory state in these patients together with intermittent episodes of hypoxia, characteristic of OSAHS pathogenesis,may lead to an enhanced inflammatory response mediated by a positive feedback loop mechanism that implicates HIF-1 and NF????.Thus, the severity of liver involvement in obese NAFLD patients with a concomitant diagnosis of OSAHS could be explained. In this review, we focus on the molecularmechanisms underlying the hepatic response to chronic intermittent hypoxia and its interaction with innate immunity in obesity-related NAFLD

Innate and Adaptive Immunity Alterations in Metabolic Associated Fatty Liver Disease and Its Implication in COVID-19 Severity

The coronavirus infectious disease 2019 (COVID-19) pandemic has hit the world, affecting health, medical care, economies and our society as a whole. Furthermore, COVID-19 pandemic joins the increasing prevalence of metabolic syndrome in western countries. Patients suffering from obesity, type II diabetes mellitus, cardiac involvement and metabolic associated fatty liver disease (MAFLD) have enhanced risk of suffering severe COVID-19 and mortality. Importantly, up to 25% of the population in western countries is susceptible of suffering from both MAFLD and COVID-19, while none approved treatment is currently available for any of them. Moreover, it is well known that exacerbated innate immune responses are key in the development of the most severe stages of MAFLD and COVID-19. In this review, we focus on the role of the immune system in the establishment and progression of MAFLD and discuss its potential implication in the development of severe COVID-19 in MAFLD patients. As a result, we hope to clarify their common pathology, but also uncover new potential therapeutic targets and prognostic biomarkers for further research.Funding: This research received funding by the ISCIII (COV20/0170 and PI19/01509) and Cantabria Goverment (2020 UIC22-PUB-0019) to ML-H

Prevalence of antinuclear antibodies in inflammatory bowel disease and seroconversion after biological therapy

Background: Estimates of detectable antinuclear antibodies (ANA) prevalence vary widely, from 6% in healthy populations to 50-80% in patients with autoimmune disease. However, there is a lack of evidence about the overall prevalence in inflammatory bowel disease (IBD) and ANA seroconversion after the beginning of biological therapy. Objectives: The aim of the study was to investigate the overall prevalence of ANA in IBD patients, their relationship with different treatments, clinical outcomes and the seroconversion rate of ANA in patients treated with biological therapy. Methods: Ambispective observational study including all consecutive IBD patients was carried out. Information about the presence of ANA, disease phenotype, duration, activity, complications, and past and current treatments were transversally collected. Retrospectively, in patients with detectable ANA, data regarding previous ANA detection and the diagnosis of lupus-like syndrome (LLS) was gathered. Results: A total of 879 IBD patients were included. We observed a detectable ANA prevalence of 13.6%. The presence of ANA was frequently associated with biological therapy (36/118) and decreased when immunomodulators were combined to this therapy (7/32). Of 78 patients with ANA prior to the beginning of biological therapy, a seroconversion rate of 28.8% was observed after a mean of 3.14 years. Only 1 patient suffered LLS. Conclusion: Our study showed a prevalence of detectable ANA higher than the expected in healthy population. The presence of ANA was lower when immunomodulator therapy is associated. The ANA seroconversion rate is relevant after the initiation of biological treatment nevertheless, the risk of LLS appeared to be marginal.Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors report funding support from the Spanish Instituto de Salud Carlos III Grant (FIS–PI18/01304) related to this article

Changes in Circulating Lysyl Oxidase-Like-2 (LOXL2) Levels, HOMA, and Fibrosis after Sustained Virological Response by Direct Antiviral Therapy

Background: we aimed to assess the influence of metabolic syndrome on fibrosis regression (using liver-stiffness measurement (LSM) and serological scores) and the relationship with the expression of lysyl oxidase-like-2 as a potential goal of antifibrotic therapy. Methods: We included 271 patients treated with Direct Antiviral Therapy (DAAs) in our hospital who achieved a sustained virological response (SVR); physical examination, blood tests, and LSM were made at baseline (B) and 24 months (24 M) after SVR. Hemodynamic studies and transjugular liver biopsies were performed on 13 patients. Results: At B, 68 patients were F1 (25.1%); F2 n = 59 (21.7%); F3 n = 44 (16.05%); and 100 were F4 (36.9%). Although the LSM (absolute value) improved in 82% of patients (n = 222), it progressed in 17.5% of patients (n = 48). At 24 M, 48 patients met the metabolic syndrome (MetS) criteria and there was an increase in patients with a BMI of >25 kg/m2 (p 25 kg/m2 is a risk factor for significant fibrosis or steatosis at 24 M (p 9 kPa vs. <9 kPa (p = 0.046). Conclusion: Regression of LSM was reached in 82% of patients. Downregulated LOXL2 was demonstrated post-SVR, with overexpression in cirrhotic patients being a potential therapy goal in selected patients.Funding: This study was supported by the Health Research Institute Marqués de Valdecilla. IDIVAL. Santander. NEXT VAL15/12 grant to Dra Angela Puente Sanchez: Regresión de la fibrosis hepática tras erradicación del virus de la hepatitis C. Papel de la LOXL2. Acknowledgments: This study has been supported by competitive grants from the Instituto de Salud Carlos III (Spanish Ministries of Health and of Economy; PIE15/00079 and PI15/02138)

Cannabis consumption and non-alcoholic fatty liver disease. A three years longitudinal study in first episode non-affective psychosis patients

INTRODUCTION: Increased incidence of obesity and excess weight lead to an increased incidence of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates a protective effect of cannabis consumption on weight gain and related metabolic alterations in psychosis patients. Overall, patients are at greater risk of presenting fatty diseases, such as NAFLD, partly due to lipid and glycemic metabolic disturbances. However, there are no previous studies on the likely effect of cannabis on liver steatosis. We aimed to explore if cannabis consumption had an effect on hepatic steatosis, in a sample of first-episode (FEP) non-affective psychosis. MATERIAL AND METHODS: A total of 390 patients were evaluated at baseline and after 3?years of initiating the antipsychotic treatment. Anthropometric measurements and liver, lipid, and glycemic parameters were obtained at both time points. All but 6.7% of patients were drug-naïve at entry, and they self-reported their cannabis use at both time points. Liver steatosis and fibrosis were evaluated through validated clinical scores (Fatty Liver Index [FLI], Fibrosis-4 [FIB-4], and NAFLD). RESULTS: At 3-year follow-up, cannabis users presented significantly lower FLI scores than non-users (F?=?13.874; p?<?.001). Moreover, cannabis users less frequently met the criteria for liver steatosis than non-users (X2?=?7.97, p?=?.019). Longitudinally, patients maintaining cannabis consumption after 3?years presented the smallest increment in FLI over time, which was significantly smaller than the increment in FLI presented by discontinuers (p?=?.022) and never-users (p?=?.016). No differences were seen in fibrosis scores associated with cannabis. CONCLUSIONS: Cannabis consumption may produce a protective effect against liver steatosis in psychosis, probably through the modulation of antipsychotic-induced weight gain.Funding sources: The present study was carried out at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Next-Val 2017 (ref.: NVAL17/24) and Inn-Val 2018 (ref.: INNVAL18/30) IDIVAL grants; Instituto de Salud Carlos III PI020499, PI050427, PI060507; Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004; SENY Fundació Research Grant CI 2005–0308007; and Fundación Marqués de Valdecilla API07/011

Data regarding the effect of cannabis consumption on liver function in the prospective PAFIP cohort of first episode psychosis

The presented article describes data from secondary analyses, related to the research article entitled ?Cannabis consumption and Non-Alcoholic Fatty Liver Disease. A three years longitudinal study in first episode non-affective psychosis patients? [1]. We present detailed data regarding the socio-demographic and baseline clinical characteristics of a sample of 390 drug-naïve patients with a first episode of non-affective psychosis, and the differences between cannabis users and non-users in those characteristics. Tables also show the results from cross-sectional and longitudinal statistical analyses exploring the relation between cannabis consumption and liver function, after excluding those patients with hazardous alcohol drinking

Successful Direct Acting Antiviral Therapy in ChronicHepatitis C Normalizes IFN and IL2 Production in T Cells Together with TLR8 Expression and Functionality in Peripheral Blood Mononuclear Cells

Chronic hepatitis C infection (HCV) activates a systemic cell-mediated immune response characterized by the production of IFN? and an innate immune response addressed by the activation of TLR signaling. We aimed to investigate whether HCV eradication by direct acting antivirals (DAA) leads to a recovery in cell-mediated immune response and TLR expression and functionality. Blood samples were obtained in HCV infected patients before DAA treatment and at week +48 after the end of treatment. Results were compared to healthy controls. Cell surface expression of TLR8 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated PBMCs were cultured with specific TLR8 agonists and intracellular production of cytokines was determined by flow-cytometry after ex vivo TLR8 activation with ssRNA 40. Production of IFN?, IL2 and IL17 was assessed by flow cytometry in T cells after polyclonal activation. Included were 50 HCV-infected patients and 15 controls. TLR8 expression in PBMCs was significantly increased before treatment and recovered normal levels at week +48. Production of IL1b, IL6 and TNF? dependent on the activation of TLR8 in PBMCs was also increased in patients before DAA treatment, with a significant reduction at week +48. Combined expression of IFN? and IL2 in CD4+ T cells in HCV-infected patients was significantly increased compared to controls and recovered normal levels at week +48. DAA-mediated clearance of HCV is associated with a decreased expression and activation of TLR8 in PBMCs until healthy control levels which is accompanied by a reduction in the Th1 response.This research was funded by the Instituto de Salud Carlos III (ISCIII), grant number PIE15/00079

Bacterial antigen translocation and age as BMI-independent contributing factors on systemic inflammation in NAFLD patients

Background & Aims Low‐grade systemic inflammation is a crucial landmark in NAFLD favouring disease progression and comorbidities. We evaluated the input of circulating bacterial antigens on systemic markers of inflammation in NAFLD patients. Patients & Methods Multicenter cross‐sectional study including consecutive patients with biopsy‐proven NAFLD. Demographic, metabolic and fibrosis‐related variables were collected. Circulating bacterial antigens were quantified in blood. Toll‐like receptor SNPs were genotyped. Serum cytokine levels were evaluated. Peripheral blood mononuclear cell response to bacterial antigens was evaluated in vitro. Results Three hundred and fifteen patients from five Spanish hospitals were distributed by BMI. At least, one bacterial antigenic type was found in 66 patients with BMI 30 (77.3%) (P = .014). HOMA‐IR was significantly higher in the presence of circulating antigens among patients with BMI < 30. NASH and significant fibrosis in non‐obese patients were more frequent in the presence of at least two circulating antigenic types. Allelic frequencies of TLR variants were similar to controls and did not affect clinical or laboratory parameters. Pro‐inflammatory cytokines were significantly increased in patients with bacterial antigens, regardless of BMI. TLR gene and protein expression levels were significantly increased in PBMCs from patients with bacterial antigens. Antigen concentrations independently influenced TNF‐α and IL‐6, in both BMI subgroups of patients. Age independently influenced TNF‐α and IL‐6 in non‐obese patients, and TNF‐α in obese patients. Conclusion Serum circulating bacterial antigens as well as age were BMI‐independent factors related to increased systemic inflammation in NAFLD and provides insight on the multifaceted sources of inflammation in these patients.This work has been funded by grants PI16/0967 and PI17/0535 from Instituto de Salud Carlos III, Madrid, Spain, and PROMETEO 2016/001 from Generalitat Valenciana, Valencia, Spain. IGH was recipient of a Young Investigator Grant by CIBERehd, Instituto de Salud Carlos III, Madrid, Spain

Porto-Sinusoidal Vascular Disease Associated to Oxaliplatin: An Entity to Think about It

Portal sinusoidal vascular disease is a presinusoidal cause of portal hypertension (PHT) of unknown etiology, characterized by typical manifestations of PHT (esophageal varices, ascites, portosystemic collaterals), plaquetopenia and splenomegaly with a gradient of portal pressure slightly increased, according to the presinusoidal nature of the PHT. A few cases in the literature have shown a relationship between oxaliplatin and the development of presinusoidal portal hypertension, years after the chemotherapy for colorectal cancer (therefore, different to sinusoidal obstruction syndrome). There are three mechanisms through which oxaliplatin can cause sinusoidal damage: 1) damage at the level of endothelial cells and stimulates the release of free radicals and depletion of glutathione transferase, with altering the integrity of the sinusoidal cells. The damage in the endothelial sinusoidal cells allows to erythrocytes to across into the Dissé space and formation of perisinusoidal fibrosis, 2) the appearance of nodular regenerative hyperplasia is favored by the chronic hypoxia of the centrilobular areas and, finally, 3) oxaliplatin can generate an obliteration of the blood capillaries and zones of parenchymal extinction. These three facts can develop, in a minority of cases, the appearance of a presinusoidal increase of portal pressure, which typically appears years after the completion of chemotherapy and sometimes is underdiagnosed until variceal bleeding, ascites or encephalopathy appear. The knowledge of this pathology is essential to be able to perform an early diagnostic and consult to the hepatologist.Funding: This research received an external funding of CI18/67/02 Acuerdo de cooperación en el programa de becas de investigación científica de IDIVAL de JANSSEN-CILAG, S.A