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Larisse Longo,1,2 Jéssica Tonin Ferrari,2 Pabulo Henrique Rampelotto,2,3 Gustavo Hirata Dellavia,4 Amanda Pasqualotto,2 Claudia P Oliveira,5 Carlos Thadeu Schmidt Cerski,1,4,6 Themis Reverbel da Silveira,2 Carolina Uribe-Cruz,1,2 Mário Reis Álvares-da-Silva1,2,4,7 1Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 2Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; 3Graduate Program in Pharmaceutical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 4School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 5Department of Gastroenterology (LIM07), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; 6Unit of Surgical Pathology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; 7Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, BrazilCorrespondence: Larisse Longo Email larisselongo@hotmail.comBackground/Aim: The interactions between the gut and liver have been described in the progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to develop an experimental nutritional model of NASH simulating metabolic changes occurring in humans.Materials and Methods: Adult male Sprague Dawley rats were randomized into two groups: controls (standard diet) and intervention (high-fat and choline-deficient diet) for 16 weeks, each experimental group with 10 animals. Biochemical analysis, hepatic lipid content, microRNAs, inflammatory, gut permeability markers and gut microbiota were measured.Results: Animals in the intervention group showed significantly higher delta Lee index (p=0.017), abdominal circumference (p< 0.001), abdominal adipose tissue (p< 0.001) and fresh liver weight (p< 0.001), as well as higher serum levels of alanine aminotransferase (p=0.010), glucose (p=0.013), total cholesterol (p=0.033), LDL cholesterol (p=0.011), and triglycerides (p=0.011), and lower HDL cholesterol (p=0.006) compared to the control group. Higher TLR4 (p=0.041), TLR9 (p=0.033), MyD88 (p=0.001), Casp1 (p< 0.001), NLPR3 (p=0.019), liver inflammation index interleukin (IL)-1β/IL10 (p< 0.001), IL6/IL10 (p=0.002) and TNFα/IL10 (p=0.001) were observed in the intervention group, and also lower permeability markers Ocln (p=0.003) and F11r (p=0.041). Gene expression of miR-122 increased (p=0.041) and miR-145 (p=0.010) decreased in the intervention group. Liver steatosis, inflammation and fibrosis, along with collagen fiber deposition increment (p< 0.001), were seen in the intervention group. Regarding gut microbiota, Bray-Curtis dissimilarity index and number of operational taxonomic units were significantly different (p< 0.001) between the groups. Composition of the gut microbiota showed a significant correlation with histopathological score of NAFLD (r=0.694) and index IL-1β/IL-10 (r=0.522).Conclusion: This experimental model mimicking human NASH demonstrated gut and liver interaction, with gut microbiota and intestinal permeability changes occurring in parallel with systemic and liver inflammation, miRNAs regulation and liver tissue damage.Keywords: fatty liver disease models, fibrosis, gut microbiota, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis

The incidence of hepatocellular carcinoma (HCC) has been rising, particularly among individuals diagnosed with metabolic dysfunction-associated steatotic liver disease. In the present study, the prophylactic effects of rifaximin (RIF) on HCC, inflammatory markers and cardiovascular risk (CVR) were investigated in an animal model. Adult Sprague-Dawley rats were randomly allocated into three groups (n=10, each): Control [standard diet/water plus gavage with vehicle (Veh)], HCC [high-fat choline deficient diet (HFCD)/diethylnitrosamine (DEN) in drinking water/Veh gavage] and RIF [HFCD/DEN/RIF (50 mg/kg/day) gavage] groups. After euthanasia at week 16, biochemical/inflammatory markers and the liver histology were assessed. The results demonstrated that the HCC and RIF animals had a significant increase in fresh liver weight, liver weight/body weight ratio, serum total cholesterol (TC), high-density lipoprotein-cholesterol, triglycerides, hepatic lipid accumulation and hepatic concentration of triglycerides and TC, relative to the controls (P<0.001, for all). Additionally, the HCC and RIF animals had higher plasminogen activator inhibitor, intercellular adhesion molecule-1, E-selectin and CVR scores than the controls (P<0.001, for all). The HCC animals had higher interleukin (IL)-1β (P=0.011), IL-10 (P<0.001), toll-like receptor-2 (P=0.012), lipopolysaccharide-binding protein (P=0.018) and metalloproteinase-2 (P=0.003) levels than the RIF animals. Furthermore, liver steatosis, inflammation and fibrosis, along with increased collagen fiber deposition occurred in the HCC and RIF groups. However, HCC occurred only in 2 RIF rats. In conclusion, although most animals did not develop HCC in the present study, RIF positively affected liver inflammation markers involved in steatohepatitis pathogenesis., Competing Interests: Biolab Sanus Farmaceutica Ltd. donated the rifaximin used in our study, although this company had no influence on either the design or conduct of the study, the analysis or interpretation of the data or the writing of the manuscript. Therefore, we do not believe this constitutes a competing interest., (Copyright: © 2024 Longo et al.)

Introduction and Objectives: Public health policies in metabolic dysfunction-associated steatotic liver disease (MASLD) are still lacking. This study aims to estimate the prevalence and severity of MASLD in primary health care (PHC) through non-invasive markers., Patients and Methods: Two-phase study, including a retrospective (RETR) and a prospective (PROS) one, was carried out in PHC in Brazil. In RETR, metabolic and hepatic profiles of 12,054 patients, including FIB-4, were evaluated. In PROS, 350 patients were randomly selected and submitted to a clinical and nutritional assessment., Results: RETR (65.4 % women, mean age 55.3 years old): dyslipidemia, hypertension, and type 2 diabetes mellitus (T2DM) present in 40.8 %, 34.3 %, and 12.2 % of the electronic health records, respectively. Fasting glucose >100 mg/dL in 34.5 %, and glycated hemoglobin higher than 5.7 % in 51.5 %, total cholesterol >200 mg/dL and triglycerides >150 mg/dL in 40.8 % and 32.1 %, respectively. Median FIB-4 was of 1.33, 5 % >2.67. No one had MASLD as a diagnostic hypothesis; PROS(71.8 % women, mean age 58 years old): body mass index (BMI) ≥30 kg/m² in 31.8 %. MASLD prevalence (FLI≥ 30 + cardiometabolic features) of 62.1 %; 39.4 % of patients had FLI ≥60, with higher BMI, waist circumference, fasting glucose, triglycerides, AST, ALT and GGT, as well as lower HDL-cholesterol (p < 0.001). FIB-4>1.3 in 40 % and NAFLD Fibrosis Score (NFS)>-1.45 in 59.2 % of steatotic patients., Conclusions: There is a high prevalence of MASLD in PHC, with a significant risk of liver fibrosis. These findings reinforce we need to develop public policies to defeat MASLD epidemics., Competing Interests: Declaration of interests None., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Some evidence suggests an association between gut dysbiosis and cirrhosis progression. The authors investigated Gut Microbiome (GM) influence on 90-day mortality and hospitalization/rehospitalization rates in cirrhotic patients., Methods: Compensated/decompensated outpatients and decompensated inpatients were prospectively included and compared to healthy controls. Clinical, laboratory, GM, and two ratios between phyla were evaluated. Patients were followed up for 90 days for hospitalization/rehospitalization and mortality., Results: 165 individuals were included (50 compensated, 49 decompensated outpatients; 36 decompensated inpatients; 30 healthy), 48.5 % female, mean age was 61, main cirrhosis etiology was hepatitis C (27.3 %), and mostly Child-Pugh (CP) B patients, median MELD of 13. As liver disease progressed, microbiota diversity decreased between the groups (p = 0.05; p < 0.004). There were 9 deaths and 22 hospitalizations or rehospitalizations. GM composition had correlation with norfloxacin (p = 0.36, p = 0.04), encephalopathy (p = 0.31, p = 0.01), lactulose (p = 0.26, p = 0.01), 90-day mortality (p = 0.22, p = 0.04), CP (p = 0.17, p = 0.01), previous 6-month antibiotic use (p = 0.16, p = 0.01), MELD (p = 0.145, p = 0.01), ALBI (p = 0.1, p = 0.04) and 90-day hospitalization/rehospitalization (p = 0.08, p = 0.03). Firmicutes/Bacteroidetes (F/B) and Firmicutes/Proteobacteria (F/P) ratios were progressively lower and more significant and had an association with 90-day mortality (p < 0.001). Three MELD set-points (≥ 15, 18 and 20) were significantly associated with both ratios, with similar accuracies., Conclusions: GM dysbiosis was associated with higher CP, MELD, 90-day mortality and hospitalization/rehospitalization. F/B and F/P ratios were associated with 90-day mortality., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier España, S.L.U.)

It is known that the inflammation process leading to oxidative stress and thyroid hormone metabolism dysfunction is highly altered in metabolic dysfunction associated with steatotic liver disease (MASLD). This study aims to address the effect of ornithine aspartate (LOLA) and vitamin E (VitE) in improving these processes. Adult Sprague-Dawley rats were assigned to five groups and treated for 28 weeks: controls ( n = 10) received a standard diet (for 28 weeks) plus gavage with distilled water (DW) from weeks 16 to 28. MASLD groups received a high-fat and choline-deficient diet for 28 weeks (MASLD group) and daily gavage with 200 mg/kg/day of LOLA, or twice a week with 150 mg of VitE from weeks 16-28. LOLA diminished collagen deposition ( p = 0.006). The same treatment diminished carbonyl, TBARS, and sulfhydryl levels and GPx activity ( p < 0.001). Type 3 deiodinase increased in the MASLD group, downregulating T3-controlled genes, which was corrected in the presence of LOLA. LOLA also promoted a near-normalization of complex II, SDH, and GDH activities ( p < 0.001) and improved reticulum stress, with a reduction in GRP78 and HSPA9/GRP75 protein levels ( p < 0.05). The enhanced energy production and metabolism of thyroid hormones, probably because of GSH replenishment provided by the L-glutamate portion of LOLA, opens a new therapeutic approach for MASLD.

Background and Aim: Considering the increasing prevalence of non-alcoholic steatohepatitis (NASH) and treatment gaps, this study aimed to evaluate the effect of probiotic supplementation on liver function markers, nutritional status, and clinical parameters., Methods: This double-blind, randomized clinical trial (ClinicalTrials.gov ID: NCT0346782) included adult outpatients with biopsy-proven NASH. The intervention consisted of 24 weeks of supplementation with the probiotic mix Lactobacillus acidophilus (1 × 10 9  CFU) +  Lactobacillus rhamnosus (1 × 10 9  CFU) +  Lactobacillus paracasei (1 × 10 9  CFU) +  Bifidobacterium lactis (1 × 10 9  CFU), or placebo, twice a day. The following parameters were evaluated: demographic and clinical data, transient elastography (FibroScan), liver enzymes, NAFLD fibrosis score , fatty liver index, laboratory assessment, serum concentration of toll-like receptor-4 (sTLR-4) and cytokeratin 18 (CK-18), anthropometric data, dietary intake, and physical activity. Regarding data analysis, the comparison between the groups was based on the delta of the difference of each variable analyzed (value at the end of treatment minus the baseline value) using the t -test for independent samples or the Mann-Whitney U -test., Results: Forty-four patients with NASH completed the trial (51.4 ± 11.6 years). At baseline, 87% of participants had a mild liver fibrosis degree on biopsy, normal values of liver enzymes, transient elastography values consistent with grade 1 fibrosis in both groups, increased waist circumference (WC), a BMI of 30.97 kg/m 2 , and 76% presented with metabolic syndrome (MetS). After the intervention, no differences were observed between the probiotic and placebo groups in terms of MetS, WC, BMI scores, or liver enzyme levels ( p  > 0.05 for all). The elastography values remained consistent with grade 1 fibrosis in both groups. Although CK-18 was reduced in both groups, a larger effect size was noted in the probiotic group ( D  = 1.336). sTLR-4 was also reduced in both groups, with no difference between groups ( p  = 0.885)., Conclusion: Intervention with probiotics in the early stages of NASH demonstrated no significant change in hepatic and clinical parameters., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT0346782., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Silva-Sperb, Moraes, Barcelos, de Moura, Longo, Michalczuk, Cerski, Uribe-Cruz, da Silveira, Álvares-da-Silva and Dall’Alba.)

Background: Alcoholic liver disease (ALD) and metabolic-dysfunction associated steatotic liver disease (MASLD) are common, and gut microbiota (GM) is involved with both. Here we compared GM composition in animal models of MASLD and ALD to assess whether there are specific patterns for each disease., Methods: MASLD model- adult male Sprague Dawley rats, randomized into two groups: MASLD-control (n=10) fed a standard diet; MASLD-group (n=10) fed a high-fat-choline-deficient diet for 16 weeks. ALD model- adult male Wistar rats randomized: ALD-control (n=8) fed a standard diet and water+0.05% saccharin, ALD groups fed with sunflower seed and 10% ethanol+0.05% saccharin for 4 or 8 weeks (ALC4, n=8; ALC8, n=8). ALC4/8 on the last day received alcoholic binge (5g/kg of ethanol). Afterwards, animals were euthanized, and feces were collected for GM analysis., Results: Both experimental models induced typical histopathological features of the diseases. Alpha diversity was lower in MASLD compared with ALD (p<0.001), and structural pattern was different between them (P<0.001). Bacteroidetes (55.7%), Firmicutes (40.6%), and Proteobacteria (1.4%) were the most prevalent phyla in all samples, although differentially abundant among groups. ALC8 had a greater abundance of the phyla Cyanobacteria (5.3%) and Verrucomicrobiota (3.2%) in relation to the others. Differential abundance analysis identified Lactobacillaceae&#95;unclassified, Lachnospiraceae&#95;NK4A136&#95;group, and Turicibacter associated with ALC4 and the Clostridia&#95;UCG&#95;014&#95;ge and Gastranaerophilales&#95;ge genera to ALC8., Conclusion: In this study, we demonstrated that the structural pattern of the GM differs significantly between MASLD and ALD models. Studies are needed to characterize the microbiota and metabolome in both clinical conditions to find new therapeutic strategies., Background: •Changes in the composition of the intestinal microbiota are related to the development of alcoholic liver disease and metabolic-dysfunction associated steatotic liver disease., Background: •The diversity of the intestinal microbiota was lower in animals with MASLD compared to ALD., Background: •The structural pattern of the intestinal microbiota was significantly different among the experimental groups., Background: •Studies are needed to characterize the composition of the intestinal microbiota and metabolome to find new therapeutic strategies.

Background: Prevalence of hepatocellular carcinoma (HCC) is increasing, especially in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Aim: To investigate rifaximin (RIF) effects on epigenetic/autophagy markers in animals., Methods: Adult Sprague-Dawley rats were randomly assigned ( n = 8, each) and treated from 5-16 wk: Control [standard diet, water plus gavage with vehicle (Veh)], HCC [high-fat choline deficient diet (HFCD), diethylnitrosamine (DEN) in drinking water and Veh gavage], and RIF [HFCD, DEN and RIF (50 mg/kg/d) gavage]. Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained., Results: All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis, and cirrhosis, but three RIF-group did not develop HCC. Comparing animals who developed HCC with those who did not, miR-122, miR-34a, tubulin alpha-1c (Tuba-1c) , metalloproteinases - 2 (Mmp2) , and metalloproteinases - 9 (Mmp9) were significantly higher in the HCC-group. The opposite occurred with Becn1 , coactivator associated arginine methyltransferase-1 ( Carm1 ), enhancer of zeste homolog-2 ( Ezh2 ), autophagy-related factor LC3A/B (Map1 Lc3b) , and p62/ sequestosome-1 ( p62/ SQSTM1 )- protein . Comparing with controls, Map1 Lc3b , Becn1 and Ezh2 were lower in HCC and RIF-groups ( P < 0.05). Carm1 was lower in HCC compared to RIF ( P < 0.05). Hepatic expression of Mmp9 was higher in HCC in relation to the control; the opposite was observed for p62/Sqstm1 ( P < 0.05). Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control ( P = 0.024). There was no difference among groups for Tuba-1c , Aldolase-B, alpha-fetoprotein, and Mmp2 ( P > 0.05). miR-122 was higher in HCC, and miR-34a in RIF compared to controls ( P < 0.05). miR-26b was lower in HCC compared to RIF, and the inverse was observed for miR-224 ( P < 0.05). There was no difference among groups regarding miR-33a, miR-143, miR-155, miR-375 and miR-21 ( P > 0.05)., Conclusion: RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as Nonalcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in individuals with overweight or obesity. In this context, a panel of experts from three medical societies was organized to develop an evidence-based guideline on the screening, diagnosis, treatment, and follow-up of MASLD., Material and Methods: A MEDLINE search was performed to identify randomized clinical trials, meta-analyses, cohort studies, observational studies, and other relevant studies on NAFLD. In the absence of studies on a certain topic or when the quality of the study was not adequate, the opinion of experts was adopted. Classes of Recommendation and Levels of Evidence were determined using prespecified criteria., Results: Based on the literature review, 48 specific recommendations were elaborated, including 11 on screening and diagnosis, 9 on follow-up,14 on nonpharmacologic treatment, and 14 on pharmacologic and surgical treatment., Conclusion: A literature search allowed the development of evidence-based guidelines on the screening, diagnosis, treatment, and follow-up of MASLD in individuals with overweight or obesity.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is also an important cause of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV has the capacity to evade immune surveillance by altering the host immune response. Moreover, variations in immune-related genes can lead to differential susceptibility to HCV infection as well as interfere on the susceptibility to the development of hepatic fibrosis, cirrhosis and HCC. The human leucocyte antigen G (HLA-G) gene codes for an immunomodulatory protein known to be expressed in the maternal-foetal interface and in immune-privileged tissues. The HLA-G 3' untranslated region (3'UTR) is important for mRNA stability, and variants in this region are known to impact gene expression. Studies, mainly focusing in a 14 bp insertion/deletion polymorphism, have correlated HLA-G 3'UTR with susceptibility to viral infections, but other polymorphic variants in the HLA-G 3'UTR might also affect HCV infection as they are inherited as haplotypes. The present study evaluated HLA-G 3'UTR polymorphisms and performed linkage disequilibrium test and haplotype assembly in 286 HCV infected patients who have developed fibrosis, cirrhosis or HCC, as well as in 129 healthy control subjects. Haplotypes UTR-1, UTR-2 and UTR-3 were the most observed in HCV+ patients, in the frequencies of 0.276, 0.255 and 0.121, respectively. No statistically significant difference was observed between HCV+ and control subjects, even when patients were grouped according to outcome (HCC, cirrhosis or fibrosis). Despite that, some trends in the results were observed, and therefore, we cannot rule out the possibility that variants associated to high HLA-G expression can be involved in HCV infection susceptibility., (© 2023 John Wiley & Sons Ltd.)

Metabolic dysfunction-associated fatty liver disease (MAFLD) has gained worldwide attention as a public health problem. Nonetheless, lack of enough mechanistic knowledge restrains effective treatments. It is known that thyroid hormone triiodothyronine (T3) regulates hepatic lipid metabolism, and mitochondrial function. Liver dysfunction of type 3 deiodinase (D3) contributes to MAFLD, but its role is not fully understood., Objective: To evaluate the role of D3 in the progression of MAFLD in an animal model., Methodology: Male/adult Sprague Dawley rats (n = 20) were allocated to a control group (2.93 kcal/g) and high-fat diet group (4.3 kcal/g). Euthanasia took place on the 28th week. D3 activity and expression, Uncoupling Protein 2 (UCP2) and type 1 deiodinase (D1) expression, oxidative stress status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured., Results: We observed an increase in D3 activity/expression ( p < 0.001) related to increased thiobarbituric acid reactive substances (TBARS) and carbonyls and diminished reduced glutathione (GSH) in the MAFLD group ( p < 0.05). There was a D3-dependent decrease in UCP2 expression ( p = 0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group ( p < 0.001). Surprisingly, in an environment with lower T3 levels due to high D3 activity, we observed an augmented alpha-ketoglutarate dehydrogenase (KGDH) and glutamate dehydrogenase (GDH) enzymes activity ( p < 0.05)., Conclusion: Induced D3, triggered by changes in the REDOX state, decreases T3 availability and hepatic mitochondrial capacity. The Krebs cycle enzymes were altered as well as endoplasmic reticulum stress. Taken together, these results shed new light on the role of D3 metabolism in MAFLD.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2020 the updated recommendations for the diagnosis and treatment of HCC. Since then, new data have emerged in the literature, including new drugs approved for the systemic treatment of HCC that were not available at the time. The SBH board conducted an online single-topic meeting to discuss and review the recommendations on the systemic treatment of HCC. The invited experts were asked to conduct a systematic review of the literature on each topic related to systemic treatment and to present the summary data and recommendations during the meeting. All panelists gathered together for discussion of the topics and elaboration of the updated recommendations. The present document is the final version of the reviewed manuscript containing the recommendations of SBH and its aim is to assist healthcare professionals, policy-makers, and planners in Brazil and Latin America with systemic treatment decision-making of patients with HCC.

Introduction and Objectives: Cardiovascular disease (CVD) is the major cause of death in non-alcoholic fatty liver disease (NAFLD), a clinical condition without any approved pharmacological therapy. Probiotics are often indicated for the disease, but their results are controversial in part due to the poor quality of studies. Thus, we investigated the impact of 24-week probiotics supplementation on cardiovascular risk (CVR) in biopsy-proven non-alcoholic steatohepatitis (NASH) patients., Patients and Methods: Double-blind, placebo-controlled, single-center study (NCT03467282), adult NASH, randomized for 24 weeks daily sachets of probiotic mix (10 9 CFU of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus paracasei and Bifidobacterium lactis) or placebo. Clinical scores (atherogenic indexes, atherosclerotic cardiovascular disease-ASCVD and systematic coronary risk evaluation-SCORE), biochemistry, miR-122, miR-33a, plasminogen activator inhibitor-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), were determined before and after the intervention., Results: Forty-six patients were enrolled (23 received probiotics and 23 placebo), with a mean age of 51.7 years, most of them females and whites. Clinical and demographic features were similar between the groups at the baseline. The Median NAFLD activity score was 4.13 in both groups. Fibrosis was mild in most patients (15.2% and 65.2% F0 and F1, respectively). Treatment did not promote any clinically significant changes in body mass index or laboratory, including lipid and glucose profile. High CVR patients through atherogenic indexes decreased from baseline in both groups, as well as PAI-1 and miR-122 levels, although there was no difference between probiotics and placebo., Conclusions: A 24-week probiotic mix administration was not superior to placebo in reducing CVR markers in patients with NASH., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Introduction and Objectives: Liver fibrosis is an important prognosis marker in non-alcoholic fatty liver disease (NAFLD). Biopsy has been considered the gold-standard method for measuring liver fibrosis; however, it is an invasive procedure. Non-invasive diagnostic tools have been developed, such as clinical scores and magnetic resonance elastography (MRE), which is the most accurate non-invasive method to determine liver fibrosis. Thus, the aim was to determine the NAFLD Fibrosis Score (NFS) and the Fibrosis-4 Score (FIB-4) cut-off points that best identify NAFLD patients at risk for developing liver fibrosis., Patients and Methods: Single-center cross-sectional study with prospective recruitment of NAFLD (training-cohort) and MAFLD (validation-cohort) patients undergoing MRE. The NFS and the FIB-4 cut-off points that best-differentiated patients with fibrosis, using the MRE as the standard method, were determined., Results: Two cohorts were analyzed, a training cohort that included the initial 183 patients with NAFLD and a validation cohort that included 289 patients. In the training cohort, 60.1% had mild steatosis and 11.5% had liver fibrosis ≥ F1 by MRE. ROC curves were developed for FIB-4 and NFS, and the cut-off points chosen were 1.505 (sensitivity=85% and specificity=86%) for FIB-4 and -0.835 (sensitivity=100% and specificity=70%) for NFS, showing greater specificity than the cut-off points currently used (51% and 76%, respectively). The two cohorts exhibited similar characteristics and similar sensitivity and specificity results for the chosen cut-off points., Conclusions: This study has shown cut-off points with greater specificity and excellent sensitivity to guide the indication for further liver evaluation by MRE in NAFLD patients., Competing Interests: Declaration of interest None., (Copyright © 2022 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

The muscle fiber morphometric analysis (MusMA) is a protocol to segment and characterize the morphometry of individual cross-sectioned striated muscle fibers. Using a semi-automated Excel spreadsheet, the protocol allows the objective measurement of muscle fibers' subpopulations, aiming to characterize physiopathological conditions related to muscle tissue. The main limitation of MusMA is the need for high-quality tissue slides and images and control samples to set up the analyses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiovascular (CV) disease is the main cause of death in nonalcoholic fatty liver disease (NAFLD), a clinical condition without any approved pharmacological therapy. Thus, we investigated the effects of ornithine aspartate (LOLA) and/or Vitamin E (VitE) on CV parameters in a steatohepatitis experimental model. Adult Sprague Dawley rats were randomly assigned (10 animals each) and treated from 16 to 28 weeks with gavage as follows: controls (standard diet plus distilled water (DW)), NAFLD (high-fat choline-deficient diet (HFCD) plus DW), NAFLD+LOLA (HFCD plus LOLA (200 mg/kg/day)), NAFLD+VitE (HFCD plus VitE (150 mg twice a week)) or NAFLD+LOLA+VitE in the same doses. Atherogenic ratios were higher in NAFLD when compared with NAFLD+LOLA+VitE and controls ( p < 0.05). Serum concentration of IL-1β, IL-6, TNF-α, MCP-1, e-selectin, ICAM-1, and PAI-1 were not different in intervention groups and controls ( p > 0.05). NAFLD+LOLA decreased miR-122, miR-33a, and miR-186 ( p < 0.05, for all) in relation to NAFLD. NAFLD+LOLA+VitE decreased miR-122, miR-33a and miR-186, and increased miR-126 ( p < 0.05, for all) in comparison to NAFLD and NAFLD+VitE. NAFLD+LOLA and NAFLD+LOLA+VitE prevented liver collagen deposition ( p = 0.006) in comparison to NAFLD. Normal cardiac fibers (size and shape) were lower in NAFLD in relation to the others; and the inverse was reported for the percentage of regular hypertrophic cardiomyocytes. NAFLD+LOLA+VitE promoted a significant improvement in atherogenic dyslipidemia, liver fibrosis, and paracrine signaling of lipid metabolism and endothelial dysfunction. This association should be further explored in the treatment of NAFLD-associated CV risk factors.

Background & Aims: Gut microbiota are affected by diet, country, and affect outcomes in cirrhosis. Western diets are associated with dysbiosis. Comparisons with other diets is needed. We aimed to compare cirrhosis patients from the United States with cirrhosis patients from Brazil with respect to diet, microbiota, and impact on hospitalizations., Methods: Healthy controls and compensated/decompensated outpatients with cirrhosis from the United States and Brazil underwent dietary recall and stool for 16S ribosomal RNA sequencing. Demographics and medications/cirrhosis details were compared within and between countries. Patients with cirrhosis were followed up for 90-day hospitalizations. Regression for Shannon diversity was performed within cirrhosis. Regression for hospitalizations adjusting for clinical and microbial variables was performed., Results: Model for end-stage liver disease (MELD), diabetes, ascites, and albumin were similar, but more Americans were men, had higher hepatic encephalopathy and alcohol/hepatitis C etiology, with lower nonalcoholic fatty liver disease than Brazilians. Brazilians had higher cereal, rice, and yogurt intake vs the United States. As disease progressed, cereals, rice/beans, coffee, and chocolate consumption was reduced. Microbial diversity was higher in Brazilians. Within cirrhosis, high diversity was related to Brazilian origin (P < .0001), age, and cereal intake (P = .05), while high MELD scores (P = .009) and ascites (P = .05) did the reverse. Regardless of stage, beneficial taxa and taxa associated with grant and yogurt intake were higher (Ruminococcaceae, Christensenellacae, and Prevotellaceae), while pathobionts (Porphyromonadaceae, Sutterellaceae, and Enterobacteriaceae) were lower in Brazilians. More Americans were hospitalized vs Brazilians (P = .002). On regression, MELD (P = .001) and ascites (P = .001) were associated with higher hospitalizations, while chocolate (P = .03) and Brazilian origin (P = .001) were associated with lower hospitalizations with/without microbiota inclusion., Conclusions: Brazilian cirrhotic patients follow a diet richer in cereals and yogurt, which is associated with higher microbial diversity and beneficial microbiota and could contribute toward lower hospitalizations compared with a Western-diet-consuming American cohort., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease is the main cause of death in metabolic-associated fatty liver disease, and gut microbiota dysbiosis is associated with both of them., Aim: To assess the relationship between gut dysbiosis and cardiovascular risk (CVR) in an experimental model of steatohepatitis., Methods: Adult male Sprague-Dawley rats were randomized to a control group ( n = 10) fed a standard diet and an intervention group ( n = 10) fed a high-fat choline-deficient diet for 16 wk. Biochemical, molecular, hepatic, and cardiac histopathology. Gut microbiota variables were evaluated., Results: The intervention group had a significantly higher atherogenic coefficient, Castelli's risk index (CRI)-I and CRI-II, interleukin-1β, tissue inhibitor of metalloproteinase-1 (all P < 0.001), monocyte chemoattractant protein-1 ( P = 0.005), and plasminogen activator inhibitor-1 ( P = 0.037) than the control group. Gene expression of miR-33a increased ( P = 0.001) and miR-126 ( P < 0.001) decreased in the intervention group. Steatohepatitis with fibrosis was seen in the intervention group, and heart computerized histological imaging analysis showed a significant decrease in the percentage of cardiomyocytes with a normal morphometric appearance ( P = 0.007), reduction in the mean area of cardiomyocytes ( P = 0.037), and an increase of atrophic cardiomyocytes ( P = 0.007). There were significant correlations between the cardiomyocyte morphometry markers and those of progression and severity of liver disease and CVR. The intervention group had a lower Shannon diversity index and fewer changes in the structural pattern of gut microbiota (both P < 0.001) than controls. Nine microbial families that are involved in lipid metabolism were differentially abundant in intervention group and were significantly correlated with markers of liver injury and CVR., Conclusion: The study found a link between gut dysbiosis and significant cardiomyocyte abnormalities in animals with steatohepatitis., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C. Sofosbuvir and simeprevir are prescribed worldwide. However, there is a scarcity of information regarding their genotoxicity. Therefore, the present study assessed the cytotoxic and genotoxic effects of sofosbuvir and simeprevir, alone and combined with ribavirin. HepG2 cells were analyzed using the in vitro cytokinesis-block micronucleus cytome assay. Cells were treated for 24 h with sofosbuvir (0.011-1.511 mM), simeprevir (0.156-5.0 µM), and their combinations with ribavirin (0.250-4.0 mM). No significant differences were observed in the nuclear division cytotoxicity index, reflecting the absence of cytotoxic effects associated to sofosbuvir. However, the highest concentration of simeprevir showed a significant difference for the nuclear division cytotoxicity index. Moreover, significant results were observed for nuclear division cytotoxicity index in two combinations of sofosbuvir plus ribavirin and only in the highest combination of simeprevir plus ribavirin. Additionally, our results showed that sofosbuvir did not increase the frequency of chromosomal damage, but simeprevir significantly increased the frequency of micronuclei at the highest concentrations. The combination index demonstrated that both sofosbuvir and simeprevir produced antagonism to the genotoxic effects of ribavirin. In conclusion, our results showed that simeprevir, but not sofosbuvir, has genotoxic effects in HepG2 cells.

Introduction: Acute-on-chronic liver failure (ACLF) is an acute liver decompensation in cirrhotic patients, which leads to organ failures and high short-term mortality. The treatment is based on the management of complications and, in severe cases, liver transplantation. Since specific treatment is unavailable, we aimed to evaluate the safety and initial efficacy of bone marrow mesenchymal stem cells (BM-MSC) in patients with ACLF Grades 2 and 3, a population excluded from previous clinical trials., Methods: This is a randomized placebo-controlled phase I-II single center study, which enrolled 9 cirrhotic patients from 2018 to 2020, regardless of the etiology. The control group ( n  = 5) was treated with standard medical therapy (SMT) and placebo infusion of saline. The intervention group ( n  = 4) received SMT plus 5 infusions of 1 × 10 6 cells/kg of BM-MSC for 3 weeks. Both groups were monitored for 90 days. A Chi-square test was used for qualitative variables, and the t -test and Mann-Whitney U test for quantitative variables. The Kaplan-Meier estimator was used to build survival curves. In this study, we followed the intention-to-treat analysis, with a significance of 5%., Results: Nine patients with a mean Child-Pugh (CP) of 12.3, MELD of 38.4, and CLIF-C score of 50.7 were recruited. Hepatitis C and alcohol were the main etiologies. The average infusion per patient was 2.9 and only 3 patients (2 in control and 1 in the BM-MSC group) received all the protocol infusions. There were no infusion-related side effects, although one patient in the intervention group presented hypernatremia and a gastric ulcer, after the third and fifth infusions, respectively. The survival rate after 90 days was 20% (1/5) for placebo versus 25% (1/4) for the BM-MSC. The patient who completed the entire MSC protocol showed a significant improvement in CP (C-14 to B-9), MELD (32 to 22), and ACLF (grade 3 to 0)., Conclusion: BM-MSC infusion is safe and feasible in patients with ACLF Grades 2 and 3., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Fernando Comunello Schacher et al.)

Obesity is key to liver steatosis development and progression. Transcranial direct current stimulation (tDCS) is a promising tool for eating disorders management but was not yet evaluated in steatosis. This study investigated tDCS' effects on liver steatosis and inflammation in an experimental obesity model. Male Wistar rats (60 days-old) were randomly allocated (n = 10/group) as follows: standard-diet/sham tDCS (SDS), standard-diet/tDCS (SDT), hypercaloric-cafeteria-diet/sham tDCS (HDS), and hypercaloric-cafeteria-diet/tDCS (HDT). After 40 days of diet, animals received active or sham tDCS for eight days and were euthanized for liver fat deposition and inflammation analysis. HDS and HDT animals showed cumulative food consumption, total liver lipid deposits, IL-1β, TNF-α levels, IL-1β/IL-10 and TNF-α/IL-10 ratios significantly higher than the SDS and SDT groups (p < 0.001 for all parameters). tDCS (SDT and HDT) reduced liver lipid deposits (0.7 times for both, p < 0.05), IL-1β (0.7 times and 0.9 times, respectively, p < 0.05) and IL-1β/IL-10 index (0.6 times and 0.8 times, respectively, p < 0.05) in relation to sham (SDS and HDS). There was an interaction effect on the accumulation of hepatic triglycerides (p < 0.05). tDCS reduced 0.8 times the average liver triglyceride concentration in the HDT vs. HDS group (p < 0.05). In this obesity model, tDCS significantly decreased liver steatosis and hepatic inflammation. These results may justify looking into tDCS utility for human steatosis.

The prevalence of anti-hepatitis E virus (HEV) antibodies has a high heterogeneity worldwide. South American data are still scarce. The aim of this study was to evaluate the prevalence of HEV in populations at risk in comparison to blood donors (BD). A cross-sectional study was carried out in adults of different risk populations including crack users (CK), residents in a low income area (LIA), cirrhotic (CIR) and liver transplant patients (LT) compared with BD. The WANTAI HEV ELISA test was used and real-time PCR (in-house for screening and ALTONA as confirmatory test) for HEV RNA screening. A total of 400 participants were included. Anti-HEV IgG was positive in 19.5% of the total sample, reaching the highest rate in the CIR group, 22.5%, followed by CK, LT, and LIA (20%, 18.7%, and 17.5%, respectively). The prevalence found in BD individuals was of 18.7% (p = NS). Anti-HEV IgM was positive in only 1.5% of the sample (6/400). No blood or stools samples were positive for HEV RNA. The seroprevalence reported is among the highest rates ever found in Brazil. Considering the intense diagnostic investigation, data show that HEV circulation is more common that might be expected in our country.

Background: Hepatitis C virus (HCV) infection is a public health concern worldwide. Several factors, including genetic polymorphisms, may be evolved in the progression of HCV infection to liver diseases. Interferon lambdas (IFNLs) modulate the immune response during viral infections. IFNLs induce antiviral activity, interfering in the viral replication by promoting the expression of several genes that regulate immunological functions. The interferon lambda-4 ( IFNL4 ) rs12979860 polymorphism, which is characterized by a C to T transition in intron 1, is associated with spontaneous and treatment-induced clearance of HCV infection and may play a role in the development of HCV-associated liver diseases, including hepatocellular carcinoma (HCC)., Aim: To investigate the association of IFNL4 rs12979860 polymorphism with fibrosis, cirrhosis, and HCC in patients with chronic HCV infection., Methods: This study was comprised of 305 chronic HCV-infected patients (53 fibrosis, 154 cirrhosis, and 98 HCC cases). The control group was comprised of 260 HCV-negative healthy individuals. The IFNL4 rs12979860 polymorphism was genotyped using the TaqMan assay. Fibrosis was diagnosed based on liver biopsy findings, while cirrhosis was diagnosed through clinical, laboratory, anatomopathological, and/or imaging data. HCC was diagnosed through imaging tests, tumor, and/or anatomopathological markers., Results: The T allele was observed in the three groups of patients (fibrosis, cirrhosis, and HCC) at a significantly higher frequency when compared with the control group ( P = 0.047, P < 0.001, and P = 0.01, respectively). Also, genotype frequencies presented significant differences between the control group and cirrhosis patients ( P < 0.001) as well as HCC patients ( P = 0.002). The risk analysis was performed using the codominant and dominant T allele models. In the codominant model, it was observed that the CT genotype showed an increased risk of developing cirrhosis in comparison with the CC genotype [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.55-4.15; P < 0.001] as well as with HCC (OR = 2.54; 95%CI: 1.44-4.56; P = 0.001). A similar result was observed in the comparison of the TT vs CC genotype between the control group and cirrhosis group (OR = 2.88; 95%CI: 1.44-5.77; P = 0.001) but not for HCC patients. In the dominant T allele model, the CT + TT genotypes were associated with an increased risk for progression to cirrhosis (OR = 2.60; 95%CI: 1.63-4.19; P < 0.001) and HCC (OR = 2.45; 95%CI: 1.42-4.31; P = 0.001)., Conclusion: These findings suggest that the T allele of IFNL4 rs12979860 polymorphism is associated with the development of cirrhosis and HCC in chronic HCV-infected patients., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction and Objectives: Glecaprevir/pibrentasvir is a highly effective and well tolerated treatment for hepatitis C infection. Brazilian patients were not included in the original development studies for glecaprevir/pibrentasvir. This study aimed to assess safety and efficacy of glecaprevir/pibrentasvir in treatment-naïve Brazilian adults without cirrhosis or with compensated cirrhosis., Patients and Methods: EXPEDITION-3 was a Phase 3, open-label, multicenter study in treatment-naïve Brazilian adults with hepatitis C infection genotype 1-6. Patients without cirrhosis (F2 or F3) or with compensated cirrhosis (F4) received 8 or 12 weeks of glecaprevir/pibrentasvir, respectively. The primary efficacy endpoint was the rate of sustained virologic response at post-treatment Week 12. Secondary endpoints were on-treatment virologic failure and relapse rates. Baseline polymorphisms were assessed in NS3 and NS5A. Adverse events and laboratory abnormalities were monitored., Results: 100 patients were enrolled, 75 received 8 weeks of treatment and 25 received 12 weeks; all patients completed treatment. Overall sustained virologic response at post-treatment Week 12 rate was high (98.0%; 98/100; 95% confidence interval: 93.0-99.4) and remained high regardless of baseline viral or host factors, including demographics, hepatitis C virus RNA levels, polymorphisms in NS3 and/or NS5A, genotype, and relevant comorbidities. 55% of patients reported ≥1 adverse event, the most common being headache (18.0%). Four patients reported serious adverse events; none were considered drug related or led to study drug discontinuation. No hepatic decompensations were observed., Conclusions: Glecaprevir/pibrentasvir was effective and well tolerated in treatment-naïve Brazilian patients with hepatitis C infection without cirrhosis and with compensated cirrhosis., Trial Registration: ClinicalTrials.gov NCT03219216., (Copyright © 2020. Published by Elsevier España, S.L.U.)

Hepatic sinusoidal obstruction syndrome (HSOS) is a hepatic vascular disease histologically characterized by edema, necrosis, detachment of endothelial cells in small sinusoidal hepatic and interlobular veins and intrahepatic congestion, which leads to portal hypertension and liver dysfunction. In the Western world, most HSOS cases are associated with myeloablative pretreatment in a hematopoietic stem cell transplantation setting. Here we report a case of a 54 years old female patient, otherwise healthy, with no history of alcoholic ingestion, who presented with jaundice and signs of portal hypertension, including ascites and bilateral pleural effusion. She had no history of liver disease and denied any other risk factor for liver injury, except Senecio brasiliensis ingestion as a tea, prescribed as a therapy for menopause. Acute viral hepatitis and thrombosis of the portal system were excluded in complementary investigation, as well as sepsis, metastatic malignancy and other liver diseases, setting a RUCAM score of 6. Computed tomography demonstrated a diffuse liver parenchymal heterogeneity (in mosaic) and an extensive portosystemic collateral venous circulation, in the absence of any noticeable venous obstruction. HSOS diagnosis was confirmed through a liver biopsy. During the following-up period, patient developed refractory pleural effusion, requiring hemodialysis. Right before starting anticoagulation, she presented with abdominal pain and distention, with findings compatible of mesenteric ischemia by computed tomography. A laparotomy was performed, showing an 80cm segment of small bowel ischemia, and resection was done. She died one day after as a result from a septic shock refractory to treatment. The presented case was related to oral intake of S. brasiliensis, a plant containing pyrrolidine alkaloids, which are one of the main causes of HSOS in the East, highlighting the risk of liver injury with herbs intake., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20-30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future., (Copyright © 2020. Published by Elsevier España, S.L.U.)

In this study we investigated the impact of rs2596542A/G single nucleotide polymorphism (SNP) in the major histocompatibility complex class I chain-related sequence A (MICA) gene on HCV-induced hepatocellular carcinoma (HCC) susceptibility in a Brazilian population. In total, 252 HCV-infected patients (98 with HCV-induced HCC and 154 non-malignant HCV-induced liver cirrhosis) were enrolled and 98 healthy control subjects (negative anti-HCV). The MICA rs2596542 SNP genotypes were determined by real-time PCR assay. No differences in MICA genotype frequencies between HCV-induced cirrhosis patients and controls were observed. However, genotype frequencies of rs2596542A/G SNP were statistically different between HCV-induced HCC patients and controls (p = 0.048), and also between HCC and HCV-induced cirrhosis patients (p = 0.039). The highest frequency of the rs2596542AA genotype was observed in HCC patients (31.6%) when compared with HCV-induced cirrhosis patients (18.8%) and healthy controls (19.4%). Also, rs2596542AA genotype carriers have an increased risk for HCC when compared to HCV-induced cirrhosis status [odds ratio (OR) = 1.99; 95% confidence interval (CI) = 1.06-3.74, p = 0.020)] and healthy individuals (OR = 1.92, 95% CI = 1.00-3.70, p = 0.049). Taken together our study suggest that MICA rs2596542 SNP impacts HCV-induced HCC susceptibility suggesting that genetic variants in MICA are of clinical relevance to hepatocarcinogenesis by impacting host immune response in chronic HCV infection.

Background: Current policy for listing to liver transplant (LT) may place cirrhotic patients without MELD exception points (CIR) in a disadvantageous position if compared to patients enlisted with appealed MELD scores - patients with hepatocellular carcinoma (HCC) or special conditions other than hepatocellular carcinoma (SPE). Transplant rates, delisting, and waitlist mortality of CIR, HCC, and SPE candidates were compared., Objective: The aim of this study is to counterweight the listing rate and speed of listing of HCC, SPE, and CIR patients. To the best of our knowledge, this is the first study comparing the outcomes of patients enlisted for SPE to those of HCC and CIR. In several countries worldwide, SPE patients also receive appealed MELD scores in a similar way of HCC patients., Methods: Two cohorts of patients listed for LT in a single institution were evaluated. The first cohort (C1, n=180) included all patients enlisted on August 1st, 2008, and all additional patients listed from this date until July 31st, 2009. The second cohort (C2, n=109) included all patients present on the LT list on October 1st, 2012, and all additional patients listed from this date until May 2014., Results: In both cohorts, HCC patients had a higher chance of receiving a LT than CIR patients (C1HR =2.05, 95%CI=1.54-2.72, P<0.0001; C2HR =3.17, 95%CI =1.83-5.52, P<0.0001). For C1, 1-year waiting list mortality was 21.6% (30.0% for CIR vs 9.5% for HCC vs 7.1% for SPE) (P<0.001). For C2, 1-year waiting list mortality was 13.3% (25.7% for CIR, 8.3% for HCC, and 4.0% for SPE) (P<0.001). Post-transplant survival was similar among the three groups., Conclusion: Compared to CIR, SPE and HCC patients had lower wait list mortality. CIR patients had the highest waitlist mortality and the lowest odd of LT. Current LT allocation system does not allow equitable organ allocation.

Background & Aims: Gaucher disease (GD) is a multisystemic disease. Liver involvement in GD is not well characterised and ranges from hepatomegaly to cirrhosis and hepatocellular carcinoma. We aim to describe, and assess the effect of treatment, on the hepatic phenotype of a cohort of patients with GD types I and II., Methods: Retrospective study based on the review of the medical files of the Gaucher Reference Centre of the Hospital de Clínicas de Porto Alegre, Brazil. Data from all GD types I and III patients seen at the centre since 2003 were analysed. Variables were compared as pre- ("baseline") and post-treatment ("follow-up")., Results: Forty-two patients (types I: 39, III: 3; female: 22; median age: 35 y; enzyme replacement therapy: 37; substrate reduction therapy: 2; non-treated: 3; median time on treatment-MTT: 124 months) were included. Liver enzyme abnormalities, hepatomegaly, and steatosis at baseline were seen in 19/28 (68%), 28/42 (67%), and 3/38 patients (8%), respectively; at follow-up, 21/38 (55%), 15/38 (39%) and 15/38 (39%). MRI iron quantification showed overload in 7/8 patients (treated: 7; MTT: 55 months), being severe in 2/7 (treated: 2/2; MTT: 44.5 months). Eight patients had liver biopsy (treated: 6; MTT: 58 months), with fibrosis in 3 (treated: 1; time on treatment: 108 months) and steatohepatitis in 2 (treated: 2; time on treatment: 69 and 185 months). One patient developed hepatocellular carcinoma., Conclusions: GD is a heterogeneous disease that causes different patterns of liver damage even during treatment. Although treatment improves the hepatocellular damage, it is associated with an increased rate of steatosis. This study highlights the importance of a follow-up of liver integrity in these patients., (© 2020 The Authors.)

Background: Despite being the world's most widely used system for staging and therapeutic guidance in hepatocellular carcinoma (HCC) treatment, the Barcelona clinic liver cancer (BCLC) system has limitations, especially regarding intermediate-grade (BCLC-B) tumors. The recently proposed Hong Kong liver cancer (HKLC) staging system appears useful but requires validation in Western populations., Aim: To evaluate the agreement between BCLC and HKLC staging on the management of HCC in a Western population, estimating the overall patient survival., Methods: This was a retrospective study of HCC patients treated at a university hospital in southern Brazil between 2011 and 2016. Demographic, clinical, and laboratory data were collected. HCC staging was carried out according to the HKLC and BCLC systems to assess treatment agreement. Overall survival was estimated based on the treatment proposed in each system., Results: A total of 519 HCC patients were assessed. Of these, 178 (34.3%) were HKLC-I; 95 (18.3%) HKLC-IIA; 47 (9.1%) HKLC-IIB; 29 (5.6%) HKLC-IIIA; 30 (5.8%) HKLC-IIIB; 75 (14.4%) HKLC-IV; and 65 (12.5%) HKLC-V. According to the BCLC, 25 (4.9%) were BCLC-0; 246 (47.4%) BCLC-A; 107 (20.6%) BCLC-B; 76 (14.6%) BCLC-C; and 65 (12.5%) BCLC-D. The general agreement between the two systems was 80.0% - BCLC-0 and HKLC-I (100%); BCLC-A and HKLC-I/HKLC-II (96.7%); BCLC-B and HKLC-III (46.7%); BCLC-C and HKLC-IV (98.7%); BCLC-D and HKLC-V (41.5%). When sub-classifying BCLC-A, HKLC-IIB, HKLC-IIIA and HKLC-IIIB stages according to the up-to-7 in/out criterion, 13.4, 66.0, 100 and 36.7%, respectively, of the cases were classified as up-to-7 out., Conclusion: In a Western population, the general agreement between the two systems was 80.0%, although in BCLC-B cases the agreement was low, suggesting that some individuals could be candidates for the curative treatment recommended by the HKLC. The authors suggest that the BCLC system should be routinely employed, although for BCLC-B cases it should be associated with the HKLC system., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

A 63-year-old female patient with recent diagnosis of hepatitis C and cirrhosis and no other comorbidities, on no medications, was found to have Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma and began systemic therapy with sorafenib 400mg twice daily. Five days after starting treatment, the patient went to an emergency department with pruritic, target-shaped, erythematous papules compatible with erythema multiforme, painful oral aphthous ulcers, and fever. Sorafenib was suspended and the patient underwent oral corticosteroid treatment for 5 days, showing significant improvement of the lesions. One month after discharge, the patient was reassessed at an outpatient clinic. As she was asymptomatic and had no skin lesions, sorafenib was resumed at a lower dose (200mg daily). Three hours after ingesting a single dose of sorafenib, the patient experienced chills, fever, rash, angioedema and stridor. She immediately sought the emergency department and was diagnosed with anaphylaxis. The patient received intravenous corticosteroid therapy, which improved her respiratory and cutaneous symptoms in 72h. Sorafenib was permanently suspended, and regorafenib could not be prescribed as second-line therapy. This is the first description of anaphylaxis to sorafenib., (Copyright © 2019. Published by Elsevier España, S.L.U.)

Liver and biliary tract diseases are common causes of morbidity and mortality worldwide. Invasive procedures are usually performed in those patients with hepatobiliary diseases for both diagnostic and therapeutic purposes. Defining proper indications and restraints of commonly used techniques is crucial for proper patient selection, maximizing positive results and limiting complications. In 2018, the Brazilian Society of Hepato-logy (SBH) in cooperation with the Brazilian Society of Interventional Radiology and Endovascular surgery (SOBRICE) and the Brazilian Society of Digestive Endoscopy (SOBED) sponsored a joint single-topic meeting on invasive procedures in patients with hepatobiliary diseases. This paper summarizes the proceedings of the aforementioned meeting. It is intended to guide clinicians, gastroenterologists, hepatologists, radiologists, and endoscopists for the proper use of invasive procedures for management of patients with hepatobiliary diseases.

Liver cancer ranks fifth in incidence and fourth in overall cancer-related mortality, with approximately 854,000 new cases and 810,000 deaths per year worldwide. Hepatocellular carcinoma (HCC) accounts for 90% of these cases, and, over time, both the incidence and mortality of this cancer have been rising in many regions. Several staging systems are used to assess the extent of primary tumor, presence of metastasis, and underlying liver disease, and thereby aid in the definition of treatment strategies and prognosis for these patients. The consequence of this heterogeneity in HCC staging is that no consensual definition of advanced disease exists, and there is still ongoing debate on the optimal treatment for these patients. Patients with advanced tumors can be candidates for multiple therapies, ranging from potentially curative options such as transplantation and resection-to locoregional and systemic treatments; these should be evaluated on an individual basis by a multidisciplinary team. This paper provides an overview of treatment options for advanced stage HCC, based on a review of the latest relevant literature and the personal experience of the authors., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare.

Background: Hepatitis C is an important health problem. In Brazil, 1-2 million people are infected. Despite this expressive number, and the availability of very successful treatment, many patients remained undiagnosed mainly because of the asymptomatic nature of the infection., Objectives: To describe epidemiological characteristics of HCV-infected patients seen at referral centers in Brazil, the source of referral, and the time spanned to reach a reference center, in order to improve the identification of undiagnosed patients., Methods: Multicenter observational, cross-sectional study carried out in 15 centers of Brazil, between January/2016 and June/2017. Data of patients with a confirmed diagnosis (anti-HCV and HCV-RNA) were collected by interview using standard questionnaires and by review of charts., Results: Two thousand patients were included; 55.1% were male, mean age 58±11 years. Only 14.9% had higher education and 84.2% received up to five monthly minimum Brazilian wages (approximately US$260.00/month). The time between diagnosis and beginning of follow-up was 22.9 months. The most common reasons for testing were check-up (33.2%) and blood donation (19%). General practitioners diagnosed most of the patients (30.1%). Fibrosis stage was mainly evaluated by liver biopsy (61.5%) and 31.3% of the patients were cirrhotic at diagnosis., Conclusions: This multicenter Brazilian study showed that the mean time to reach a referral center for treatment was almost two years. Primary care physicians diagnoses most hepatitis C cases in the country. Population campaigns and medical education should be encouraged to intensify screening of asymptomatic individuals, considering the efficiency of check-ups in identifying new patients., (Copyright © 2019 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Aim: Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an openlabel multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection., Material and Methods: All patients received coformulated OBV/PTV/r daily + DSV twice daily (3-DAA). GT1a-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/RBV nonresponders with cirrhosis who were treated for 24 weeks. GT1b-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA &lt; 15 IU/mL) at post-treatment Week 12 (SVR12)., Results: The study enrolled 222 patients, 214 achieved an SVR12 (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR12 was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event., Discussion: The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).

Background: Infection by hepatitis C virus is one of the leading causes of chronic hepatitis C and cause severe burden for patients, families and the health care system., Objective: The aims of this research were to assess the severity of liver fibrosis, comorbidities and complications of hepatitis C virus; to examine health-related quality of life (HRQoL), productivity loss and resource use and costs in a sample of Brazilian chronic hepatitis C, genotype 1, patients., Methods: This was a cross-sectional multicenter study performed in genotype-1 chronic hepatitis C patients to assess disease burden in the Brazilian public health care system between November 2014 and March 2015. Patients were submitted to a liver transient elastography (FibroScan) to assess liver fibrosis and answered an interview composed by a questionnaire specifically developed for the study and three standardized questionnaires: EQ-5D-3L, HCV-PRO and WPAI:HepC., Results: There were 313 subjects enrolled, with predominance of women (50.8%), caucasian/white (55.9%) and employed individuals (39.9%). Mean age was 56 (SD=10.4) years old. Moreover, 42.8% of patients who underwent FibroScan were cirrhotic; the most frequent comorbidity was cardiovascular disease (62.6%) and the most frequent complication was esophageal varices (54.5%). The results also showed that "pain and discomfort" was the most affected HRQoL dimension (55.0% of patients reported some problems) and that the mean HCV-PRO overall score was 69.1 (SD=24.2). Regarding productivity loss, the most affected WPAI:HepC component was daily activity (23.5%) and among employed patients, presenteeism was more frequent than absenteeism (18.5% vs 6.5%). The direct medical costs in this chronic hepatitis C sample was 12,305.72USD per patient in the 2 years study period; drug treatment costs represented 95.9% of this total., Conclusion: This study showed that most patients are cirrhotic, present high prevalence of cardiometabolic diseases and esophageal varices, reduced HRQoL mainly in terms of pain/discomfort, and work productivity impairment, especially presenteeism. Additionally, we demonstrated that hepatitis C virus imposes an economic burden on Brazilian Health Care System and that most of this cost is due to drug treatment.

Introduction: Occidental diet and metabolic profile seems to increase hepatic fibrosis (HF) in patients with chronic hepatitis C virus (HCV) infection, but there is scarce information about the diet components and their role in this setting., Objectives: This study aims to evaluate the dietary intake, metabolic profile, presence of metabolic syndrome (MetS) and cardiovascular risk in patients with chronic HCV infection according to the presence of fibrosis., Methods: Cross-sectional study which 58 patients with HCV infection without active antiviral therapy and non-cirrhotic were assessed. All patients were subjected to clinical, laboratorial and dietary evaluation, and classified according to the METAVIR score. Patients were divided as the presence of hepatic fibrosis., Results: In this sample, fifty-five percent of patients were females, the average age was 51.6 ± 9.7 years, and 79.3% were carriers of HCV genotype 1. Patients with HF presented higher energy, and fat intake as well as higher glycemic load of meals in comparison to those without HF. Patients with HF presented higher systolic and diastolic arterial pressure and higher levels of insulin., Conclusions: In conclusion, patients with HF had higher total daily energy and total fat intakes, and worse metabolic profile, characterized by a higher insulin resistance and blood pressure.

Vitamin D deficiency is prevalent in liver disease and vitamin D has been shown to decrease hepatic fibrosis through an anti-TGFβ-1/SMAD3 effect mediated by the vitamin D receptor. Thus, we hypothesized that genetic variants involved in vitamin D metabolism and/or VDR/TGFβ-1/SMAD3 interaction could impact on the progression of chronic HCV. We obtained or imputed genotypes for 40 single nucleotide polymorphisms (SNPs) located in genes implicated in vitamin D metabolism from the HALT-C cohort via dbGaP. The HALT-C study followed 692 chronic HCV patients over 4 years, evaluating clinical outcomes including worsening of fibrosis, hepatic decompensation (gastric/esophageal bleeding, CTP>7, ascites, spontaneous bacterial peritonitis and encephalopathy), development of hepatocellular carcinoma, and liver death. We tested the selected SNPs for association with these outcomes in 681 HALT-C subjects. Eleven SNPs presented tendency towards significance (P<0.05): four SNPs in DHCR7 related to with hepatic decompensation (rs4944957, rs12800438, rs3829251 and rs4945008); two in GC to worsening of fibrosis and liver death (rs7041 and rs222020); two in CYP2R1 to ascites and hepatocellular carcinoma (rs7116978 and rs1562902); two in VDR to gastric/esophageal bleeding and hepatocellular carcinoma (rs4516035 and rs2239186); and one in SMAD3 to worsening of fibrosis and encephalopathy (rs2118610). Only rs1800469 in TGFB1 was statistically associated with hepatic decompensation after Bonferroni's correction (P<0.00125). In conclusion, rs1800469 in TGFB1 was associated to hepatic decompensation in chronic hepatitis C, while the other 11 described polymorphisms must be evaluated in a larger cohort to determine the possible role of vitamin D in hepatitis C.

Introduction and Aim: Vitamin D has been associated with chronic liver diseases and low vitamin levels may contribute to progression of chronic hepatitis C. The aim of this study was to evaluate the influence of vitamin D serum levels and GC gene polymorphisms in the severity of liver fibrosis in patients with chronic hepatitis C genotype 1., Material and Methods: Cross-sectional study that enrolled 132 adult patients with chronic hepatitis C genotype 1 attended at the outpatient Clinic of Gastroenterology Division at Hospital de Clínicas de Porto Alegre. At the time of enrollment patients had a blood withdraw for serum 25(OH)D determination and genotypic analysis of rs7041 and rs4588 polymorphisms in GC gene. None/mild fibrosis was considered as METAVIR F0, F1 and F2 and severe fibrosis as METAVIR F3 and F4., Results: Median 25(OH)D levels in the sample were 19.9 ng/mL (P25-P75: 14.0-29.4). Fifty percent of patients presented vitamin D deficiency (< 20 ng/mL). In stepwise multiple linear regression the variables associated with 25(OH)D levels were blood withdrawn in Winter/spring season, the haplotypes AT/AT + AG/AT of rs7041 and rs4588 and female sex. For evaluation of severe fibrosis, variables associated in logistic regression were age, vitamin D severe deficiency (< 10 ng/mL), glucose levels, BMI and platelets count., Conclusions: Vitamin D levels are associated with severity of liver fibrosis in chronic hepatitis C genotype 1 patients. Although the rs7041 and rs4588 GC polymorphisms are strong predictors of vitamin D levels, they do not play a direct role in liver fibrosis.

Background: Reliable measurement of basal energy expenditure (BEE) in liver transplant (LT) recipients is necessary for adapting energy requirements, improving nutritional status and preventing weight gain. Indirect calorimetry (IC) is the gold standard for measuring BEE. However, BEE may be estimated through alternative methods, including electrical bioimpedance (BI), Harris-Benedict Equation (HBE), and Mifflin-St. Jeor Equation (MSJ) that carry easier applicability and lower cost., Aim: To determine which of the three alternative methods for BEE estimation (HBE, BI and MSJ) would provide most reliable BEE estimation in LT recipients., Methods: Prospective cross-sectional study including dyslipidemic LT recipients in follow-up at a 735-bed tertiary referral university hospital. Comparisons of BEE measured through IC to BEE estimated through each of the three alternative methods (HBE, BI and MSJ) were performed using Bland-Altman method and Wilcoxon Rank Sum test., Results: Forty-five patients were included, aged 58±10 years. BEE measured using IC was 1664±319 kcal for males, and 1409±221 kcal for females. Average difference between BEE measured by IC (1534±300 kcal) and BI (1584±377 kcal) was +50 kcal (p=0.0384). Average difference between the BEE measured using IC (1534±300 kcal) and MSJ (1479.6±375 kcal) was -55 kcal (p=0.16). Average difference between BEE values measured by IC (1534±300 kcal) and HBE (1521±283 kcal) was -13 kcal (p=0.326). Difference between BEE estimated through IC and HBE was less than 100 kcal for 39 of all 43patients., Conclusions: Among the three alternative methods, HBE was the most reliable for estimating BEE in LT recipients., Competing Interests: none

Background: Topical hypothermia (TH) and ischemic preconditioning (IPC) are used to decrease I/R injury. The efficacy of isolated or combined use of TH and IPC in the liver regarding inflammation and cytoprotection in early ischemia/reperfusion (I/R) injury needs to be evaluated., Material and Methods: Wistar rats underwent 70% liver ischemia for 90 min followed by 120 min of reperfusion. Livers of animals allocated in the sham, normothermic ischemia (NI), IPC, TH, and TH+IPC groups were collected for molecular analyses by ELISA and Western blot, aiming to compare proinflammatory, anti-inflammatory, and antioxidant profiles., Results: Compared with NI, TH presented decreased tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-12 concentrations and increased IL-10 levels. TH animals displayed lower inducible nitric oxide synthase (iNOS) and higher endothelial nitric oxide synthase (eNOS) expressions. NAD(P)H-quinone oxidoreductase-1(NQO1) expression was also lower with TH. Isolated IPC and NI were similar regarding all these markers. TH+IPC was associated with decreased IL-12 concentration and reduced iNOS and NQO1 expressions, similarly to isolated TH. Expression of Kelch-like ECH-associated protein (Keap)-1 was increased and expression of nuclear and cytosolic nuclear erythroid 2-related factor 2 (Nrf2) was decreased with TH+IPC vs. NI., Conclusion: TH was the most effective method of protection against early I/R injury. Isolated IPC entailed triggering of second-line antioxidant defense enzymes. Combined TH+IPC seemed to confer no additional advantage over isolated TH in relation to the inflammatory process, but had the advantage of completely avoid second-line antioxidant defense enzymes.

Background: Hepatitis C is a liver disease that causes significant changes in metabolism, and also has an impact on nutritional status., Objective: To evaluate the nutritional status and cardiovascular risk in patients with chronic hepatitis C., Methods: This cross-sectional study investigated 58 patients with chronic hepatitis C, non-cirrhotic and were not under active pharmacological treatment. Patients with significant alcohol consumption (greater than 10 g ethanol/day) were excluded. Patients underwent nutritional assessment through anthropometric measurements and functional assessment using hand grip strength by dynamometry. The physical activity was assessed using the International Physical Activity Questionnaire. Patients also underwent clinical and laboratory evaluation. Cardiovascular risk was calculated by the Framingham score., Results: The mean age of patients was 51.6±9.7 years, 55.2% were female, and 79.3% had genotype 1. The most prevalent degree of fibrosis was F1 (37.9%) followed by F2 (27.6%) and F3 (1.7%). The prevalence of overweight/obesity considering the body mass index was 70.7%. However, 57.7% of men and 68.8% of women were considered malnourished according to hand grip strength. These patients also had waist circumference (93.5±10.7 cm) and neck circumference (37.0±3.6 cm) high. Almost 60% of patients were considered sedentary or irregularly active. In relation to cardiovascular risk, 50% of patients had high risk of suffering a cardiovascular event within 10 years., Conclusion: Although most patients with hepatitis C presented overweight, associated with high cardiovascular risk, they also have reduced functional capacity, indicative of protein-caloric commitment. Therefore, body mass index can not be considered the only method of assessment for nutritional diagnosis of patients with liver disease. Adopting methods such as hand grip strength can be important for a better understanding of nutritional status of these patients.

Background: The hepatitis C virus is one of the main causes of liver disease worldwide and may develop nutritional deficiencies., Objective: The objective of this study was to assess and compare different nutritional status methods of adult patients with chronic hepatitis C virus, and to describe inadequacies in dietary intake., Methods: A cross-sectional study was conducted with adult outpatients with hepatitis C virus at a Brazilian hospital. Nutritional assessment included the 24-hour dietary recall, anthropometry (body weight, height, body mass index, triceps skinfold, mid-upper arm circumference, mid-arm muscle circumference, mid-upper arm muscle area, adductor policis muscle), Subjective Global Assessment, Royal Free Hospital Global Assessment and handgrip strength., Results: A total of 94 outpatients (ages 30 to 76 years), was included, 46 were men. The prevalence of malnutrition as measured by the different methods was 6.4% (body mass index); 60.6% (handgrip strength), and 53.2% (Royal Free Hospital Global Assessment). There was correlation between mid-upper arm circumference and mid-arm muscle circumference (r=0.821), mid-upper arm circumference and triceps skinfold (r=0.575) and mid-upper arm circumference and mid-upper arm muscle area (r=0.781). Energy and protein intakes were below recommended levels in 49 (52.1%) and 44 (46.8%) of patients, respectively. Inadequate calcium, potassium, zinc and vitamin C intakes occurred in 92.6%, 97.9%, 63.8% and 60.6% of patients. There was an association between dietary energy and protein intake with Royal Free Hospital Global Assessment (P<0.001) and a tendency for them to be associated with handgrip strength (P=0.076 and P=0.054)., Conclusion: Malnutrition is frequently in hepatitis C virus patients. They have high prevalence of inadequate energy, protein and micronutrients intake, even in the absence of cirrhosis.