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Background: Hepatocellular carcinoma (HCC) is a prevalent tumor with high mortality rates. Computed tomography (CT) is crucial in the non-invasive diagnosis of HCC. Recent advancements in artificial intelligence (AI) have shown significant potential in medical imaging analysis. However, developing these AI algorithms is hindered by the scarcity of comprehensive, publicly available liver imaging datasets., Objectives: This study aims to detail the tools, data organization, and database structuring used in creating HepatIA, a medical imaging annotation platform and database at a Brazilian tertiary teaching hospital. HepatIA supports liver disease AI research at the institution., Material and Methods: The authors collected baseline characteristics and CT scans of 656 patients from 2008 to 2021. The database, designed using PostgreSQL and implemented with Django and Vue.js, includes 692 CT volumes from a four-phase abdominal CT protocol. Radiologists made segmentation annotations using the OHIF medical image viewer, incorporating MONAI Label for pre-annotation segmentation models. The annotation process included detailed descriptions of liver morphology and nodule characteristics., Results: The HepatIA database currently includes healthy individuals and those with liver diseases such as HCC and cirrhosis. The database dashboard facilitates user interaction with intuitive plots and histograms. Key patient demographics include 64% males and an average age of 56.89 years. The database supports various filters for detailed searches, enhancing research capabilities., Conclusion: A comprehensive data structure was successfully created and integrated with the IT systems of a teaching hospital, enabling research on deep learning algorithms applied to abdominal CT scans for investigating hepatic lesions such as HCC., Competing Interests: Declaration of competing interest The authors B.A.R., L.G.R.V., and A.C.M.C. are co-founders of Machiron SA. FMUSP, HCFMUSP, and Machiron SA. have established a collaborative partnership, with the terms of this arrangement having been reviewed and approved by the University of São Paulo in accordance with its conflict-of-interest policies. Meanwhile, L.C.F., J.M.C.F., L.S.L.N., M.R.M.S.F., C.C.L., C.H.N., G.G.C., F.J.C., and S.K.O. have declared no competing interests., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: The primary objective was to evaluate Liver-Related Events (LREs), including hepatic decompensation (ascites, hemorrhagic varices and encephalopathy) and Hepatocellular Carcinoma (HCC), as well as changes in liver stiffness during the follow-up period among patients who achieved a Sustained Virological Response (SVR) after treatment for chronic Hepatitis C Virus (HCV) infection., Methods: A total of 218 patients with HCV were treated, and those who achieved an SVR were followed up for 3-years. Transient Elastography (TE) using FibroScan® was performed at various time points: before treatment, at the end of treatment, at 6-months post-treatment, at 1-year post-treatment, at 2-years post-treatment, and at 3-years post-treatment., Results: At 6-months post-treatment, a Liver Stiffness Measurement (LSM) cutoff of > 19 KPa was identified, leading to a 14.5-fold increase in the hazard of negative outcomes, including decompensation and/or HCC. The analysis of relative changes in liver stiffness between pre-treatment and 6-months posttreatment revealed that a reduction in LSM of -10 % was associated with a -12 % decrease in the hazard of decompensation and/or HCC, with this trend continuing as the LSM reduction reached -40 %, resulting in a -41 % hazard of decompensation and/or HCC. Conversely, an increase in the relative change during this period, such as an LSM increase of +10 %, led to a + 14 % increase in the hazard of decompensation. In cases where this relative change in LSM was +50 %, the hazard of decompensation increased to +92., Conclusion: Transient elastography using FibroScan® can be a good tool for monitoring HCV patients with SVR after treatment to predict LREs in the long term., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: The aim of the present study was to evaluate the clinical features, Hepatocellular Carcinoma (HCC) screening, treatment modalities, and Overall Survival (OS) in a series of Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma (NAFLD-HCC) Brazilian patients., Methods: This was a cross-sectional study at the Instituto do Cancer do Estado de São Paulo, at the Faculdade de Medicina da Universidade de São Paulo with the approval of the local research ethics committee. NAFLD patients with HCC diagnosed, from May 2010 to May 2019, were included., Results: A total of 131 patients were included. Risk factors for NAFLD were present in 94.7% of the patients. Only 29% of patients were in the HCC screening program before diagnosis. HCC treatment was performed in 84.7% of patients. Cumulative survival at the end of the first year was 72%, second-year 52%, and fifth-year 32%. HCC screening before diagnosis was not significantly associated with higher cumulative survival. The independent factors associated with shorter general survival were BCLC C-D, p < 0.001, and the size of the largest nodule > 42 mm, p = 0.039., Conclusions: Although the efficacy of screening in our population regarding overall survival was hampered due to the sample size (29% had screening), BCLC stages C‒D and the size of the largest nodule larger than 42 mm were identified as independent factors of worse prognosis., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: To evaluate results of patients undergoing liver resection in a single center over the past two decades with a particular look at Colorectal Liver Metastasis (CRLM) and Hepatocellular Carcinoma (HCC)., Method: Patients were divided into two eras, from 2000 to 2010 (Era 1) and 2011 to 2020 (Era 2). The most frequent diagnosis was CRLM and HCC, with 738 (52.4%) and 227 (16.1%) cases respectively. An evaluation of all liver resection cases and a subgroup analysis of both CRLM and HCC were performed. Preoperative and per operative variables and long-term outcomes were evaluated., Results: 1409 liver resections were performed. In Era 2 the authors observed higher BMI, more: minimally invasive surgeries, Pringle maneuvers, and minor liver resections; and less transfusion, less ICU necessity, and shorter length of hospital stay. Severe complications were observed in 14.7% of patients, and 90-day mortality was 4.2%. Morbidity and mortality between eras were not different. From 738 CRLM resections, in Era 2 there were significantly more patients submitted to neoadjuvant chemotherapy, bilateral metastases, and smaller sizes with significantly less transfusion, the necessity of ICU, and shorter length of hospital stay. More pedicle clamping, minimally invasive surgeries, and minor resections were also observed. From 227 HCC resections, in Era 2 significantly more minimally invasive surgeries, fewer transfusions, less necessity of ICU, and shorter length of hospital stay were observed. OS was not different between eras for CRLM and HCC., Conclusions: Surgical resection in a multidisciplinary environment remains the cornerstone for the curative treatment of primary and metastatic liver tumors., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: Co-infection with hepatitis A or B viruses may aggravate liver injury in patients infected with hepatitis C virus (HCV). However, few studies have assessed co-infection with hepatitis E virus (HEV) and HCV. Therefore, this study aimed to assess the prevalence and impact of HEV infection among Brazilian patients with chronic HCV infection., Methods: This observational study included adult patients with chronic HCV infection who were naive to antiviral therapy from January 2013 to March 2016. A total of 181 patients were enrolled, and HEV serology and PCR were performed for all patients., Results: Seropositivity for anti-HEV IgG was detected in 22 (12.0%) patients and anti-HEV immunoglobulin M in 3 (1.6%). HEV RNA showed inconclusive results in nine (4.9%) patients and was undetectable in the remaining patients. HEV serology positive patients had more severe liver disease, characterized by liver fibrosis ≥3 versus ≤2 (p<0.001), Aspartate Aminotransferase-to-Platelet Ratio Index of ≥1.45 (p=0.003), and Fibrosis-4 score of ≥3.25 (p=0.001). Additionally, the odds of HEV-positive patients developing diabetes mellitus were 3.65 (95% CI 1.40-9.52) times the corresponding odds of HEV-negative patients. A case-control-based histological analysis (n=11 HEV-HCV-positive patients and n=22 HCV-positive patients) showed no significant differences between the groups., Conclusions: This prevalence is higher than that reported in previous studies of the general population in Brazil. Thus, HEV infection may influence the severity of liver disease and may represent an additional risk of developing diabetes mellitus in patients with HCV infection.

Objectives: Despite higher rates of sustained virologic response (SVR), important concerns remain when patients with decompensated cirrhosis due to hepatitis C virus (HCV) are treated with direct-acting antiviral agents (DAA). Questions include efficacy, safety, and the magnitude of liver function improvement. Here, we aimed to evaluate HCV treatment data in this specific population in Brazil., Methods: We included 85 patients with decompensated cirrhosis submitted to HCV therapy with DAA followed at two academic tertiary centers in the southeastern region of Brazil., Results: Seventy-nine patients (92.9%) were Child-Pugh (CP) score B, and six (7.1%) were CP score C. The mean MELD score was 12.86. The most common treatment was sofosbuvir plus daclatasvir±ribavirin for 24 weeks. The overall intention-to-treat (ITT) SVR rate was 87.4% (74/85) and modified-ITT 96.1% (74/77). ITT SVR was associated with lower baseline INR values (p=0.029). Adverse events (AE) occurred in 57.9% (44/76) of patients. Serious AE were reported in 12.8% (10/78), and were related to the presence of hepatic encephalopathy (p=0.027). SVR was associated with improvement in CP (p<0.0001) and MELD scores (p=0.021). Among baseline CP score B patients with SVR, 46% (29/63) regressed to CP score A. Ascites was independently associated with no improvement in liver function in patients who achieved SVR (p=0.001; OR:39.285; 95% CI:4.301-258.832)., Conclusions: Patients with decompensated HCV cirrhosis showed a high SVR rate with interferon-free therapy. Early liver function improvement occurred after successful HCV eradication. However, long-term follow-up of these patients after SVR remains strongly advised.

Objective: The folate pathway is involved in hepatic carcinogenesis and angiogenesis. Polymorphisms in genes related to such processes, including methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF)] may play an important role in the development of hepatocellular carcinoma (HCC). The objective of this study was to evaluate MTHFR and VEGF polymorphisms in Brazilian patients with hepatitis C virus (HCV)-related HCC., Methods: A total of 119 patients diagnosed with confirmed HCC and HCV were included in the study. SNP genotyping assays were performed using real-time PCR. VEGFA (rs2010963, rs3025039, and rs833061) and MTHFRC677T (rs1801133, rs1801131) polymorphisms were evaluated., Results: The C alleles of MTHFR (rs1801131) and VEGF (rs2010963) were associated with protection against the development of multinodular HCC, while the T allele of MTHFR (rs1801133) was associated with a higher risk of multinodular presentation [p=0.04 OR 1.835 CI (1.022-3.297)]. Multivariate analysis revealed that the GG/GC genotypes of VEGF rs2010963 were independently associated with multinodular tumors at diagnosis (p=0.013; OR 4.78 CI (1.38-16.67)]., Conclusion: Our results suggest that these polymorphisms may increase the risk of rapid tumor progression in patients with HCV infection. This subgroup of patients with HCC and who present polymorphism is more likely to be diagnosed with multinodular disease and not be amenable to receiving curative treatments. These data must be validated in larger cohorts, and the screening intervals can be customized based on genetic history.

Background and Aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies., Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays., Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved., Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature., Lay Summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC., Competing Interests: Conflict of interest J.M.L. receives research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Leerink Swann LLC, Fortress Biotech, Nucleix, Can-Fite Biopharma, Sirtex, Mina Alpha Ltd and AstraZeneca. S.L.F consults for the following companies: 89 Bio, Amgen, Axcella Health, Blade Therapeutics, Bristol Myers Squibb, Can-Fite Biopharma, ChemomAb, Escient Pharmaceuticals, Forbion, Foresite laboratories, Galmed, Gordian Biotechnology, Glycotest, Glympse Bio, Hepgene, In sitro, Morphic Therapeutics, North Sea Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Scholar Rock Surrozen. He has stock options in the following companies: Blade Therapeutics, Escient, Galectin, Galmed, Genfit, Glympse, Hepgene, Lifemax, Metacrine, Morphic Therapeutics, Nimbus, North Sea Therapeutics, Scholar Rock, Surrozen. He receives research support from Morphic Therapeutics, Novo Nordisk, and Galmed, and has an SBIR grant with Abalone Bio. A.L. is a consultant for Neuwave and Histosonics. C.P.M.S.O. consults for Bayer, Novartis, Novonordisk, Allergan, Pfizer, Roche and Zambon. P.S. is receiving research grants from BMS, Roche, Incyte, Chugai and consulting fees from BMS, MSD, Incyte, Janssen, Roche, AstraZeneca and Amgen. H.W., P.T., and A.V.U. are or were salaried employees of Sema4 at the time of the study. H.W., P.T., and A.V.U. hold Sema4 stock options. B.M. received consultancy fees from Bayer-Shering Pharma, and speaker fees from Eisai and MSD. The rest of authors have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: A good health care does not only depend on good medical practice, but also needs great management of its resources, which are generally short. In this sense, PROAHSA has been training new health managers since 1972. With the arrival of the COVID-19 pandemic, it was clear that medicine will go through a new phase, where telehealth will be present in this "Improved Normal". This report is about how a pilot teleconsultation study was carried out for HCFMUSP patients through the Scrum-like framework. It is to deploy a pilot of remote assistance involving a doctor and a patient in the Ambulatory of Hepatology and Liver Transplantation of HCFMUSP., Methods: We applied the Scrum-like framework to carry out this work with an interdisciplinary multifunctionality team., Results: A full telemedicine service flow was implemented within eight weeks using existing infrastructure and resources implementing the Scrum methodology. Twenty-three teleconsultations were scheduled and eight guides built., Conclusion: Scrum framework has a great potential to improve the training of students and to conclude pilot projects.

Objectives: To determine the frequency of the antineutrophil cytoplasmic antibodies (ANCA), antiproteinase-3 and antimyeloperoxidase, in primary sclerosing cholangitis (PSC) with or without inflammatory bowel disease (IBD+ or IBD-) and in different types of autoimmune hepatitis (AIH). Additionally, to verify the agreement between ANCA patterns by indirect immunofluorescence and their antigenic specificities by ELISA., Methods: For this study, 249 patients were enrolled (42 PSC/IBD+; 33 PSC/IBD-; 31 AIH type-1; 30 AIH type-2; 31 AIH type-3; 52 primary biliary cirrhosis; 30 healthy controls) whose serum samples were tested for ANCA autoantibodies., Results: There were fewer female subjects in the PSC/IBD- group (p=0.034). Atypical perinuclear-ANCA was detected more frequently in PSC/IBD+ patients than in PSC/IBD- patients (p=0.005), and was significantly more frequent in type-1 (p<0.001) and type-3 AIH (p=0.012) than in type-2 AIH. Proteinase-3-ANCA was detected in 25 samples (only one with cytoplasmic-ANCA pattern), and more frequently in PSC/IBD+ than in PSC/IBD- patients (p=0.025). Myeloperoxidase-ANCA was identified in eight samples (none with the perinuclear-ANCA pattern). Among the 62 reactive samples for atypical perinuclear-ANCA, 13 had antigenic specific reactions for proteinase-3 and myeloperoxidase., Conclusions: PSC/IBD+ differed from PSC/IBD- in terms of sex and proteinase 3-ANCA and atypical perinuclear-ANCA reactivity, the latter of which was more frequently detected in type-1 and type-3 AIH than in type-2 AIH. There was no agreement between ANCA patterns and antigenic specificities in IBD and autoimmune liver diseases, which reinforces the need for proteinase-3 and myeloperoxidase antibody testing.

Non-tumoral portal vein thrombosis (PVT) is associated with higher morbidity and mortality in liver transplantation (LT). In this study, we aimed to evaluate the impact of PVT in LT outcomes and analyze the types of surgical techniques used for dealing with PVT during LT. A systematic review was conducted in Cochrane, MEDLINE, and EMBASE databases, selecting articles from January 1990 to December 2019. The MESH-terms used were ("Portal Vein"[Mesh] AND "Thrombosis"[Mesh] NOT "Neoplasms"[Mesh]) AND ("Liver Transplantation"[Mesh]). The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendation was used, and meta-analysis was performed with Review Manager Version 5.3 software. A total of 1,638 articles were initially found: 488 in PubMed, 289 in Cochrane Library, and 861 in EMBASE, from which 27 were eventually selected for the meta-analysis. Surgery time of LT in patients with PVT was longer than in patients without LT (p<0.0001). Intraoperative red blood cell (p<0.00001), fresh frozen plasma (p=0.01), and platelets (p=0.03) transfusions during LT were higher in patients with PVT. One-year (odds ratio [OR] 1.17; p=0.002) and 5-year (OR 1.12; p=0.01) patient survival after LT was worse in the PVT group. Total occlusive PVT presented higher mortality (OR 3.70; p=0.00009) and rethrombosis rates (OR 3.47 [1.18-10.21]; p=0.02). PVT Yerdel III/IV classification exhibited worse 1-year [2.04 (1.21-3.42); p=0.007] and 5-year [0.98 (0.59-1.62); p=0.93] patient survival. Thrombectomy with primary anastomosis was associated with better outcomes. LT in patients with non-tumoral PVT demands more surgical time, needs more intraoperative transfusion, and presents worse 1- and 5-year patient survival. Total occlusive PVT and Yerdel III/IV PVT classification were associated with higher mortality. (PROSPERO, registration number: CRD42020132915).

Background: Thrombocytopenia is a possible risk factor for bleeding after band ligation of esophageal varices. However, elevated von Willebrand factor (VWF) in cirrhosis improves platelet function and could decrease this risk. Our objective was to assess platelet function in patients with cirrhosis undergoing esophageal variceal ligation (EVL)., Methods: The assessment consisted of platelet count, antigen and activity of VWF and VWF-cleaving protease ADAMTS-13 activity, and a platelet adhesion and aggregation test simulating vascular flow in vivo (Impact-R Ⓡ ) prior to EVL., Results: Totally 111 patients were divided into three groups according to platelet count: (1) < 50 × 10 9 /L (n = 38, 34.2%); (2) 50 × 10 9 /L to 100 × 10 9 /L (n = 47, 42.3%); and (3) > 100 × 10 9 /L (n = 26, 23.4%). No statistically significant difference was found in the aggregate size of platelets [group 1: 41.0 (31.8-67.3) µm 2 ; group 2: 47.0 (33.8-71.3) µm 2 ; and group 3: 47.0 (34.0-66.0) µm 2 ; P = 0.60] and no significant correlation was found between aggregate size and platelet count (Spearman r = 0.07; P = 0.47). Surface coverage was 4.1% (2.8%-6.7%), 8.5% (4.0%-10.0%), and 9.0% (7.1%-12.0%) (P < 0.001) in groups 1, 2 and 3, respectively and correlated with platelet count (Spearman r = 0.39; P < 0.0001). There was no significant difference between groups in VWF or ADAMTS-13. Post-EVL bleeding occurred in six (5.4%) patients (n = 2 in group 1, n = 1 in group 2, and n = 3 in group 3; P = 0.32). Patients with bleeding had higher MELD scores [15.0 (11.3-20.3) versus 12.0 (10.0-15.0); P = 0.025], but no difference was demonstrated for platelet function parameters., Conclusion: Platelet function is preserved even in the presence of thrombocytopenia, including in the patients with post-EVL bleeding., (Copyright © 2020 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

More than 18 million people in 188 countries have been diagnosed as having coronavirus disease (COVID-19), and COVID-19 has been responsible for more than 600,000 deaths worldwide. Brazil is now the second most affected country globally. Faced with this scenario, various public health measures and changes in the daily routines of hospitals were implemented to stop the pandemic. Patients with hepatocellular carcinoma (HCC) are at an increased risk for severe COVID-19 as they present with two major diseases: cancer and concomitant chronic liver disease. The COVID-19 pandemic can significantly impact the management of HCC patients from diagnosis to treatment strategies. These patients need special attention and assistance at this time, especially since treatment for tumors cannot be delayed in most cases. The aim of this guideline was to standardize the management of HCC patients during the COVID-19 pandemic. This document was developed, on the basis of the best evidence available, by a multidisciplinary team from Instituto do Câncer do Estado de São Paulo (ICESP), and Instituto Central of the Hospital das Clínicas da Universidade de São Paulo (HC-FMUSP), which are members of the São Paulo Clínicas Liver Cancer Group.

Objectives: Brazil has rapidly developed the second-highest number of COVID-19 cases in the world. As such, proper symptom identification, including gastrointestinal manifestations, and relationship to health outcomes remains key. We aimed to assess the prevalence and impact of gastrointestinal symptoms associated with COVID-19 in a large quaternary referral center in South America., Methods: This was a single-center cohort study in a COVID-19 specific hospital in São Paulo, Brazil. Consecutive adult patients with laboratory confirmed SARS-CoV-2 were included. Baseline patient history, presenting symptoms, laboratory results, and clinically relevant outcomes were recorded. Regression analyses were performed to determine significant predictors of the gastrointestinal manifestations of COVID-19 and hospitalization outcomes., Results: Four-hundred patients with COVID-19 were included. Of these, 33.25% of patients reported ≥1 gastrointestinal symptom. Diarrhea was the most common gastrointestinal symptom (17.25%). Patients with gastrointestinal symptoms had higher rates of concomitant constitutional symptoms, notably fatigue and myalgia (p<0.05). Gastrointestinal symptoms were also more prevalent among patients on chronic immunosuppressants, ACE/ARB medications, and patient with chronic kidney disease (p<0.05). Laboratory results, length of hospitalization, ICU admission, ICU length of stay, need for mechanical ventilation, vasopressor support, and in-hospital mortality did not differ based upon gastrointestinal symptoms (p>0.05). Regression analyses showed older age [OR 1.04 (95% CI, 1.02-1.06)], male gender [OR 1.94 (95% CI, 1.12-3.36)], and immunosuppression [OR 2.60 (95% CI, 1.20-5.63)], were associated with increased mortality., Conclusion: Based upon this Brazilian study, gastrointestinal manifestations of COVID-19 are common but do not appear to impact clinically relevant hospitalization outcomes including the need for ICU admission, mechanical ventilation, or mortality.

Background and Aims: Hepatic epithelioid hemangioendothelioma is an ultra-rare hepatic vascular tumor, diagnosed more frequently in females. The knowledge about this tumor derives mainly from small case series with sub-optimal treatment outcomes. The aim of this study is to identify the clinical and radiological issues helpful to develop an international prospective registry., Methods: We conducted an international multicentric and retrospective study of patients with hepatic hemangioendothelioma. The clinical, pathological and radiological images collected during follow-up were reviewed. Central radiological revision was performed and 3 patterns of contrast were defined., Results: Between 1994 and 2016, 27 patients with hepatic hemangioendothelioma were identified in three institutions but the final diagnosis was hepatic angiosarcoma in one. The majority were females, median age was 38.7-years and 17 patients were asymptomatic at diagnosis. No patient had Two out of ten (20%) patients had surgical specimens with positive macro-vascular invasion and 50% had extrahepatic disease, and the most frequent pattern was the progressive-central-contrast-uptake. After a median follow-up of 6.7-years, the 5- and 10-year survival rates are 91.5% and 51.9%, respectively., Conclusions: This multicentric study shows the heterogeneous profile of patients with hepatic hemangioendothelioma, reflecting the need to establish a reference network in order to better characterize these patients and ultimately develop a personalized treatment strategy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: The efficacy of fresh frozen plasma (FFP) transfusion in enhancing thrombin generation in patients with cirrhosis and impaired conventional coagulation tests has not been sufficiently explored. Thus, we aimed to assess the effect of FFP transfusion on thrombin generation in these patients., Methods: Fifty-three consecutive patients receiving a standard dose of FFP to treat bleeding and/or before invasive procedures - if international normalized ratio (INR)/prothrombin time (PT) ratio were ≥1.5 - were prospectively enrolled. The primary endpoint was the amelioration of endogenous thrombin potential (ETP) with thrombomodulin (ETP-TM) after transfusion, which corresponds to the total amount of generated thrombin. INR/PT ratio and activated partial thromboplastin time (aPTT) were also assessed before and after transfusion., Results: FFP enhanced ETP-TM by 5.7%, from 973 (731-1,258) to 1,028 (885-1,343 nM × min; p = 0.019). Before transfusion, evidence of normal or high ETP-TM was found in 94% of patients, even in those with bacterial infections. Only 1 (1.9%) patient had ETP-TM values reverting to the normal range after transfusion. Notably, no patients with low ETP-TM had bleeding. The median decrease in ETP-TM was 8.3% and the mean was 12.8% in 18 (34%) patients after transfusion (from 1,225 [1,071-1,537] to 1,124 [812-1,370] nM × min; p ≤0.0001). Similar responses to FFP transfusion were observed in patients with compensated and acute decompensated cirrhosis, acute-on-chronic liver failure, infection or shock. FFP significantly ameliorated INR and aPTT values (p <0.0001), but in a minority of patients the values were reduced to less than the cut-off point of 1.5., Conclusions: FFP transfusion enhanced thrombin generation and ameliorated conventional coagulation tests to normal values in a limited number of patients, and slightly decreased thrombin generation in 34% of cases., Lay Summary: Transfusion of fresh frozen plasma in patients with cirrhosis only slightly improves coagulation test values in a limited number of patients and even appears to worsen them in a third of cases. Transfusion for the purpose of preventing or treating bleeding events could cause inherent risks and costs without clear benefits., (Copyright © 2019. Published by Elsevier B.V.)

Background & Aims: Currently there is no FDA-approved therapy for nonalcoholic steatohepatitis (NASH). Increased n-6/n-3 polyunsaturated fatty acids (PUFA) ratio can induce endoplasmic reticulum (ER) stress and mitochondrial dysfunction that characterize NASH. Our recent study with n-3 PUFA showed improvement in individual histologic parameters like steatosis, ballooning and lobular inflammation. We hypothesized that n-3 PUFA therapy mediated improvement in histologic parameters is modulated by lipidomic and proteomic changes., Methods: We therefore evaluated hepatic proteomic and plasma lipidomic profiles before and after n-3 PUFA therapy in subjects with NASH. In a double-blind, randomized, placebo-controlled trial, patients with NASH received 6-month treatment with n-3 PUFA (0.945 g/day [64% alpha-linolenic (ALA), 21% eicosapentaenoic (EPA), and 16% docosahexaenoic (DHA) acids]). Paired liver biopsy and plasma collected before and after-n-3 PUFA therapy were assessed using mass spectrometry and gas chromatography for hepatic proteomics and plasma lipidomics. Data were matched to UniProt and LIPID MAPS database, respectively. Cytoscape software was used to analyze functional pathways. Twenty-seven NASH patients with paired liver histology and plasma before and after n-3 PUFA treatment were studied., Results: Treatment with n-3 PUFA significantly increased ALA, EPA, and glycerophospholipids, and decreased arachidonic acid (p < 0.05 for all). Further, proteomic markers of cell matrix, lipid metabolism, ER stress and cellular respiratory pathways were also modulated. Interestingly, these alterations reflected functional changes highly suggestive of decreased cellular lipotoxicity potential; reduced ER proteasome degradation of proteins and induction of chaperones; and a shift in cell energy homeostasis towards mitochondrial beta-oxidation., Conclusion: Six-month treatment with omega-3 PUFAs significantly improved hepatic proteomic and plasma lipidomic markers of lipogenesis, endoplasmic reticulum stress and mitochondrial functions in patients with NASH., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Oxidative stress has been implicated in the progression of severe forms of non-alcoholic fatty liver disease (NAFLD). NADPH oxidase produces reactive oxygen species. In the present study, we investigated for the first time two single nucleotide polymorphisms (SNPs) in the regulatory region of genes encoding NADPH oxidase 4 (NOX4) and p22phox (CYBA) in NAFLD., Methods: A total of 207 biopsy-proven NAFLD patients [simple steatosis (n = 27); nonalcoholic steatohepatitis (NASH) (n = 180)] were evaluated. Genomic DNA was extracted from peripheral blood cells, and polymorphisms in CYBA (unregistered) and NOX4 (rs3017887) were determined by direct sequencing of PCR., Results: Associations of CYBA-675 T/A with high-density lipoprotein (HDL) (TT vs TA vs AA; P < 0.01) and triglycerides (TGL) (TT vs XA; P < 0.01) were observed only in NASH patients. For polymorphisms in the NOX4 gene, NOX4 (rs3017887) CA + AA genotypes was significant associated with alanine aminotransferase (ALT) (CA + AA vs CC; P = 0.02). However, there was no association of SNPs in the CYBA and NOX4 genes encoding the NADPH oxidase system proteins and the presence of NASH. Regarding the clinical results, it was observed that the most advanced degrees of fibrosis occurred in patients diagnosed with type 2 diabetes mellitus (66.9% vs 37.5%, P < 0.01) and those who were more obese (32.2 vs 29.0 kg/m 2 , P < 0.01). In addition, serum glucose and insulin levels increased significantly in the presence of NASH., Conclusions: There were associations between the presence of the allele A in the NOX4 SNP and a higher concentration of ALT in the NAFLD population; between the presence of the AA genotype in the polymorphism of the CYBA-675 T/A CYBA gene and a higher level of TGL and lower HDL in NASH patients. The presence of metabolic syndrome was associated with advanced degrees of fibrosis in NAFLD patients., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background and Aim: The aim of the study was to compare the gut microbiomes from obese and lean patients with or without NASH to outline phenotypic differences., Methods and Results: We performed a cross-sectional pilot study comprising biopsy-proven NASH patients grouped according to BMI. Microbiome DNA was extracted from stool samples, and PCR amplification was performed using primers for the V4 region of the 16S rRNA gene. The amplicons were sequenced using the Ion PGM Torrent platform, and data were analyzed using QIIME software. Macronutrient consumption was analyzed by a 7-day food record. Liver fibrosis ≥ F2 was associated with increased abundance of Lactobacilli (p = 0.0007). NASH patients showed differences in Faecalibacterium, Ruminococcus, Lactobacillus and Bifidobacterium abundance compared with the control group. Lean NASH patients had a 3-fold lower abundance of Faecalibacterium and Ruminococcus (p = 0.004), obese NASH patients were enriched in Lactobacilli (p = 0.002), and overweight NASH patients had reduced Bifidobacterium (p = 0.018). Moreover, lean NASH patients showed a deficiency in Lactobacillus compared with overweight and obese NASH patients. This group also appeared similar to the control group with regard to gut microbiome alpha diversity. Although there were qualitative differences between lean NASH and overweight/obese NASH, they were not statistically significant (p = 0.618). The study limitations included a small sample size, a food questionnaire that collected only qualitative and semi-quantitative data, and variations in group gender composition that may influence differences in FXR signaling, bile acids metabolism and the composition of gut microbiota., Conclusion: Our preliminary finding of a different pathogenetic process in lean NASH patients needs to be confirmed by larger studies, including those with patient populations stratified by sex and dietary habits., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objectives: Although liver biopsy is the gold standard for determining the degree of liver fibrosis, issues regarding its invasiveness and the small amount of liver tissue evaluated can limit its applicability and interpretation in clinical practice. Non-invasive evaluation methods for liver fibrosis can address some of these limitations. The aim of this study was to evaluate the accuracy of transient elastography-FibroScan®, acoustic radiation force impulse (ARFI), enhanced liver fibrosis (ELF), the aspartate aminotransferase-to-platelet ratio index (APRI), and the FIB-4 index compared with liver biopsy in hepatitis C., Methods: We evaluated chronic hepatitis C patients who were followed at the Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology of University of São Paulo School of Medicine, São Paulo, Brazil, and who underwent liver biopsy. The accuracy of each method was determined by a receiver operating characteristic (ROC) curve analysis, and fibrosis was classified as significant fibrosis (≥F2), advanced fibrosis (≥F3), or cirrhosis (F4). The Obuchowski method was also used to determine the diagnostic accuracy of each method at the various stages of fibrosis. In total, 107 FibroScan®, 51 ARFI, 68 ELF, 106 APRI, and 106 FIB-4 analyses were performed., Results: A total of 107 patients were included in the study. The areas under the ROC curve (AUROCs) according to fibrosis degree were as follows: significant fibrosis (≥F2): FibroScan®: 0.83, FIB-4: 0.76, ELF: 0.70, APRI: 0.69, and ARFI: 0.67; advanced fibrosis (≥F3): FibroScan®: 0.85, ELF: 0.82, FIB-4: 0.77, ARFI: 0.74, and APRI: 0.71; and cirrhosis (F4): APRI: 1, FIB-4: 1, FibroScan®: 0.99, ARFI: 0.96, and ELF: 0.94. The accuracies of transient elastography, ARFI, ELF, APRI and FIB-4 determined by the Obuchowski method were F0-F1: 0.81, 0.78, 0.44, 0.72 and 0.67, respectively; F1-F2: 0.73, 0.53, 0.62, 0.60, and 0.68, respectively; F2-F3: 0.70, 0.64, 0.77, 0.60, and 0.67, respectively; and F3-F4: 0.98, 0.96, 0.82, 1, and 1, respectively., Conclusion: Transient elastography remained the most effective method for evaluating all degrees of fibrosis. The accuracy of all methodologies was best at F4.

Objectives:: This study sought to assess the adherence of newly diagnosed hepatocellular carcinoma patients to the Barcelona Clinic Liver Cancer system treatment guidelines and to examine the impact of adherence on the survival of patients in different stages of the disease., Methods:: This study included all patients referred for the treatment of hepatocellular carcinoma between 2010 and 2012. Patients (n=364) were classified according to the Barcelona Clinic Liver Cancer guidelines. Deviations from the recommended guidelines were discussed, and treatment was determined by a multidisciplinary team. The overall survival curves were estimated with the Kaplan-Meier method and were compared using the log-rank test., Results:: The overall rate of adherence to the guidelines was 52%. The rate of adherence of patients in each scoring group varied as follows: stage 0, 33%; stage A, 45%; stage B, 78%; stage C, 35%; and stage D, 67%. In stage 0/A, adherent patients had a significantly better overall survival than non-adherent patients (hazard ratio=0.19, 95% confidence interval (CI): 0.09-0.42; p<0.001). Among the stage D patients, the overall survival rate was worse in adherent patients than in non-adherent patients (hazard ratio=4.0, 95% CI: 1.67-9.88; p<0.001), whereas no differences were observed in patients in stages B or C., Conclusions:: The rate of adherence to the Barcelona Clinic Liver Cancer staging system in clinical practice varies according to clinical disease stage. Adherence to the recommended guidelines positively impacts survival, especially in patients with early-stage disease.

Objectives:: To present the clinical features and outcomes of outpatients who suffer from refractory ascites., Methods:: This prospective observational study consecutively enrolled patients with cirrhotic ascites who submitted to a clinical evaluation, a sodium restriction diet, biochemical blood tests, 24 hour urine tests and an ascitic fluid analysis. All patients received a multidisciplinary evaluation and diuretic treatment. Patients who did not respond to the diuretic treatment were controlled by therapeutic serial paracentesis, and a transjugular intrahepatic portosystemic shunt was indicated for patients who required therapeutic serial paracentesis up to twice a month., Results:: The most common etiology of cirrhosis in both groups was alcoholism [49 refractory (R) and 11 non-refractory ascites (NR)]. The majority of patients in the refractory group had Child-Pugh class B cirrhosis (p=0.034). The nutritional assessment showed protein-energy malnutrition in 81.6% of the patients in the R group and 35.5% of the patients in the NR group, while hepatic encephalopathy, hernia, spontaneous bacterial peritonitis, upper digestive hemorrhage and type 2 hepatorenal syndrome were present in 51%, 44.9%, 38.8%, 38.8% and 26.5% of the patients in the R group and 9.1%, 18.2%, 0%, 0% and 0% of the patients in the NR group, respectively (p=0.016, p=0.173, p=0.012, p=0.012, and p=0.100, respectively). Mortality occurred in 28.6% of the patients in the R group and in 9.1% of the patients in the NR group (p=0.262)., Conclusion:: Patients with refractory ascites were malnourished, suffered from hernias, had a high prevalence of complications and had a high postoperative death frequency, which was mostly due to infectious processes.

Background: & aims: Few clinical trials have addressed the potential benefits of omega-3 polyunsaturated fatty acids (PUFAs) on non-alcoholic steatohepatitis (NASH). We evaluated the effects of supplementation with omega-3 PUFAs from flaxseed and fish oils in patients with biopsy-proven NASH., Methods: Patients received three capsules daily, each containing 0.315 g of omega-3 PUFAs (64% alpha-linolenic [ALA], 16% eicosapentaenoic [EPA], and 21% docosahexaenoic [DHA] acids; n-3 group, n = 27) or mineral oil (placebo group, n = 23). Liver biopsies were evaluated histopathologically by the NASH activity score (NAS). Plasma levels of omega-3 PUFAs were assessed as a marker of intake at baseline and after 6 months of treatment. Secondary endpoints included changes in plasma biochemical markers of lipid metabolism, inflammation, and liver function at baseline and after 3 and 6 months of treatment., Results: At baseline, NAS was comparable between the groups (p = 0.98). After intervention with omega-3 PUFAs, plasma ALA and EPA levels increased (p ≤ 0.05). However in the placebo group, we also observed increased EPA and DHA (p ≤ 0.05), suggesting an off-protocol intake of PUFAs. NAS improvement/stabilization was correlated with increased ALA in the n-3 group (p = 0.02) and with increased EPA (p = 0.04) and DHA (p = 0.05) in the placebo group. Triglycerides were reduced after 3 months in the n-3 group compared to baseline (p = 0.01)., Conclusions: In NASH patients, the supplementation of omega-3 PUFA from flaxseed and fish oils significantly impacts on plasma lipid profile of patients with NASH. Plasma increase of these PUFAs was associated with better liver histology. (ID 01992809)., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: The majority of cases of hepatocellular carcinoma have been reported in individuals with cirrhosis due to chronic viral hepatitis and alcoholism, but recently, the prevalence has become increasingly related to nonalcoholic steatohepatitis around the world. The study aimed to evaluate the clinical and histophatological characteristics of hepatocellular carcinoma in Brazilians' patients with nonalcoholic steatohepatitis at the present time., Methods: Members of the Brazilian Society of Hepatology were invited to complete a survey regarding patients with hepatocellular carcinoma related to nonalcoholic steatohepatitis. Patients with a history of alcohol intake (>20 g/day) and other liver diseases were excluded. Hepatocellular carcinoma diagnosis was performed by liver biopsy or imaging methods according to the American Association for the Study of Liver Diseases' 2011 guidelines., Results: The survey included 110 patients with a diagnosis of hepatocellular carcinoma and nonalcoholic fatty liver disease from nine hepatology units in six Brazilian states (Bahia, Minas Gerais, Rio de Janeiro, São Paulo, Paraná and Rio Grande do Sul). The mean age was 67±11 years old, and 65.5% were male. Obesity was observed in 52.7% of the cases; diabetes, in 73.6%; dyslipidemia, in 41.0%; arterial hypertension, in 60%; and metabolic syndrome, in 57.2%. Steatohepatitis without fibrosis was observed in 3.8% of cases; steatohepatitis with fibrosis (grades 1-3), in 27%; and cirrhosis, in 61.5%. Histological diagnosis of hepatocellular carcinoma was performed in 47.2% of the patients, with hepatocellular carcinoma without cirrhosis accounting for 7.7%. In total, 58 patients with cirrhosis had their diagnosis by ultrasound confirmed by computed tomography or magnetic resonance imaging. Of these, 55% had 1 nodule; 17%, 2 nodules; and 28%, ≥3 nodules., Conclusions: Nonalcoholic steatohepatitis is a relevant risk factor associated with hepatocellular carcinoma in patients with and without cirrhosis in Brazil. In this survey, hepatocellular carcinoma was observed in elevated numbers of patients with steatohepatitis without cirrhosis.

Objectives: Fibrolamellar hepatocellular carcinoma is a rare primary malignant liver tumor that differs from conventional hepatocellular carcinoma in several aspects. The aim of this study was to describe the clinical, surgical and histopathological features of fibrolamellar hepatocellular carcinoma and to analyze the factors associated with survival., Methods: We identified 21 patients with histopathologically diagnosed fibrolamellar hepatocellular carcinoma over a 22-year period. Clinical information was collected from medical records and biopsies, and surgical specimens were reviewed., Results: The median age at diagnosis was 20 years. Most patients were female (67%) and did not have associated chronic liver disease. Most patients had a single nodule, and the median tumor size was 120 mm. Vascular invasion was present in 31% of patients, and extra-hepatic metastases were present in 53%. Fourteen patients underwent surgery as the first-line therapy, three received chemotherapy, and four received palliative care. Eighteen patients had "pure fibrolamellar hepatocellular carcinoma," whereas three had a distinct area of conventional hepatocellular carcinoma and were classified as having "mixed fibrolamellar hepatocellular carcinoma." The median overall survival was 36 months. The presence of "mixed fibrolamellar hepatocellular carcinoma" and macrovascular invasion were predictors of poor survival. Vascular invasion was associated with an increased risk of recurrence in patients who underwent surgery., Conclusion: Fibrolamellar hepatocellular carcinoma was more common in young female patients without chronic liver disease. Surgery was the first therapeutic option to achieve disease control, even in advanced cases. Vascular invasion was a risk factor for tumor recurrence. The presence of macrovascular invasion and areas of conventional hepatocellular carcinoma were directly related to poor survival.

Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare disease with an indolent behavior. Its prognosis is better than that of patients with hepatocellular carcinoma. The authors present their experience with resection of FLHCC., Methods: Twenty-one patients with FLHCC were treated at our institution between 1990 and 2012. Of these patients, 14 were subjected to resection of the tumor. Patient demographics, medical history, results of imaging studies and laboratory tests, surgical data, and pathologic findings were evaluated., Results: The median age of the patients at the diagnosis of the tumor was 20 years and 14 patients were female. None of the patients had tumor-associated chronic liver disease or cirrhosis. The mean tumor size was 12.8 cm (range 6-19) and 18 patients had a single liver nodule. Fourteen patients were subjected to hepatectomy and six of them had lymph node metastases resected. Pathologic evaluation revealed that 5 (35.7%) patients had major vascular invasion. Tumor recurrence was seen in 8 patients (66.7%), during a follow-up. The median survival time for patients who were subjected to resection was 36 months. The 5-year overall survival rate and disease free survival rate were 28.0% and 8.5%, respectively. Univariate analysis showed that vascular invasion was the only variable associated with the disease free survival rate., Conclusions: Despite an aggressive treatment, patients with FLHCC presented unexpected low survival rates. It seems that an underestimated malignant behavior is attributed to this disease, and that the forms of adjuvant treatment should be urgently evaluated.

Background/objective: The early detection of focal hepatic lesions using ultrasound scanning is challenging, and this challenge becomes even greater in the presence of diffuse parenchymal disease. This study aimed to evaluate the diagnostic performance of elastography and contrast-enhanced ultrasonography (CEUS) in the early detection of hepatocellular lesions in an experimental rat model of nonalcoholic steatohepatitis (NASH)., Methods: B-mode and Doppler ultrasonography was performed weekly in 30 rats divided into a NASH group (n = 20) and a group without liver disease (n = 10). The animals underwent elastography and CEUS and were then euthanized. Liver nodules were assessed by histopathology., Results: Doppler mapping results of lesions with vascularization were considered indicative of malignancy, with a sensitivity of 29% before and 71% after contrast injection. The specificity was 71% before and 96% after CEUS. Elastograms of positive lesions showed areas of high stiffness, which were indicative of malignancy. This malignancy was confirmed by the histologic evaluation, with a sensitivity of 90% and a specificity of 60%. After CEUS analysis, 4 nodules were identified that were not observed on B-mode ultrasonography. Early wash-in was significantly associated with malignancy (sensitivity of 88% and specificity of 67%)., Conclusions: Both techniques allow for the correct diagnosis of well-differentiated to moderately differentiated hepatocellular carcinomas with good accuracy in an experimental rat model of NASH.

The role of hepatitis C virus (HCV) in the pathogenesis of atherosclerosis and cardiovascular events is unclear. The aim of this study was to evaluate the direct effect of HCV on cardiovascular risk and correlate it with pro and anti-inflammatory cytokines in patients with HCV. HCV monoinfected patients, genotype 1, naive, non-obese (BMI<30) and non-diabetics were included and compared to controls (blood donors). Patients with prior diagnosis of cardiovascular diseases, hypertension, chronic renal failure, cancer and chronic use of lipid-lowering drugs or immunosuppressants were excluded. Age, BMI, systolic blood pressure (SBP) and diastolic (DBP), fasting glucose and lipid levels were determined. Serum cytokines (IL-6, IL-10 and TNF-α) and Framingham score were also evaluated. 62 HCV patients, 34 (54.8%) were males and none of them was smoking. The Framingham scores (median and 25th and 75th percentiles) were 12% (6.5-14%), showing an intermediate cardiovascular risk in patients with HCV. There was significant direct correlation between Framingham and total cholesterol (p=0.043) and DBP (p=0.007). HDL-C (p=0.002) was inversely correlated with the Framingham score. HCV patients had higher levels of proinflammatory cytokines (IL-6 and TNF-α) compared to controls (p<0.0001) and the relation of proinflammatory/anti-inflammatory TNF-α/IL10 and IL-6/IL10 were higher in HCV patients (p<0.01). The Framingham score was directly correlated to IL-6 and TNF-α, but differences were not statistically significant. Patients with HCV monoinfected, nonobese, naïve and non diabetic have an intermediate cardiovascular risk, as measured by the Framingham score and high levels of proinflammatory cytokines (IL-6 and TNF)., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Urinary copper excretion higher than 100 μg/24 h is useful for diagnosing Wilson's disease. d-Penicillamine challenge test may produce higher levels than 1400 μg/24 h, allowing for better diagnostic accuracy. This study investigated whether heterozygotes reach this value and compared copper serum levels, ceruloplasmin, and urinary copper excretion before and after administering d-penicillamine to the parents of Wilson's disease patients., Methods: Fifty parents of adult patients were enrolled to obtain copper serum levels and ceruloplasmin along with 24-h urinary copper excretion before and after administering 1g d-penicillamine., Results: Serum ceruloplasmin and copper levels were significantly lower in fathers than in mothers (mean 21.8×27.8 mg%; 71.4×88.0 μg%; p ≤ 0.001). The mean of basal 24-h urinary copper excretion was higher in fathers (26.2×18.7 μg/24 h, p=0.01), but did not differ between the genders after d-penicillamine (521.7×525.3, range 31.6-1085.1 μg/24h, p=0.8)., Conclusions: The mean values of serum copper, ceruloplasmin, and basal urinary copper excretion were different between males and females. The current diagnostic threshold of 24-h urinary copper excretion after d-penicillamine was not reached by heterozygotes. The increased urinary copper excretion after d-penicillamine challenge was much higher than fivefold the upper limit of normal urinary copper excretion in the majority of heterozygotes and should not be taken into account when diagnosing Wilson's disease., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Nitric oxide (NO) has been shown to act as a potent antifibrogenic agent by decreasing myofibroblast differentiation. S-Nitroso-N-acetylcysteine (SNAC), a NO donor, attenuates liver fibrosis in rats, but the cellular and molecular mechanisms on liver myofibroblast-like phenotype still remain unknown. Here, we investigate the antifibrotic effects of SNAC on hepatic stellate cells, the major fibrogenic cell type in the liver. A murine GRX cell line was incubated with SNAC (100μM) or vehicle (control group) for 72h. Cell viability was measured by MTT colorimetric assay and the conversion of myofibroblast into quiescent fat-storing cell phenotype was evaluated by Oil-Red-O staining. TGFβ-1, TIMP-1, and MMP-13 levels were measure in the supernatant by ELISA. Profibrogenic- and fibrolytic-related gene expression was quantified using real-time qPCR. SNAC induced phenotype conversion of myofibroblast-like phenotype into quiescent cells. SNAC decreased gene and protein expression of TGFβ-1 and MMP-2 compared to control groups. Besides, SNAC down-regulated profibrogenic molecules and up-regulated MMP-13 gene expression, which plays a key role in the degradation of interstitial collagen in liver fibrosis. In conclusion, these findings demonstrate that SNAC efficiently can modulate the activation and functionality of murine hepatic stellate cells and could be considered as an antifibrotic treatment to human liver fibrosis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Clinical trial is considered a breakthrough method in medicine and essential to the development of new drugs. Clinical trials that comply with international and national regulations require an appropriate infrastructure and team qualification. The goal of this study was to evaluate clinical trial groups in Brazil: professional qualification, site structure regulatory knowledge and Good Clinical Practice (GCP) adherence. This is a transversal study with investigators (PI) and sub investigator (SI). PI and SI data were initially identified from Curriculum Lattes from National Advice of Scientific and Technological Development. The study participants were submitted to a questionnaire, which was composed of qualitative and quantitative questions. A hundred PI and SI were interviewed. The most representative Brazilian regions were Southeast (68%) and South (18%). The main institutions involved were HCFMUSP complex and UNIFESP among others institutions. Academic graduation is observed in 86% of them and the higher degree is Doctorate (62%). 91% had GCP knowledge although only 74% had formal training. About the team, all of them are multidisciplinary with majority of nurses and pharmaceuticals. 88% had GCP knowledge although only 77% had formal training. 36%, 60% and 44% of clinical trials were in phase II, III and IV. In conclusion, researchers have appropriate skills and knowledge to perform clinical studies however there is still a need for training. The centers where the researchers work, have trained staff and adequate infrastructure for conducting clinical trials phase II, III and IV., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objectives: We performed a national survey to update hepatocellular carcinoma (HCC) epidemiology in Brazil and determined the clinical and epidemiological profiles of patients with HCC in different Brazilian regions., Methods: Data from 29 centers included 1,405 patients diagnosed with HCC from 2004 to 2009., Results: The median age was 59 (1-92 years old; 78% male). At diagnosis, females were older than males (median age: 62 vs. 59 years old respectively; p<0.0001). Ninety-eight percent of the patients had cirrhosis (1279/1308). Hepatitis C virus was the main etiology (54%), followed by hepatitis B virus (16%) and alcohol (14%). In Southeastern and Southern Brazil, hepatitis C virus accounted for over 55% of cases. In the Northeast and North, hepatitis C virus accounted for less than 50%, and hepatitis B virus accounted for 22-25% of cases; hepatitis B was more prevalent in the Northern than in the Southern regions. Some 43%, 35%, and 22% of patients were in early, intermediate, and advanced stages respectively. Initial therapies for HCC included chemoembolization or embolization (36%), percutaneous ablation (13%), liver resection (7%), and sorafenib (1%). Liver transplantation was performed in 242 patients (19%), but it was the initial therapy for only 56 patients (4%)., Conclusion: The epidemiology, classification, and therapy selection for HCC varied among Brazilian regions. Hepatitis C infection was the most common etiology of liver cirrhosis; chemoembolization was the most common therapy employed. Liver cirrhosis was the main risk factor for HCC development in Brazil.

Background: Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH) are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2) and ferroportin 1 (SCL40A1)., Aims: To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH., Patients and Methods: Nineteen male subjects (median age 42 [range: 20-72] years) with HH were evaluated using the Haemochromatosis StripAssay A. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del., Results: In our cohort, nine (47%) patients were homozygous for the C282Y mutation, two (11%) were heterozygous for the H63D mutation, and one each (5%) was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients., Conclusions: One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.

Background/aims: Hepatocellular carcinoma (HCC) is a well recognized complication of advanced NASH (non-alcoholic steatohepatitis). We sought to produce a rat model of NASH, cirrhosis and HCC., Methods: Adult Sprague-Dawley rats, weighing 250-300g, were fed a choline-deficient, high trans-fat diet and exposed to DEN in drinking water. After 16 weeks, the animals underwent liver ultrasound (US), sacrifice and assessment by microscopy, immunohistochemistry and transmission electron microscopy (TEM)., Results: US revealed steatosis and focal lesions in 6 of 7. All had steatohepatitis defined as inflammation, advanced fibrosis and ballooning with Mallory-Denk bodies (MDB) with frank cirrhosis in 6. Areas of more severe injury were associated with anti-CK19 positive ductular reaction. HCC, present in all, were macro-trabecullar or solid with polyhedral cells with foci of steatosis and ballooned cells. CK19 was positive in single or solid nests of oval cells and in neoplastic hepatocytes. TEM showed ballooning with small droplet fat, dilated endoplasmic reticulum and MDB in non-neoplastic hepatocytes and small droplet steatosis in some cancer cells., Conclusions: This model replicated many features of NASH including steatohepatitis with ballooning, fibrosis, cirrhosis and hepatocellular carcinoma. Oval cell proliferation was evident and the presence anti-CK 19 positivity in the cancer suggests oval cell origin of the malignancy.

Hepatitis D virus (HDV) is a defective hepatotropic virus whose infectivity is dependent on hepatitis B virus (HBV). HDV super- or co-infection leads to an increased risk of fulminant hepatitis or progression to severe chronic liver disease in HBV infected patients. The Brazilian Amazon Basin has been reported to be endemic for HBV and HDV, especially in the Western Amazon Basin. In this region, HDV infection is frequently associated with acute fulminant hepatitis with characteristic histologic features. HDV is classified into seven major clades (HDV-1 to HDV-7) and HBV is subdivided into eight genotypes (A-H). HDV and HBV genotypes have been shown to have a distinct geographic distribution. The aim of this study was to determine the HBV and HDV genotypes harbored by chronically infected patients from the Eastern Amazon Basin, Brazil. We studied 17 serum samples from HBV and HDV chronically infected patients admitted to a large public hospital (Santa Casa de Misericórdia) at Belém, state of Pará, Brazil, between 1994 and 2002. HDV-3 and HBV genotype A (subtype adw2) have been identified in all cases, in contrast to previous studies from other regions of the Amazon, where HBV genotype F has been found co-infecting patients that harbored HDV-3. The HDV-3/HBV-A co-infection suggests that there is not a specific interaction between HBV and HDV genotypes, and co-infection might merely reflect the most frequent genotypes found in a particular geographic area. The analysis of the carboxy-terminal region of the large hepatitis D antigen (L-HDAg), which interacts with the hepatitis B surface antigen (HBsAg) and is essential for HDV assembly, showed some diversity between the different isolates from the Eastern Amazon. This diversity is not observed among HDV-3 sequences from other South American regions.

Background/aims: To understand the molecular mechanisms underlying non-alcoholic steatohepatitis (NASH) prevention by S-nitroso-N-acetylcysteine (SNAC), an NO donor that inhibits lipid peroxidation, we examined hepatic differentially expressed genes between ob/ob mice receiving or not SNAC treatment concomitantly with a methionine-choline deficient (MCD) diet., Methods: Ob/ob mice were assigned to receive oral SNAC fed solution (MCD+SNAC group) or vehicle (MCD group) by gavage. After four weeks, histopathological analysis and microarray hybridizations were conducted in liver tissues from groups. GeneSifter system was used to identify differentially expressed genes and pathways according to Gene Ontology., Results: NASH was absent in the MCD+SNAC group and no significant changes in food intake or body weight were observed in comparison to MCD group. After SNAC treatment, several genes belonging to oxidative phosphorylation, fatty acid biosynthesis, fatty acid metabolism and glutathione metabolism pathways were down-regulated in comparison to the MCD group., Conclusions: SNAC treatment promotes down regulation of several genes from fatty acid (FA) metabolism related pathways, possibly through abrogation of the cytotoxic effects of reactive oxygen species and lipid peroxides with consequent prevention of mitochondrial overload. Further studies are required to investigate the clinical implications of these findings, in attempt to develop novel therapeutic strategies for NAFLD treatment.

Background/aims: Susceptibility to autoimmune hepatitis (AIH) has been linked to different HLA-DR antigens. Recently, AIH type 1 was associated with polymorphisms in the tumor necrosis factor alpha gene promoter (TNFA) at position -308. In this respect, the frequency of the TNFA*2 allele, in linkage disequilibrium with HLA-DRB1*0301, was shown to be significantly increased in whites with AIH type 1. The aim of this study was to assess the role of TNFA alleles in conferring susceptibility to AIH, studying a population where the disease is not primarily associated with HLA-DRB1*03., Methods: The determination of HLA-DRB1 and TNFA alleles was performed in 92 patients with AIH type 1, 29 subjects with AIH type 2 and 83 healthy controls by polymerase chain reaction-based techniques., Results: The distribution of TNFA alleles was similar in patients with AIH types 1 and 2, when compared with controls. In addition, the TNFA*2 allele was identified in patients carrying HLA-DR antigens other than HLA-DRB1*03. Interestingly, higher gammaglobulin levels were observed in TNFA*2 positive patients., Conclusions: Our data indicate that susceptibility to AIH remains primarily linked to the HLA-DRB1 locus, and suggest that the association of AIH with TNFA*2 previously observed in whites might be secondary to a linkage disequilibrium with HLA-DRB1*0301.