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May - June, 2018

Vol. 17 Issue 3

On the cover: The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver

EDITORIAL

OPINIONS

  • The Presence and Severity of Nonalcoholic Steatohepatitis Is Associated with Specific Changes in Circulating Bile Acids Aline Gottlieb, Lars Bechmann, Ali Canbay Page 341-342

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease nowadays with currently no approved therapies for the disease. The liver plays a pivotal role in lipid and glucose metabolism. The interactions of molecular mechanisms on the gut for example influences the development still needs to be understood. Bile acids (BA) have been shown to impact metabolic homeostasis and insulin sensitivity. Here, we comment on a study analyzing BA profiles in NAFLD patients addressing novel pathways involved in NAFLD progression.

VIEWPOINTS

  • Viewpoint: "Alcohol Consumption in Late Adolescence is Associated With an Increased Risk of Severe Liver Disease Later in Life" Adriana Tamburello, Marco Marando, Stefano Bellentani Page 343-344

    Drinking alcohol during adolescence predispose to severe liver disease in the adult phase. This is the main message of this prospective study. Each daily gram of alcohol men consumed in their youth was linked with a two percent increase in the risk of severe liver disease. No threshold level emerged for liver damage and this is a warning for all the sociologists and politics. New legiferation and educational campaigns addressed to young people, with particular attention to the access to alcohol, prices and advertising are necessary.

CONCISE REVIEW

  • Non-Alcoholic Fatty Liver Disease in Children and Adolescents: Lifestyle Change - a Systematic Review and Meta-Analysis Melina Utz-Melere, Cristina Targa-Ferreira, Bernardo Lessa-Horta, Matias Epifanio, Marialena Mouzaki, Angelo A. Mattos Page 345-354

    Introduction and aim. This manuscript seeks to analyze the impact of lifestyle changes on body mass index (BMI), aminotransferases and steatosis in children and adolescents with nonalcoholic fatty liver disease (NAFLD). Materials and methods. A review of PubMed, BIREME, Scopus, EMBASE, Medline and Web of Science databases 2015 was performed seeking studies addressing the impact of lifestyle interventions on children and/or adolescents with NAFLD. Inclusion were manuscripts written in Portuguese, English and Spanish, as well as age less than 18 years. Two reviewers performed the data extraction independently and differences were resolved by consensus. Outcome measures were BMI, serum aminotransferase levels and the presence of hepatic steatosis. Results. The literature search identified 71,012 articles. After excluding 46,397 duplicates and other clearly irrelevant studies, 89 publications were reviewed in detail. Another 55 studies were excluded at this stage. Subsequently, 18 were excluded due to lack of data and three new articles were found in the review of the references of previously identified manuscripts. Therefore, 19 studies that had evaluated 923 subjects (477 boys and 446 girls) aged 6-18 years were included in the review. In most studies, the intervention included aerobic exercise and diet. In nine studies, BMI improved significantly following the intervention. The vast majority of studies reported a benefit from the intervention on aminotransferase levels. Lifestyle changes also had a significant impact on steatosis, reducing the risk by 61%. Conclusions. Lifestyle changes lead to significant improvements in BMI, aminotransferase levels and hepatic steatosis in children and adolescents with NAFLD.

  • LncRNA-Regulated Autophagy and its Potential Role in Drug-Induced Liver Injury Juan Zhou, Yi Li, XinYu Liu, Yunzhu Long, Jun Chen Page 355-363

    Introduction and aim. Autophagy and its regulated pathways participate in many important cellular physiology and pathological processes involving protein aggregates, damaged mitochondria, excessive peroxisomes, ribosomes, and invading pathogens. This study aimed to review recently published studies and further describe the long noncoding RNA (lncRNA)-regulated autophagy during drug-induced liver injury (DILI). Material and methods. DILI, autophagy, autophagy-related genes (ATGs), and lncRNA were used as key words to search published studies from PubMed, Google Scholar, and Web of Science. All related studies were reviewed and analyzed. Results. Many studies explicitly indicated that DILI and its progression to acute liver failure were causatively linked to endoplasmic reticulum stress and subsequently induced autophagy, which protects hepatocytes during DILI. LncRNA, as a noncoding RNA, influences the regulation of the expression of ATGs to manipulate autophagy. Conclusions. This review described the recent findings on autophagy and its possible lncRNA-miRNA-associated pathways, thereby providing new insights for further studies on the pathogenesis of DILI.

  • Association Between Hepatitis C Virus and Chronic Kidney Disease: A Systematic Review and Meta-Analysis Fabrizio Fabrizi, Francesca M. Donato, Piergiorgio Messa Page 364-391

    Introduction and aim. The role of hepatitis C virus infection as a risk factor for the development and progression of chronic kidney disease in the general population remains unclear. Material and methods. A systematic review of the published medical literature was performed to assess whether positive anti-HCV serologic status is associated with higher frequency of chronic kidney disease in the adult general population. We used a random-effects model to generate a summary estimate of the relative risk of chronic kidney disease (defined by lowered glomerular filtration rate or detectable proteinuria) with HCV across the published studies. Meta-regression and stratified analysis were also carried out. Results. Forty studies were eligible (n = 4,072,867 patients), and separate meta-analyses were conducted according to the outcome. Pooling results of longitudinal studies (n = 15 studies, n = 2,299,134 unique patients) demonstrated an association between positive anti-HCV serologic status and increased incidence of CKD, the summary estimate for adjusted HR with HCV across the surveys, 1.54 (95% CI, 1.26; 1.87) (P < 0.001). Between-study heterogeneity was observed (Q value by Chi-squared [χ2] test 500.3, P < 0.0001). The risk of chronic kidney disease related to HCV, in the subset of surveys from Asia was 1.45 (1.27; 1.65) (P < 0.001) (no heterogeneity). According to our meta-regression, ageing (P < 0.0001) and duration of follow-up (P < 0.0001) increased the risk of chronic kidney disease among HCV-positive subjects. We observed a relationship between anti-HCV positive serologic status and frequency of proteinuria, adjusted effect estimate of proteinuria with HCV among surveys was 1.633 (95% CI, 1,29; 2.05) (P < 0.001) (n = 10 studies; 315,404 unique patients). However, between-studies heterogeneity was noted (P value by Q test < 0.0001). Conclusion. An association between HCV infection and increased risk of chronic kidney disease in the general population exists. The mechanisms underlying such association are currently under active investigation.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • A Dynamic Model for Predicting Outcome in Patients with HBV Related Acute-On-Chronic Liver Failure Wei Lin, Jing Zhang, Xiaohui Liu, Hongqun Liu, Jinqiu He, Ming Li, Shuqin Zhang, Yuexin Zhang, Hong Chen, Changqing Zhang, Wenfang Wu, Chenggang Jin, Samuel S. Lee, Zhongping Duan Page 392-402

    Introduction and aim. Accurately predicting the prognosis of individual patient is crucial in the management of ACLF. We aimed to establish a specific prognostic model for HBV-related ACLF patients treated with nucleoside analog (NA). Material and methods. We prospectively collected 205 ACLF cases diagnosed according to the APASL criteria. A dynamic prognostic model based on APASL criteria was established and validated. To demonstrate that the model is also applicable to those within EASL criteria, we divided the patients into two groups: met APASL criteria only (group A, n = 123); met both APASL and EASL criteria (group B, n = 82). Its prognostic accuracy was also compared with chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score in group B. Results. The model is: R = 0.94 x Bilirubin + 0.53 x evolution of Bilirubin - 0.45 x PT-A - 0.22 x evolution in PT-A -0.1 x PLT + 10 x anti-HBe. The area under receiver operating characteristic curve (AUC) of the model for predicting 90-day mortality was 0.86, which was significantly higher than that of model for end stage liver disease(MELD), MELD-Na, CLIF-SOFA, ΔMELD (7d) and ΔMELD-Na (7d), ΔCLIF- SOFA(7d) (all p < 0.01). The AUC of our model in the validation group was 0.79 which was superior to MELD (0.45) CLIF-SOFA (0.53) score in group B patients (p < 0.01). Conclusion. In conclusion, the model was superior to the conventional methods in predicting the outcomes of patients with HBV related ACLF treated with NA. It is the first description of a novel prognostic model using consecutive data in patients with HBV-induced acute-on-chronic liver failure (ACLF) treated by nucleoside analogs.

  • Comparison of Dynamic Changes Among Various Prognostic Scores in Viral Hepatitis-Related Acute Liver Failure Shalimar ., Ujjwal Sonika, Saurabh Kedia, Soumya J. Mahapatra, Baibaswata Nayak, Dawesh P. Yadav, Deepak Gunjan, Bhaskar Thakur, Harpreet Kaur, Subrat K. Acharya Page 403-412

    Introduction and aim. Multiple prognostic scores are available for acute liver failure (ALF). Our objective was to compare the dynamicity of model for end stage liver disease (MELD), MELD-sodium, acute liver failure early dynamic model (ALFED), chronic liver failure (CLIF)-consortium ACLF score and King's College Hospital Criteria (KCH) for predicting outcome in ALF. Materials and methods. All consecutive patients with ALF at a tertiary care centre in India were included. MELD, MELD-Na, ALFED, CLIF-C ACLF scores and KCH criteria were calculated at admission and day 3 of admission. Area under receiver operator characteristic curves (AUROC) were compared with DeLong method. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio (LR) and diagnostic accuracy (DA) were reported. Results. Of the 115 patients included in the study, 73 (63.5%) died. The discrimination of mortality with baseline values of prognostic scores (MELD, MELD-Na, ALFED, CLIF-C ACLF and KCH) was modest (AUROC: 0.65-0.77). The AUROC increased on day 3 for all scores, except KCH criteria. On day 3 of admission, ALFED score had the highest AUROC 0.95, followed by CLIF-C ACLF 0.88, MELD 0.81, MELD-Na 0.77 and KCH 0.52. The AUROC for ALFED was significantly higher than MELD, MELD-Na and KCH (P < 0.001 for all) and CLIF-C ACLF (P = 0.05). ALFED score β 4 on day 3 had the best sensitivity (87.1%), specificity (89.5%), PPV (93.8%), NPV (79.1%), LR positive (8.3) and DA (87.9%) for predicting mortality. Conclusions. Dynamic assessment of prognostic scores better predicts outcome. ALFED model performs better than MELD, MELD, MELD-Na, CLIF-C ACLF scores and KCH criteria for predicting outcome in viral hepatitis- related ALF.

  • Direct Acting Antivirals Improve HCV Treatment Initiation and Adherence Among Underserved African Americans Kendall R. Beck, Nicole J. Kim, Mandana Khalili Page 413-418

    Introduction and aim. Adherence to hepatitis C (HCV) care was suboptimal in the interferon era among underserved African Americans (AA), but adherence data in the era of direct acting antivirals (DAA) is lacking in this population. We aimed to evaluate the impact of DAA on HCV care in underserved AA. Material and methods. Clinical records of AAs undergoing HCV evaluation attending a safety net health system liver clinic were reviewed from 2006 to 2011 (pre-DAA), and January 1, 2014, to December 31, 2016 (post-DAA). Results. 291 patients were identified (129 pre-DAA, and 162 post-DAA). Median age was 58, 66% were male, 91% had HCV genotype 1, and 70% had fibrosis ≥ stage 2. Post-DAA patients were older (60 vs. 53 years; p < 0.001), had higher rates of insurance (98 vs. 88%; p < 0.001), liver fibrosis ≥ stage 2 (77 vs. 61%; p = 0.048), ≥ 2 medical comorbidities (19 vs. 0.8%; p < 0.001), and median baseline log10 HCV RNA (6.07 vs. 5.81 IU/mL; p < 0.001), but lower median ALT (46 vs. 62 U/L; p < 0.001). Post-DAA, fewer patients were treatment ineligible (5.6 vs. 39%; p < 0.001) and more initiated therapy (71 vs. 8.5%; < 0.001), were adherent to HCV care (82 vs. 38%; p < 0.001), and achieved cure (95.7 vs. 63.6%, p < 0.001). Availability of DAA was independently associated with improved adherence to HCV care (OR 10.3, 95% CI 4.84-22.0). Conclusion. Availability of DAA is associated with increased treatment eligibility, initiation, adherence to HCV care, and cure in HCV-infected underserved AAs; highlighting the critical role of access to DAA in this population.

Non alcoholic fatty liver disease (NAFLD)
  • Vitamin D Deficiency is not Associated with Fatty Liver in a Mexican Population Fabiola López-Bautista, Carlos Posadas-Romero, Luz Y. Ruiz-Vargas, Guillermo Cardoso-Saldaña, Juan G. Juárez-Rojas, Aida Medina-Urrutia, Nonanzit Pérez-Hernández, José M. Rodríguez-Pérez, Gilberto Vargas-Alarcón, Rosalinda Posadas-Sánchez Page 419-425

    Introduction and aim. Association of vitamin D deficiency (VDD) with fatty liver (FL) disease is controversial. The purpose of this study was to analyze the association of VDD with FL. Material and methods. Cross-sectional study. Data on cardiovascular risk factors, medications, alcohol intake, smoking, diet, and physical activity were obtained. Biochemical, anthropometric, and blood pressure variables were measured. The 25-hydroxyvitamin D (25(OH)D) was quantified through chemoluminescence. The presence of FL, defined as a liver/spleen attenuation index lower than 1.0, was identified through computed axial tomography (CAT). Results. The study included 1,467 subjects (49.7% men) with a mean age of 53.3 ± 9.3 years and BMI of 28.3 ± 4.0 kg/m2. Only 11% had optimum values of vitamin D, and 25(OH)D concentration was lower in participants with FL. Multivariate logistic regression models, adjusted for age, gender, BMI, sampling season, glucose, total cholesterol, triglycerides, HOMA-IR, hs-CRP, ALT, AST, and elevated VAT, revealed an association between FL and vitamin D (VD) insufficiency (RM 1.61 [0.99-2.61]) and with VDD (RM 1.68 [1.02-2.77]); however, statistical significance was lost when including caloric consumption and physical activity in the model. Conclusions. In Mexican adults, deficient VD concentration and FL were not independently associated of caloric consumption and physical activity.

Liver transplantation
  • An Overview of Liver Transplant Pathology: Data from a Tertiary Referral Centre in Western India Fiona Fonseca, Bijal Kulkarni, Meenal Hastak, Vinay Kumaran, Vibha Varma, Sorabh Kapoor Page 426-436

    Introduction and aim. 1. Study of liver explants - Etiologic types of end-stage chronic liver disease (ESCLD) and acute liver failure (ALF) in adults and children. 2. Assessment of donor steatosis and incidental granulomas. 3. Post-transplant liver biopsies. Material and methods. Specimens of 180 explant hepatectomies, 173 donor wedge and 30 core liver biopsies, and 58 post transplant liver biopsies received in our department from April 2013 to March 2017. Results. 1. Most common causes of ESCLD in adults were: alcohol related (30.32%), hepatitis virus related (18.71%) and non-alcoholic steatohepatitis related (18.06%); and in children ≤ 12 years were: biliary atresia (27.27%), autoimmune disease (18.18%) and Wilson's disease (18.18%). Most common causes of ALF in adults and children were anti-tubercular therapy induced and idiopathic, respectively. 2. Prevalence rate of moderate steatosis (between 30-60%) was 4.28%. Incidental granulomas were seen in 5 cases. 3. Most common diagnoses of post-transplant biopsies in adults included acute cellular rejection (ACR) (36.17%), recurrence of viral disease (8.51%) and moderate non-specific portal triaditis (8.51%). Among children ≤ 12 years, most common diagnoses included unremarkable liver parenchyma, ACR and ischemia/reperfusion injury. Conclusion. 1. Alcohol- and hepatitis- virus related ESCLD, and biliary atresia are leading indications for liver transplantation in adults and children, respectively. 2. Prevalence of 4.28% of moderate steatosis, is much lower than that documented in western literature. Only 5 cases of incidental granulomas is unexpectedly low in a country endemic for tuberculosis. 3. Most common diagnoses of post-transplant liver biopsies in adults has been acute rejection, which is similar to the findings from much larger published series.

  • Sofosbuvir-Based Therapy in the Pre-Liver Transplant Setting: The Canadian National Experience Bandar Al-Judaibi, Benson Thomas, Philip Wong, Amine Benmassaoud, Jo-Hua Chen, M. Katherine Dokus, Trana Hussaini, Marc Bilodeau, Kelly W. Burak, Paul Marotta, Eric. M. Yoshida Page 437-443

    Introduction and aim. Sofosbuvir (SOF)-based regimen has been shown to have high efficacy even in patients with decompensated cirrhosis. Treated patients may experience various degrees of hepatic recovery ranging from stabilization of liver function, to removal from liver transplant wait lists. The frequency of these occurrences in larger transplant eligible patient populations is unknown. The aim of this study was to assess the efficacy of SOF-based therapy in HCV infected transplant eligible patients and to evaluate short term changes in liver function and the effect on their liver transplant status. Material and methods. A retrospective multicenter Canadian study of liver transplant candidates with advanced HCV cirrhosis treated with SOF-based therapy. Outcomes included sustained virologic response (SVR), and liver transplant status. Results. 105 liver transplant candidates with advanced liver disease due to HCV were evaluated. The overall SVR was 83.8%. Hepatocellular carcinoma was diagnosed in 39 (37.1%) prior to transplant evaluation. In short term follow-up, 14 (13.3%) remained active on the list at the time of SVR12, 22 (20.9%) patients underwent liver transplantation, 7 (6.6%) patients were deactivated due to clinical improvement, 3 patients were delisted, and 10 deaths were reported. Conclusions. SOF-based therapy for patients progressing to liver transplantation leads to high SVR rates, short term stability in liver function, and deactivation from the transplant list .

Hepatobiliary Malignancies
  • Antiproliferative Effects of Epigenetic Modifier Drugs Through E-cadherin Up-regulation in Liver Cancer Cell Line Diego Uribe, Andres Cardona, Davide Degli Esposti, Marie-Pierre Cros, Cyrille Cuenin, Zdenko Herceg, Mauricio Camargo, Fabian M. Cortés-Mancera Page 444-460

    Introduction and aim. Epigenetic alterations play an essential role in cancer onset and progression, thus studies of drugs targeting the epigenetic machinery are a principal concern for cancer treatment. Here, we evaluated the potential of the combination of the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5aza-dC) and the pan-deacetylase inhibitor Trichostatin A (TSA), at low cytotoxic concentrations, to modulate the canonical Wnt/β-catenin pathway in liver cancer cells. Material and methods. Pyrosequencing was used for DNA methylation analyses of LINE-1 sequences and the Wnt/β-catenin pathway antagonist DKK3, SFRP1, WIF1 and CDH1. qRT-PCR was employed to verify the expression of the antagonist. Pathway regulation were evaluated looking at the expression of β-catenin and E-cadherin by confocal microscopy and the antitumoral effects of the drugs was studied by wound healing and clonogenic assays. Results. Our result suggest that 5aza-dC and TSA treatments were enough to induce a significant expression of the pathway antagonists, decrease of β-catenin protein levels, re-localization of the protein to the plasma membrane, and pathway transcriptional activity reduction. These important effects exerted an antitumoral outcome shown by the reduction of the migration and clonogenic capabilities of the cells. Conclusion. We were able to demonstrate Wnt/ β-catenin pathway modulation through E-cadherin up-regulation induced by 5aza-dC and TSA treatments, under an activation-pathway background, like CTNNB1 and TP53 mutations. These findings provide evidences of the potential effect of epigenetic modifier drugs for liver cancer treatment. However, further research needs to be conducted, to determine the in vivo potential of this treatment regimen for the management of liver cancer.

Miscellaneous
  • Prognostic Significance of The New Criteria for Acute Kidney Injury in Cirrhosis Emília T. O. Bansho, Pedro Eduardo S. Silva, Bruno S. Colombo, Letícia M. Wildner, Maria Luiza Bazzo, Esther B. Dantas-Corrêa, Leonardo L. Schiavon, Janaína L. Narciso-Schiavon Page 461-469

    Introduction and aim. New criteria for acute kidney injury (AKI) in cirrhosis have been proposed, but its prognostic significance is unclear. This study aims to evaluate the prognostic significance of the AKI criteria in cirrhotic patients hospitalized for acute decompensation. Material and methods. This is a prospective cohort study. AKI was defined as an increase in creatinine (Cr) levels ≥ 0.3 mg/dL in 48 h or ≥ 50% of the basal value in the last 7d. AKI was divided into stages 1 (elevation: < 2x basal), 2 (2 or 3x), and 3 (> 3x). Results. In this study, 227 patients aged 53.9 ± 11.5 years were included, of whom 37% had AKI (28% AKI1, 5% AKI2, and 4% AKI3). Thirty percent of the patients died or were transplanted within 90 days from causes related to the presence of ascites at hospital admission and higher values of Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) scores, but not to the presence of AKI. In a regression analysis conducted to assess the effect of the final Cr level in patients with AKI, 90-day mortality was associated with ascites, higher CLIF-SOFA score, and AKI with final Cr level ≥ 1.5 mg/dL. The patients with AKI with Cr levels ≥ 1.5 mg/dL showed lower transplant-free survival rates than those without AKI, and those with AKI1 with final Cr level < 1.5 mg/dL. Conclusions. Early AKI was frequent and associated with 90-day mortality or transplantation only when the final Cr level was ≥ 1.5 mg/dL. Distinct approaches are needed for patients with AKI1 according to final Cr.

  • Alcohol Consumption Influences Clinical Outcome in Patients Admitted to a Referral Center for Liver Disease Suyan G.R. dos Santos, Angelo A. Mattos, Marcela M. Guimarães, Bibiana de S. Boger, Gabriela P. Coral Page 470-475

    Introduction and aim. Excessive alcohol consumption is a public health concern worldwide and has been associated with high mortality rates. This study aimed to determine the prevalence of alcohol consumption and its influence on the prognosis of hospitalized cirrhotic patients in a tertiary care hospital. Material and methods. We reviewed the medical records of all patients with hepatic cirrosis admitted between January 2009 and December 2014, in a referral center for liver disease in southern Brazil. Data on clinical outcomes, associated conditions, infections, and mortality were collected and compared between alcoholic and nonalcoholic patients. Results. The sample consisted of 388 patients; 259 (66.7%) were men. One hundred fifty-two (39.2%) were classified as heavy use of alcohol. Most alcoholic patients were men (n = 144; 94.7%). Mean age was 55.6 ± 8.9 years. Hepatic decompensations and infections were more prevalent in alcoholic patient. Spontaneous bacterial peritonitis and respiratory tract infection accounted for most of the infections. Excessive alcohol consumption was associated with mortality (P = 0.009) in multivariate analysis. Conclusion. On the present study, the prevalence of heavy use of alcohol was high and associated with a poorer prognosis in hospitalized cirrhotic patients, increasing the risk of infection and death.

  • Thrombosis of the Portal Venous System in Cirrhotic vs. Non-Cirrhotic Patients Vania Cruz-Ramón, Paulina Chinchilla-López, Oscar Ramírez-Pérez, Nancy E. Aguilar-Olivos, Luis F. Alva-López, Ericka Fajardo-Ordoñez, Guadalupe Ponciano-Rodríguez, Patrick G. Northup, Nicolas Intagliata, Stephen H. Caldwell, Xingshun Qi, Nahum Méndez-Sánchez Page 476-481

    Introduction and aim. Thrombosis is a vascular disorder of the liver often associated with significant morbidity and mortality. Cirrhosis is a predisposing factor for portal venous system thrombosis. The aim of this study is to determine differences between cirrhotics and non-cirrhotics that develop thrombosis in portal venous system and to evaluate if cirrhosis severity is related to the development of portal venous system thrombosis. Material and methods. We studied patients diagnosed with portal venous system thrombosis using contrast-enhanced computed tomography scan and doppler ultrasound at Medica Sur Hospital from 2012 to 2017. They were categorized into two groups; cirrhotics and non-cirrhotics. We assessed the hepatic function by Child-Pugh score and model for end-stage liver disease. Results. 67 patients with portal venous system thrombosis (25 with non-cirrhotic liver and 42 with cirrhosis) were included. The mean age (± SD) was 65 ± 9.5 years in cirrhotic group and 57 ± 13.2 years (p = 0.009) in non-cirrhotic group. Comparing non-cirrhotics and cirrhotics, 8 non-cirrhotic patients showed evidence of extra-hepatic inflammatory conditions, while in the cirrhotic group no inflammatory conditions were found (p < 0.001). 27 (64.29%) cirrhotic patients had thrombosis in the portal vein, while only 9 cases (36%) were found in non-cirrhotics (p = 0.02). Conclusions. In cirrhotic patients, hepatocellular carcinoma and cirrhosis were the strongest risk factors to develop portal venous system thrombosis. In contrast, extrahepatic inflammatory conditions were main risk factors associated in non-cirrhotics. Moreover, the portal vein was the most frequent site of thrombosis in both groups.

Basic studies

  • Modulatory Effect of Dietary Inclusion of Aegle marmelos Fruits against Cisplatin - Induced Hepatotoxicity In Wistar Rats Saket S. Chandel, Mrunal Shirsat, Ram K. Sahu, Siva S. Nayak Page 482-489

    Introduction and Aim. Aegle marmelos is an important traditional herbal medicine used in India. The dietary inclusion of the plant has never exposed earlier for its hepatoprotective activity. This study aimed to investigate the modulator efficacy of dietary inclusion of Aegle marmelos against Cisplatin - induced hepatotoxicity in Wistar albino rats. Material and methods. Animals were divided into five different groups; Group I was given basal diets only, Group II was fed basal diets with Aegle marmelos in 4% concentration, while Group III was fed basal diets co-administered with Cisplatin. Group IV and V were administered diets containing 2 and 4% Aegle marmelos respectively, for 27 days prior to Cisplatin administration. Cisplatin was administered to the rats for 3 days leads to a reduction in the activities of the antioxidant enzymes like lipid peroxidation (LPO) and endogenous antioxidant systems such as reduced superoxide dismutase (SOD), glutathione (GSH) and catalase in liver homogenate caused to produce the impairment of hepatic functions. Results. The administration of fruit part of Aegle marmelos to Wistar rats showed a significant fall in the elevated Lipid peroxidation, superoxide dismutase, glutathione and catalase concentration, moreover, it diminished the increased serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), acid phosphatase (ACP) and bilirubin. Conclusions. We can conclude that the hepatoprotective activity of Aegle marmelos was due to its antioxidant effect as evidenced by increasing activity of antioxidant enzymes with enhanced hepatic function and significantly changed the physiological parameters.

  • Potential Molecular Targets of Statins in the Prevention of Hepatocarcinogenesis Ezequiel Ridruejo, Giselle Romero-Caími, María J. Obregón, Diana Kleiman de Pisarev, Laura Alvarez Page 490-500

    Introduction and aim. Hepatocellular carcinoma (HCC) represents 90% of liver tumors. Statins, may reduce the incidence of various tumors, including HCC. Antitumoral activities may be mediated by changes in transforming growth factor-beta (TGF-β1) and thyroid hormones (TH) regulation. The aim of our study is to establish the statins mechanism of action and the potential key molecules involved in an in vivo and in vitro HCC model. Materials and methods. We used two models: in vivo (in rats) using diethylnitrosamine (DEN) and hexachlorobenzene (HCB) to develop HCC. We analyzed cell proliferation parameters (proliferating cell nuclear antigen, PCNA) and cholesterol metabolism (hydroxy-methylglutaryl-CoA reductase, HMGCoAR). In vitro (Hep-G2 cells) we evaluated the effects of different doses of Atorvastatin (AT) and Simvastatin (SM) on HCB induced proliferation and analyzed proliferative parameters, colesterol metabolism, TGF-β1 mRNA, c-Src and TH levels. Results. In vivo, we observed that cell proliferation significantly increased as well as cholesterol serum levels in rats treated with HCB. In vitro, we observed the same results on PCNA as in vivo. The statins prevented the increase in HMG-CoAR mRNA levels induced by HCB, reaching levels similar to controls at maximum doses: AT (30 βM), and SM (20 βM). Increases in PCNA, TGF-β1, and pc-Src, and decreases in deiodinase I mRNA levels induced by HCB were not observed when cells were pre-treated with AT and SM at maximum doses. Conclusion. Statins can prevent the proliferative HCB effects on Hep-G2 cells. TGF-β1, c-Src and TH may be the statins molecular targets in hepatocarcinogenesis.

  • Therapeutic Effect of HGF on NASH Mice Through HGF/c-Met and JAK2-STAT3 Signalling Pathway Ning Li, Zhangfeng Dou, Jinchun Liu, Bao Chai, Yue Li, Xiuqin An, Peiling Chu, Xiaolan Zhang Page 501-510

    Introduction and aim. Hepatocyte growth factor (HGF) has been shown to ameliorate liver inflammation and fibrosis; however, the mechanism underlying its effects in non-alcoholic steatohepatitis (NASH) is unclear. This study aimed to analyse the relationship between the JAK2-STAT3 signalling pathway and the ameliorating effect of HGF on NASH. Material and methods. Mice were fed a high-fat diet (HFD) for 16 weeks, and then plasma and hepatic tissues were collected. Histological and clinical chemistry assays were performed to assess liver disease. The mRNA and protein levels of JAK2, STAT3, and c-Met were assessed by real-time PCR and western blotting, respectively. Results. Serum ALT, AST, and TG levels were increased in NASH mice. Histological analysis showed different degrees of steatosis, inflammatory infiltrates, and fibrosis in HFD animals. Exogenous administration of recombinant human (rh) HGF via the tail vein for 14 days markedly decreased ALT and AST to levels lower than those in the control group. Compared with the levels in HFD mice, c-Met, p-c-Met, JAK2, p-JAK2, and p-STAT3 levels were increased in mice that were administered HGF (P < 0.05). Furthermore, silencing of HGF or blocking of its receptor c-Met affected JAK2 and STAT3 protein phosphorylation. Conclusions. Excess HGF highly probable improved NASH liver function. Combined with its ligand, c-Met, HGF may promote the phosphorylation of JAK2-STAT3 and inhibit inflammation in NASH. Therefore, it may be potentially useful treatment for NASH.

  • HCBP6 Is Involved in the Development of Hepatic Steatosis Induced by High-Fat Diet and CCL4 in Rats Yong-Ping Zhen, Xian-Yang Zhong, Yu-Shu Huang, Can-Bin Zheng Page 511-518

    Introduction and aim. Hepatitis C virus core-binding protein 6 (HCBP6) was previously found to be an hepatitis C virus corebinding protein, its biological function remains unclear. Our research aims to investigate the role of HCBP6 in the development of hepatic steatosis induced by high-fat diet and carbon tetrachloride (CCL4) in rats. Material and methods. Eighteen Wistar rats were randomly allocated into 3 groups: control group, model group 1, and model group 2. The control group was treated with a standard diet for 5 weeks. Model groups were treated with high-fat diet and CCL4 injection twice a week for 3 weeks in Group 1 and 5 weeks in Group 2, respectively. After the intervention, hepatic steatosis was observed by histological staining with hematoxylin and eosin (H&E) and Oil Red O staining. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total colesterol (TC), and triglycerides (TGs) were measured. The TG content in liver homogenates was evaluated. Expressions of HCBP6 and SREBP-1c were determined by immunofluorescence, quantitative real-time PCR, and Western blot analysis. Results. Hepatic steatosis was successfully induced in model groups. ALT, AST, TC, and TGs elevated in model groups compared with those in control group (P < 0.05). Hepatic steatosis induced by high-fat diet and CCL4 resulted in low expression of HCBP6 and high expression of SREBP-1c in the liver of rats (P < 0.05). Conclusion. HCBP6 is involved in the development of high-fat diet- and CCL4-induced hepatic steatosis and related negatively with SREBP-1c.

CASE REPORTS

  • Mucinous Cystic Neoplasm of the Liver or Intraductal Papillary Mucinous Neoplasm of the Bile Duct? A Case Report and a Review of Literature Lumir Kunovsky, Zdenek Kala, Roman Svaton, Petr Moravcik, Jan Mazanec, Jakub Husty, Vladimir Prochazka Page 519-524

    Mucinous cystic neoplasm of the liver (MCN-L) and intraductal papillary mucinous neoplasm of the bile duct (IPMN-B) are diagnoses that were classified by the World Health Organization in 2010 as mucin-producing bile duct tumors of the hepatobiliary system. The preoperative differential diagnosis between these two entities is difficult; the presence of a communication with the bile duct is usually considered as a typical sign of IPMN-B. However, the presence of an ovarian-like stroma (OLS) has been established to define the diagnosis of MCN-L. We present the case of a 33-year-old woman with a rapid progression of a cystic tumor of the liver. In 2 years, the lesion increased from 27 to 64 mm and a dilation of the left hepatic duct appeared. Percutaneous transhepatic drainage with a biopsy was performed. No malignant cells were found on biopsy. Because of the rapid progression of the cystic tumor and unclear malignant potential, left hemihepatectomy was performed. Even though tumor masses were present in the biliary duct, on the basis of the presence of OLS, histology finally confirmed MCN-L with intermediate-grade intraepithelial dysplasia to high-grade intraepithelial dysplasia. The patient is currently under oncologic follow-up with no signs of recurrence of the disease. We present a rare case where MCN-L caused a dilation of the left hepatic duct, a sign that is usually a characteristic of IPMN-B.

  • The Observed Effect of Gastric Bypass Surgery on Direct-acting Antiviral Treatment: a Case Report Elise J. Smolders, Sophie B. Willemse, Omar El-Sherif, Saye Khoo, David M. Burger Page 525-529

    Chronic hepatitis C virus (HCV) infection can be cured with treatment using direct-acting antivirals (DAAs). Although these drugs have been widely studied, information about certain special populations is missing. In this case report we describe a treatment-experienced patient with chronic HCV infection genotype 1b, treated with 150 mg/day simeprevir, 400 mg/day sofosbuvir, and 1,000 mg/ day ribavirin for 24 weeks, after a Roux-and-Y gastric bypass. At steady-state a pharmacokinetic curve was recorded of sofosbuvir, GS-331007, and simeprevir. Ribavirin trough plasma concentration (Ctrough) was determined. The simeprevir area under the-concentration time curve (AUClast) and Ctrough were 9.42 h.mg/L and 0.046 mg/L, respectively. Compared to what was described in the literature, simeprevir exposure was low and therefore the simeprevir dose was increased to 300 mg/day. The increased dose of simeprevir was well tolerated and Ctrough was 0.532 mg/L. Sofosbuvir AUClast and Ctrough were 0.63 h.mg/L and 0.0013 mg/L. GS-331007 AUClast and Ctrough were 21.02 h.mg/L and 0.35 mg/L. Ribavirin Ctrough was 2.5 mg/L. Sofosbuvir, GS-331007, and ribavirin exposure were comparable with levels described in literature. The patient achieved a sustained virological response twelve weeks after the completion of treatment.

The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver

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