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Background: Hepatocellular carcinoma (HCC) is the second most common malignancy with increasing cancer deaths worldwide. HCC is mainly diagnosed at its advanced stage, and treatment with FDA-approved sorafenib, the multikinase inhibitor drug, is advised. Acquired resistance against sorafenib develops through several pathways involving hypoxia, autophagy, high glycolysis, or glutaminolysis. Small non-coding RNAs, similar to microRNAs (miRNAs), are also known to affect sorafenib resistance in HCC. However, there is a lack of information regarding the significance of differentially expressed miRNA (if any) on autophagy and glutamine regulation in sorafenib-resistant HCC. Methods: The expression of autophagy and glutaminolysis genes was checked in both parental and sorafenib resistant HepG2 cell lines by real-time PCR. MTT and Annexin/PI assays were also performed in the presence of inhibitors such as chloroquine (autophagy inhibitor) and BPTES (glutaminolysis inhibitor). Next generation sequencing and in silico analysis were performed to select autophagy and glutamine addiction-specific microRNA. Selected miRNA were transfected into both HepG2 cells to examine its effect on autophagy and glutamine addiction in regulating sorafenib-resistant HCC. Results: Our in vitro study depicted a higher expression of genes encoding autophagy and glutaminolysis in sorafenib-resistant HepG2 cells. Moreover, inhibitors for autophagy (chloroquine) and glutaminolysis (BPTES) showed a diminished level of cell viability and augmentation in cell apoptosis of sorafenib-resistant HepG2 cells. NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results. Conclusion: Our study highlights the cytoprotective role of autophagy and glutamine addiction modulated by miR-23b-3p (tumor suppressor), suggesting new approaches to curb sorafenib resistance in HCC.

Hepatic encephalopathy (HE) is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Besides ascites and variceal bleeding, it is the most serious complication of decompensated liver cirrhosis. Ammonia and inflammation are major triggers for the appearance of HE, which in patients with liver cirrhosis involves pathophysiologically low-grade cerebral oedema with oxidative/nitrosative stress, inflammation and disturbances of oscillatory networks in the brain. Severity classification and diagnostic approaches regarding mild forms of HE are still a matter of debate. Current medical treatment predominantly involves lactulose and rifaximin following rigorous treatment of so-called known HE precipitating factors. New treatments based on an improved pathophysiological understanding are emerging.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Renal dysfunction is very common among patients with chronic liver disease, and concomitant liver disease can occur among patients with chronic kidney disease. The spectrum of clinical presentation and underlying etiology is wide when concomitant kidney and liver disease occur in the same patient. Management of these patients with dual onslaught is challenging and requires a team approach of hepatologists and nephrologists. No recent guidelines exist on algorithmic approach toward diagnosis and management of these challenging patients. The Indian National Association for Study of Liver (INASL) in association with Indian Society of Nephrology (ISN) endeavored to develop joint guidelines on diagnosis and management of patients who have simultaneous liver and kidney disease. For generating these guidelines, an INASL-ISN Taskforce was constituted, which had members from both the societies. The taskforce first identified contentious issues on various aspects of simultaneous liver and kidney diseases, which were allotted to individual members of the taskforce who reviewed them in detail. A round-table meeting of the Taskforce was held on 20–21 October 2018 at New Delhi to discuss, debate, and finalize the consensus statements. The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system with minor modifications. The strength of recommendations (strong and weak) thus reflects the quality (grade) of underlying evidence (I, II, III). We present here the INASL-ISN Joint Position Statements on Management of Patients with Simultaneous Liver and Kidney Disease.

Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed.

Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.

Background & objective: It has been shown that the combined use of alcohol before radiofrequency ablation (RFA) helps to augment the therapeutic advantage of RFA. The present study was conducted to compare the outcome of treatment with RFA alone and RFA with alcohol as ablative technique in patients with small hepatocellular carcinomas (HCCs), who were not candidates for surgery. Methods: Fifty patients with chronic liver disease and concurrent HCC were enrolled in this prospective study. The patients were treated with either RFA alone (n=25) or RFA combined with alcohol (n=25). Patient outcome was evaluated, and the tumour recurrence and survival of the patients were assessed in the two groups. Results: The survival rates at six months in patients who completed at least six months of follow up were 84 and 80 per cent in patients treated with RFA alone and combination therapy, respectively. During the follow up period, 11 and four patients treated with RFA alone showed local and distant intrahepatic tumour recurrence, respectively. All local recurrences were at one to 18 months of the follow up period. The distant recurrences occurred at 6-36 months of the follow up period. During the follow up period, eight and six patients treated with combination therapy showed local and distant intrahepatic tumour recurrence, respectively. All local recurrences were at 1.5-15 months during the follow up period. The distant intrahepatic recurrences occurred at 6-72 months during the follow up period. Interpretation & conclusions: No significant difference was seen between the survival time of the patients treated with RFA alone and RFA with alcohol as well as in the local recurrences and distant intrahepatic recurrences in RFA compared to RFA and alcohol group patients. Combined use of RFA and alcohol did not improve the local tumour control and survival in patients with HCC compared to RFA alone.

Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively. Their focus was on the hepatic aspects of the disease. Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition. A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings. Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines. A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed. Members voted on each recommendation, using the nominal voting technique. The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence. Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed. While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm. A new scoring system - Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl. Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system. Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included. Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated. The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties.

Background Majority of patients of hepatocellular carcinoma (HCC) in India present in advanced stages, when curative treatment options are limited. We undertook this study to assess the cost-effectiveness of treating advanced HCC patients with sorafenib compared with best supportive care (BSC). Methods A Markov model was parameterized to model the lifetime costs and consequences of treating advanced HCC patients with sorafenib versus BSC using a societal perspective. Cost of routine care, diagnostics, management of complications in both the arms and management of adverse effects of sorafenib treatment were considered. A probabilistic sensitivity analysis was undertaken to assess the effect of parameter uncertainty. Results The incremental cost and benefit gained by treating HCC using sorafenib was Indian rupees 94,182 ($1459) and 0.19 quality adjusted life years (QALYs) per patient, implying an incremental cost of Indian rupees 507,520 ($7861) per QALY gained. Conclusions Sorafenib is not cost-effective for use in advanced hepatocellular carcinoma treatment in India.

Stunted cellular immune response against a narrow range of epitopes is the hallmark of chronic hepatitis C infection, but the underneath molecular mechanisms have not been well elucidated. Suboptimal antigen presentation through defective antigen presenting cells, have been suggested. The myeloid dendritic cells as professional antigen presenting cells have been found to be phenotypically and functionally defective in chronic hepatitis C-infected patients in our recently published study. In order to find out if the maturation defects in dendritic cells (DC) are induced by the persistence of virus, we tried to differentiate CD14+ monocytes isolated from the peripheral blood of a healthy volunteer in dendritic cell culture medium containing GM-CSF and IL-4 supplemented with hepatitis C virus (HCV) proteins, core and NS5. The results indicated that a lesser number of monocytes differentiated to DC in presence of HCV proteins. Moreover, the differentiated cells depicted immature phenotype, which will not respond to the TLR-4 mediated stimulation ex vivo with significantly lesser upregulation of activation markers, HLA-DR, CD83, CD80 and CD86 as compared to cells differentiated in the absence of HCV proteins. Besides, these immature cells showed characteristics of defective antigen presentation, with significantly lower allostimulatory capacity towards lymphocytes from a healthy donor. Semi-quantitative reverse-transcription polymerase chain reaction (RT- PCR) showed upregulated expression of negative regulatory genes SOCS3, PDL1 and IDO in cells grown in presence of HCV proteins, suggesting the role of HCV and associated antigens in functional down- modulation of dendritic cells. This may correlate with the antigen persistence and maturation-defective status of dendritic cells in chronic HCV infection.

Background To study the differences in outcome and predictors of mortality in acute-on-chronic liver failure (ACLF) precipitated by hepatic or extrahepatic insults. Methods Consecutive patients of cirrhosis with acute decompensation were prospectively included and followed up for 90 days from admission. ACLF was defined based on chronic liver failure (CLIF) acute-on-chronic liver failure in cirrhosis (CANONIC study) criteria. Acute worsening due to acute viral hepatitis A and E, hepatitis B flare, alcoholic hepatitis, autoimmune hepatitis flare, or drug-induced liver injury were categorized as hepatic ACLF and that due to bacterial infection, upper gastrointestinal bleed or surgery as extrahepatic ACLF. Patients with both hepatic and extrahepatic insults were included in combined insult group. Results Of 179 patients of acute decompensation, 122 had ACLF (hepatic insults 47 and extrahepatic insults 51). Alcohol (64.8%) was the most common etiology of cirrhosis while infection (36%) was the most common acute insult followed by alcoholic hepatitis (24.6%). Higher proportion of extrahepatic ACLF patients had history of prior decompensation than hepatic ACLF patients (62.7% vs. 27.7%, P P =0.715 and 85% vs. 74.5%, P =0.193, respectively). Area under receiver-operating curve (AUROC) for 28-day mortality in extrahepatic ACLF group was 0.788, 0.724, 0.718, 0.634, and 0.726 and in hepatic-ACLF group was 0.786, 0.625, 0.802, 0.761, and 0.648 for chronic liver failure-sequential organ failure assessment (CLIF-SOFA), model for end stage liver disease (MELD), integrated MELD score (iMELD), acute physiology and chronic health evaluation score (APACHE-II), and Child–Turcotte–Pugh score scores, respectively. Conclusion There is no difference in mortality among hepatic and extrahepatic ACLF groups at 28 and 90 days. iMELD and CLIF-SOFA have highest AUROC to predict 28-day mortality in hepatic and extrahepatic ACLF groups, respectively.

Introduction Burkholderia cepacia complex (Bcc) is non-fermenting Gram-negative bacillus and has been rarely reported to cause spontaneous bacterial peritonitis (SBP) in decompensated cirrhosis. Objective This study was done to evaluate the clinical presentation of cirrhotic patients with SBP due to Bcc and to determine its impact on clinical outcome. Methods This is a retrospective, observational study conducted during the period from 1st January 2013 through 31st March 2015. Medical records and microbiology laboratory files were reviewed to identify all cases of Bcc associated SBP among patients hospitalized at the liver intensive care unit and analyzed. Results During the study period, out of 252 SBP patients, 11 (4.3%) patients with a positive ascitic fluid culture for Bcc were identified. Pain abdomen was the predominant symptom present in 9 (81%) patients followed by hepatic encephalopathy in 7 (63%) patients. Acute kidney injury (AKI) was universally present, seen in 6 (54%) patients at the time of presentation and 4 (36%) patients developed AKI during hospital stay. The mean CTP score was 11.2 ± 1.1 (10–13), and the mean MELD was 24.3 ± 5.9 (14–35). The mean SOFA and APACHE II score at presentation were 11 ± 4.2 (4–18) and 19.4 ± 5.2 (11–28), respectively. A total of 8 (72%) patients (6-ACLF, 2-NASH) succumbed to the illness during hospitalization due to severe sepsis and multiorgan dysfunction and 3 (27%) patients are doing well on follow-up after 3 months. Conclusion SBP caused by Bcc has been rarely reported in cirrhotic patients. This organism is intrinsically resistant to third generation cephalosporins, which are the initial antibiotic of choice for SBP patients, hence associated with multi organ failure and high mortality rates.

Background Liver fibrosis and its sequel cirrhosis represent a major health care burden, and assessment of fibrosis by biopsy is gradually being replaced by noninvasive methods. In clinical practice, the determination of fibrosis stage is important, since patients with advanced fibrosis have faster progression to cirrhosis and antiviral therapy is indicated in these patients. Aims To assess the role of transient elastography (TE) and compare it with APRI and FIB4 for predicting liver fibrosis and assessing the effect of host and viral factors on fibrosis and treatment outcome in CHC patients. Methods In a retrospective analysis, 330 CHC patients underwent liver stiffness measurement (LSM) by TE and tests needed for calculating APRI and FIB4 scores at baseline. 228 patients received a combination of Pegylated IFN-based antiviral therapy and were analyzed for therapeutic response. Results The study included 330 patients (median age 39 years [range 18–67]), predominantly males ( n =227, 68.8%) with baseline LSMs. The median liver stiffness was 7.8kPa (range 3.2–69.1kPa). LSMs and its thresholds for severe fibrosis progression (≥9.5kPa) and cirrhosis (≥12.5kPa) were significantly higher in patients with age ≥40 years, diabetes mellitus, and patients with significant alcohol intake ( P =0.003 to P P =0.023) and HCV genotype ( P =0.008) were independent predictors of SVR. Conclusion The study shows that LSM by TE and fibrosis assessment by FIB4/APRI scores can be used with fair reliability to predict fibrosis and treatment response in patients with CHC infection.

Globally, around 150 million people are infected with hepatitis C virus (HCV). India contributes a large proportion of this HCV burden. The prevalence of HCV infection in India is estimated at between 0.5% and 1.5%. It is higher in the northeastern part, tribal populations and Punjab, areas which may represent HCV hotspots, and is lower in western and eastern parts of the country. The predominant modes of HCV transmission in India are blood transfusion and unsafe therapeutic injections. There is a need for large field studies to better understand HCV epidemiology and identify high-prevalence areas, and to identify and spread awareness about the modes of transmission of this infection in an attempt to prevent disease transmission.

Background Attempts to shorten the overall length of treatment have focused on immediate loading, subsequent to implant placement. Prosthetic rehabilitation immediately after implant placement can be either functional or non-functional in nature. There is paucity of literature on the comparative evaluation of immediate functional and immediate non-functional loading of implants. This in-vivo study was undertaken to comparatively evaluate Immediate Functional Loading and Immediate Non-Functional Loading of monocortical implants with a follow-up period of 18 months. Methods 50 partially edentulous cases were selected for the study. The cases were divided into two groups. In first group (Group-1), 25 implants were subjected to immediate functional loading. In second group (Group-2), 25 implants were subjected to immediate non-functional loading. The crestal bone loss, clinical stability and degree of osseointegration of these two groups were comparatively evaluated. Results The crestal bone loss in both groups was within acceptable limits. The implant stability, which is a reflection of the status of bone-to-implant interface, was comparable in both the groups at different time intervals. Although, the ISQ values in Group-2 were slightly higher than those in Group-1, the results were not statistically significant. Radiodensity indicating degree of osseointegration at different time intervals in both groups was also comparable. Conclusion Both the IFL and INFL protocols can be undertaken satisfactorily in rehabilitation using endosseous implants; however, the main factors for success in IFL and INFL are case selection, meticulous treatment planning and the precision of technique.

The Journal of Clinical and Experimental Hepatology (JCEH) has completed two years of publication and is entering its third year. It has the enviable record of not having missed or delayed a single issue so far. It has gone from strength to strength with every issue, which is thicker, slicker and better received than the previous one. It is now poised to do even better in its third year. The Indian National Association for the Study of Liver (INASL) is a vibrant body which disseminates knowledge about hepato-biliary diseases to healthcare providers, basic scientists and lay public, promotes research in pathophysiology, treatment and prevention of hepato-biliary diseases and develops training programs in the field of Hepatology. JCEH, the official Journal of the Association, was launched during the INASL Annual Conference at Chandigarh on 25th March 2011 and supports these activities by disseminating knowledge on all aspect of the liver and promoting excellence in research and education. All articles published in the Journal are peer-reviewed. The Journal has published papers which are of interest equally to basic research scientists in labs and to clinicians directly involved in patient care. Besides original articles, it also publishes review articles in special sections such as "From Bench to Bedside", "Liver Transplant Forum" and "Seminars", authored by experts in the field. Its MCQs are a compulsive read among Gastroenterology and Hepatology fellows. In 2013, its third year, the Journal, for the first time, plans to come out with three supplement issues. These would be in addition to the Supplement issue of abstracts of 21st Annual Meeting of INASL to be held at Hyderabad from 22-24 March 2013. These Supplements will focus on three important areas, namely "Portal Cavernoma Cholangiopathy (PCC)", "Hepatocellular Carcinoma (HCC)" and "Hepatic Encephalopathy (HE)". Supplements on PCC and HCC are proceedings of INASL Working Parties on the subjects and include a set of focussed reviews as well as Consensus Statements. I am sure these supplements will be of great help to readers of the Journal. Future issues of the Journal will also include consensus statements and practice guideline on topics of interest to hepatologists around the world. My goal is to ensure that the contents of the Journal are useful and of interest to its readers. Active participation by the readers through the "Letter to Editor" section will not only generate a lively debate on the contents and go a long way in sustaining high standards of science and education in the Journal but also reassure the Editorial Board that the contents of the Journal are truly of interest to its readership. I am confident that the JCEH will achieve these goals and will be successful in attaining high standards of science and education.

Introduction Oxidative stress and cytokines play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We compared the presence of oxidative stress and cytokines in 25 patients with NAFLD with 25 age, sex and BMI-matched patients with chronic viral hepatitis (CVH) and 25 healthy volunteers (HV). Methodology Oxidative stress was studied biochemically by markers of lipid peroxidation and biochemical assessment of anti-oxidant status and various cytokines were studied by ELISA. Results Patients with NAFLD had significantly higher levels of malondialdehyde (MDA) ( p = 0.000) and conjugated dienes (CD) ( p = 0.000) in comparison to HVs. Patients with NAFLD also had significantly higher MDA levels ( p = 0.000) in comparison to CVH patients. Patients with NAFLD had significantly lower GSH levels ( p = 0.004) in comparison to HVs. Patients with NAFLD had higher GPx activity ( p = 0.028) in comparison to HVs. Catalase activity was significantly decreased in both NAFLD ( p = 0.001) and CVH patients ( p = 0.000) in comparison to HVs. Patients with NAFLD had significantly higher SOD activity ( p = 0.000) in comparison to CVH patients. There was no difference in serum levels of IL-1β and TNF-α amongst three groups. Patients with CVH were found to have higher IL-8 serum levels ( p = 0.039) in comparison to HVs. CVH patients also had higher TGF-β levels ( p = 0.002) in comparison to both NAFLD patients and HVs. Conclusion Differences in the markers of oxidative stress and anti-oxidant status between NAFLD, CVH and healthy volunteers suggest presence of higher oxidative stress in patients with NAFLD.