Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction.

e16199 Background: Primary liver cancer is the third most frequent cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) composing 75% of cases. Recent preclinical models suggest that immunotherapy targeting programmed cell death protein 1 (PD-1) leads to CD8+ T-cell activation but not tumor regression in nonalcoholic fatty liver disease (NAFLD) induced HCC. However, additional studies are required to understand the response of NAFLD-associated HCC patients to PD-1 and programmed death-ligand 1 (PD-L1) therapies. Methods: Our team conducted a retrospective, single center study to determine the best responses to anti-PD-1/PD-L1 containing regimens in patients with HCC and underlying NAFLD cirrhosis. There were 2 groups included in this study: patients with HCC associated with NAFLD cirrhosis and those who had HCC without NAFLD cirrhosis. All patients included in this study received either an anti-PD-1/PD-L1 targeted agent as monotherapy or combined with other systemic treatment. Radiologic evaluations were conducted between February 2018 and January 2022. Results: There were 81 patients were included in this study: 15 in the NAFLD cirrhosis HCC group and 66 in the HCC group without NAFLD cirrhosis. When determining the best responses to anti-PD-1/PD-L1 therapies, 6 patients (40%) with HCC and NAFLD cirrhosis had disease progression as their best responses versus 7 patients (10.6%) who had HCC without NAFLD cirrhosis (risk ratio 3.8, p = 0.012). Furthermore, in the HCC group without NAFLD cirrhosis, 59 patients (89.4%) experienced disease control (defined as stable disease, partial response, or complete response) from anti-PD-1/PD-L1 containing regimens compared to 9 patients (60%) in the NAFLD cirrhosis-related HCC group (risk ratio 1.5, p = 0.012). No significant differences were found in gender, patient age, or treatment regimens received between the two groups. See the table below for details on immunotherapy regimens and treatment responses. Conclusions: In this study, HCC patients with NAFLD cirrhosis experienced significantly higher rates of disease progression as the best response to anti-PD-1/PD-L1 therapies compared to HCC patients without NAFLD cirrhosis. As the use of immunotherapy in the HCC population continues to expand, additional prospective studies are necessary to clarify the impact of underlying liver disease on treatment response.[Table: see text]

Multi-omic Analyses Reveal Complex Interactions Between HCVand Hepatocytes Demonstrating That the Red Queen IsUpand Running.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and, indeed, worldwide. It has become a global public health issue. In the United States, the prevalence in the general population is estimated at approximately 20%, while that in the morbidly obese population at approximately 75-92% and in the pediatric population at approximately 13-14%. The progressive form of NAFLD, nonalcoholic steatohepatitis, is estimated at approximately 3-5%, with approximately 3-5% of these having progressed to cirrhosis. Thus, the numbers of individuals at risk for end-stage liver disease and development of primary liver cancer is large. NAFLD is an independent risk factor for cardiovascular disease, leads to increased all-cause mortality, and to increased liver-related mortality. This review focuses on recent advances in our understanding of the NAFLD disease spectrum, including etiology, diagnosis, treatment, and genetic and environmental risk factors and suggests future directions for research in this important area.

Primary liver cancer is the sixth most common cancer and the third highest cause of cancer-related deaths, globally. Hepatocellular carcinoma (HCC) is the predominate form of primary liver cancer, comprising 75-85% of the cases. Approximately 60% of HCCs are associated with a chronic hepatitis B virus (HBV) infection. Additionally, the increasing number of obese individuals in the United States has been linked to an increase in obesity-associated liver diseases such as non-alcoholic fatty liver disease (NAFLD). In Western countries, the incidence of NAFLD associated HCC is also on the rise and has been linked to 4-22% of HCC. In studies described here, we examined whether localization of the Hepatitis B Virus (HBV) HBx protein with mitochondria affects HBV replication and separately analyzed the interplay of changes in the gut microbiome and the liver transcriptome in the context of NAFLD development. HBx is required for efficient HBV replication and is thought to contribute to the development of HBV-associated HCC. Several studies have shown that a fraction of cytosolic HBx localizes to mitochondria in established cell lines and primary hepatocytes. Numerous studies have shown that HBx localizes to mitochondria and affects mitochondrial physiology. However, prior to our study, it was not known whether HBx affects on mitochondria or on HBV replication requires HBx localization to mitochondria. We now report that HBx localization to mitochondria is associated with efficient HBV replication in HepG2 cells and cultured primary rat hepatocytes. We also show that HBx localization to mitochondria is associated with activating signaling pathways directly or indirectly linked with HBx-induced elevation of cytosolic calcium levels, an essential function of HBx that is also required for HBV replication. Cumulatively, our research suggests that HBx association with mitochondria contributes to efficient HBV replication and is responsible for activating signaling pathways associated with HBx-induced elevation of calcium. NAFLD arises from the accumulation of lipids in hepatocytes, the major cell type of the liver, and the resulting liver inflammation as immune cells enter the liver in response to lipid accumulation. Recently, studies in mice and humans have shown that there are alterations in the composition of the gut microbiome in individuals with NAFLD as compared to healthy individuals. However, the mechanism by which the gut microbiome contributes to NAFLD is unclear. While previous studies characterized microbiome changes during NAFLD development, no previous studies have correlated changes in the gut microbiome with changes in liver gene expression. Feeding mice a high-fat diet (HFD) is a model system for studying obesity and associated metabolic disorders such as NAFLD. We characterized changes in gut bacteria and liver gene expression associated with the development of NAFLD in both male and female mice fed a HFD. We also analyzed the effect of non-fermentable fiber on the development of NAFLD. We analyzed the effect of supplementing the HFD and a standard diet (SD) with non-fermentable fiber on liver lipid content. Our research demonstrated that only SD supplemented with non-fermentable fiber resulted in decreased liver lipid content as compared to HFD, with or without non-fermentable fiber supplementation, and SD without non-fermentable fiber supplementation. While numerous studies have shown positive effects of supplementing diets with fiber, before our study, it was unknown whether supplementing diets with non-fermentable fiber could affect the accumulation of lipids in the liver and, consequently, the development of NAFLD. Our results suggest that fiber content, specifically non-fermentable fiber, in the diet is important in preventing the accumulation of lipids in hepatocytes and the development of NAFLD.

Two drinks per day does not take your fatty liver away.

Background The drug-eluting beads transarterial chemoembolization (DEB-TACE) has already been used in hepatic malignancies. We aim to evaluate the efficacy and safety of DEB-TACE in treating primary or secondary liver cancer. Methods We retrospectively evaluated 59 patients with hepatic malignancies, including 41 patients with primary liver cancer and 18 patients with secondary liver cancer, between September 2016 and February 2019. All patients were treated with DEB-TACE. Objective response rate (ORR) and disease control rate (DCR) were evaluated by mRECIST. The pain was assessed using a numerical rating scale (NRS) where 0 represented no pain, and a score of ten was unbearable. Adverse reactions were assessed according to Common Terminology Criteria for Adverse Events 4.0 (CTCAE4.0). Results In the subgroup of primary liver cancer, 3 patients (7.32%) got complete response, 13 patients (31.71%) got partial response, 21 patients (51.22%) experienced stable disease, and 4 patients (9.76%) suffered progressive disease; ORR was 39.02% and DCR was 90.24%. In the subgroup of secondary liver cancer, 0 patients (0%) got complete response, 6 patients (33.33%) got partial response, 11 patients (61.11%) experienced stable disease, and 1 patient (5.56%) suffered progressive disease; ORR was 33.33% and DCR was 94.44%. We did not find any difference when comparing the efficacy between primary and secondary liver cancer (P=0.612). The one-year survival rate was 70.73% for primary liver cancer and 61.11% for secondary liver cancer. There was no significant difference between the two groups (P=0.52). For the patients with CR or PR, no factor could predict the efficacy of DEB-TACE. The most common treatment-related adverse reactions were short-term liver function disorders. The symptoms included fever (20.34%), abdomen pain (16.95%), and vomiting (5.08%), all patients with adverse reactions got remission after treatment. Conclusions DEB-TACE has a promising effect in the treatment of primary or secondary liver cancer. The treatment-related adverse reactions are tolerable.

Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.

We aimed to elucidate the frequency of polymorphic genotypes and alleles of patatin-like phospholipase domain containing 3 rs738409 polymorphism and its possible associations with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis in a cohort from Turkey.We enrolled 200 patients diagnosed with NAFLD and genotyped for rs738409 I148M polymorphism by real-time polymerase chain reaction, particularly by melting curve analysis. SPSS analysis software was used for statistical significance. Continuous variable values were expressed as mean ± standard deviation. Significant statistical level was chosen as p = 0.05.Our results demonstrate in a cohort from Turkey that rs738409 C > G polymorphism (I148M) of patatin-like phospholipase domain containing 3 gene is significantly able to affect individuals to have NAFLD in unadjusted regression model.Consistent with the previous studies in other populations, our study group showed a significantly higher risk of having NAFLD in unadjusted regression model but not in the adjusted model indicating that non-genetic factors such as age and sex may be responsible for the association. However, independent studies need to validate our findings with a larger group of NAFLD patients, as well as in different ethnic cohorts.

Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progress to cirrhosis, a significant risk factor of hepatocellular carcinoma (HCC), the commonest malignant primary liver cancer (PLC). We investigated the association between the individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity), PLC and cirrhosis. A total of 509,436 participants from the Swedish AMORIS cohort, recruited between January 1985 and December 1996 (end-date December 2011), aged ≥20 with baseline triglycerides (TG), total cholesterol (TC), glucose and liver enzymes were included. Those with baseline benign liver tumours, PLC or cirrhosis were excluded. Multivariate Cox regression, adjusted for age, gender, socio-economic status, liver disease (excluding cirrhosis) and MetS factors were used to estimate the association with PLC and cirrhosis. There were 766 PLC and 2,775 cirrhosis cases over 13 years. Raised TG, low TC, raised glucose, diabetes and low HDL were associated with an increased risk of developing PLC and cirrhosis. ApoB/ApoA-I ratio were also associated with PLC, whilst low LDL, raised TG/HDL, low ApoA-I and low ApoB were associated with cirrhosis. Obesity was significantly associated with PLC but not cirrhosis. Raised TG, low TC, raised glucose and diabetes showed stronger associations with PLC in participants with cirrhosis but many participants developed PLC without cirrhosis. Individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity) were associated with an increased risk of developing PLC or cirrhosis. MetS components were more strongly associated with PLC with preceding cirrhosis history but many participants developed PLC without cirrhosis.

Organoid models in viral hepatitis, primary liver cancer, and non-alcoholic fatty liver disease: Advances and challenges.

MYC determines lineage commitment in KRAS-driven primary liver cancer development

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

From the Editor’s desk…: August 2019