Factor In Development Of Hepatocellular Carcinoma Research Articles

Hepatocyte nuclear factor 1 alpha variants as risk factor for hepatocellular carcinoma development with and without diabetes mellitus

BackgroundHNF1A gene variants have been reported to be involved in developing mature onset diabetes mellitus (DM). Many studies reported the role of DM as a risk factor for hepatocellular carcinoma (HCC) development. To date, it has not been reported whether HNF1A gene variants are associated with the risk of DM in cirrhotic patients and their subsequent HCC. ObjectiveTo evaluate the HNF1A (the hepatocyte nuclear factor 1 homeobox A) genetic variants as a cofactor with DM for HCC development in hepatitis C virus (HCV)-infected patients. Subjects and methodsThis study was conducted on 140 subjects; 30 had HCC without DM, 30 HCC with DM, and 40 patients had DM with no HCV infection or had HCC; in addition, 80 healthy volunteers with matched ages and genders were enrolled in the study as a control group. Liver function tests, hepatitis viral markers, alpha-fetoprotein (AFP), fasting sugar and HBA1c and HNF1A (rs2464196 and rs1169310) using real-time polymerase chain reaction (PCR) were done for all participants. ResultsThe frequency of HNF1A rs2464196 (AA) genotype in patient groups (DM, HCC, HCC + DM) was significantly higher compared to the control group (P = 0.006, P = 0.018, P < 0.001 respectively). The combined dominant model (AA + GA) of rs 2464196 was significantly higher than the (GG) genotype in patient groups (DM, HCC, HCC + DM) than the control group. In addition, the frequency of the AA genotype is more prevalent in HCC + DM (73 %) compared to the group of DM or HCC patients. In contrast, the HNF1A rs1169310 (TT, TC or CC genotypes) showed no significant difference among the four studied groups and their T or C allele distributions. ConclusionThis finding suggested that the HNF1A rs2464196 (AA) genotype could be associated with DM and may raise the possibility of HCC development among HCV-infected patients who harbour this genotype more than (GG). On the contrary, the HNF1A rs1169310 polymorphism was of no significance as a risk factor in the current study. However, as we limited our study to Egyptian participants, more research on other ethnic groups would be required. Also, large scale studies are recommended on other variants of HNF1A to clarify the role of this gene in HCC development.

Potential value and advances in research on bone mineral density (BMD) measurement in the auxiliary clinical assessment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide and its prognosis is highly heterogeneous, being related not only to underlying chronic liver disease but also to the severity of cancer cachexia. Nutritional factors play a crucial role in influencing the prognosis of HCC. Despite musculoskeletal imbalance being consistently reported as a predictor of perioperative mortality in patients with HCC, this condition is often overlooked in clinical management. Bone mineral density (BMD), which serves as a marker of nutritional status, can be assessed through CT by measuring the pixel density of the vertebral bone. Recent clinical studies have indicated that BMD serves not only as a significant risk factor for development of HCC in cirrhotic patients but also potentially functions as an independent prognostic indicator for post-treatment outcomes in patients with HCC. Preoperative abdominal CT scans provide a convenient and cost-effective method to measure BMD, offering significant assistance in prognostic evaluation of patients with HCC. A thorough grasp of the liver-bone connection, along with the conduct of higher-quality studies and the establishment of standardized methods and cutoff values for BMD measurement, could enhance approaches to manage HCC.

Value of autotaxin for hepatocellular carcinoma risk assessment in chronic hepatitisB patients treated with nucleos(t)ide analogs.

Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitisB virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitisB based on their clinical characteristics. This retrospective study included 179 patients with hepatitisB virus infection treated with NAs for >2years. First, we measured the ATX levels before and up to 10years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX. The ATX levels showed a gradual and significant decrease during the observation period of up to 10years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis. A decrease in ATX levels up to 10years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups.

Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver malignancy. The interplay between bile acids (BAs) and the gut microbiota has emerged as a critical factor in HCC development and progression. Under normal conditions, BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs. The gut microbiota plays a critical role in BA metabolism, and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis. Of note, dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis, thereby leading to liver inflammation and fibrosis, and ultimately contributing to HCC development. Therefore, understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis. In this review, we comprehensively explore the roles and functions of BA metabolism, with a focus on the interactions between BAs and gut microorganisms in HCC. Additionally, therapeutic strategies targeting BA metabolism and the gut microbiota are discussed, including the use of BA agonists/antagonists, probiotic/prebiotic and dietary interventions, fecal microbiota transplantation, and engineered bacteria. In summary, understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

HEPATOCELLULAR CARCINOMA IN OCCULT HEPATITIS B VIRUS INFECTION: A CASE REPORT

Occult hepatitis B virus infection is defined as the presence of hepatitis B virus DNA in the hepatocytes or serum of individuals who had tested negative for serum HBV surface antigen. Controversies remain as to the role of the occult HBV infection in the development of hepatocellular carcinoma (HCC) in immunocompetent individuals. It has been shown that the persistence of very low viral replicative activity during occult hepatitis B virus infection may induce mild liver necro-inflammation continuing for life, and substantial clinical evidence indicates that occult hepatitis B virus infection can accelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for hepatocellular carcinoma development. The aim of this case is to describe the clinical symptoms and laboratory data of the first case we encountered of HCC occurring in an OBI patient. A 52-year-old man came to the Infectious Diseases Unit because of right upper quadrant pain. Blood test showed negative for HBsAg, positivity for both anti-HBs and anti-HBc total, the quantitative assay of HBV DNA based on TaqMan technology was 2012 copies/mL, elevated serum alpha-fetoprotein level, the findings in abdominal ultrasonography and computed tomography showed a tumor in the right liver lobe with 12cm in size. The patient was transferred to the Military Hospital 175 Ho Chi Minh City for diagnosis of intermediate stage HCC, treated with transarterial chemoembolization (TACE) and antiviral treatment with tenofovir disoproxil fumarate (TDF).

Hepatitis B Virus X Protein Is Stabilized by the Deubiquitinating Enzyme VCPIP1 in a Ubiquitin-Independent Manner by Recruiting the 26S Proteasome Subunit PSMC3.

ABSTRACTHepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, and the viral X protein (HBx) is an etiological factor in HCC development. HBx is a high-turnover protein, but knowledge of the role of deubiquitinating enzymes (DUBs) in maintaining HBx homeostasis is very limited. We used a 74-DUB library-based yeast two-hybrid assay and determined that a novel DUB, valosin-containing protein-interacting protein 1 (VCPIP1), interacted with HBx. VCPIP1 and its C-terminal amino acids 863 to 1221 upregulated the HBx protein expression, with or without HBV infection. Mechanistically, VCPIP1 stabilized HBx protein through a ubiquitin-independent pathway, which was validated by the HBx ubiquitination site mutant plasmid. Coimmunoprecipitation assays demonstrated the potency of VCPIP1 in recruiting 26S proteasome regulatory subunit 6A (PSMC3) and forming a ternary complex with HBx through mutual interaction. In vitro, purified His-tagged PSMC3 protein rescued HBx degradation induced by the 20S proteasome, and in vivo VCPIP1 synergized the mechanism. Functionally, HBx specifically binding to VCPIP1 significantly enhanced the transcriptional transactivation of HBx by activating NF-κB, AP-1, and SP-1 and inhibited hepatoma cell clonogenicity in Huh7 and HepG2 cells. Moreover, we further demonstrated that overexpression of VCPIP1 significantly affected the HBV covalently closed circular DNA (cccDNA) transcription in HBV-infected HepG2-NTCP cells. Altogether, our results indicate a novel mechanism by which VCPIP1 recruits PSMC3 to bind with HBx, stabilizing it in a ubiquitin-independent manner, which might be critical for developing DUB inhibitors in the future.IMPORTANCE HBx is a multifunctional viral oncoprotein that plays an essential role in the viral life cycle and hepatocarcinogenesis. HBx degradation occurs through the ubiquitin-proteasome system (UPS). However, whether novel compartments of the DUBs in the UPS also act in regulating HBx stability is not fully understood. Here, for the first time, we defined VCPIP1 as a novel DUB for preventing HBx degradation by the 20S proteasome in a ubiquitin-independent manner. PSMC3, encoding the 26S proteasome regulatory subunit, directly stabilized HBx through physical binding instead of a common approach in protein degradation, serving as the key downstream effector of VCPIP1 on HBx. Therefore, the ternary binding pattern between VCPIP1, HBx, and PSMC3 is initiated for the first time, which eventually promotes HBx stability and its functions. Our findings provide novel insights into host-virus cross talk by targeting DUBs in the UPS.

Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma.

BackgroundGlutaminolysis is a critical metabolic process that promotes cancer cell proliferation, including hepatocellular carcinoma (HCC). Delineating the molecular control of glutaminolysis could identify novel targets to ameliorate this oncogenic metabolic pathway. Here, we evaluated the role of general control of amino acid synthesis 5 like 1 (GCN5L1), a regulator of mitochondrial protein acetylation, in modulating the acetylation and activity of glutaminase to regulate HCC development.MethodsCell proliferation was determined by MTT, 2D and soft agar clone formation assays and orthotopic tumour assays in nude mice. GLS1/2 acetylation and activities were measured in cells and tumours to analyse the correlation with GCN5L1 expression and mTORC1 activation.ResultsHepatic GCN5L1 ablation in mice markedly increased diethylnitrosamine (DEN)‐induced HCC, and conversely, the transduction of mitochondrial‐restricted GCN5L1 protected wild‐type mice against HCC progression in response to DEN and carbon tetrachloride (CCl4) exposure. GCN5L1–depleted HepG2 hepatocytes enhanced tumour growth in athymic nude mice. Mechanistically, GCN5L1 depletion promoted cell proliferation through mTORC1 activation. Interestingly, liver–enriched glutaminase 2 (GLS2) appears to play a greater role than ubiquitous and canonical tumour–enriched glutaminase 1 (GLS1) in promoting murine HCC. Concurrently, GCN5L1 promotes acetylation and inactivation of both isoforms and increases enzyme oligomerisation. In human HCC tumours compared to adjacent tissue, there were variable levels of mTORC1 activation, GCN5L1 levels and glutaminase activity. Interestingly, the levels of GCN5L1 inversely correlated with mTORC1 activity and glutaminase activity in these tumours.ConclusionsOur study identified that glutaminase activity, rather than GLS1 or GLS2 expression, is the key factor in HCC development that activates mTORC1 and promotes HCC. In the Kaplan–Meier analysis of liver cancer, we found that HCC patients with high GCN5L1 expression survived longer than those with low GCN5L1 expression. Collectively, GCN5L1 functions as a tumour regulator by modulating glutaminase acetylation and activity in the development of HCC.

Bridge-to-transplant stereotactic body radiation therapy in patients with hepatocellular carcinoma and advanced cirrhosis.

TPS496 Background: Liver cancer is the third most common cause of cancer related death worldwide, and hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers, with pre-existing cirrhosis being a very strong risk factor for HCC development. Liver transplantation (LTx) is the best treatment for patients with HCC and advanced cirrhosis as both conditions can be very effectively treated at once. As LTx wait-lists can be many months, liver-directed therapies (LDT), including stereotactic body radiation therapy (SBRT) to one or few lesions are essential as oncologic temporizing measures to bridge patients to LTx and prevent progression outside of LTx criteria. However, due to the fear of further hepatic decompensation, many patients with advanced cirrhosis are excluded from receiving LDT. Rather, recent studies suggest that SBRT be of safe and practical use in this fragile patient population with advanced cirrhosis and HCC, and thereby reduce the rate of transplantation drop-out. This pilot prospective study will assess the feasibility, safety and efficacy of bridge-to-transplantation SBRT for patients with advanced cirrhosis and HCC. Methods: Patients with non-metastatic and unresectable HCC and Child-Pugh (CP)-B8 or worse cirrhosis who are within Milan criteria (one tumor ≤ 5 cm in diameter or no more than 3 tumors each ≤ 3 cm in diameter) and have been listed or recommended to be listed for liver transplantation will be eligible for participation. Eligible participants will undergo SBRT consisting of 40 Gy to be given in 5 fractions every other day to the only or largest lesion, provided that criteria for normal organ constraints are met. In cases where normal organ constraints are not met, the dose will be iteratively de-escalated to two dose levels (35 Gy in 5 fractions, then 30 Gy in 5 fractions). If normal organ constraints are unable to be met at 30 Gy in 5 fractions, the participant will be considered ineligible for SBRT and considered a screen failure. The primary endpoint is the proportion of participants who are transplanted or with localized disease control that meets Milan criteria within a year of SBRT. Secondary endpoints will include localized control rate (mRECIST), incidence of intra- or extra-hepatic progressive disease (mRECIST), overall survival, incidence of liver toxicity per CTCAE v5.0, incidence of non-classical radiation-induced liver disease (defined as CTCAE grade 4 AST/ALT elevation or an increase in CP score of ≥ 2 within 3 months of SBRT) and quality of life scores per QLQ-C30 and FACT-Hep questionnaires. The study is open, aiming to enroll 15 patients with 8 patients enrolled at time of submission. Clinical trial information: NCT03812289.

A Risk Factor In The Development of Hepatocellular Carcinoma: Insulin Analogues Running Title: Insulin Analogues as a Risk Factor for Liver Cancer

Aim: The most important mechanisms in the pathogenesis of the relationship between diabetes mellitus and cancer; hyperglycemia, insulin resistance and the inflammation resulting from the activation of insulin receptors. Apart from insulin resistance, hyperinsulinemia may also occur with the use of exogenous insulin. We aimed to investigate the effect of diabetes mellitus and insulin use as a risk factor for hepatocellular carcinoma development in a large patient population with chronic hepatitis B cirrhosis. Materials and Methods: 493 chronic hepatitis B-associated cirrhotic patients were included in the study. The patients were evaluated at 3-6month intervals during follow-up for hepatocellular carcinoma screening. Demographic and laboratory variables, presence of diabetes mellitus, insülin usage, and hepatocellular carcinoma occurrence were recorded. Results: The mean age of patients was 53.5±13.9 years, and 66.2% were male. 18.7% of the patients had a diagnosis of diabetes mellitus and 12% of the patients had insulin use. 68 patients (13.8%) were decompensated cirrhotic. The mean follow-up period was 50.6±33.6 months, during which 43 patients (8.7%) developed hepatocellular carcinoma. In the multivariable analysis, older age, male gender, presence of decompensation, use of exogenous insulin were associated with HCC occurrence (all p&lt;0.05) Conclusion: Diabetes mellitus and insulin resistance have been associated with many cancers due to insulins’ mitogenic effects. We showed that insulin use is a risk factor for hepatocellular carcinoma development in our chronic hepatitis B-associated cirrhotic patients. Further studies including antidiabetic treatment subgroups are needed.

The TM6SF2 variant as a risk factor for hepatocellular carcinoma development in chronic liver disease patients.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. A non-synonymous single nucleotide polymorphism (SNP) of the transmembrane 6 superfamily member 2 (TM6SF2) gene is associated with non-alcoholic fatty liver disease. SNPs of the TM6SF2 gene play an important role in the pathogenesis of HCC in alcoholic cirrhosis, but there are limited data regarding other possible etiologies. We aimed to evaluate the role of the rs58542926 polymorphism in the development of HCC in Egyptian chronic liver disease (CLD) patients. A total of 120 participants, including 40 HCC patients, 40 CLD patients, and 40 healthy controls, were selected. Real-time polymerase chain reaction (RT-PCR) was used to detect the TM6SF2 rs58542926 polymorphism. There were no significant differences among the three studied groups regarding age (p = 0.06) and gender (p = 0.75). Frequencies of the CT, TT, CT + TT genotypes and the T allele were significantly higher in HCC patients than in the CLD and control groups (p < 0.001, p = 0.005, and p < 0.001, respectively). CLD patients with the CT genotype had a significantly increased risk of HCC development (OR = 4.67, 95% CI: 1.67-12.90). Patients with the TT genotype had a significantly increased risk of HCC (OR = 9.33, 95% CI: 1.72-50.61). Moreover, the T allele was correlated with an increased risk of HCC (OR = 5.44, 95% CI: 2.09-14.17) compared to the C allele. The TM6SF2 rs58542926 genotype is associated with an increased risk of HCC in the Egyptian population.

Predictive Factors for Hepatocellular Carcinoma Development after Direct-Acting Antiviral Treatment of HCV

Chronic hepatitis C virus infection is still one of the major risk factors for the development of hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer. Direct-acting antivirals have substantially improved the cure rate of the virus, but the risk of hepatitis C virus-related HCC remains high, mainly in patients with advanced liver fibrosis and cirrhosis. HCC is often asymptomatic and, therefore, remains undetected until the late tumor stage, which is associated with poor survival rates. Therefore, to improve the surveillance programs following HCV eradication, there is a need to summarize predictive factors or potential biomarkers, to specifically identify patients likely to develop HCC after direct-acting antiviral treatment. This review outlines the most recent data about different predictive factors for HCC development after direct-acting antiviral treatment of hepatitis C virus-infected patients, to improve the clinical management of patients with chronic hepatitis C virus.

Spontaneous Cholemia in C57BL/6 Mice Predisposes to Liver Cancer in NASH.

C57BL/6 mice are widely used for metabolic, cancer, and immunologic studies. High-caloric diets induce a heterogeneous phenotype in C57BL/6 mice, with the majority developing obesity and metabolic syndrome, while others remain lean and metabolically healthy.1 Western diets (WDs), methionine-deficient or choline deficient–based diets are used to study nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH), important risk factors for hepatocellular carcinoma development.2–4

Diagnostic Accuracy of Two-Dimensional Shear Wave Elastography for Liver Fibrosis: A Multicenter Prospective Study

Chronic liver disease (CLD) leads to the development of hepatocellular carcinoma, which is one of the leading causes of cancer-related deaths globally.1 Liver fibrosis is the most important prognostic factor for hepatocellular carcinoma development and prognosis in CLD, and accurate staging of liver fibrosis is pivotal in clinical practice.2 Although liver biopsy is the gold standard for evaluating liver fibrosis, liver biopsy has several limitations including invasiveness, sampling error, and intraobserver and interobserver reproducibility.3 To resolve these problems, several noninvasive methods for evaluating liver fibrosis have been developed using serum fibrosis markers, ultrasound-based modalities, and magnetic resonance imaging-based modalities.4.

Environmental Risk Factors Implicated in Liver Disease: A Mini-Review.

Liver disease is a global health issue, resulting in about two million deaths per year. It encompasses a wide spectrum of varied or unknown etiologies, ranging from lifestyle choices to pre-existing comorbidities. In recent decades, exposure to environmental toxins and subsequent liver health outcomes have captured public interest, due to the extensive application of pesticides, consumption of aflatoxin contaminated foodstuff, and cyanobacterial harmful algae blooms in endemic regions of liver disease. Hepatocellular carcinoma is a serious and debilitating condition of the liver, characterized by abdominal pain and unexplained weight loss. Established risk factors for hepatocellular carcinoma include alcohol consumption, cigarette smoking, and viral infections of hepatitis B and C. However, mounting evidence suggests that environmental toxins may represent an important contributing factor in hepatocellular carcinoma development. This mini-review synthesizes epidemiological investigations, providing evidence for environmental toxins as one potential risk factor for liver disease.

Role of hepatitis D virus infection in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide/nucleoside analogues

Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11–19.46, P < 0.001), followed by HDV RNA positivity (HR/ CI 5.73/1.35–24.29, P = 0.02), age > 50 years old (HR/CI 3.64/2.03–6.54, P < 0.001), male gender (HR/CI 2.69/1.29–5.60, P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03–1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04–19.09, P = 0.04) and BMI (HR/CI 1.11/1.03–1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.

Circulating microRNA-221 as a diagnostic biomarker for hepatitis C virus-related hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third cause of cancer-related mortality as estimated by the World Health Organization (WHO). A major risk factor for HCC development; is Hepatitis C virus (HCV). According to WHO, approximately 55–85% of patients with HCV will develop chronic hepatitis, which lead to progressive fibrosis and cirrhosis. There are no biomarkers for early detection of HCC, and most patients are diagnosed at advanced stages, which is associated with poor prognosis. MicroRNAs have been reported as biomarkers for various pathologic conditions and recently HCC is one of them. Aim: Explore the potential usefulness of serum miR-221 as a diagnostic biomarker of HCV-related HCC. Methods: This study was conducted on 40 chronic HCV patients and 10 healthy control subjects. Patients were divided into two groups: HCC and cirrhosis. All patients and controls were subjected to clinical assessment and laboratory investigations in addition to the evaluation of the level of serum miRNA-221 expression by RT-PCR. Results: MiRNA- 221 showed significant fold increase in both HCC and cirrhosis (P = 0.005) when compared to normal controls. ROC curve analysis for miR-221 yielded 85% sensitivity and 40% specificity for differentiation of HCC patients from non-HCC. Conclusion: Serum miR-221 has a strong potential to serve as one of the biomarkers of early HCC development. This can modify liver carcinogenesis, and can be used to improve preventive, diagnostic, and therapeutic strategies in HCC.Key words: MiRNA; Hepatocellular carcinoma; Hepatitis C Virus

Presence of Hepatic Steatosis Does Not Increase the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Over Long Follow-Up.

Background:Chronic hepatitis B (CHB) infection and nonalcoholic fatty liver disease (NAFLD) are liver diseases which may lead to hepatocellular carcinoma (HCC) formation. Both disease entities have been attributed independently to increase risk of HCC development. While concomitant hepatic steatosis in patients with CHB are becoming more frequent in view of increasing NAFLD prevalence, there is no conclusive evidence linking presence of hepatic steatosis and increased HCC risk in patients with CHB infection. This study explores the association of hepatic steatosis among CHB-infected individuals in HCC development.Methods:This is a retrospective study on a cohort of patients with CHB who underwent liver biopsy between January 2000 and December 2014. They were stratified according to presence and severity of histologically proven hepatic steatosis and subsequently followed up to evaluate the association between hepatic steatosis and HCC development.Results:Among 289 patients with a median follow-up of 111.1 months, hepatic steatosis was present in 185 patients (64.0%). In all, 27 patients developed HCC on follow-up and 21 of them had hepatic steatosis. Univariate Cox analysis showed that age (hazard ratio [HR] = 1.08, 95% CI = 1.042-1.12), type 2 diabetes mellitus (T2DM) (HR = 4.00, 95% CI = 1.622-9.863), and Ishak score (HR = 1.221, 95% CI = 1.014-1.472) were associated with HCC development, whereas multivariate Cox analysis demonstrated that age and T2DM (HR = 2.69, 95% CI = 1.072-6.759) were significant risk factors for development of HCC.Conclusions:Concurrent hepatic steatosis in patients with CHB infection is not a risk factor for hepatocellular carcinoma formation.

Burdock (Arctium lappa L.) root attenuates preneoplastic lesion development in a diet and thioacetamide-induced model of steatohepatitis-associated hepatocarcinogenesis.

Nonalcoholic steatohepatitis (NASH) is considered growing risk factor for hepatocellular carcinoma development in high-income countries. Diet- and chemically induced rodent models have been applied for the translational study of NASH-associated hepatocarcinogenesis due to their morphological and molecular similarities to the corresponding human disease. Arctium lappa L. (burdock) root tea has been extensively consumed in Traditional Chinese Medicine due to its potential therapeutic properties. Indeed, the bioactive compounds of A. lappa root, as the polyphenols, have already showed antioxidant and anti-inflammatory properties in different in vivo and in vitro bioassays. In this study, we investigated whether burdock root ethanolic extract (BRE) administration attenuates NASH-associated hepatocarcinogenesis. Eight-week-old male Wistar rats received choline-deficient high-fat diet for 8 weeks and multiple thioacetamide doses for 4 weeks in order to induce NASH and preneoplastic glutathione-S-transferase pi (GST-P)+ preneoplastic foci. Subsequently, rats were treated with BRE (100 or 200 mg/kg body weight) or vehicle by oral gavage for 2 weeks. BRE displayed high levels of chlorogenic and caffeic acids and BRE administration reduced total fatty acid and lipid hydroperoxide levels, while increasing the activities of antioxidant superoxide dismutase and catalase enzymes in the liver. Furthermore, burdock intervention diminished the size of GST-P+ remodeling preneoplastic lesions (PNLs) and displayed a trend on reducing hepatocyte proliferation (Ki-67) inside them. These findings suggest that short-term exposure to BRE alleviated remodeling PNL development in NASH-associated hepatocarcinogenesis.

Abstract 5046: Gallbladder disease and the risk of hepatocellular carcinoma: US case-control study

Abstract BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with a five-year survival rate of less than 5 percent. Gallbladder disease (GBD) is defined as the presence of cholelithiasis or cholecystitis. Both cholelithiasis and cholecystitis have been reported as risk factors in the development of gastrointestinal cancers, such as biliary tract and pancreatic cancers. Moreover, patients with GBD tend to develop chronic liver diseases, which may progress to cirrhosis. However, the role of GBD in the development of non-cirrhotic related HCC has not been elucidated. We aimed to investigate the role of GBD and the risk of HCC development in the absence of cirrhosis. METHODS: We conducted a case-control study at The University of Texas M.D. Anderson Cancer Center. Cases were defined as pathologically confirmed HCC. Controls were healthy individuals without prior history of cancer, who were spouses of other cancer patients seen at MD Anderson. All subjects were USA residents. Participants were personally interviewed for prior history of GBD and for several HCC risk factors (environmental, behavioral, chronic medical conditions, and family history of cancer). Blood samples of all participants were tested for markers of hepatitis B and C viruses. We reviewed the pathology and radiology records of HCC patients to assess presence and absence of cirrhosis. Multivariable logistic regression analysis was conducted to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for the association between GBD and HCC in the absence of cirrhosis and with adjustment for potential confounders. RESULTS: Between 2000 and 2017, a total of 1333 cases and 1104 controls were enrolled in the study. After review, 347 HCC case patients showed no evidence of cirrhosis and were eligible for this analysis. The prevalence of GBD based on the participants’ recall during personal interview was 22.7% in the cases. Upon further assessment by review of medical records, the prevalence of GBD was 40.3% in the cases. Individuals with GBD were two times more likely to develop HCC than individuals with no history of GBD (AOR = 2.0; 95% CI: 1.4 – 2.8). The estimated AOR did not meaningfully change when we rely on the prevalence of GBD recalled by cases (22.7%) versus prevalence of GBD obtained from medical records (40.3%). The association between GBD and HCC continue to be significant in the absence of viral hepatitis, through a restricted analysis among non-viral non-cirrhotic population after controlling for age, sex race, alcohol use, cigarette smoking, diabetes mellitus, and family history of cancer. CONCLUSIONS: We conclude that GBD is a significant risk factor for HCC development in absence of cirrhosis. Future research aiming at investigating the underlying mechanism of GBD-induced HCC in absence of cirrhosis should be warranted. In addition, patients with GBD should be screened for evidence of cirrhosis. Citation Format: Kenda Al-Assi, Rikita Hatia, Vijayashri Rallapalli, Yehia I. Abugabal, Ahmed Abdelhakeem, Reham Abdel-Wahab, Kanwal Raghav, Prasun K. Jalal, Ahmed Kaseb, Asif Rashid, Donghui Li, Manal Hassan. Gallbladder disease and the risk of hepatocellular carcinoma: US case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5046.

N-3 PUFAs reduce tumor load and improve survival in a NASH-tumor mouse model

Background:With 9.1% of all cancer deaths, hepatocellular carcinoma is the second leading cause of cancer deaths worldwide. Due to the increasing prevalence of metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has evolved into a major risk factor for hepatocellular carcinoma development. Herein, we investigated whether a dietary n-3 polyunsaturated fatty acid (PUFA) supplementation improves the outcome of progressive NAFLD.Methods:Feeding three high-fat diets, differing in n-3 and n-6 PUFA contents and ratios (n-3/n-6: 1:8, 1:1, 5:1), the impact of n-3 PUFAs and n-3/n-6 PUFA ratios on NAFLD-related liver fibrosis and tumorigenesis was analyzed in 12- and 20-week-old streptozotocin/high-fat diet (STZ/HFD)-treated mice.Results:Feeding of n-3 PUFA-rich diets (1:1 and 5:1) resulted in increased hepatic n-3 PUFA content and n-3/n-6 PUFA ratio with decreased hepatic lipid accumulation. In 20-week-old mice, n-3 PUFA-rich diets alleviated tumor load significantly, with reduced liver/body weight index, tumor size, and tumor number. Finally, these effects were accompanied by a significant improvement of survival of these mice.Conclusions:Herein, we showed that increased n-3 PUFA content and n-3/n-6 PUFA ratios lead to improved survival and attenuated tumor progression in STZ/HFD-treated mice. Thus, n-3 PUFAs could be the basis for new therapeutic options against NAFLD-related tumorigenesis.