Clinicopathological characteristics of non‐B non‐C hepatocellular carcinoma without past hepatitis B virus infection

Kimura, Takefumi; Kobayashi, Adam; Sakai, Kenji; Komatsu, Michiharu; Fujimori, Naoyuki; Yamazaki, Tomoo; Shibata, Soichiro; Ichikawa, Yūki; Joshita, Satoru; Umemura, Takeji; Matsumoto, Akihiro; Horiuchi, Akira; Mori, Hiromitsu; Wada, Shinpei; Kiyosawa, Kendo; Miyagawa, Shinichi; Tanaka, Naoki

doi:10.1111/hepr.12762

Cited by 32 publications

(34 citation statements)

References 51 publications

(83 reference statements)

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“…HCC is a leading cause of cancer mortality, with poor prognosis and very few effective therapeutic options. Risk factors for HCC include persistent infection with hepatitis B and C viruses, obesity, metabolic syndrome, nonalcoholic steatohepatitis, alcohol consumption, exposure to aflatoxins, and inborn errors of metabolism, such as α‐1 antitrypsin deficiency, tyrosinemia, and citrin deficiency . Recently, gut microbiota and BAs were also shown to be associated with HCC development …”

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confidence: 99%

Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development

et al. 2018

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Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, and an association between altered bile acid (BA) metabolism, down‐regulation of farnesoid X receptor (FXR), which is a master regulator of BA metabolism, and hepatocarcinogenesis has been documented. While global FXR deficiency in mice results in spontaneous HCC with aging, the contribution of tissue‐specific FXR deficiency to hepatocarcinogenesis remains unclear. In this study, the prevalence of hepatic tumors, expression of genes related to tumorigenesis, and serum/liver BA levels were compared among male whole‐body Fxr‐null, hepatocyte‐specific Fxr‐null (Fxr ∆Hep), and enterocyte‐specific Fxr‐null (Fxr ∆IE) mice at the age of 3, 14, and 20 months. More than 90% of 20‐month‐old whole‐body Fxr‐null mice had hepatic tumors with enhanced hepatic expression of myelocytomatosis oncogene (Myc) and cyclin‐dependent kinase 4 (Cdk4) messenger RNAs (mRNAs) and elevated serum taurocholate (TCA) and tauromuricholate (TMCA) and their respective unconjugated derivatives. The incidence of hepatic tumors was significantly lower in Fxr ∆Hep and Fxr ∆IE mice (20% and 5%, respectively), and the increases in Myc and Cdk4 mRNA or serum BA concentrations were not detected in these mice compared to Fxr floxed [fl]/fl mice; a similar tendency was observed in 14‐month‐old mice. However, increased hepatic c‐Myc protein expression was found only in Fxr‐null mice at the age of 3, 14, and 20 months. Treatment with TCA induced Myc expression in Fxr‐null cultured primary mouse hepatocytes but not in wild‐type (WT) mouse hepatocytes, demonstrating that the combination of hepatocyte FXR disruption with elevated TCA is required for Myc induction and ensuing age‐dependent hepatocarcinogenesis in Fxr‐null mice. Conclusion: There is a relatively low risk of hepatic tumors by inhibition of FXR in enterocytes, likely due to the lack of increased TCA and Myc induction.

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confidence: 99%

Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development

et al. 2018

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“…In Europe, NAFLD-related HCC comprised 35% of all HCC cases in 2010. HCC that is not related to hepatitis B or C is becoming increasingly frequent in Japan as well; however, here, it comprises only 10% of all HCC cases [53]. NASH is responsible for higher percentage of HCC in Western than in Eastern societies [12].…”

Section: Nash-induced Hccmentioning

confidence: 87%

“…Although previously it was considered that HCC risk is limited to cirrhotic patients, currently at least 25-30% of NAFLD-related hepatocellular carcinomas develop in the absence of cirrhosis [9]. In Japanese group, 33% of NAFLD-related HCC occurred in the background of none or mild fibrosis contrasting with only 16% in alcohol-induced HCC [53]. According to other researchers, up to 65% of NAFLD-associated HCC evolve in the absence of fibrosis [49].…”

Section: Nash-induced Hccmentioning

confidence: 96%

Non-Alcoholic Steatohepatitis, Liver Cirrhosis and Hepatocellular Carcinoma: The Molecular Pathways

Mezale¹,

Štrumfa²,

Vanags³

et al. 2017

Liver Cirrhosis - Update and Current Challenges

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Non-alcoholic steatohepatitis (NASH) is growing into global problem, mainly due to NASH-induced cirrhosis and hepatocellular carcinoma (HCC), that can develop either subsequently to cirrhosis or preceding it. In addition, NASH-induced cirrhosis constitutes a significant fraction of cases diagnosed as cryptogenic cirrhosis. Thus, there is a need for deeper understanding of the molecular basis, leading to liver steatosis, then-to the associated inflammation seen in NASH, loss of liver architecture and cirrhosis, followed or paralleled by carcinogenesis and HCC. Insulin resistance, increased hepatic iron level, and certain cytokines, including TNF-α and IL-6 derived from extrahepatic adipose tissues, can trigger the chain of events. The imbalance between leptin and adiponectin is important as well. These markers remain important during the whole course from NASH through liver cirrhosis to HCC. The molecular pathogenesis substantiates treatment: hypertriglyceridemia can be lowered by low calorie diet; mTOR complex can become inhibited by physical activity and metformin; cholesterol synthesis, RAF/ MAPK1/ERK and p21 pathway by statins; inflammation by pentoxyfillin, and kinases (in HCC) by sorafenib. Bidirectional regulation of telomere attrition, senescence and p21 pathway, restoration of wild-type p53 activity and regulation of miRNA network represent attractive future treatment options. Focusing on relevant molecular pathways allows deeper understanding of NASH pathogenesis, leading to identification of predictive markers and treatment targets.[10] and other Western industrialised countries, facing high occurrence of the major risk factors for NAFLD, namely, central obesity, type 2 diabetes mellitus, dyslipidemia and metabolic syndrome [11]. In a recent meta-analysis of 86 studies, comprising 8,515,431 persons from 22 countries, the global prevalence of NAFLD was 25.24% (95% confidence interval [CI], showing the highest occurrence in the Middle East and South America and the lowest in Africa [5].Liver Cirrhosis -Update and Current Challenges 2 Thus, 90% of patients suffering from morbid obesity (defined as having body mass index 40 kg/m 2 or higher) and 74% patients affected by diabetes mellitus develop NAFLD. In addition, NAFLD has been observed even in non-obese, non-diabetic patients who have increased insulin levels in blood and resistance to insulin action. Consequently, NAFLD affects up to 20-30% of adults in Europe and 46% in the USA: a tremendously high prevalence for a condition that can cause any significant complications [9, 10]. Non-Alcoholic Steatohepatitis, Liver Cirrhosis and Hepatocellular Carcinoma: The Molecular Pathways http://dx.doi.org/10.5772/intechopen.68771 3Most patients are diagnosed with NAFLD in their 40s or 50s. Studies vary in regard to the gender distribution of NAFLD, with some suggesting that it is more common in women and others suggesting more frequent occurrence in men [11,12].Since 1998, non-alcoholic fatty liver disease has been considered a condition with a "two-hit" course of...

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“…Other glucose‐lowering agents had already been administered in three patients. Non‐alcoholic steatohepatitis was suspected based on the criteria of: (i) the presence of hepatorenal contrast and increased hepatic echogenicity on abdominal ultrasonography; (ii) ethanol consumption of <20 g/day; (iii) the absence of other causes of liver dysfunction, such as viral hepatitis, drug‐induced liver injury, autoimmune liver diseases, primary sclerosing cholangitis, Wilson disease, hereditary hemochromatosis, and citrin deficiency; and (iv) histologically confirmed using biopsied specimens. Body weight (BW) and height were measured before liver biopsy in a fasting state.…”

Section: Methodsmentioning

confidence: 99%

“…The presence of obesity was defined as a body mass index (BMI) >25 kg/m 2 according to criteria released by the Japan Society for the Study of Obesity. Clinical information was also recorded, with the presence of hypertension and hyperlipidemia being evaluated as described previously …”

Section: Methodsmentioning

confidence: 99%