The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020.This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid-defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P-positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH. Supplementary material for this article can be found on the HEPATOLOGY website

Vascular endothelial growth factor (VEGF) has been identified as a vascular permeability factor, angiogenic cytokine, and a survival factor. To address its role in mammary carcinogenesis, we used transgenic mice with human VEGF(165) targeted to mammary epithelial cells under the control of the mouse mammary tumor virus (MMTV) promoter. Metastatic mammary carcinomas were induced by mating the MMTV-VEGF mice with MMTV-polyoma virus middle T-antigen (MT) mice to generate VEGF/MT mice. Tumor latency was decreased in the VEGF/MT mice, which developed mammary carcinomas with increased vasodilatation at 4 weeks of age. There was increased incidence, multiplicity, and weight of the mammary tumors in 6- and 8-week-old VEGF/MT mice, compared to their MT-only littermates. Macro- and microscopic lung metastases were detected in the VEGF/MT mice but not the MT mice at 6 and 8 weeks of age. Enhanced tumor growth was attributed to increased microvascular density (MVD), as well as increased tumor cell proliferation and survival. Angiogenesis array analysis showed that 24 of 25 differentially expressed genes were upregulated in the VEGF/MT tumors. In vitro studies revealed increased proliferative activity and upregulation of Flk-1 in the VEGF/MT tumor cells, compared with the MT-only tumor cells. Moreover, there was decreased proliferative activity with downregulation of Flk-1 in tumor cells isolated from conditional knockout (VEGF(-/-)) MT-induced mammary carcinomas. The slow growing VEGF(-/-) tumor cells were accumulated in the G(1)/G(0) phase of the cell cycle and this was associated with stimulation of p16(ink4a) and p21(WAF1). Similarly, p16(ink4a) was stimulated in VEGF(lox/lox)/MT mammary tumor cells following Adeno-cre-mediated VEGF gene inactivation. Collectively, the data from these transgenic models indicate that VEGF contributes to mammary tumor growth through increased neovascularization, as well as autocrine stimulation of growth and inhibition of apoptosis.