Cholelithiasis is one of the commonest diseases in gastroenterology. Remarkable improvements in therapeutic modalities for cholelithiasis and its complications are evident. The Japanese Society of Gastroenterology has revised the evidence-based clinical practice guidelines for cholelithiasis. Forty-three clinical questions, for four categories-epidemiology and pathogenesis, diagnosis, treatments, and prognosis and complications-were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This article preferentially describes the clinical management of cholelithiasis and its complications. Following description of the diagnosis performed stepwise through imaging modalities, treatments of cholecystolithiasis, choledocholithiasis, and hepatolithiasis are introduced along with a flowchart. Since there have been remarkable improvements in endoscopic treatments and surgical techniques, the guidelines ensure flexibility in choices according to the actual clinical environment. The revised clinical practice guidelines are appropriate for use by clinicians in their daily practice.

We compared the effects of 12-week programs of resistance training (RT), high-intensity interval aerobic training (HIAT), and moderate-intensity continuous aerobic training (MICT). The primary goal was to evaluate the therapeutic effects of the exercise modalities for the management of nonalcoholic fatty liver disease (NAFLD). A total of 61 sedentary obese men with NAFLD were randomized into one of the following exercise regimens (RT, HIAT, or MICT). Hepatic fat content was decreased to a similar extent in the RT, HIAT, and MICT groups (−14.3% vs. −13.7% vs. −14.3%) without significant changes in weight and visceral fat. The gene expression levels of fatty acid synthesis were significantly decreased in the subjects’ monocytes. Hepatic stiffness was decreased only in the HIAT group (−16.8%). The stiffness change was associated with restored Kupffer cell phagocytic function (+17.8%) and decreased levels of inflammation such as leptin (−13.2%) and ferritin (−14.1%). RT, HIAT, and MICT were equally effective in reducing hepatic fat content, but only HIAT was effective in improving hepatic stiffness and restoring Kupffer cell function. These benefits appeared to be independent of detectable weight and visceral fat reductions; the benefits were acquired through the modulation of in vivo fatty acid metabolism and obesity-related inflammatory conditions.

Purpose: We present results of patients with hepatocellular carcinoma (HCC) treated with proton beam therapy. Experimental Design: We reviewed 162 patients having 192 HCCs treated from November 1985 to July 1998 by proton beam therapy with or without transarterial embolization and percutaneous ethanol injection.The patients in the present series were considered unsuitable for surgery for various reasons, including hepatic dysfunction, multiple tumors, recurrence after surgical resection, and concomitant illnesses. The median total dose of proton irradiation was 72 Gy in 16 fractions over 29 days. Results: The overall survival rate for all of the162 patients was 23.5% at 5 years.The local control rate at 5 years was 86.9% for all 192 tumors among the 162 patients.The degree of impairment of hepatic functions attributable to coexisting liver cirrhosis and the number of tumors in the liver significantly affected patient survival. For 50 patients having least impaired hepatic functions and a solitary tumor, the survival rate at 5 years was 53.5%.The patients had very few acute reactions to treatments and a few late sequelae during and after the treatments. Conclusions: Proton beam therapy for patients with HCC is effective, safe, well tolerable, and repeatable. It is the useful treatment mode for either cure or palliation for patients with HCC irrespective of tumor size, tumor location in the liver, insufficient feeding of the tumor with arteries, presence of vascular invasion, impaired hepatic functions, and coexisting intercurrent diseases.

Inchin-ko-to (ICKT), an herbal medicine, and its ingredients exert potent choleretic effects by a "bile acid-independent" mechanism. The current study was designed to determine whether ICKT or its ingredients potentiate multidrug resistance-associated protein 2 (Mrp2; Abcc2)-mediated choleresis in vivo. Biliary secretion of Mrp2 substrates and the protein mass, subcellular localization, and messenger RNA (mRNA) level of Mrp2 were assessed in rat liver after infusion of genipin, an intestinal bacterial metabolite of geniposide, a major ingredient of ICKT. The function of Mrp2 was also assessed by the adenosine triphosphate (ATP)-dependent uptake of Mrp2-specific substrates using canalicular membrane vesicles (CMVs) from the liver. Infusion of genipin increased bile flow by 230%. It also increased biliary secretion of bilirubin conjugates and reduced glutathione (GSH) by 513% and 336%, respectively, but did not increase bile acid secretion. The ATP-dependent uptake of estradiol 17-␤-D-glucuronide (E 2 17␤G; by 265%), leukotriene C4 (LTC 4 ; by 161%), taurolithocholate-3-sulfate (TLC-3S; by 266%), and methotrexate (MTX; by 234%) was significantly stimulated in the CMVs from the liver. These effects were not observed in Mrp2-deficient rats. Under these conditions, genipin treatment increased the protein mass of Mrp2 in the CMVs but not the mRNA level. In immunoelectron microscopic studies, a marked increase in Mrp2 density in the canalicular membrane (CM) and microvilli was observed in the genipin-treated liver tissue sections when compared with the vehicle-treated liver tissue sections. In conclusion, genipin may enhance the bile acid-independent secretory capacity of hepatocytes, mainly by stimulation of exocytosis and insertion of Mrp2 in the bile canaliculi. ICKT may be a potent therapeutic agent for a number of cholestatic liver diseases. (HEPATOLOGY 2004;39:167-178.)

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Oxidative stress is a critical mediator in liver injury of steatohepatitis. The transcription factor Nrf2 serves as a cellular stress sensor and is a key regulator for induction of hepatic detoxification and antioxidative stress systems. The involvement of Nrf2 in defense against the development of steatohepatitis remains unknown. We aimed to investigate the protective roles of Nrf2 in nutritional steatohepatitis using wild-type (WT) and Nrf2 gene-null (Nrf2-null) mice. WT and Nrf2-null mice were fed a methionine- and choline-deficient (MCD) diet for 3 and 6 wk, and the liver tissues were analyzed for pathology and for expression levels of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. In WT mice fed an MCD diet, Nrf2 was potently activated in the livers, and steatohepatitis did not develop over the observation periods. However, in Nrf2-null mice fed an MCD diet, the pathological state of the steatohepatitis was aggravated in terms of fatty changes, inflammation, fibrosis, and iron accumulation. In the livers of the Nrf2-null mice, oxidative stress was significantly increased compared with that of WT mice based on the increased levels of 4-hydroxy-2-nonenal and malondialdehyde. This change was associated with the decreased levels of glutathione, detoxifying enzymes, catalase, and superoxide dismutase activity. Correlating well with the liver pathology, the mRNA levels of factors involved in fatty acid metabolism, inflammatory cytokines, and fibrogenesis-related genes were significantly increased in the livers of the Nrf2-null mice. These findings demonstrate that Nrf2 deletion in mice leads to rapid onset and progression of nutritional steatohepatitis induced by an MCD diet. Activation of Nrf2 could be a promising target toward developing new options for prevention and treatment of steatohepatitis.

Recently, the beneficial effects of increased physical activity (PA) on nonalcoholic fatty liver disease (NAFLD) in obese subjects were reported. However, the optimal strength and volume of PA in lifestyle modification to improve NAFLD pathophysiology and be recommended as an appropriate management of this condition are unclear. The primary goal of this retrospective study was to estimate the beneficial effects of a varying volume of moderate to vigorous intensity PA (MVPA) on the improvement of NAFLD. A total of 169 obese, middle-aged men were enrolled in a 12-week weight reduction program through lifestyle modification consisting of dietary restrictions plus aerobic exercise. Among these obese subjects, 40 performed MVPA for <150 minÁwk 21 , 42 performed MVPA for 150-250 minÁwk 21 , and 87 performed MVPA for >250 minÁwk 21 . The subjects in the MVPA !250 minÁwk 21 group, in comparison with those in the MVPA <250 minÁwk 21 group, showed significantly attenuated levels of hepatic steatosis (231.8% versus 223.2%). This attenuation was likely independent of the detectable weight reduction. MVPA for !250 minÁwk 21 in comparison with that for <150 minÁwk 21 led to a significant decrease in the abdominal visceral adipose tissue severity (240.6% versus 212.9%), levels of ferritin (213.6% versus 11.5%), and lipid peroxidation (215.1% versus 22.8%), and a significant increase in the adiponectin levels (117.1% versus 15.6%). In association with these changes, the gene expression levels of sterol regulatory element-binding protein-1c and carnitine palmitoyltransferase-1 in peripheral blood mononuclear cells also significantly decreased and increased, respectively. Conclusion: MVPA for !250 minÁwk 21 as part of lifestyle management improves NAFLD pathophysiology in obese men. The benefits seem to be acquired through reducing inflammation and oxidative stress levels and altering fatty acid metabolism. (HEPATOLOGY 2015;61:1205-1215

The protective action of ursodeoxycholic acid (UDCA) in cholestatic liver diseases may be mediated by choleresis, detoxification, and cytoprotection against oxidative stress. Nrf2, one transcription factor, serves as a cellular stress sensor and is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes, and numerous Mrp family members. We aimed to investigate whether UDCA induces hepatic Mrp expression along with that of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. The protein level, subcellular localization, and mRNA level of Mrp family members were assessed in livers of Keap1 gene-knockdown (Keap1-kd) mice and those of UDCA-fed wild-type (WT) and Nrf2 gene-null (Nrf2-null) mice. Nuclear levels of Nrf2 in livers of Keap1-kd mice markedly increased, resulting in constitutive activation of Nrf2. Keap1-kd mice have high-level expression of hepatic Mrp2, Mrp3, and Mrp4 relative to WT mice. UDCA potently increased nuclear Nrf2 expression level in livers of WT mice, and the treatment showed maximal hepatic induction of Mrp2, Mrp3, and Mrp4 in association with enhanced membranous localizations in an Nrf2-dependent manner. UDCA similarly increased nuclear Nrf2 expression level in rat hepatocytes. Chromatin immunoprecipitation assays using mouse hepatocytes revealed the binding of Nrf2 to antioxidant response elements in the promoter regions of Mrp2, Mrp3, and Mrp4. These findings demonstrate an important role of Nrf2 in the induction of Mrp family members in livers and suggest that a therapeutic mechanism of UDCA action is, via Nrf2 activation, a stimulation of detoxification and antioxidative stress systems, along with Mrp-mediated efflux transport.