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This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy‐proven NAFLD were enrolled. After propensity‐score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis‐4 (FIB‐4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4‐7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB‐4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4‐7S. The AUROCs in patients with diabetes were 0.790 for the FIB‐4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4‐7S. The AUROC of COL4‐7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4‐7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4‐7S was better than that of the other NITs, especially in patients with diabetes. Conclusion: COL4‐7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.

The FIB4 index is clinically useful, but because its formula includes age, the appropriate cutoff point may differ by age group. Here, new FIB4 index cutoff points were validated using cohort data from 14 hepatology centers in Japan. The FIB4 index was determined in biopsy-confirmed NAFLD patients (n = 1050) who were divided into four groups: ≤ 49, 50–59, 60–69, and ≥ 70 years. ROC analysis predicted advanced fibrosis in each age group; low and high cutoff points were defined by a sensitivity and specificity of 90%. The new and conventional cutoffs were compared for detecting advanced fibrosis. The modified low and high cutoff points were 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50–59 years, 1.88 and 3.24 in 60–69 years, and 1.95 and 4.56 in ≥ 70 years. In ≥ 60 years, the false-negative rate was increased using the modified high cutoff point, and the high cutoff point was better with the conventional cutoff point. The new proposed low and high cutoff points are 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50–59 years, 1.88 and 2.67 in 60–69 years, and 1.95 and 2.67 in ≥ 70 years; these cutoff points improved the accuracy of advanced fibrosis diagnosis. FIB4 index cutoff points for predicting advanced fibrosis in NAFLD increased with age. Cutoff points modified by age improved the diagnostic accuracy of estimations of advanced liver fibrosis using the FIB4 index.

Aim Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy-proven NAFLD. Methods In this retrospective cohort study, we analyzed hepatocarcinogenesis in 238 patients. PNPLA3 rs738409 genotype was determined by allelic discrimination in 130 patients. Among them, 86 patients who were followed up for >5 years and without liver cirrhosis were analyzed to clarify the relationship between PNPLA3 genotype and long-term changes in biomarkers. Results Of 238 patients, PNPLA3 genotype frequencies were: CC, 0.14; CG, 0.46; and GG, 0.40. During a follow-up period of 6.1 years, 10 patients (4.2%) with non-alcoholic steatohepatitis developed HCC. The cumulative rate of HCC was 1.9% at the end of the 5th year and 8.3% at the end of the 10th year. Multivariate analysis identified PNPLA3 genotype GG (hazard ratio, 6.36; P = 0.019) and fibrosis stage (fibrosis stage 3/4; hazard ratio, 24.4; P = 0.011) as predictors of HCC development. In the long follow-up cohort, a larger reduction in platelet count was found in the GG group (P = 0.032) despite a larger reduction in alanine aminotransferase (P = 0.023) compared to that in the CC/CG group. Conclusions In Japanese patients with NAFLD, severe fibrosis and PNPLA3 GG genotype were predictors of HCC development, independent of other known risk factors. Patients with the PNPLA3 GG genotype have the potential for a decreased platelet count, even when alanine aminotransferase levels are well controlled.

Aim No pharmacological therapies have been established for non-alcoholic fatty liver disease (NAFLD). Sodium glucose cotransporter 2 inhibitor (SGLT2I) was developed for the treatment of adults with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM. Methods Twenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24 weeks were retrospectively enrolled as the SGLT2I group. Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibitor (DPP4I) for 24 weeks were selected as the DPP4I group. Clinical data were evaluated at baseline and at 4, 12, and 24 weeks. Seventeen patients in the SGLT2I group were evaluated by body composition before and after therapy. Results Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased in the SGLT2I group. Reductions in transaminase activities were similar between SGLT2I and DPP4I groups. In the SGLT2I group, body mass index and fasting plasma glucose also decreased after the treatment. Conclusion Sodium glucose cotransporter 2 inhibitor can be a novel promising agent for the treatment for NAFLD patients with T2DM. Prospective randomized controlled trials are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM.

Aims No pharmacological therapies have been established for non-alcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy and safety of dulaglutide, a novel glucagon-like peptidase-1 receptor agonist, in Japanese NAFLD patients with T2DM. Methods Fifteen biopsy-proven NAFLD patients with T2DM refractory to diet intervention who received once weekly dulaglutide 0.75 mg for 12 weeks were retrospectively enrolled after exclusion of two patients by 12 weeks. In five patients, transient elastography and body composition were also evaluated before and after the treatment. Results Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased after the 12-week therapy with dulaglutide. Total body fat mass and liver stiffness measurement also decreased after the treatment. Conclusion Dulaglutide, a new glucagon-like peptidase-1 receptor agonist, could be a novel promising agent for the treatment for NAFLD patients with T2DM due to its efficacy in body weight reduction, the nature of weekly injection, and patient preference. Prospective randomized controlled trials are warranted to confirm this impact of dulaglutide on NAFLD with T2DM.

The coauthor Masashi Yoneda's affiliation has been incorrectly published in the original publication of the article. The correct affiliation is provided in this correction.

There are limited studies on incidence rates of metachronous neoplastic lesions after resecting large colorectal polyps. In the present study, we analyzed metachronous lesions after endoscopic resection of colorectal polyps ≥20 mm in size.We retrospectively analyzed consecutive patients who underwent endoscopic resection of polyps from 2006 to 2013 at two affiliated hospitals. All patients underwent at least two total colonoscopies before follow up to ensure minimal missed polyps. Only patients who had follow-up colonoscopy annually after resection were recruited. We separated patients according to size of polyp resected; there were 239 patients in the ≥20-mm group and 330 patients in the20-mm group. Clinical characteristics and cumulative rates of metachronous advanced adenoma and cancer in both groups were analyzed. Advanced adenoma was defined as a neoplastic lesion ≥10 mm in size and adenoma with a villous component.Cumulative rate of development of metachronous advanced adenoma and cancer in the ≥20-mm group was significantly higher than in the20-mm group (22.9% vs. 9.5%, P 0.001) at 36 months. There was also more development of small polyps 5-9 mm in the ≥20-mm group than in the20-mm group (45.2% vs. 28.8%, P 0.001). With respect to metachronous lesions, there were more right-sided colonic lesions in the ≥20-mm group than in the20-mm group (78.8% vs. 50.0%, P = 0.015).High incidence rates of development of metachronous neoplastic lesions were detected after resection of colorectal polyps ≥20 mm in size.

In Japan, the prevalence of hepatocellular carcinoma (HCC) associated with nonviral liver disease, especially with nonalcoholic fatty liver disease (NAFLD-HCC) and alcoholic liver disease (ALD-HCC), has been increasing. Clarification of the clinical features of NAFLD-HCC and ALD-HCC is needed. We performed a large retrospective multicenter survey to clarify the clinical course of these two types of HCC. Clinical characteristics, survival, and recurrence were examined in 532 patients with ALD-HCC and 209 patients with NAFLD-HCC who were diagnosed between January 2000 and December 2013. The ALD-HCC patients were predominantly male and were younger than the patients with NAFLD-HCC. Lifestyle-related diseases were significantly more common in the NAFLD-HCC group, but the prevalence of cirrhosis was significantly higher in the ALD-HCC group. The histological diagnosis of NAFLD-HCC showed a gender difference (F4; 72.7 % in the females vs. 37.6 % in the males). The characteristic features of HCC including histology, survival rate, and recurrence rate were quite similar in the NAFLD-HCC and ALD-HCC groups: 5-year survival rates 49.1 vs. 43.7 %; 5-year recurrence rates 69.6 vs. 65.4 %, respectively. However, the risk factors for recurrence differed between the two groups: des-gamma-carboxy prothrombin was a risk factor in NAFLD-HCC and α-fetoprotein was a risk factor in ALD-HCC. Although the characteristic features underlying these two diseases are different, the two HCC groups showed a similar clinical course. The recurrence rates of the two HCC groups were relatively high. We found that critical tumor markers for recurrence differed between the two diseases.

Clinical data regarding Helicobacter pylori (H. pylori) infection in nonalcoholic fatty liver disease (NAFLD) are limited. The aim was to evaluate H. pylori infection in patients with NAFLD and its association with disease severity.One hundred and thirty patients with biopsy-proven NAFLD [43 with nonalcoholic fatty liver (NAFL) and 87 with nonalcoholic steatohepatitis (NASH)] were recruited for blood samples for anti-H. pylori immunoglobulin G (IgG) and standard biochemical tests were obtained after overnight fasting. Glucose tolerance was evaluated by 75-g oral glucose tolerance test. Liver biopsies were scored for NAFLD activity score (NAS), fibrosis and iron deposits.H. pylori IgG seropositivity was found in 40 % of patients overall. The prevalence of NASH was significantly higher in the patients with H. pylori IgG seropositivity (81 %) than in those without (58 %, p = 0.008). Glucose intolerance was similar between the two groups. The total NAS and the grade of hepatocyte ballooning were higher in the patients with H. pylori IgG seropositivity than in those without, while the hepatic iron grade was lower in the patients with H. pylori IgG seropositivity than in those without. H. pylori infection (p = 0.030), female gender (p = 0.029), and NAFIC score ≥ 2 points (p0.001) could independently predict NASH in logistic regression analysis, independent of age, obesity and glucose tolerance.The association of H. pylori seropositivity with hepatocyte ballooning suggests that H. pylori infection may represent another contributing factor in the progression from NAFL to NASH. Eradicating H. pylori infection may have therapeutic prospects in NASH treatment.

Aim Some cases with non-alcoholic fatty liver disease (NAFLD), particularly non-alcoholic steatohepatitis (NASH), can ultimately progress to liver cirrhosis. However, studies to clarify factors predictive of histological change in patients with NASH remain scarce. Our aim is to determine predictors of histological progression in Japanese patients with biopsy-proven NASH. Methods This retrospective cohort study enrolled 52 patients with NASH who underwent serial liver biopsies. Histological evaluation included NAFLD activity score (NAS) and liver fibrosis. The median interval between initial and second liver biopsies was 968 days. An alanine aminotransferase (ALT) response was defined as a decrease of 30% or more from baseline. Results Of 52 patients, NAS was ameliorated in 30.8%, deteriorated in 30.8% and remained unchanged in 38.4%. Liver fibrosis was improved in 25.0% of patients, progressed in 25.0% and remained stable in 50.0%. Multivariate analysis identified ALT non-response as a predictor of deterioration of NAS (hazard ratio [HR], 5.85; P = 0.031) and progression of liver fibrosis (HR, 4.50; P = 0.029). The mean annual rate of fibrosis was 0.002 stages/year overall, increasing to 0.15 stages/year in ALT non-responders. Conclusion A lack of reduction in serum ALT level by at least 30% from baseline was a predictor for histological progression in patients with NASH. Serum ALT level is a better predictor of histological change than insulin resistance or bodyweight and can be a valid index in treatment. Serum ALT should be strictly controlled to prevent liver histological progression in patients with NASH.

Aim No pharmacological therapies have been established for non-alcoholic steatohepatitis (NASH), which can lead to liver-related mortality. Human placental extract (HPE), which has anti-inflammatory effects, has been expected to be a promising treatment for chronic liver disease. This pilot study was conducted to evaluate the efficacy of HPE for biopsy-diagnosed NASH. Methods After a lifestyle intervention for 12 weeks, 10 subjects with abnormal alanine aminotransferase (≥30 IU/L) and biopsy-proven NASH (Non-Alcoholic Fatty Liver Disease Activity Score [NAS], ≥4) received i.m. injections of HPE (Laennec) at a dose of 4 mL/day twice per week for 24 weeks, and seven of them underwent a second liver biopsy after the treatment. Liver biopsies were scored for NAS and fibrosis. Histological response was defined as a decrease of 2 points or more in NAS and no increase in fibrosis. Results Serum transaminase activities were significantly lower at 8 weeks compared with pretreatment levels in nine patients who continued treatment for 24 weeks. One patient refused to continue the treatment soon after starting therapies. In seven patients undergoing post-treatment biopsies, NAS (mean [standard deviation]) mildly decreased from 5.29 (0.95) to 4.00 (1.83) without reaching statistical significance (P = 0.078). Histological response was observed in all three obese patients and in only one of four non-obese ones. No significant changes were observed in body mass index, lipid profiles and diabetic control/insulin resistance. Conclusion In NASH patients who received HPE treatment, significant reductions in serum liver enzymes were obtained after 8 weeks. Histological efficacy may be better in obese patients than in non-obese ones.

Aim Growth hormone (GH) deficiency may be associated with histological progression of non-alcoholic fatty liver disease (NAFLD) which includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Insulin-like growth factor 1 (IGF-1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF-1 in Japanese patients. Methods Serum samples were obtained in 199 Japanese patients with biopsy-proven NAFLD and in 2911 sex- and age-matched healthy people undergoing health checkups. The serum levels of IGF-1 were measured using a commercially available immunoradiometric assay. The standard deviation scores (SDS) of IGF-1 according to age and sex were also calculated in NAFLD patients. Results The serum IGF-1 levels in NAFLD patients were significantly lower (median, 112 ng/mL) compared with the control population (median, 121 ng/mL, P

Aim Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC) and have higher mortality than others. The evidence causally linking NAFLD to extrahepatic malignancies is scarce. Our aim was to determine the incidence of and risk factors for HCC, extrahepatic cancer and mortality in Japanese patients with biopsy-proven NAFLD. Methods This retrospective cohort study analyzed outcomes including onset of malignant tumors and death in 312 patients with NAFLD diagnosed by liver biopsy. Results Of 312 patients, 176 (56.4%) were diagnosed with non-alcoholic steatohepatitis. During a median follow-up period of 4.8 years (range, 0.3–15.8), six patients (1.9%) developed HCC, and 20 (6.4%) developed extrahepatic cancer. Multivariate analysis identified fibrosis stage (≥3; hazard ratio [HR], 12.3; 95% confidence interval [CI], 1.11–136.0; P = 0.041) as a predictor for HCC and type IV collagen 7s (>5 ng/mL; HR, 1.74; 95% CI, 1.08–2.79; P = 0.022) as a predictor for extrahepatic cancer. Eight patients (2.6%) died during the follow-up period. The most common cause of death was extrahepatic malignancy. None died of cardiovascular disease. Multivariate analysis identified type IV collagen 7s (>5 ng/mL; HR, 3.38; 95% CI, 1.17–9.76; P = 0.024) as a predictor for mortality. Conclusion The incidence of extrahepatic cancer was higher than that of HCC. Severe fibrosis was a predictor for HCC. Patients with NAFLD and elevated type IV collagen 7s levels are at increased risk for extrahepatic cancer and overall mortality.

The prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome have been increasing worldwide. The associations between metabolic factors and the histologic severity of NAFLD have not yet been clarified. Therefore, we studied the relationships between relevant metabolic factors and the histological severity of NAFLD. In a cross-sectional multicenter study conducted in Japan, we examined 1,365 biopsy-proven NAFLD patients. The frequencies of underlying lifestyle-related diseases and their relationships to the NAFLD histology were investigated. The hepatic fibrosis stages (Stage 0/1/2/3/4) were 22.6/34.1/26.7/14.5/2.1 (%) in the male patients, and 16.2/31.7/23.9/21.6/6.6 (%) in the female patients. Dyslipidemia was present in 65.7 % (hypertriglyceridemia, 45.3 %; increased low-density lipoprotein cholesterol, 37.5 %; decreased high density lipoprotein cholesterol, 19.5 %) of patients. Hypertension was present in 30.2 %, and diabetes mellitus (DM) in 47.3 %. The fibrosis stage increased with age, especially in postmenopausal females. The body mass index was positively correlated with the fibrosis stage. Deterioration of glucose control was positively correlated with the fibrosis stage, this correlation being more prominent in females. Multivariate analysis identified age and DM as significant risk factors for advanced fibrosis. No significant correlation of the fibrosis stage was observed with hypertension. There was a negative correlation between the serum triglyceride levels and the fibrosis stage. DM appeared to be a significant risk factor for advanced fibrosis in patients with NAFLD, and would therefore need to be properly managed to prevent the progression of NAFLD.

Physicians often experience difficulties in motivating patients with non-alcoholic fatty liver disease (NAFLD) to undergo lifestyle changes. The aim of this study is to examine whether 'Donations for Decreased alanine aminotransferase (ALT)' (D4D) prosocial behavior incentive can serve as an effective intrinsic motivational factor in comparison with conventional dietary and exercise intervention alone for NAFLD patients.Twenty-five NAFLD patients with elevated ALT were randomly assigned to a control group that received conventional dietary and exercise intervention alone, or a donation group whereby, as an incentive, we would make a monetary donation to the United Nations World Food Programme (WFP) based on the decrease in their ALT levels achieved over 12 weeks, in addition to receiving control intervention. In a donation group, we would donate US$1 to the WFP for every 1 IU/l of decrease in their ALT levels.There were no differences of pre-treatment clinical characteristics between the two groups. Significant reductions of ALT levels were achieved only in a donation group, although post-treatment ALT levels were not different between the two groups. These patients raised a total of $316 for the WFP.Promoting patients' intrinsic motivation by incorporating 'D4D' prosocial behavior incentive into conventional dietary and exercise intervention may provide a means to improve NAFLD.

No pharmacological therapies have been established for non-alcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy and safety of dulaglutide, a novel glucagon-like peptidase-1 receptor agonist, in Japanese NAFLD patients with T2DM.Fifteen biopsy-proven NAFLD patients with T2DM refractory to diet intervention who received once weekly dulaglutide 0.75 mg for 12 weeks were retrospectively enrolled after exclusion of two patients by 12 weeks. In five patients, transient elastography and body composition were also evaluated before and after the treatment.Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased after the 12-week therapy with dulaglutide. Total body fat mass and liver stiffness measurement also decreased after the treatment.Dulaglutide, a new glucagon-like peptidase-1 receptor agonist, could be a novel promising agent for the treatment for NAFLD patients with T2DM due to its efficacy in body weight reduction, the nature of weekly injection, and patient preference. Prospective randomized controlled trials are warranted to confirm this impact of dulaglutide on NAFLD with T2DM.

Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy-proven NAFLD.In this retrospective cohort study, we analyzed hepatocarcinogenesis in 238 patients. PNPLA3 rs738409 genotype was determined by allelic discrimination in 130 patients. Among them, 86 patients who were followed up for5 years and without liver cirrhosis were analyzed to clarify the relationship between PNPLA3 genotype and long-term changes in biomarkers.Of 238 patients, PNPLA3 genotype frequencies were: CC, 0.14; CG, 0.46; and GG, 0.40. During a follow-up period of 6.1 years, 10 patients (4.2%) with non-alcoholic steatohepatitis developed HCC. The cumulative rate of HCC was 1.9% at the end of the 5th year and 8.3% at the end of the 10th year. Multivariate analysis identified PNPLA3 genotype GG (hazard ratio, 6.36; P = 0.019) and fibrosis stage (fibrosis stage 3/4; hazard ratio, 24.4; P = 0.011) as predictors of HCC development. In the long follow-up cohort, a larger reduction in platelet count was found in the GG group (P = 0.032) despite a larger reduction in alanine aminotransferase (P = 0.023) compared to that in the CC/CG group.In Japanese patients with NAFLD, severe fibrosis and PNPLA3 GG genotype were predictors of HCC development, independent of other known risk factors. Patients with the PNPLA3 GG genotype have the potential for a decreased platelet count, even when alanine aminotransferase levels are well controlled.

No pharmacological therapies have been established for non-alcoholic fatty liver disease (NAFLD). Sodium glucose cotransporter 2 inhibitor (SGLT2I) was developed for the treatment of adults with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM.Twenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24 weeks were retrospectively enrolled as the SGLT2I group. Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibitor (DPP4I) for 24 weeks were selected as the DPP4I group. Clinical data were evaluated at baseline and at 4, 12, and 24 weeks. Seventeen patients in the SGLT2I group were evaluated by body composition before and after therapy.Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased in the SGLT2I group. Reductions in transaminase activities were similar between SGLT2I and DPP4I groups. In the SGLT2I group, body mass index and fasting plasma glucose also decreased after the treatment.Sodium glucose cotransporter 2 inhibitor can be a novel promising agent for the treatment for NAFLD patients with T2DM. Prospective randomized controlled trials are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM.

One of the important issues associated with colonic diverticular bleeding is the low rate at which the stigmata of recent hemorrhage is identified [1-2]. The space of a colonic diverticulum is often narrow, which makes observations of this area challenging. We attempted to overcome this issue using water immersion. This article is protected by copyright. All rights reserved.

Nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) share common features. Both are associated with visceral obesity, type 2 diabetes mellitus, metabolic syndrome, and insulin resistance. However, the relationship between NAFLD and CKD is poorly understood. We examined the prevalence of and risk factors for CKD in patients with NAFLD. We analyzed 174 Japanese patients with liver biopsy-proven NAFLD using a cross-sectional design. Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min per 1.73 m(2) and/or overt proteinuria. Of 174 NAFLD patients, 92 (53%) exhibited histologic characteristics of nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD; and 82 (47%) had non-NASH NAFLD. Chronic kidney disease was present in 24 (14%) of 174 NAFLD patients. The prevalence of CKD was significantly higher in NASH patients (19 of 92; 21%) than non-NASH patients (5 of 82; 6%). The presence of CKD was associated with a higher body mass index and the presence of hypertension and NASH. Our results demonstrated a high prevalence of CKD among patients with NASH.

Background and Aim: The hepatitis C virus (HCV) core protein induces hepatic steatosis and glucose intolerance in transgenic mice. The aim of this study was to clarify the impact of mutations in the HCV core region on hepatic steatosis and glucose tolerance in patients with chronic hepatitis C. Methods: Seventy-four Japanese patients (27 men, 47 women; mean age, 61.9 years) infected with HCV 1b with high viral load (>5 log IU/ml), without cirrhosis and overt diabetes, were enrolled. Substitutions in amino acids 70 and 91 of the HCV genotype 1b core region, the percentage of hepatic steatosis by liver histology, and glucose tolerance evaluated by the oral glucose tolerance test were investigated in all patients. Results: Steatosis was observed in 40 patients (54%). Transaminase activities, γ-glutamyl-transpeptidase, serum ferritin levels, homeostasis model assessment of insulin resistance index, and substitutions of amino acid 70 were significantly associated with the presence of steatosis, upon univariate analysis. Glucose intolerance was more prevalent in patients with steatosis (63%) than in those without steatosis (32%, P = 0.012). Multivariate analysis showed that substitution of amino acid 70 (odds ratio: 4.924; 95% confidence interval: 1.442–16.815; P = 0.014) and glucose intolerance (odds ratio: 3.369; 95% confidence interval: 1.076–10.544; P = 0.040) were independent factors related to liver steatosis. Levels of plasma glucose and serum insulin after glucose load were similar between patients with and without substitutions of amino acids 70 and 91. Conclusions: Amino acid substitutions in the HCV genotype 1b core region are associated with hepatic steatosis in patients with chronic hepatitis C, independent of glucose intolerance.

Background and Aim: Endoscopic mucosal resection (EMR) is the standard procedure for colorectal tumors. High mucosal elevation by submucosal injection is important for definite en bloc resection and the prevention of perforation. Hyaluronic acid (HA) is a reportedly useful injection solution for high and long-lasting mucosal elevation, but the ideal HA concentration for optimization of mucosal elevation maintenance, injection pres- sure, and cost is unknown. In the present study, we assessed the appropriate concentration of HA for EMR. Methods: A resected porcine colon and esophagus were used. The injection solutions examined were 0.9% normal saline (NS) and four concentrations of an 800-KDa HA preparation (0.4%, 0.2%, 0.13%, and 0.1%). Each solution (2 mL) was injected into the submucosa; injection pressure was calculated, and elevation was measured. The durations of mucosal elevation and EMR were additionally assessed in the living minipig colon. Results: In the resected porcine colon, the mucosal elevation was measured 0, 2, 4, and 6 min after the submucosal injection.All concentrations of HAsolution maintained greater mucosal elevation at all times than NS (P < 0.05).An almost similar result was obtained in the resected porcine esophagus. The injection pressure correlated with the HA concentra- tion. In the living minipig colon, mucosal elevation diminished 2 min after the submucosal injection with NS, but was maintained 2 min after injection with 0.4%, 0.2%, and 0.13% HA. The average duration of EMR was 139 s. Conclusions: Mucosal elevation by HAwas greater than that by NS in resected and living animal models. We recommend 0.13% HA for maintaining mucosal elevation, injection pressure, and cost.

Liver histology is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). Noninvasive, simple, reproducible, and reliable biomarkers are greatly needed to differentiate NASH from nonalcoholic fatty liver disease (NAFLD). To construct a scoring system for predicting NASH, 177 Japanese patients with biopsy-proven NAFLD were enrolled. To validate the scoring system, 442 biopsy-proven NAFLD patients from eight hepatology centers in Japan were also enrolled. In the estimation group, 98 (55%) patients had NASH. Serum ferritin [≥200 ng/ml (female) or ≥300 ng/ml (male)], fasting insulin (≥10 μU/ml), and type IV collagen 7S (≥5.0 ng/ml) were selected as independent variables associated with NASH, by multilogistic regression analysis. These three variables were combined in a weighted sum [serum ferritin ≥200 ng/ml (female) or ≥300 ng/ml (male) = 1 point, fasting insulin ≥10 μU/ml = 1 point, and type IV collagen 7S ≥5.0 ng/ml = 2 points] to form an easily calculated composite score for predicting NASH, called the NAFIC score. The area under the receiver operating characteristic (AUROC) curve for predicting NASH was 0.851 in the estimation group and 0.782 in the validation group. The NAFIC AUROC was the greatest among several previously established scoring systems for detecting NASH, but also for predicting severe fibrosis. NAFIC score can predict NASH in Japanese NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.

Aim The biological basis of variability in histological progression of non-alcoholic fatty liver disease (NAFLD) remains unknown. Dehydroepiandrosterone (DHEA), the most abundant steroid hormone, has been shown to influence sensitivity to reactive oxygen species, insulin sensitivity and expression of peroxisome proliferator-activated receptor-α. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA in Japanese patients. Methods Serum samples were obtained in 133 Japanese patients with biopsy-proven NAFLD and in 399 sex- and age-matched healthy people undergoing health checkups. Serum levels of sulfated DHEA (DHEA-S) were measured by chemiluminescent enzyme immunoassay. Results Serum DHEA-S levels in NAFLD patients were similar to those in the control group. Of 133 patients, 90 patients were diagnosed as non-alcoholic steatohepatitis (NASH): 73 patients had stage 0-2, and 17 had stage 3 or 4. Patients with advanced NAFLD (NASH with fibrosis stage 3 or 4) had lower plasma levels of DHEA-S than patients with mild NAFLD (simple steatosis or NASH with fibrosis stage 0-2). The area under the receiver operating characteristic curve for DHEA in separating patients with and without advanced fibrosis was 0.788. A "dose effect" of lower DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 170.4 ± 129.2, 137.6 ± 110.5, 96.2 ± 79.3, 61.2 ± 46.3 and 30.0 ± 32.0 µg/dL for fibrosis stages 0, 1, 2, 3, and 4, respectively. The association between DHEA-S and severity of NAFLD persisted after adjusting for age, sex and insulin resistance. Conclusion Low circulating DHEA-S might have a role in the development of advanced NASH.

Background and Aim: The prevalence of allergic disorders, including asthma, atopic dermatitis, and allergic rhinitis has been increasing, and the prevalence of Helicobacter pylori (H. pylori) infection has been decreasing. Chronic bacterial infection during childhood is reported to protect the development of allergic diseases. The aim of the present study was to identify whether H. pylori infection influences the prevalence of allergic rhinitis, which has become a serious social problem, especially in the developed countries. Methods: We initially investigated the association between the prevalence of H. pylori and pollinosis symptoms in 97 healthy volunteers. We had investigated the association between the serum H. pylori–immunoglobulin (Ig) G antibodies and specific IgE antibodies for pollen, mites, and house dust in 211 consecutive patients. Results: There were 52.2% (36/69) of H. pylori-negative volunteers with allergic symptoms, which was significantly higher than H. pylori-positive volunteers (14.3%, 4/28, P

Endoscopic submucosal dissection (ESD) has been reported to be effective for the en bloc resection of large colorectal tumors. Our study investigated whether ESD was suitable for elderly people with large colorectal tumors in terms of its invasiveness.We studied 119 colorectal tumors that were treated with ESD at Kyoto Prefectural University of Medicine or Nara City Hospital between 2006 and 2009. We classified each patient as either elderly, i.e., more than 75 years old, or non-elderly, i.e., less than 75 years old. Thirty-two of the cases were classified as elderly. Performance status, tumor size, operation time, rate of en bloc resection, histopathological diagnosis, complications, and hospital stay after ESD were analyzed retrospectively in both groups.In the elderly group, the average tumor size was 32.6 mm; the average operation time, 96 min; the rate of en bloc resection, 81.2%; the rate of perforation, 3.1%; and hospital stay after ESD, 5.1 days. Histopathological diagnosis for 16 tumors was adenoma; for 13, carcinoma with invasion into the mucosa; and for three, carcinoma with invasion into the submucosa. There were no statistical differences between the two groups in any of these data. The case with perforation was treated conservatively without urgent surgery in the elderly group.ESD for colorectal tumors resulted in favorable rates of en bloc resection in elderly people. Perforation occurred in elderly people, but these patients were cured with conservative treatment. ESD is a safe and minimally invasive treatment for elderly people with colorectal tumors.

Background and study aim Endoscopic submucosal dissection (ESD) for colorectal tumors is not generally recommended because of the technical difficulties and complications, including perforation. These aspects of ESD are thoroughly analyzed in our retrospective study. Patients and methods We studied 105 colorectal tumors, from 100 patients, that were treated by ESD at the Kyoto Prefectural University of Medicine or Nara City Hospital between 2005 and 2008. We analyzed tumor size, operation time, rate of en bloc resection, and complications. In addition, we thoroughly investigated the cases of perforation. Results The average tumor size was 30.4 mm; average operation time, 102 min; and rate of en bloc resection, 88.5 %. Perforation occurred in 10.4 % of the ESD procedures. Of the 11 perforations, 8 were detected during ESD and treated by clip closure during endoscopy, while 3 were evident only on subsequent routine computed tomography (CT); these were also managed conservatively. A case of postoperative hemorrhage was also observed. Conclusions ESD effectively achieved a high rate of en bloc resection. However, the perforation rate was substantial; hence, improvement in the ESD method is required. The outcomes of ESD, especially for early colorectal malignancies, need to be assessed further.

Helicobacter pylori infection of the gastric mucosa is characterized by a marked infiltration of inflammatory cells whose migration and activation are believed to depend on the H. pylori–induced production of proinflammatory cytokines (reviewed in [1]). The immune response to H. pylori infection is thought to be predominantly of the Th1 type and is associated with a significant increase in interferon (IFN)–γ–secreting T cells. The proinflammatory cytokine interleukin (IL)–18, previously known as an IFN-γ–inducing factor, is a Th1 cytokine in the IL-1 superfamily [2, 3]. IL-18, in synergy with IL-12, promotes the production of IFN-γ from Th1 and NK cells [4–6]. Because the Th1 response is believed to be predominant in H. pylori–infected gastric mucosa, we hypothesized that IL-18 should play a role in the process. However, the effect of H. pylori infection on IL-18 production remains unclear, because one report suggested that antral, but not corporal, IL-18 mRNA levels were up-regulated during H. pylori infection [7] and another indicated that mucosal IL-18 mRNA levels were independent of H. pylori infection [8]. In addition, no previous studies have investigated the relationship between the induction of gastric mucosal IL-18 and that of IL-12 and IFN-γ. It is generally recognized that polymorphisms in genes that regulate inflammation may be associated with different clinical outcomes in diseases for which inflammation is a critical variable [9, 10]. Two single-nucleotide polymorphisms (SNPs) in the promoter region of the IL18 gene (at positions –607 and –137) have been linked to type I diabetes [11], rheumatoid arthritis [12], and the progression of ovarian cancer [13]. No relationship was found between IL18 polymorphisms and gastric intestinal metaplasia in a Chinese population [14]; however, the relationship between IL18 polymorphisms and gastric mucosal IL-18 levels has not been studied. In the present study, we investigated the relationship between H. pylori infection and IL-18 induction in H. pylori–infected and H. pylori–uninfected gastric mucosa as well as whether the induction of mucosal IL-18 was associated with that of IL-12 and INF-γ. We further investigated whether IL18 polymorphisms play a role in mucosal IL-18 induction.

Background/Aim: Insulin resistance and hepatic iron overload are frequently demonstrated in hepatitis C virus (HCV)-related liver diseases. We investigated the relationship between insulin resistance and hepatic iron deposition in patients with chronic HCV infection. Methods: Insulin resistance was evaluated using the homeostasis model assessments for insulin resistance (HOMA-IR) in 56 non-diabetic non-obese patients with biopsy proven chronic hepatitis C. The relationship between insulin resistance and serum ferritin levels or the grade of hepatic iron deposition was assessed. Results: The levels of plasma immunoreactive insulin (IRI) and HOMA-IR were significantly correlated with serum ferritin levels and the grade of hepatic iron deposition (P = 0.003).Although IRI and HOMA-IR increased in parallel with the development of hepatic fibrosis, insulin resistance (HOMA-IR > 2) was observed in 11 (26.2%) of 42 patients even without severe fibrosis (F0–2). Among patients without severe fibrosis, IRI and HOMA-IR were significantly higher in patients with iron deposits than in those without iron deposits. Conclusion: Hepatic iron overload may be associated with insulin resistance in patients with chronic hepatitis C, especially in patients with mild to moderate fibrosis.

Aim: Testosterone deficiency in men is associated with an increased risk of obesity, metabolic syndrome and type 2 diabetes. However, the relationship between nonalcoholic fatty liver disease (NAFLD) and the levels of free testosterone (FT) in the serum remains unknown. Our aim was to investigate the association of serum levels of FT in male patients with NAFLD. Methods: Serum levels of FT were measured in 66 Japanese men with NAFLD and in 82 age-matched healthy men. Liver histology was also evaluated in 44 patients with NAFLD. Results: The serum levels of FT in male patients with NAFLD were significantly lower (median, 7.0 pg/ml) compared with those in the control population (median, 9.1 pg/ml, P

Increased hepatic iron deposition may play a role in the pathogenesis of nonalcoholic steatohepatitis (NASH). This study aimed to test whether iron removal by phlebotomy improves serum transaminase activities in patients with NASH. Eleven patients (six males and five females) with biopsy-proven NASH underwent phlebotomy biweekly until they reached near-iron deficiency (NID) (serum ferritin concentration lower than or equal to 30 ng/ml). Nine patients completed this study. Serum ferritin levels in these patients fell from 563 ± 322 to 18 ± 9 ng/ml (p = 0.001). The treatment reduced mean serum alanine aminotransferase (ALT) activity from 126 ± 47 to 56 ± 17 IU/l (p = 0.002). Their weight did not change significantly throughout the study period. Although two patients withdrew from the study, none was affected by any side effects of repeated phlebotomy that required discontinuing the treatment. In conclusion, this pilot study suggests that iron reduction therapy by phlebotomy will be one of the promising therapies for NASH.

Some cases with non-alcoholic fatty liver disease (NAFLD), particularly non-alcoholic steatohepatitis (NASH), can ultimately progress to liver cirrhosis. However, studies to clarify factors predictive of histological change in patients with NASH remain scarce. Our aim is to determine predictors of histological progression in Japanese patients with biopsy-proven NASH.This retrospective cohort study enrolled 52 patients with NASH who underwent serial liver biopsies. Histological evaluation included NAFLD activity score (NAS) and liver fibrosis. The median interval between initial and second liver biopsies was 968 days. An alanine aminotransferase (ALT) response was defined as a decrease of 30% or more from baseline.Of 52 patients, NAS was ameliorated in 30.8%, deteriorated in 30.8% and remained unchanged in 38.4%. Liver fibrosis was improved in 25.0% of patients, progressed in 25.0% and remained stable in 50.0%. Multivariate analysis identified ALT non-response as a predictor of deterioration of NAS (hazard ratio [HR], 5.85; P = 0.031) and progression of liver fibrosis (HR, 4.50; P = 0.029). The mean annual rate of fibrosis was 0.002 stages/year overall, increasing to 0.15 stages/year in ALT non-responders.A lack of reduction in serum ALT level by at least 30% from baseline was a predictor for histological progression in patients with NASH. Serum ALT level is a better predictor of histological change than insulin resistance or bodyweight and can be a valid index in treatment. Serum ALT should be strictly controlled to prevent liver histological progression in patients with NASH.

No pharmacological therapies have been established for non-alcoholic steatohepatitis (NASH), which can lead to liver-related mortality. Human placental extract (HPE), which has anti-inflammatory effects, has been expected to be a promising treatment for chronic liver disease. This pilot study was conducted to evaluate the efficacy of HPE for biopsy-diagnosed NASH.After a lifestyle intervention for 12 weeks, 10 subjects with abnormal alanine aminotransferase (≥30 IU/L) and biopsy-proven NASH (Non-Alcoholic Fatty Liver Disease Activity Score [NAS], ≥4) received i.m. injections of HPE (Laennec) at a dose of 4 mL/day twice per week for 24 weeks, and seven of them underwent a second liver biopsy after the treatment. Liver biopsies were scored for NAS and fibrosis. Histological response was defined as a decrease of 2 points or more in NAS and no increase in fibrosis.Serum transaminase activities were significantly lower at 8 weeks compared with pretreatment levels in nine patients who continued treatment for 24 weeks. One patient refused to continue the treatment soon after starting therapies. In seven patients undergoing post-treatment biopsies, NAS (mean [standard deviation]) mildly decreased from 5.29 (0.95) to 4.00 (1.83) without reaching statistical significance (P = 0.078). Histological response was observed in all three obese patients and in only one of four non-obese ones. No significant changes were observed in body mass index, lipid profiles and diabetic control/insulin resistance.In NASH patients who received HPE treatment, significant reductions in serum liver enzymes were obtained after 8 weeks. Histological efficacy may be better in obese patients than in non-obese ones.

Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC) and have higher mortality than others. The evidence causally linking NAFLD to extrahepatic malignancies is scarce. Our aim was to determine the incidence of and risk factors for HCC, extrahepatic cancer and mortality in Japanese patients with biopsy-proven NAFLD.This retrospective cohort study analyzed outcomes including onset of malignant tumors and death in 312 patients with NAFLD diagnosed by liver biopsy.Of 312 patients, 176 (56.4%) were diagnosed with non-alcoholic steatohepatitis. During a median follow-up period of 4.8 years (range, 0.3-15.8), six patients (1.9%) developed HCC, and 20 (6.4%) developed extrahepatic cancer. Multivariate analysis identified fibrosis stage (≥3; hazard ratio [HR], 12.3; 95% confidence interval [CI], 1.11-136.0; P = 0.041) as a predictor for HCC and type IV collagen 7s (5 ng/mL; HR, 1.74; 95% CI, 1.08-2.79; P = 0.022) as a predictor for extrahepatic cancer. Eight patients (2.6%) died during the follow-up period. The most common cause of death was extrahepatic malignancy. None died of cardiovascular disease. Multivariate analysis identified type IV collagen 7s (5 ng/mL; HR, 3.38; 95% CI, 1.17-9.76; P = 0.024) as a predictor for mortality.The incidence of extrahepatic cancer was higher than that of HCC. Severe fibrosis was a predictor for HCC. Patients with NAFLD and elevated type IV collagen 7s levels are at increased risk for extrahepatic cancer and overall mortality.

Vitamin E is one of the most promising treatments for non-alcoholic steatohepatitis (NASH). However, the long-term efficacy of this treatment remains unknown.We retrospectively examined 17 patients with biopsy-proven NASH who received vitamin E at a dose of 300 mg/day for=2 yr, and underwent second liver biopsies after treatment. Variables were compared between patients with (group R) and without (group NR) fibrosis regression.The median interval between basal and second liver biopsies was 2.4 yr (range, 2.0-5.8 yr). Overall, transaminase activities, insulin resistance index, and hepatic fibrosis markers were significantly improved. Although histological steatosis, inflammation, and fibrosis did not change after treatment, liver fibrosis improved in seven patients (41.2%), progressed in five (29.4%), and remained unchanged in five (29.4%). At baseline, subjects in group R (n = 7) were more likely to have diabetes, insulin resistance, and severe fibrosis compared to those in group NR (n = 10). Lower NAFLD activity score and larger decrease of ALT and insulin resistance after treatment were observed in group R compared with group NR.Two years or longer treatment can be expected to ameliorate NASH fibrosis, especially in those whose serum transaminase activities and insulin resistance can be improved.

It is suggested that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), can be associated with insomnia and gastro-esophageal reflux disease (GERD). The relationship between GERD and insomnia in subjects with biopsy-proven NAFLD was investigated. This study enrolled 123 patients with biopsy-proven NAFLD. Insomnia was assessed by the Athens Insomnia Scale (AIS), a self-assessment psychometric instrument designed to quantify sleep difficulty based on ICD-10 criteria; AIS scores ≥ 6 were considered positive for insomnia. GERD symptoms were evaluated using a frequency scale for the symptoms of GERD (FSSG); FSSG scores ≥ 8 were considered positive. Logistic regression models were used to evaluate the association of insomnia with GERD, after adjusting for potential confounders. Thirteen patients with GERD were treated with the proton pump inhibitor rabeprazole (RPZ; 10 mg/day), for 12 weeks. Of the 123 patients, 76 (62 %) were female and 87 (71 %) were obese, with 34 (28 %) having AIS scores ≥ 6 and 31 (25 %) having FSSG scores ≥ 8. Liver biopsy revealed that 40 patients (33 %) had NAFL and 83 (67 %) had NASH. FSSG and AIS scores were similar in the two groups. HOMA-IR, FSSG scores and γGT (GGT) concentrations were significantly higher in insomniacs than in non-insomniacs. Logistic regression analysis demonstrated that FSSG score and GGT concentration were independently associated with insomnia. RPZ treatment resulted in significantly reductions in both AIS and FSSG scores. Nearly 30 % of patients with biopsy-proven NAFLD had insomnia, which was related to GGT and GERD and could be relieved by RPZ treatment.

Biliobiliary fistula is a rare clinical entity. The case of a 72 year old female, who presented with epigastric pain and jaundice, is detailed herein. Endoscopic retrograde cholangiopancreatography (ERCP) revealed two stones, one each in the common bile duct and the gallbladder. Continuous endoscopic nasobiliary drainage (ENBD) was performed to relieve obstructive jaundice. Further study with contrast medium administered via the ENBD tube revealed a fistula between the neck of the gallbladder and the common bile duct. The cystic duct was intact. A stone was considered to have migrated into the common bile duct through the fistula. A diagnosis of biliobiliary fistula, Corlette type I was made. However, in this particular case, a biliobiliary fistula was noted at a site below the junction of the cystic duct and common bile duct. Removal of the gallbladder stones was followed by cholecystectomy. The common bile duct was then repaired by utilizing a T-tube. No evidence of malignancy was recognized in the resected gallbladder specimen. In the one year to date since surgery, the patient has been asymptomatic and without signs of biliary disease.

To investigate the possible role of the brainstem in cysteamine-induced peptic ulceration, we examined the expression of VGF mRNA, which is induced in PC12 cells following application of nerve growth factor [23], in the nucleus tractus solitarius (NTS)/dorsal motor nucleus of vagus (DMV) complex of the medulla oblongata by in situ hybridization histochemistry. In control saline-treated rats, weak VGF mRNA signals were only rarely detected in neurons of the NTS and none were observed in those in the DMV. After 12 h of cysteamine administration (450 mg/kg, s.c.), the time at which duodenal ulcer was detected in all cases, heavily labeled VGF mRNA-expressing neurons appeared in the NTS and DMV. By quantitative analysis on macroautoradiogram, the VGF mRNA signals of the NTS/DMV complex in cysteamine-treated rats were twice as much as those in saline-treated rats. In situ hybridization histochemistry combined with the use of the retrograde neuronal tracer cholera toxin-B subunit revealed that the induced VGF mRNA-expressing neurons of the DMV projected directly to the stomach. The present results suggest that ulceration accompanies the induction of VGF mRNA in neurons of vagal afferent and efferent areas of the brainstem.

Endoscopic mucosal resection (EMR) of colorectal polyps should be curative and safe. This study aimed to determine the efficacy and safety of colorectal EMR using 0.13 % hyaluronic acid (HA) solution. This was a single-armed multicenter prospective open trial conducted at 11 Japanese institutions. Lesion characteristics and various measures of clinical outcome, including en bloc resection, histopathologically complete resection, and postoperative bleeding were analyzed for 624 consecutive patients who underwent EMR of colorectal polyps at ≤20 mm in size from August 2010 to September 2011. En bloc and complete resection were achieved in 93.3 and 78.3 % of 624 lesions. The median EMR procedure time was 2.1 ± 1.5 min. The rates of postoperative bleeding and perforation were 1.1 and 0 %. The rate of en bloc resection was higher for polyps at 5–10 mm than for polyps at 11–20 mm (95.1 vs. 85.1 %; P

The severity of liver fibrosis must be estimated to determine the prognosis, for surveillance, and for optimal treatment of nonalcoholic fatty liver disease (NAFLD). However, the severity of hepatic fibrosis tends to be underestimated in patients with normal ALT.We investigated histological data and scoring systems (FIB-4 index, NAFLD fibrosis score, BARD score, and AST/ALT ratio) of 1,102 liver-biopsy-confirmed NAFLD patients.A total of 235 NAFLD patients with normal ALT were estimated to exist. The ratio of advanced fibrosis (stage 3-4) was seen in 16.1 % of subjects with normal ALT. Scoring systems, especially the FIB-4 index and NAFLD fibrosis score, were clinically very useful (AUROC0.8), even in patients with normal ALT. Furthermore, with resetting of the cutoff values, the FIB-4 index (1.659) and NAFLD fibrosis score (0.735) were found to have a higher sensitivity and higher specificity for the prediction of advanced fibrosis, and all of these scoring systems (FIB-4 index, NAFLD fibrosis score, BARD score, and AST/ALT ratio) had higher negative predictive values (90.3 %). By using the resetting cutoff value, liver biopsy could have been avoided in 60.4 % (FIB-4), 66.4 % (NAFLD fibrosis score), 51.9 % (BARD score), and 62.1 % (AST/ALT ratio).We reset the cutoff values of numerous non-invasive scoring systems to improve their clinical usefulness in the prediction of liver fibrosis in NAFLD patients with normal ALT, and these non-invasive scoring systems with the reset cutoff values could be of substantial benefit to reduce the number of liver biopsies performed.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease (CLD) in many developed countries and results in a serious public health problem worldwide. NAFLD includes a wide spectrum of liver diseases, ranging from simple fatty liver, which is usually a benign and nonprogressive condition, to nonalcoholic steatohepatitis (NASH) which may progress to liver cirrhosis (LC), hepatic failure and hepatocellular carcinoma (HCC) in the absence of significant alcohol consumption (Ludwig et al., 1980, Matteoni et al. 1999). About a third of people with NAFLD will develop NASH, and about 20% of people with NASH will go on to liver fibrosis and cirrhosis, with its accompanying risk of liver failure and even HCC (Yasui et al. 2011). In Japan, current best estimates make the prevalence of NAFLD approximately 20% and of NASH 2% to 3% in the general population. Pathophysiology of primary NASH still hasn’t been completely clarified. According to the “two-hits” model of NASH pathogenesis proposed by Day and James (Day & James. 1999), excessive triglyceride accumulation is the most likely first step. The second step may relate to an increase in oxidative stress (Sumida et al. 2011a), which, in turn, triggers liver cell necrosis and activation of hepatic stellate cells, both leading to fibrosis and ultimately to the development of LC. Although the number of NASH cases in women is known to be higher than in men over 50 years of age, the mechanisms remain unknown (Hashimoto & Tokushige, 2011). According to our study produced by Japan Study Group of NAFLD (JSG-NAFLD) including nine hepatology centers in Japan (Sumida et al., 2011b), NASH patients with significant or advanced fibrosis (Brunt stage 2-4) was more prevalent in females than in males (Fig.1). Although plausible mechanisms have been proposed, including estrogen deficiency after menopause, iron accumulation generating hydroxylradicals via Fenton reaction (Sumida et al., 2009), and so on, precise mechanisms have not been clarified. Although several factors have been associated with more advanced NAFLD, the biological basis of the histological diversity of severity of NAFLD [i.e., why some patients develop simple fatty liver and others develop NASH with advanced fibrosis] remains unknown. More advanced NAFLD is characterized by insulin resistance, oxidative stress, and advanced fibrosis.

The severity of liver fibrosis is known to be a good indicator for surveillance, and for determining the prognosis and optimal treatment of nonalcoholic fatty liver disease (NAFLD). However, it is virtually impossible to carry out liver biopsies in all NAFLD patients. The purpose of this study was to investigate the clinical usefulness of measuring the platelet count for predicting the severity of liver fibrosis in a large retrospective cohort of Japanese patients with NAFLD.A total of 1,048 patients with liver-biopsy-confirmed NAFLD seen between 2002 and 2008 were enrolled from nine hepatology centers in Japan. Laboratory evaluations were performed for all patients.A linear decrease of the platelet count with increasing histological severity of hepatic fibrosis was revealed. The area under the receiver operating characteristic curve estimating the diagnostic performance of the platelet count for hepatic fibrosis Stage 3 was 0.774 (optimal cutoff value, 19.2 × 10(4)/μl; sensitivity, 62.7%; specificity, 76.3%), and that for Stage 4 was 0.918 (optimal cutoff value, 15.3 × 10(4)/μl; sensitivity, 80.5%; specificity, 88.8%).The platelet count may be an ideal biomarker of the severity of fibrosis in NAFLD patients, because it is simple, easy to measure and handle, cost-effective, and accurate for predicting the severity of fibrosis. Furthermore, by using the platelet count cutoff value validated in our multiple large trials, efficient recruitment of NAFLD patients may be facilitated.

Endoscopic mucosal resection (EMR) is the standard procedure for colorectal tumors. High mucosal elevation by submucosal injection is important for definite en bloc resection and the prevention of perforation. Hyaluronic acid (HA) is a reportedly useful injection solution for high and long-lasting mucosal elevation, but the ideal HA concentration for optimization of mucosal elevation maintenance, injection pressure, and cost is unknown. In the present study, we assessed the appropriate concentration of HA for EMR.A resected porcine colon and esophagus were used. The injection solutions examined were 0.9% normal saline (NS) and four concentrations of an 800-KDa HA preparation (0.4%, 0.2%, 0.13%, and 0.1%). Each solution (2 mL) was injected into the submucosa; injection pressure was calculated, and elevation was measured. The durations of mucosal elevation and EMR were additionally assessed in the living minipig colon.In the resected porcine colon, the mucosal elevation was measured 0, 2, 4, and 6 min after the submucosal injection. All concentrations of HA solution maintained greater mucosal elevation at all times than NS (P0.05). An almost similar result was obtained in the resected porcine esophagus. The injection pressure correlated with the HA concentration. In the living minipig colon, mucosal elevation diminished 2 min after the submucosal injection with NS, but was maintained 2 min after injection with 0.4%, 0.2%, and 0.13% HA. The average duration of EMR was 139 s.Mucosal elevation by HA was greater than that by NS in resected and living animal models. We recommend 0.13% HA for maintaining mucosal elevation, injection pressure, and cost.

The hepatitis C virus (HCV) core protein induces hepatic steatosis and glucose intolerance in transgenic mice. The aim of this study was to clarify the impact of mutations in the HCV core region on hepatic steatosis and glucose tolerance in patients with chronic hepatitis C.Seventy-four Japanese patients (27 men, 47 women; mean age, 61.9 years) infected with HCV 1b with high viral load (5 log IU/ml), without cirrhosis and overt diabetes, were enrolled. Substitutions in amino acids 70 and 91 of the HCV genotype 1b core region, the percentage of hepatic steatosis by liver histology, and glucose tolerance evaluated by the oral glucose tolerance test were investigated in all patients.Steatosis was observed in 40 patients (54%). Transaminase activities, γ-glutamyl-transpeptidase, serum ferritin levels, homeostasis model assessment of insulin resistance index, and substitutions of amino acid 70 were significantly associated with the presence of steatosis, upon univariate analysis. Glucose intolerance was more prevalent in patients with steatosis (63%) than in those without steatosis (32%, P = 0.012). Multivariate analysis showed that substitution of amino acid 70 (odds ratio: 4.924; 95% confidence interval: 1.442-16.815; P = 0.014) and glucose intolerance (odds ratio: 3.369; 95% confidence interval: 1.076-10.544; P = 0.040) were independent factors related to liver steatosis. Levels of plasma glucose and serum insulin after glucose load were similar between patients with and without substitutions of amino acids 70 and 91.Amino acid substitutions in the HCV genotype 1b core region are associated with hepatic steatosis in patients with chronic hepatitis C, independent of glucose intolerance.