Eicosapentaenoic acid ameliorates hyperglycemia in high-fat diet-sensitive diabetes mice in conjunction with restoration of hypoadiponectinemia.

BACKGROUND/OBJECTIVE: Eicosapentaenoic acid (EPA) exerts pleiotropic effects on metabolic disorders such as atherosclerosis and dyslipidemia, but its effectiveness in the treatment of type 2 diabetes mellitus remains controversial. METHODS: We examined the antidiabetic effect of EPA in insulin receptor mutant (Insr(P1195L/+)) mice that exhibit high-fat diet (HFD)-dependent hyperglycemia. RESULTS: EPA supplementation was found to alleviate hyperglycemia of Insr(P1195L/+) mice fed HFD (Insr(P1195L/+)/HFD mice), which was accompanied by amelioration of increased gluconeogenesis and impaired insulin signaling, as assessed by glucose-6-phosphatase (G6pc) expression on refeeding and insulin-induced phosphorylation of Akt in the liver, respectively. We found that serum levels of adiponectin, the antidiabetic adipokine, were decreased by HFD along with the body weight gain in Insr(P1195L/+) mice but not in wild-type mice, suggesting that Insr(P1195L/+) mice are prone to hypoadiponectinemia in response to obesity. Interestingly, the blood glucose levels of Insr(P1195L/+) mice were in reverse proportion to their serum adiponectin levels and EPA supplementation ameliorated their hyperglycemia in conjunction with the restoration of hypoadiponectinemia. CONCLUSIONS: EPA exerts an antidiabetic effect in Insr(P1195L/+)/HFD mice, an HFD-sensitive, insulin-resistant animal model, possibly through its action against hypoadiponectinemia.

A randomized controlled trial comparing a prepackaged low-residue diet with a restricted diet for colonoscopy preparation: the impact on the results of colonoscopy in adenoma detection.

AIM: This study aimed to investigate the clinical utility of a prepackaged low-residue diet (PLD) compared with a restricted diet (RD) for colonoscopic bowel preparation. METHOD: A prospective randomized controlled trial was carried out with patients undergoing colonoscopy. One hundred patients were randomly assigned to PLD and RD groups. In the RD group, the patients received an information sheet containing acceptable low-residue options and instructions from the medical staff. All patients received 10 ml sodium picosulphate the day before colonoscopy and 1 l of polyethylene glycol with ascorbic acid (PEG-A) on the day of the colonoscopy. If the bowel preparation was not adequate, an additional PEG-A solution was given. The primary outcome was the efficacy of colonic cleansing as rated by the Boston Bowel Preparation Scale (BBPS). The additional amount of PEG-A solution, adenoma detection rate and patient tolerance were assessed as secondary outcomes. RESULTS: The BBPS score in the PLD group was 7.3 ± 1.7 compared with 6.5 ± 1.7 in the RD group. The quality of bowel preparation was significantly better in the PLD group (P < 0.05). The mean amount of additional PEG-A solution in the PLD group was smaller than in the RD group (293.8 ± 474.8 vs 444.1 ± 625.0 ml), but there was no statistical difference between the two groups. Adenoma detection rates and patient tolerance were similar in the two groups. CONCLUSION: Prepackaged low-residue diets PLD is superior to RD for bowel preparation for colonoscopy.

Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese individuals.

Significant associations of HLA-DP alleles with chronic hepatitis B (CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1(*) 05:01 and (*) 09:01, and three protective alleles, DPB1(*) 02:01, (*) 04:01, and (*) 04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules.

Virological efficacy of combination therapy with corticosteroid and nucleoside analogue for severe acute exacerbation of chronic hepatitis B.

The short-term prognosis of patients with severe acute exacerbation of chronic hepatitis B (CHB) leading to acute liver failure is extremely poor. We have reported the efficacy of corticosteroid in combination with nucleoside analogue in the early stages, but virological efficacy has not been documented. Our aim was to elucidate the virological efficacy of this approach. Thirteen patients defined as severe acute exacerbation of CHB by our uniform criteria were prospectively examined for virological responses to treatment. Nucleoside analogue and sufficient dose of corticosteroids were introduced as soon as possible after the diagnosis of severe disease. Of the 13 patients, 7 (54%) survived, 5 (38%) died and 1 (8%) received liver transplantation. The decline of HBV DNA was significant between the first 2 weeks (P = 0.02) and 4 weeks (P < 0.01). Mean reduction in HBV DNA during the first 2 weeks was 1.7 ± 0.9 log copies per mL in overall patients, 2.1 ± 0.8 in survived patients and 1.2 ± 0.9 in dead/transplanted patients. The decline of HBV DNA was significant between the first 2 weeks (P = 0.03) and 4 weeks (P = 0.02) in survived patients, but not in dead/transplanted patients. Our study shows that corticosteroid treatment in combination with nucleotide analogue has sufficient virological effect against severe acute exacerbation of CHB, and a rapid decline of HBV DNA is conspicuous in survived patients.

Sonographic and clinical features of collateral vessels at the splenic hilum in cirrhosis.

AIM: To examine the sonographic features of shunt vessels derived from the splenic vein at splenic hilum (SS), and explore the relationship between the SS pattern and clinical presentations. MATERIALS AND METHODS: This prospective study in cirrhotic patients consisted of study I (n = 15), which compared the anatomical features of SS at ultrasonography versus angiography, and study II (n = 233), which examined the incidence/haemodynamics of SS and SS-related presentations. RESULTS: Study I showed that SS1 (running toward the upper pole of the spleen) corresponded to short gastric veins, and SS2 (running toward the lower pole of the spleen) corresponded to splenorenal/retroperitoneal shunts. In study II, SS were detected in 47.6% of patients (111/233), SS1 in 77.5% (86/111), SS2 in 17.1% (19/111), and SS3 (both SS1 and SS2) in 5.4% (6/111). The incidence of gastric cardia varices was significantly higher in patients with SS2 (6/19) than in those with SS1 (8/86, p = 0.0097), whereas the incidence of gastric fundal varices was significantly higher in patients with SS1 (44/86) than in those with SS2 (1/19, p = 0.00025) or SS3 (0/6, p = 0.015). There was no difference in the incidence of oesophageal varices among the three SS groups. The Child-Pugh score and grade of ascites was significantly worse in patients with SS3 than in those with SS1 (p < 0.0001, p = 0.0009). Hepatic encephalopathy grade was significantly worse in patients with SS2 (p = 0.0047) or SS3 (p < 0.0001) compared to SS1. CONCLUSION: The SS pattern facilitates estimation of the possible manifestations, indicating the direction of clinical management of cirrhosis patients. Potential poor liver function is noted in patients with SS3.

Clinical outcomes of endoscopic resection for nonampullary duodenal high-grade dysplasia and intramucosal carcinoma.

This study retrospectively analyzed the clinical outcomes of endoscopic resection of 26 sporadic (i. e., not associated with polyposis syndrome) nonampullary duodenal lesions representing high-grade dysplasia or intramucosal carcinoma (duodenal HGD/IMC) in 23 patients. No severe complications such as perforation were observed, but three cases of delayed bleeding were seen. The use of endoscopic clips significantly decreased the delayed bleeding rate (0/19, 0%) compared with cases in which clips were not used (3/7, 42.9%; P = 0.013, χ2 test). Eighteen lesions (69.2%) were removed by en bloc resection. The follow-up period after resection was 25.5 ± 23.3 months. Two lesions (7.7%) that recurred locally were detected at the first surveillance endoscopy 3 months after resection. These lesions were 22 and 15 mm in size respectively and were resected piecemeal. Endoscopic resection is an effective and safe procedure for treating duodenal HGD/IMC. En bloc resection and prophylactic clip usage are encouraged.

Concomitant use of enteral nutrition therapy is associated with sustained response to infliximab in patients with Crohn's disease.

BACKGROUND/OBJECTIVES: A significant proportion of Crohn's disease (CD) patients receiving infliximab (IFX) maintenance therapy show loss of responsiveness despite a good initial response. The factors other than immunomodulators that prevent IFX dose escalation have yet to be fully elucidated. This study was performed to identify clinical factors or concomitant therapies associated with sustained response to IFX. SUBJECTS/METHODS: Seventy-four consecutive CD patients who had successful IFX induction therapy between 2002 and 2010 underwent IFX maintenance therapy. Patients showing loss of response to IFX were treated with IFX intensification therapy. Factors involved in the sustained response to IFX were investigated retrospectively. RESULTS: After a median follow-up of 85 weeks, loss of response to IFX was observed in 30 (40.5%) cases. On logistic regression analysis, concomitant use of enteral nutrition (EN) therapy (elemental and/or polymeric formulas) was identified as an independent factor associated with sustained response to IFX. Receiver operating characteristic curve analysis indicated a cutoff value of 600 kcal/day. We divided the patients into the 'EN group' (≥ 600 kcal/day) and 'control group' (<600 kcal/day). The cumulative number of loss of response was significantly lower in the EN group (odds ratio: 0.23, P = 0.0043). Kaplan-Meier analysis confirmed the significantly lower rate of loss of response in the EN group (P = 0.013). Multivariate hazard ratio was 0.37 (P = 0.025). Type of EN formula did not affect the results. CONCLUSIONS: Concomitant use of EN ≥ 600 kcal/day is likely to yield a sustained response to IFX in CD patients.

Predictive factors of response to intravenous ciclosporin in severe ulcerative colitis: the development of a novel prediction formula.

BACKGROUND: When treating patients with severe ulcerative colitis (UC), accurate prediction of drug efficacy contributes to early clinical decision-making. AIM: To identify predictive factors and to develop a reliable prediction formula and a decision tree of response to intravenous ciclosporin treatment for severe UC. METHODS: Patients included in this study were those diagnosed with refractory severe UC who had undergone ciclosporin treatment between December 2004 and March 2011 at a tertiary referral centre in Japan. Demographic and clinical parameters from all patients were analysed by multivariate statistics. RESULTS: Fifty-two patients were included in this study (36.5% men with an average age of ciclosporin initiation of 40.2 ± 15.6 years). Thirty-four patients (65.4%) were responders to the treatment with ciclosporin and avoided colectomy, 18 patients (34.6%) were nonresponders and underwent colectomy. Stepwise multiple logistic regression analysis identified four independent predictive factors of response to intravenous ciclosporin: age at hospitalisation (AGE), platelet count (×10(4) /µL) on the first day (PLA), Lichtiger score on the third day (LIC) and total protein (g/dL) on the third day minus total protein on the first day (ΔTP). The calculation formula (8.5 - 0.16 × AGE + 0.21 × PLA - 0.61 × LIC + 2.3 × ΔTP < 0) predicted colectomy with an accuracy of 88.5% and the decision tree predicted colectomy with an accuracy of 90.4%. CONCLUSION: The novel calculation formula and the decision tree effectively predict the clinical outcome of ciclosporin treatment for severe ulcerative colitis as early as on day 3 after starting ciclosporin treatment.

Longitudinal changes of the laboratory data of chronic hepatitis C patients with sustained virological response on long-term follow-up.

There is no study that follows up longitudinal changes in laboratory data of patients with C-viral chronic liver disease (C-CLD) who achieved sustained virological esponse (SVR) with interferon treatment in a long-term study. We investigated the laboratory data in a long-term retrospective cohort study of 581 patients with C-CLD who underwent liver biopsy between January 1986 and December 2005. 467 were treated with interferon and 207 of these patients achieved SVR with follow-up periods of 8.36 ± 5.13 years. Alanine aminotransferase (ALT) levels, albumin levels, platelet counts, and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) values were serially examined during the follow-up period. None of the 207 patients with SVR exhibited hepatitis C virus (HCV) RNA positivity more than 6 months after the end of IFN treatment. Platelet counts and albumin levels increased only in those with eradication of HCV. APRI values decreased more in patients with SVR than in those with nonsustained virological responses (non-SVR). Patients who achieved SVR and had fibrosis stage 0-1 and 2-4 at enrolment had platelet counts that longitudinally increased by 2.81 ± 3.95 and 5.49 ± 4.53 × 10(3) /µL during the 10-year follow-up period, respectively. Albumin levels continuously increased during the first 2 years by 0.15 ± 0.31 and 0.33 ± 0.37 in fibrosis stage 0-1 and 2-4, respectively and then plateaued. ALT levels decreased rapidly one year after the start of treatment by 110.3 ± 140.0 and 100.5 ± 123.4 in fibrosis 0-1 and 2-4, respectively. HCV RNA negativity persisted in all patients with SVR, and laboratory data including APRI longitudinally improved during the long-term follow-up period.

Contrast-enhanced ultrasound for characterisation of hepatic lesions appearing non-hypervascular on CT in chronic liver diseases.

OBJECTIVES: The purpose of this prospective study was to elucidate the efficacy of using contrast-enhanced ultrasound to characterise focal hepatic lesions appearing non-hypervascular on contrast-enhanced CT in chronic liver diseases. METHODS: The study population included 22 patients with cirrhosis or chronic hepatitis, who between them had 27 focal hepatic lesions smaller than 20 mm (mean 13.9 ± 3.4) that appeared non-hypervascular on contrast-enhanced CT. Contrast-enhanced ultrasound with perflubutane microbubble agent (Sonazoid, 0.0075 ml kg(-1)) was performed prior to ultrasound-guided needle biopsy, and intensity analysis was done for hepatic lesions in the early phase (-60 s) and late phase (600 s post injection). RESULTS: All seven early-phase hyperenhanced lesions were hepatocellular carcinoma (HCC). 20 lesions iso- or hypoenhanced during the early phase consisted of 11 regenerative nodules (RNs) and 9 HCCs. HCC was more frequent in early-phase hyperenhanced lesions than in iso- or hypoenhanced lesions (p=0.0108). Both late-phase hypoenhanced lesions were HCCs, whereas 25 late-phase isoenhanced lesions consisted of 11 RNs and 14 HCCs. The enhancement patterns of the 11 RNs included isoenhanced appearance in both the early and late phases in 8 lesions, and early-phase hypoenhancement combined with late-phase isoenhancement in the remaining 3. Both of these enhancement patterns (i.e. either iso-iso or hypo-iso) were found in 9 malignant lesions, 9 (75%) of the 12 well-differentiated HCCs. CONCLUSION: Hypervascularity on contrast-enhanced ultrasound with Sonazoid strongly suggested HCC regardless of non-hypervascularity on CT, and late-phase hypoenhancement was another possible finding of HCC. However, characterisation of hepatic lesions with other enhancement patterns was difficult using our technique.

Non-invasive portography: a microbubble-induced three-dimensional sonogram for discriminating idiopathic portal hypertension from cirrhosis.

OBJECTIVES: The aim of this prospective study was to elucidate the efficacy of contrast-enhanced three-dimensional (3D) ultrasound with Sonazoid(®) (GF Healthcare, Oslo, Norway) as a non-invasive tool to discriminate idiopathic portal hypertension (IPH) from cirrhosis by demonstration of portal vein structure. METHODS: There were 16 patients: 11 with biopsy-proven cirrhosis and 5 with biopsy-proven IPH. Intrahepatic right portal vein images were taken by 3D ultrasound from 1 min after the injection of Sonazoid (0.0075 ml kg(-1)). Portal vein appearances were compared between 3D ultrasound and percutaneous transhepatic portography (PTP) by four independent reviewers. Sensitivity, specificity and area under the receiver operating characteristic curve (Az) of the images were used for the diagnosis of cirrhosis/IPH, and interimaging, inter-reviewer and interoperator agreement were examined. RESULTS: Sensitivity, specificity and Az of PTP for the diagnosis of cirrhosis/IPH were 63.6%/100%, 100% and 0.9 (0.71-1.0) by Reviewer I and 90.9%/100%, 100% and 1.0 by Reviewer III, respectively. Similarly, sensitivity, specificity and Az of 3D ultrasound for diagnosis of cirrhosis/IPH were 54.5%/80%, 100% and 0.96 (0.84-1.0) by Reviewer II and 72.7%/80%, 100% and 0.97 (0.9-1.0) by Reviewer IV, respectively. Diagnostic agreement between PTP and 3D ultrasound was good between Reviewers I and II (κ=0.793) and good between Reviewers III and IV (κ=0.732). Inter-reviewer agreement was good between Reviewers I and III for PTP diagnosis (κ=0.735), and good between Reviewers II and IV for 3D ultrasound diagnosis (κ=0.792). Interoperator agreement of diagnostic results was good (κ=0.740). CONCLUSION: Non-invasive visualisation of intrahepatic portal vein structure by contrast-enhanced 3D ultrasound with Sonazoid may have the potential to discriminate IPH from cirrhosis.

Contrast-enhanced ultrasound for non-tumor liver diseases.

Contrast-enhanced ultrasound (CEUS) is a simple, safe and reliable technique for the clinical management of patients with various liver diseases. Although the major target of the technique may be focal hepatic lesions, it is also effective for the diagnosis of non-tumor liver diseases, such as grading hepatic fibrosis, characterization of chronic liver diseases and diagnosis of portal vein thrombosis. This review article aimed to overview the recent application of CEUS in the assessment of non-tumor liver diseases.

Clinical importance of serum hepatitis B surface antigen levels in chronic hepatitis B.

Quantitative serology for hepatitis B surface antigen (HBsAg) is a new candidate marker for prediction of clinical outcome. The aim of this study was to investigate the clinical significance of quantifying HBsAg in patients with hepatitis B virus (HBV) infection. A total of 424 patients who tested positive for HBsAg and were referred to Chiba University Hospital between January 1985 and April 2008 were included in the study, and the following characteristics were analyzed: age, gender, status of hepatitis B e antigen (HBeAg), alanine aminotransferase level (ALT), HBV DNA level, number of platelets and development of hepatocellular carcinoma. Measurement of HBsAg was performed using the chemiluminescent enzyme immunoassay method. The study group consisted of 239 men and 185 women, and their average age was 40.6 ± 14.0 years. HBsAg showed a positive correlation with HBV DNA level (Pearson's product moment correlation, r = 0.586, P < 0.001) and a weak inverse correlation with age (r = 0.3325, P < 0.001). A control study, matched with age and sex, was performed between two groups with and without HBeAg seroconversion during follow-up period. Compared with the age and sex-matched controls, the change in HBsAg levels per year showed a significant decrease 2 years before seroconversion (paired t-test, P < 0.05). The serial measurement of quantitative HBsAg level has the possibility of predicting the occurrence of HBeAg seroconversion.

Quantification of hepatitis C virus in patients treated with peginterferon-alfa 2a plus ribavirin treatment by COBAS TaqMan HCV test.

Extremely low levels of serum hepatitis C virus (HCV) RNA can be detected by COBAS TaqMan HCV test. To investigate whether the COBAS TaqMan HCV test is useful for measuring rapid virological response (RVR) and early virological response (EVR) to predict sustained virological response (SVR), we compared the virological response to PEG-IFN-alfa 2a plus RBV in 76 patients infected with HCV genotype 1 when undetectable HCV RNA by the COBAS TaqMan HCV test was used, with those when below 1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test was used, which corresponded to the use of traditional methods. Among the 76 patients, 28 (36.8%) had SVR, 13 (17.1%) relapsed, 19 (25.0%) did not respond, and 16 (21.0%) discontinued the treatment due to side effects. The positive predictive values for SVR based on undetectable HCV RNA by COBAS TaqMan HCV test at 24 weeks after the end of treatment [10/10 (100%) at week 4, 21/23 (91.3%) at week 8 and 26/33 (78.7%) at week 12] were superior to those based on <1.7 log IU/mL HCV RNA [17/19 (89.4%) at week 4, 27/38 (71.0%) at week 8, and 27/43 (62.7%) at week 12]. The negative predictive values for SVR based on <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test [46/57 (80.7%) at week 4, 37/38 (97.3%) at week 8, and 32/33 (96.9%) at week 12] were superior to those based on undetectable HCV RNA [48/66 (72.7%) at week 4, 46/53 (86.7%) at week 8, and 41/43 (95.3%) at week 12]. The utilization of both undetectable RNA and <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test is useful and could predict SVR and non-SVR patients with greater accuracy.

Pegylated interferon-alfa plus ribavirin therapies for chronic hepatitis C.

Until HCV NS3/4A protease inhibitors become available at the end of 2011, the combination pegylated-interferon (PEG-IFN)-alfa and ribavirin (RBV) will remain the standard treatment for chronic hepatitis C patients. In some hepatitis C virus-infected patients, PEG-IFN plus RBV treatment against HCV should continue to be used because of side effects of new drugs such as anemia. Our Japanese experiences should provide new information for the treatment of chronic hepatitis C.