Hiroshi Tobita

Clinical significance of the highly sensitive fucosylated fraction of α‐fetoprotein in patients with chronic liver disease

Background and Aim:  The purpose of the present study was to investigate the clinical significance of the highly sensitive fucosylated fraction of α‐fetoprotein (hs‐AFP‐L3) in patients with chronic liver disease (CLD) and low serum α‐fetoprotein (AFP) concentration.

Fibroblast-derived HB-EGF promotes Cdx2 expression in esophageal squamous cells

The molecular basis of attaining columnar phenotype in Barretts esophagus is poorly understood. One hypothesis states that factors locally produced by cells of mesenchymal origin in chronic reflux esophagitis induce metaplastic transformation. This study was performed to elucidate the factors secreted from fibroblasts that cause columnar phenotype in adjacent squamous epithelium. Human fibroblast cells were exposed to acidified medium for 20 min, followed by medium neutralization for 2 h, and then total RNA was hybridized to Sentrix Human-6 Expression BeadChips. Furthermore, esophageal mucosal biopsy specimens from reflux esophagitis patients were examined for HB-EGF expression using immunohistochemistry. In addition, cells from the human esophageal squamous epithelial cell line HET1A were treated with recombinant HB-EGF, and changes in expressions of Cdx2 and columnar markers were analyzed. The gene expression profile revealed significant upregulation of a variety of growth factors and inflammatory chemokines in response to acid exposure. Among them, HB-EGF was upregulated more than 10-fold. Biopsy specimens from reflux esophagitis patients showed a strong expression of HB-EGF in fibroblast cells underlying the damaged epithelium. Furthermore, in vitro stimulation of HET1A cells with HB-EGF increased Cdx2 in dose-dependent manners. Functional analysis of human Cdx2 promoter also revealed its upregulation by HB-EGF stimulation, showing the role of potential responsive elements (AP-1 and NF-κB) for its transcriptional activation. Moreover, the columnar markers cytokeratin 7 and villin were also upregulated by HB-EGF stimulation. HB-EGF induces several genes characteristics of columnar phenotypes of esophageal squamous epithelium in a paracrine manner.

Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study

Background Nonalcoholic steatohepatitis (NASH) is an active form of nonalcoholic fatty liver disease. Risk factors for NASH include type 2 diabetes mellitus (T2DM) and obesity. Sodium–glucose cotransporter 2 (SGLT2) inhibitors used to treat T2DM prevent glucose reabsorption in the kidney and increase glucose urinary excretion. Dapagliflozin is a potent, selective SGLT2 inhibitor that reduces hyperglycemia in patients with T2DM and has been demonstrated to reduce some complications associated with NASH in rodent models. Objective To assess the efficacy and safety profile of dapagliflozin for the treatment of NASH-associated with T2DM. Methods In this single-arm, nonrandomized, open-label study, 16 patients with percutaneous liver biopsy-confirmed NASH and T2DM were enrolled to be prescribed dapagliflozin 5 mg/d for 24 weeks. Of these, 11 patients were evaluable. Patients with chronic liver disease other than NASH were excluded. Body composition, laboratory variables related to liver tests and metabolism, and glucose homeostasis were assessed at baseline and periodically during the study. Changes from baseline were evaluated with the Wilcoxon signed-rank test. Results Administration of dapagliflozin for 24 weeks was associated with significant decreases in body mass index (P < 0.01), waist circumference (P < 0.01), and waist-to-hip ratio (P < 0.01). Changes in body composition were driven by reductions in body fat mass (P < 0.01) and percent body fat (P < 0.01), without changes in lean mass or total body water. Liver tests (ie, serum concentrations of aspartate aminotransferase, alanine aminotransferase, ferritin, and type IV collagen 7S) also significantly improved during the study. Insulin concentrations decreased (P < 0.01 by Week 24) in combination with significant reductions in fasting plasma glucose (P < 0.01) and glycated hemoglobin (P < 0.01) levels and increases in adiponectin (P < 0.01) levels from Week 4 onward. Conclusions Dapagliflozin was associated with improvements in body composition, most likely a reduction in visceral fat, which occurred together with improvements in liver tests and metabolic variables in patients with NASH-associated with T2DM. UMIN Clinical Trial Registry identifier: UMIN000023574.

Bleeding in abdominal cavity revealed by contrast-enhanced ultrasonography

Bleeding in the abdominal cavity can lead to hypovolemic shock and is a life-threatening condition; thus, its detection in real time is critical. Although dynamic computed tomography (CT) is useful for detecting extravasation, it may be difficult to detect slight bleeding in the abdominal cavity with that modality. We treated a patient with intraabdominal bleeding from a ruptured hepatocellular carcinoma (HCC), which was revealed in still images obtained with contrast-enhanced ultrasonography (US) as accumulation with maximum intensity. Such accumulation with maximum intensity in still images is useful for detecting slight bleeding in the abdominal cavity.

Influence of Full-body Water Immersion on Esophageal Motor Function and Intragastric Pressure

Background/Aims In Japan, it is customary to take a daily bath during which the body is immersed in water to the neck. During full-body immersion, hydrostatic pressure is thought to compress the chest and abdomen, which might influence esophageal motor function and intra-gastric pressure. However, whether water immersion has a significant influence on esophageal motor function or intragastric pressure has not been shown. The aim of this study was to clarify the influence of full-body water immersion on esophageal motor function and intragastric pressure. Methods Nine healthy male volunteers (mean age 40.1 ± 2.8 years) were enrolled in this study. Esophageal motor function and intragastric pressure were investigated using a high-resolution 36-channel manometry device. Results All subjects completed the study protocol. Intragastric pressure increased significantly from 4.2 ± 1.1 to 20.6 ± 1.4 mmHg with full-body water immersion, while the lower esophageal high pressure zone (LEHPZ) value also increased from 20.5 ± 2.2 to 40.4 ± 3.6 mmHg, with the latter being observed regardless of dietary condition. In addition, peak esophageal peristaltic pressure was higher when immersed as compared to standing out of water. Conclusions Esophageal motor function and intragastric pressure were altered by full-body water immersion. Furthermore, the pressure gradient between LEHPZ and intragastric pressures was maintained at a high level, and esophageal peristaltic pressure was elevated with immersion.

Elderly Fitz-Hugh–Curtis syndrome observed with superb microvascular imaging system

Fitz-Hugh–Curtis syndrome (FHCS) is defined as inflammation on the surface of the liver following sexually transmitted chlamydia infection. We successfully observed the microvascular structure of the inflamed portion between the abdominal wall and surface of the liver in an elderly patient with FHCS using a superb microvascular imaging (SMI) system, a new technology developed for observing minute vascular flow. An 80-year-old Japanese female with right dorsal to lateral abdominal pain and fever came to our hospital. Anti-chlamydia antibodies were positive. SMI revealed signals suggesting small vessels passing from the liver surface to the hypoechoic space.

Oral microbiome alterations of healthy volunteers with proton pump inhibitor: Influence of PPI on oral microbiota

Acid suppressive agents including proton pump inhibitors (PPIs) are used as first‐line treatment for various acid‐related gastrointestinal disorders. Although known to profoundly reduce gastric acid production, their influence on inhibition of acid secretion as part of the function of the gastrointestinal tract microbiome remains to be elucidated. The aim of the present study was to examine the effects of PPI usage on oral and gut microbiota in healthy volunteers.

Progression of Hepatic Hypovascular Nodules with Hypointensity in the Hepatobiliary Phase of Gd-EOB-DTPA-enhanced MRI in Hepatocellular Carcinoma Cases

Objective We investigated the possible factors for predicting the future progression to hepatocellular carcinoma (HCC) from hypovascular nodules detected in the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-MRI). Methods A total of 91 hypovascular nodules detected by Gd-EOB-DTPA-MRI in 28 patients without any past history of treatment for HCC were retrospectively examined. The nodules were categorized into those with and without HCC progression, then comparisons were made to identify any factors possibly related to a progression to HCC in each case. In addition, we performed a receiver operating characteristics (ROC) analysis to determine the cut-off value for the initial nodule size for predicting HCC progression within 12 months. Results The observation period of the 28 patients was 1,172.6±95.6 (mean±standard error) days. The number of hypovascular nodules that changed to hypervascular ones was 15 (16.5%), and the cumulative incidence of hypervascular transformation was 7.1% at 12 months and 12.7% at 24 months. Of all 91 hypovascular nodules, 33 in 18 patients were diagnosed as HCC based on hypervascular transformation and/or size enlargement, while the remaining 58 did not progress to HCC. There was no significant difference regarding the background characteristics between the HCC progressed and non-progressed groups according to a multivariate analysis, or between the patients who had nodules that progressed to HCC and those with nodules that did not progress to HCC. Regarding HCC progression at 12 months, the area under the ROC (AUROC) had a level of 0.745 and showed that an initial nodule cut-off size of 9.5 mm (sensitivity, 57.9%; specificity, 87.3%) was predictive. Conclusion In patients without a past HCC treatment history, it is difficult to determine whether hypovascular nodules have a high risk of progression to HCC based on background factors alone.

Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts the development of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: WFA+-M2BP predicts HCC in NAFLD

As it is not practical to perform regular screening for hepatocellular carcinoma (HCC) in all patients with non‐alcoholic fatty liver disease (NAFLD), there is a need to identify NAFLD patients who are at high risk for HCC. Wisteria floribunda agglutinin‐positive Mac‐2 binding protein (WFA+‐M2BP) has been shown to be a surrogate marker for predicting HCC as well as a liver fibrosis marker in patients with chronic hepatitis B and C. The aim of this study was to investigate whether WFA+‐M2BP predicts HCC development in NAFLD patients.

Proton pump inhibitor alters oral microbiome in gastrointestinal tract of healthy volunteers

Acid suppressive agents including proton pump inhibitors (PPIs) are used as first‐line treatment for various acid‐related gastrointestinal disorders. Although known to profoundly reduce gastric acid production, their influence on inhibition of acid secretion as part of the function of the gastrointestinal tract microbiome remains to be elucidated. The aim of the present study was to examine the effects of PPI usage on oral and gut microbiota in healthy volunteers.