Publications by authors named "Hiroshi Tobita"

31 Publications

Oxaliplatin-related Portal Hypertension Complicated with Esophageal Varices and Refractory Massive Ascites - Case Report.

Intern Med 2022 Apr 2. Epub 2022 Apr 2.

Department of Internal Medicine II, Shimane University Faculty of Medicine, Japan.

Oxaliplatin, widely used as a chemotherapy drug for colorectal cancer, is known to cause various adverse reactions. In particular, special attention for the development of portal hypertension associated with porto-sinusoidal vascular disease is necessary, as it is a serious adverse life-threating reaction, although rare. We herein report a case of oxaliplatin-related portal hypertension that developed several years after oxaliplatin administration and led to esophageal varices and refractory massive ascites. Clinical physicians should be aware of the possibility of oxaliplatin-induced portal hypertension and its possible development over a long period after discontinuation of the drug.
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http://dx.doi.org/10.2169/internalmedicine.9266-21DOI Listing
April 2022

Clinical Outcomes in Biopsy-Proven Nonalcoholic Fatty Liver Disease Patients: A Multicenter Registry-based Cohort Study.

Clin Gastroenterol Hepatol 2022 Jan 17. Epub 2022 Jan 17.

Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background & Aims: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage.

Methods: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients.

Results: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality.

Conclusions: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
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http://dx.doi.org/10.1016/j.cgh.2022.01.002DOI Listing
January 2022

The Simultaneous Onset of Pancreatitis and Colitis as Immune-related Adverse Events in a Patient Receiving Nivolumab Treatment for Renal Cell Carcinoma.

Intern Med 2022 May 6;61(10):1485-1490. Epub 2021 Nov 6.

Department of Internal Medicine II, Shimane University Faculty of Medicine, Japan.

Immune checkpoint inhibitors (ICIs), which have anti-tumor effects, are currently approved for treatment of several kinds of advanced malignancies. However, with their increasing use, a variety of immune-related adverse events (irAEs) in administered patients have been reported. We herein report a rare case of the simultaneous onset of acute pancreatitis and colitis as irAEs during nivolumab treatment given to a patient with renal cell carcinoma, who then shown marked improvement with corticosteroid therapy.
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http://dx.doi.org/10.2169/internalmedicine.7911-21DOI Listing
May 2022

Primary Extragastrointestinal Stromal Tumor of Greater Omentum with Intraperitoneal Bleeding.

Intern Med 2021 Nov 22;60(21):3413-3419. Epub 2021 May 22.

Department of Internal Medicine II, Shimane University Faculty of Medicine, Japan.

Gastrointestinal stromal tumors (GISTs) develop in the digestive tract, mainly in the stomach, small intestine, colon, or esophagus. However, primary tumors with the same pathologic features as GISTs have been reported to occur outside of the digestive tract and are called extragastrointestinal stromal tumor (EGIST). We herein report a rare case of EGIST arising from the greater omentum in a patient with abdominal pain caused by intraperitoneal bleeding from the tumor.
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http://dx.doi.org/10.2169/internalmedicine.6519-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627809PMC
November 2021

Comparison of dapagliflozin and teneligliptin in nonalcoholic fatty liver disease patients without type 2 diabetes mellitus: a prospective randomized study.

J Clin Biochem Nutr 2021 Mar 26;68(2):173-180. Epub 2020 Dec 26.

Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan.

There are no reports regarding the efficacy of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and dipeptidyl peptidase 4 inhibitor (DPP4i) administrations in nonalcoholic fatty liver disease (NAFLD) patients without type 2 diabetes mellitus. The purpose of this study was to evaluate the efficacy of those drugs in such patients. NAFLD patients without type 2 diabetes mellitus were enrolled in this single center double-blind randomized prospective study, and allocated to receive either dapagliflozin (SGLT2i) or teneligliptin (DPP4i) for 12 weeks. Laboratory variables and body compositions were assessed at the baseline and end of treatment. The primary endpoint was alanine aminotransferase (ALT) reduction level at the end of treatment. Twenty-two eligible patients (dapagliflozin group,  = 12; teneligliptin group,  = 10) were analyzed. In both groups, the serum concentration of ALT was significantly decreased after treatment (<0.05). Multiple regression analysis results showed that decreased body weight of patients with dapagliflozin administration was significantly related to changes in total body water and body fat mass. Administration of dapagliflozin or teneligliptin decreased the serum concentration of ALT in NAFLD patients without type 2 diabetes mellitus. With dapagliflozin, body weight decreased, which was related to changes in total body water and body fat mass (UMIN000027304).
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http://dx.doi.org/10.3164/jcbn.20-129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046003PMC
March 2021

High expression of a vascular stricture-related marker is predictive of an early response to tolvaptan, and a low fractional excretion of sodium is predictive of a poor long-term survival after tolvaptan administration for liver cirrhosis.

Hepatol Res 2020 Dec 9;50(12):1347-1354. Epub 2020 Dec 9.

Departments of Gastroenterology and Hepatology, and Medical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.

Aim: Tolvaptan is a newly available diuretic that has a specific function in water reabsorption inhibition. Given that spironolactone or furosemide induces the aggravation of cirrhotic hyponatremia and dehydration, tolvaptan affects the management strategy of liver cirrhosis. Representative predictive markers of its response include renal function-related markers such as urea nitrogen or creatinine. However, vascular function-related markers have not been well investigated. We investigated the effect of the vascular function-related marker asymmetric dimethylarginine (ADMA) and the effective arterial blood volume (EABV) marker, fractional excretion of sodium (FENa), on the early tolvaptan response and survival in liver cirrhosis.

Methods: We prospectively recruited 49 patients who required add-on tolvaptan for refractory ascites or edema. Laboratory data were obtained immediately before and 1 day after tolvaptan administration. Patients exhibiting >1.5 kg weight loss after 1 week were categorized as early responders to tolvaptan. Patients were followed for a median of 200 days and were assessed for survival.

Results: Early responders showed lower creatinine levels (<1.0 mg/dL), and higher ADMA levels (≥0.61 nmol/mL) than others in a multivariate analysis. Patients with a shorter survival were positive for hepatocellular carcinoma and had a low FENa (<0.35%).

Conclusion: Early responders showed higher ADMA levels reflecting vascular stricture, suggesting that higher vascular tonus is required for a tolvaptan early response. Patients with a shorter survival showed a lower FENa, reflecting a lower EABV and suggesting that adequate EABV is required for the prolonged survival after tolvaptan administration.
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http://dx.doi.org/10.1111/hepr.13573DOI Listing
December 2020

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Int J Mol Sci 2020 Jul 13;21(14). Epub 2020 Jul 13.

Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.
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http://dx.doi.org/10.3390/ijms21144939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404115PMC
July 2020

Prevalence of functional dyspepsia-like symptoms in ulcerative colitis patients in clinical remission and overlap with irritable bowel syndrome-like symptoms.

Scand J Gastroenterol 2020 May 15;55(5):560-564. Epub 2020 May 15.

Department of Internal Medicine II, Shimane University School of Medicine, Izumo, Japan.

Quiescent ulcerative colitis (UC) patients often have irritable bowel syndrome (IBS)-like symptoms and we recently showed that the prevalence of IBS-like symptoms in UC patients in clinical remission was significantly higher as compared to healthy control subjects. However, the prevalence of functional dyspepsia (FD)-like symptoms in quiescent UC patients remains unknown. The purpose of this study was to evaluate the prevalence of FD-like symptoms and the overlap with IBS-like symptoms in such patients. We reanalyzed the records of UC patients in remission using the subject cohort from our previous study. Clinical remission was defined as a clinical activity index (CAI) value ≤4 for at least 6 months. Diagnoses of FD- and IBS-like symptoms were evaluated by questionnaire according to the Rome III criteria. One hundred seventy-two UC patients in clinical remission and 330 healthy control subjects were analyzed. Of the 172 patients, 9 (5.2%) met the criteria of FD, which was comparable with the controls (22/330, 6.7%). The prevalence rate of FD-like symptoms in UC patients with IBS-like symptoms (7/46, 15.2%) was lower as compared to that of the control subjects (6/16, 37.5%). On the other hand, a high percentage of the UC patients with FD-like symptoms also had IBS-like symptoms (7/9, 77.8%). Although the prevalence of FD-like symptoms in quiescent UC patients with IBS-like symptoms was low, UC patients with FD-like symptoms frequently had IBS-like symptoms.
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http://dx.doi.org/10.1080/00365521.2020.1761998DOI Listing
May 2020

Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease.

PLoS One 2020 27;15(2):e0219412. Epub 2020 Feb 27.

Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan.

Introduction: Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker.

Methods: Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal.

Results: Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379.

Conclusions: Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219412PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046274PMC
April 2020

Evaluation of hepatic congestion in patients with heart failure using shear wave and strain imaging.

J Echocardiogr 2020 12 27;18(4):260-261. Epub 2019 Jun 27.

Division of Cardiology, Shimane University Faculty of Medicine, Izumo-shi, Shimane, Japan.

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http://dx.doi.org/10.1007/s12574-019-00435-yDOI Listing
December 2020

Retained Rice Cake: A Unique Upper Gastrointestinal Foreign Body: Case Report and a Literature Review.

Intern Med 2019 Sep 7;58(17):2485-2494. Epub 2019 Jun 7.

Department of Emergency and Critical Care Medicine, Shimane University, Faculty of Medicine, Japan.

As a rarely recognized foreign body in the upper gastrointestinal tract, rice cake frequently requires endoscopic removal. We herein report six patients with characteristic sonography, computed tomography (CT), spectroscopy, endoscopy, and histological findings. A review of all published cases, including ours, revealed that retained rice cake in the stomach typically shows the following: abdominal pain (93.3%), mucosal injury (93.3%) with bleeding (42.9%); high-density (120-206 Hounsfield units) CT findings; and indication for endoscopy (80%). In the esophagus, hot, toasted rice cake causes thermal injury. Primary physicians should be aware of this popular-food-induced, but rare, disorder.
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http://dx.doi.org/10.2169/internalmedicine.2760-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761341PMC
September 2019

Alogliptin alleviates hepatic steatosis in a mouse model of nonalcoholic fatty liver disease by promoting CPT1a expression via Thr172 phosphorylation of AMPKα in the liver.

Mol Med Rep 2018 05 1;17(5):6840-6846. Epub 2018 Mar 1.

Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan.

Pioglitazone (PIO) has been reported to be effective for nonalcoholic fatty liver disease (NAFLD) and alogliptin (ALO) may have efficacy against NAFLD progression in patients with type 2 diabetes mellitus (T2DM). The present study examined the effectiveness of ALO in a rodent model of NAFLD and diabetes mellitus. KK‑Ay mice were used to produce an NAFLD model via administration of a choline‑deficient (CD) diet. To examine the effects of alogliptin, KK‑Ay mice were provided with a CD diet with 0.03% ALO and/or 0.02% PIO orally for 8 weeks. Biochemical parameters, pathological alterations and hepatic mRNA levels associated with fatty acid metabolism were assessed. Severe hepatic steatosis was observed in KK‑Ay mice fed with a CD diet, which was alleviated by the administration of ALO and/or PIO. ALO administration increased the hepatic carnitine palmitoyltransferase 1a (CPT1a) mRNA expression level and enhanced the Thr172 phosphorylation of AMP‑activated protein kinase α (AMPKα) in the liver. PIO administration tended to decrease the hepatic fatty acid synthase mRNA expression level and increase the serum adiponectin level. Homeostasis model of assessment‑insulin resistance values tended to improve with ALO and PIO administration. ALO and PIO alleviated hepatic steatosis in KK‑Ay mice fed with a CD diet. ALO increased hepatic mRNA expression levels associated with fatty acid oxidation. In addition, the results of the present study suggested that ALO promotes CPT1a expression via Thr172 phosphorylation of AMPKα.
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http://dx.doi.org/10.3892/mmr.2018.8673DOI Listing
May 2018

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

J Med Ultrason (2001) 2018 Oct 20;45(4):611-615. Epub 2018 Feb 20.

Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan.

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.
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http://dx.doi.org/10.1007/s10396-018-0865-2DOI Listing
October 2018

Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts the development of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease.

Hepatol Res 2018 Jun 9;48(7):521-528. Epub 2018 Feb 9.

Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki.

Aim: 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.

Methods: Serum WFA -M2BP was retrospectively measured in 331 patients with histologically proven NAFLD, 51 of whom developed HCC. The association of WFA -M2BP and HCC development in NAFLD patients was investigated.

Results: The WFA -M2BP values were significantly greater in NAFLD patients with HCC than in those without HCC among patients with liver fibrosis ≥stage 3. Multivariate analysis identified WFA -M2BP as one of the predictive factors for HCC development (odds ratio, 1.57; 95% confidence interval, 1.083-2.265; P = 0.017). The optimal cut-off index of WFA -M2BP for predicting HCC was 1.255 with specificity of 78.4% and sensitivity of 70.4%. The area under the receiver operating characteristic curve value for the prediction of HCC development was 0.806. The cumulative incidence rate of HCC was significantly greater in patients with WFA -M2BP ≥ 1.255 (n = 61) than in those with WFA -M2BP < 1.255 (n = 137) among patients who were followed up for more than 2 years after the diagnosis of NAFLD.

Conclusions: Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts HCC development and is a useful surrogate marker for identifying NAFLD patients who are at a high risk for HCC.
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http://dx.doi.org/10.1111/hepr.13054DOI Listing
June 2018

Oral microbiome alterations of healthy volunteers with proton pump inhibitor.

J Gastroenterol Hepatol 2018 May 14;33(5):1059-1066. Epub 2018 Feb 14.

Department of Gastroenterology and Hepatology, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan.

Background And Aim: 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.

Methods: Ten healthy adult volunteers receiving no medications were enrolled. We obtained fecal, saliva, and periodontal pocket fluid samples from the subjects before and after 4 weeks of once daily administrations of 20-mg esomeprazole. The effects of PPI administration on bacterial communities were investigated using a 16S rRNA gene sequencing method.

Results: Species richness (alpha diversity) was significantly different among the salivary, periodontal pocket, and fecal samples. Furthermore, the measurements for UniFrac distances, despite inter-individual variations (beta diversity), of the microbiota structure of saliva and periodontal pocket and feces samples were clearly separated from each other. The salivary samples showed significant differences between alpha and beta diversity measurements before and after administration of the PPI for 4 weeks. Meanwhile, taxon-based analysis indicated that PPI administration raised the ratio of Streptococcus organisms in fecal samples, suggesting a potentially unfavorable effect leading to gut microbiota alteration. Moreover, alterations of the microbiota in the oral carriage microbiome along with bacterial overgrowth (Streptococcus) and decreases in distinct bacterial species (Neisseria and Veillonella) were observed.

Conclusions: These results suggest that PPIs cause both oral and gut microbiota alterations.
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http://dx.doi.org/10.1111/jgh.14040DOI Listing
May 2018

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

Intern Med 2018 Jan 16;57(2):165-171. Epub 2017 Oct 16.

Department of Internal Medicine II, Shimane University Faculty of Medicine, Japan.

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.
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http://dx.doi.org/10.2169/internalmedicine.8801-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820032PMC
January 2018

Efficacy of Repeated Lusutrombopag Administration for Thrombocytopenia in a Patient Scheduled for Invasive Hepatocellular Carcinoma Treatment.

Intern Med 2017 Nov 25;56(21):2887-2890. Epub 2017 Sep 25.

Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Japan.

The efficacy of repeated lusutrombopag administration for thrombocytopenia in patients with chronic liver disease who undergo two or more planned invasive procedures is unknown. We herein report our findings regarding the effects of repeated lusutrombopag administration given to avoid platelet transfusion in a patient with chronic liver disease and thrombocytopenia. The platelet count showed a positive response to lusutrombopag treatment prior to the initial invasive procedure to treat a hepatoma, so platelet transfusion was not necessary. In conclusion, lusutrombopag may be a useful drug for patients with thrombocytopenia to avoid platelet transfusion in those undergoing two or more planned invasive procedures.
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http://dx.doi.org/10.2169/internalmedicine.8791-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709632PMC
November 2017

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.

Curr Ther Res Clin Exp 2017;87:13-19. Epub 2017 Jul 8.

Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Japan.

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 ( < 0.01), waist circumference ( < 0.01), and waist-to-hip ratio ( < 0.01). Changes in body composition were driven by reductions in body fat mass ( < 0.01) and percent body fat ( < 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 ( < 0.01 by Week 24) in combination with significant reductions in fasting plasma glucose ( < 0.01) and glycated hemoglobin ( < 0.01) levels and increases in adiponectin ( < 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.
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http://dx.doi.org/10.1016/j.curtheres.2017.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587885PMC
July 2017

Proton pump inhibitor is a risk factor for recurrence of common bile duct stones after endoscopic sphincterotomy - propensity score matching analysis.

Endosc Int Open 2017 Apr;5(4):E291-E296

Department of Internal Medicine II, Shimane University School of Medicine, Japan.

Recurrence of common bile duct stones (CBDS) in patients treated with endoscopic sphincterotomy (ES) can lead to deterioration in their quality of life. Although the pathology and related factors are unclear, we speculated that proton pump inhibiter (PPI) administration increases the risk of CBDS recurrence by altering the bacterial mixture in the bile duct. The primary endpoint of this retrospective study was recurrence-free period. Several independent variables considered to have a relationship with CBDS recurrence including PPI use were analyzed using a COX proportional hazard model, with potential risk factors then evaluated by propensity score matching analysis. A total of 219 patients were analyzed, with CBDS recurrence found in 44. Analysis of variables using a COX proportional hazard model demonstrated that use of PPIs and ursodeoxycholic acid (UDCA), as well as the presence of periampullary diverticula (PD) each had a hazard ratio (HR) value greater than 1 (HR 2.2,  = 0.007; HR 2.0,  = 0.02; HR 1.9,  = 0.07; respectively). Furthermore, propensity score matching analysis revealed that the mean recurrence-free period in the oral PPI cohort was significantly shorter as compared with the non-PPI cohort (1613 vs. 2587 days,  = 0.014). In contrast, neither UDCA administration nor PD presence was found to be a significant factor in that analysis (1557 vs. 1654 days,  = 0.508; 1169 vs. 2011 days,  = 0.121; respectively). Our results showed that oral PPI administration is a risk factor for CBDS recurrence in patients who undergo ES.
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http://dx.doi.org/10.1055/s-0043-102936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378546PMC
April 2017

Bleeding in abdominal cavity revealed by contrast-enhanced ultrasonography.

J Med Ultrason (2001) 2013 Jul 26;40(3):289-91. Epub 2013 Apr 26.

Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Japan.

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http://dx.doi.org/10.1007/s10396-013-0430-yDOI Listing
July 2013

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

J Neurogastroenterol Motil 2012 Apr 9;18(2):194-9. Epub 2012 Apr 9.

Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Shimane, Japan.

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.
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http://dx.doi.org/10.5056/jnm.2012.18.2.194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325305PMC
April 2012

A sub-centimeter HCC with bright loop appearance diagnosed by contrast-enhanced ultrasonography.

J Med Ultrason (2001) 2011 Jan 27;38(1):27-31. Epub 2010 Nov 27.

Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, 89-1 Enya, Izumo, Shimane, 693-8501, Japan.

Detection of a hepatocellular carcinoma (HCC) in the early stage is critical, as clinical stage influences treatment selection and patient prognosis. Carcinogenetic development of an HCC is a multi-step process, and a differential diagnosis between a dysplastic nodule and a well-differentiated HCC is often difficult. A bright loop appearance is a significant finding that indicates disappearance of fatty deposition in the central area of the nodule during the progression toward HCC, however such a finding is rare in cases of sub-centimeter-sized HCCs. We encountered a case of HCC that developed a bright loop appearance on ultrasound (US) without enlargement approximately 2 years after diagnosis as a dysplastic nodule. Moreover, the hypoechoic area in the center of the nodule showed an HCC pattern in contrast enhanced US with Sonazoid™. Vascularity in the nodule could not be observed on dynamic contrast-enhanced CT or Gd-EOB-DTPA-enhanced MRI. When a change in the intranodular echo pattern is observed in sub-centimeter-sized nodules, examination of intranodular vascularity by contrast-enhanced US is important to evaluate borderline lesions.
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http://dx.doi.org/10.1007/s10396-010-0291-6DOI Listing
January 2011

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

J Gastroenterol Hepatol 2011 Apr;26(4):739-44

Department of Gastroenterology and Hepatology, Shimane University, Faculty of Medicine, Izumo, Japan.

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.

Methods: A total of 241 patients being treated at our institute with CLD and low serum AFP concentration (3-10 ng/mL) were investigated retrospectively. We measured total AFP and the percentage of AFP-L3 using a µTAS Wako i30 device. The possible presence of hepatocellular carcinoma (HCC) was thoroughly investigated by various examinations carried out from 1 month before to 1 month after measurements. In addition, hs-AFP-L3 elevated and non-elevated groups, divided by the cut-off value based on a receiver-operator characteristic (ROC) curve, were followed for possible future development of HCC.

Results: hs-AFP-L3 was above the detectable range in 60 patients (24.9%). Among those AFP-L3 positive cases, 20 (33.3%) were found to be HCC prevalent, whereas HCC was found in just 16 patients (8.8%) with undetectable hs-AFP-L3 levels. We determined the cut-off value of hs-AFP-L3%, which shows the proportion of AFP L3 in total AFP, to be 5.75%. During the follow-up period, HCC was newly detected in six patients (22.2%) in the hs-AFP-L3% elevated group and in 10 (5.6%) in the non-elevated group. Analysis using the Kaplan-Meier method showed the HCC-free rate of the hs-AFP-L3% elevated group was significantly lower than that of the non-elevated group (P=0.0038). Independent predicting variants were female sex (P=0.0024) and hs-AFP-L3% elevation (P=0.0036).

Conclusion: Our results suggest hs-AFP-L3 level is a useful tumor marker for HCC in patients with CLD and low serum AFP concentration.
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http://dx.doi.org/10.1111/j.1440-1746.2010.06585.xDOI Listing
April 2011

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

Lab Invest 2010 Jul 29;90(7):1033-48. Epub 2010 Mar 29.

Department of Internal Medicine II, Shimane University School of Medicine, Izumo, Shimane, Japan.

The molecular basis of attaining columnar phenotype in Barrett's 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-kappaB) 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.
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http://dx.doi.org/10.1038/labinvest.2010.71DOI Listing
July 2010

[Development and verification of the Izumo Scale, new questionnaire for quality of life assessment of patients with gastrointestinal symptoms].

Nihon Shokakibyo Gakkai Zasshi 2009 Oct;106(10):1478-87

Department of Gastroenterology and Hepatology, Shimane University School of Medicine.

The Izumo Scale is a new questionnaire for the assessment of quality of life of the patients with gastrointestinal symptoms comprehensively. The validity and reliability of the scale were verified in 170 patients with gastrointestinal symptoms. Spearman's rank correlation coefficient between the Izumo Scale and visual analog scale (VAS) showed a positive correlation of 0.581-0.753. Internal consistency was also good with Cronbach's coefficient alpha of 0.616-0.805. The reproducibility was good with an intra-class correlation coefficient of 0.755-0.887. The results suggest that the Izumo Scale may be useful as a disease-specific quality of life assessment scale for patients with gastrointestinal symptoms.
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October 2009

A dose-up of ursodeoxycholic acid decreases transaminases in hepatitis C patients.

World J Gastroenterol 2009 Jun;15(22):2782-6

Department of Gastroenterology and Hepatology, Shimane University, School of Medicine, Izumo, Shimane, Japan.

Aim: To examine whether a dose-up to 900 mg of ursodeoxycholic acid (UDCA) decreases transaminases in hepatitis C patients.

Methods: From January to December 2007, patients with chronic hepatitis C or compensated liver cirrhosis with hepatitis C virus (HCV) (43-80 years old) showing positive serum HCV-RNA who had already taken 600 mg/d of UDCA were recruited into this study. Blood parameters were examined at 4, 8 and 24 wk after increasing the dose of oral UDCA from 600 to 900 mg/d.

Results: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) levels were significantly decreased following the administration of 900 mg/d as compared to 600 mg/d. The decrease in ALT from immediately before the dose-up of UDCA to 8 wk after the dose-up was 14.3 IU/L, while that for AST was 10.5 IU/L and for GGT was 9.8 IU/L. Platelet count tended to increase after the dose-up of UDCA, although it did not show a statistically significant level (P = 0.05). Minor adverse events were observed in 3 cases, although no drop-outs from the study occurred.

Conclusion: Oral administration of 900 mg/d of UDCA was more effective than 600 mg/d for reducing ALT, AST, and GGT levels in patients with HCV-related chronic liver disease.
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http://dx.doi.org/10.3748/wjg.15.2782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695895PMC
June 2009

Gene expression profile of DNA binding protein A transgenic mice.

Int J Oncol 2006 Sep;29(3):673-9

Department of Pathology, Juntendo University School of Medicine, Hongo, Tokyo 113-8421, Japan.

We recently reported that the expression of dbpA (DNA binding protein A) is associated with advanced stages of human hepatocellular carcinoma (HCC) and that its transcription is positively regulated by E2F1, which is also implicated in hepatocarcinogenesis. To study the in vivo effect of dbpA on hepatocarcinogenesis, we generated the dbpA-transgenic mouse that specifically expressed a transgene in hepatocytes. Here, we studied the effect of dbpA on the expression of other cellular genes by using microarray analyses. The expression profiles from livers of 31- and 32-week-old male transgenic mice [Tg(+)] that did not show any morphological changes and from livers of their male wild-type littermates [Tg(-)] were compared. Expression differences detected by microarray analyses were validated by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA samples from livers of 3 pairs of Tg(+) and (-) mice. The 11 up-regulated genes included 7 carcinogenesis-related genes (Igfbp1, Tff3, Hpx, Orm2, Ctsl, Plg, Jdp1), and the 9 down-regulated genes included Car3 that is associated with the protection of cells from attack by oxygen radicals. We confirmed that the expression of Igfbp1 (insulin like growth factor binding protein 1) was reduced by siRNA targeting dbpA in the human HCC cell line. In conclusion, our present data suggested that dbpA could be positively involved in carcinogenesis by changing the expression profiles of cellular genes.
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September 2006

The up-regulation of Y-box binding proteins (DNA binding protein A and Y-box binding protein-1) as prognostic markers of hepatocellular carcinoma.

Clin Cancer Res 2005 Oct;11(20):7354-61

Second Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Purpose: The development of hepatocellular carcinoma is associated with the chronic inflammation of the liver caused by various factors such as hepatitis B or C virus infection. Previously, we reported DNA binding protein A (dbpA) as a candidate molecule that can accelerate inflammation-induced hepatocarcinogenesis. DbpA belongs to the Y-box binding protein family, and Y-box binding protein-1 (YB-1), the prototype member of this family, is reported to be a prognostic marker of malignant diseases other than hepatocellular carcinoma. The purpose of this study is to examine the significance of the expression of dbpA or of the T-to-G transversion in the dbpA promoter region, which enhances the promoter activity in vitro, for the progression of hepatocellular carcinoma.

Experimental Design: We studied the expression of dbpA (as well as of YB-1) in 82 formalin-fixed hepatocellular carcinoma tissues by immunohistochemistry and determined the sequence of the dbpA promoter region in 42 frozen hepatocellular carcinoma tissues. We examined the relationship between these findings and the clinicopathologic factors of hepatocellular carcinoma patients.

Results: DbpA expression was associated with the advanced stages of hepatocellular carcinoma, and the cases with the nuclear dbpA expression had a poor prognosis. DbpA contributed more significantly to this association than YB-1. Furthermore, the T-to-G transversion in the dbpA promoter region was related to the nuclear localization of dbpA.

Conclusion: DbpA was a more significant prognostic marker of hepatocellular carcinoma than YB-1. The T-to-G transversion in the dbpA promoter region was suggested to be a predisposing factor for the progression of hepatocellular carcinoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-1027DOI Listing
October 2005

[Molecular mechanism of HBV-related hepatocarcinogenesis].

Nihon Rinsho 2004 Aug;62 Suppl 8:367-71

Department of Experimental Pathology, Cancer Institute.

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August 2004

Transcription of dbpA, a Y box binding protein, is positively regulated by E2F1: implications in hepatocarcinogenesis.

Biochem Biophys Res Commun 2004 Sep;322(1):297-302

Department of Experimental Pathology, Cancer Institute, Japanese Fundation of Cancer Research, Tokyo, Japan.

Human hepatocellular carcinoma is one of the most common cancers in the world. We previously showed that dbpA, a member of the Y box family of proteins, could accelerate the process of inflammation-induced hepatocarcinogenesis, and that dbpA is more abundantly expressed in hepatocellular carcinoma than in non-tumorous tissue. In this study, to clarify the mechanism by which expression of dbpA is enhanced in the proliferative state, we examined the transcriptional activity of the dbpA promoter region. We focused on the sequence 5'-TTTGGGGC-3' (-8 to -1 in the promoter region) resembling the E2F binding site (one base mismatch, TFSEARCH score 86.2). By overexpressing E2F1 in Huh-7 cells, transcriptional activity of dbpA was significantly increased, and this increase was abolished by mutating or deleting this sequence. Thus, expression of dbpA was positively regulated by E2F1, suggesting that one of the effects of E2F1 on cell proliferation might be mediated by dbpA at the carcinogenesis step.
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http://dx.doi.org/10.1016/j.bbrc.2004.04.208DOI Listing
September 2004
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