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Sarcopenia is well recognized as a prognostic factor of chronic liver diseases. However, its impact on the clinical course of primary sclerosing cholangitis (PSC) is unclear. This study aimed to clarify the importance of trunk muscles evaluated by computed tomography (CT) in the pathophysiology of patients with PSC.22 PSC patients (12 men, mean age 42.8 years) were enrolled in this study. Patients who died of hepatic failure or had to receive liver transplantation were defined as event group. 44 age- and gender-matched individuals without hepatic disorder were served as controls. At the level of third lumbar vertebrae, the area of psoas muscle and trunk muscle as well as the CT values of multifidus muscle and subcutaneous fat were evaluated. Based on these, skeletal muscle index (SMI), psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) were calculated. Then we analyzed the relationship between these parameters and laboratory data, Fibrosis-4 index, MELD score and Mayo risk score.At baseline evaluation, SMI and PMI were statistically lower in male PSC patients compared with those in controls (P 0.05). In male PSC, regarding the laboratory data, PMI was associated with total bilirubin, ALT, ALP, and platelet count (P 0.05). We found close relationship between PMI and MELD score (RSkeletal muscle mass evaluated by CT scan can be suitable for evaluating clinical and prognostic marker in male PSC.

Predictive factors for intrahepatic cholangiocarcinoma in long-term follow-up of hepatolithiasis are unknown. We thus conducted a cohort study to investigate the predictive factors for developing intrahepatic cholangiocarcinoma in hepatolithiasis.This cohort is comprised of 401 patients registered in a nationwide survey of hepatolithiasis for 18 years of follow-up. Cox regression analysis was used to elucidate predictive factors for developing intrahepatic cholangiocarcinoma.The median follow-up period of patients was 134 months. Twenty-two patients developed intrahepatic cholangiocarcinoma and all died. Identified independent significant factors were as follows: age 63 years or older (hazard ratio [HR] 3.344), residual stones at the end of treatment (HR 2.445), and biliary stricture during follow-up (HR 4.350). The incidence of intrahepatic cholangiocarcinoma in patients with three factors was significantly higher than that in patients with one or two factors. The incidence in the groups with one or two predictive factors was not different. In 88.9% of patients with both biliary stricture and intrahepatic cholangiocarcinoma, the duration between the diagnoses of biliary stricture and intrahepatic cholangiocarcinoma was ≥ 5 years. However, once intrahepatic cholangiocarcinoma developed, 77.8% of patients died within 1 year. Of 24 patients with no symptoms, no previous choledocoenterostomy, no signs of malignancy, no biliary stricture, and no treatment for hepatolithiasis during follow-up, only one developed intrahepatic cholangiocarcinoma.Regarding carcinogenesis, complete stone clearance and releasing biliary stricture can prevent the development of intrahepatic cholangiocarcinoma and improve the prognosis of hepatolithiasis.

Background: An increased focus on quality and patient safety led to the evolution of the hospitalist specialty. The number of hospitalists, who cover ward and outpatient care, is on the rise in Japan. However, it is unclear what roles hospitalists themselves consider important in their practice. Therefore, this study aimed to investigate what hospitalists and non-hospitalist generalists in Japan consider important for the practice of their specialty. Methods:This was an observational study that included Japanese hospitalists (1) currently working in a general medicine (GM) or general internal medicine department and (2) working at a hospital. Using originally developed questionnaire items, we surveyed what they think are important to hospitalists and what are important compared to that for non-hospitalist generalists. Results: There were 971 participants (733 hospitalist, 238 non-hospitalist) in the study. The response rate was 26.1％. Both hospitalists and non-hospitalists ranked evidence-based medicine as most important for their practice. Hospitalists ranked diagnosis and patient management as the second and third most important roles for their practice while non-hospitalists ranked patient management and elderly care as second and third. Conclusions: This is the first study investigating what roles Japanese hospitalists consider important and compare those to that of non-hospitalist generalists. Many of the items that hospitalists responded to that they actually consider important were those that hospitalists in Japan are actually working on within and outside of academic societies. We found that diagnostic medicine, and quality and safety are likely to be evolved by hospitalists because they specifically emphasized them, while the care of the elderly is an issue that hospitalists should be more concerned about. Future expected research includes proposals on how to further enhance items that hospitalists emphasize and should focus on, as well as international comparisons regarding the items.

Background: When monitoring patients with an intraductal mucinous neoplasm (IPMN), it is important to consider both IPMN-derived carcinoma and concomitant ductal adenocarcinoma (PDAC). The latter is thought to have a poorer prognosis. We retrospectively analyzed risk factors for concomitant PDAC in IPMN.Methods: In total, 547 patients with pancreatic cysts, including IPMN inappropriate for surgery on initial diagnosis, encountered from April 2005 to June 2019, were reviewed. We performed surveillance via imaging examination once or twice a year. Results: There were five intraductal papillary mucinous adenocarcinoma encountered. In comparison, there were 14 concomitant PDAC encountered. The prognosis was very poor in concomitant PDAC. All 14 PDAC patients had IPMN. In patients with IPMN, long-standing diabetes mellitus was the only significant risk factor for concomitant PDAC in both univariate and multivariate analysis ( P < 0.001 and P < 0.01, respectively). Further, patients with IPMN and diabetes mellitus had high frequency of concomitant PDAC (9.5%, 9/95) in a median 48-month surveillance period.Conclusions: When monitoring IPMN, concomitant PDAC should be considered, rather than IPMN-derived carcinoma. During this period, it may be prudent to concentrate on patients with other risk factors for PDAC, such as long-standing diabetes mellitus.

The present study investigated the possible risk factors, including relationship/HLA matching between donor and recipient, and immunosuppressive therapies on the recurrence of primary sclerosing cholangitis (PSC) after liver transplantation (LT). Subjects were 197 recipients of LT for PSC, among whom 180 surviving more than 1 year after LT were further analyzed for risk factors of recurrence. The 5- and 10-year patient- and graft survival rates were 83% and 68%, and 71% and 62%, respectively. The overall PSC recurrence rate was 25% with a 5- and 10-year graft survival rate of 34% and 18%, which was significantly lower than the survival rate of those without recurrence (P 0.001). Univariate analysis identified the following as risk factors for recurrence: donor age (P 0.001), cyclosporine use (P = 0.012), mono or no immunosuppressive agent (P 0.001), postoperative biliary complication (P 0.001), and active intestinal bowel disease after LT (P 0.001). Among these factors, donor age ≥45 years [hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.21-2.69; P = 0.003] and mono or no immunosuppressive agent 1-year after LT (HR, 2.38; 95% CI, 1.23-3.45; P = 0.011) were identified as independent risk factors in the final multivariate Cox regression model. The results were similar in sub-analysis for ABO-identical/compatible adult living donor LT cases.

It remains unclear whether ursodeoxycholic acid (UDCA) treatment improves long-term outcomes in patients with primary sclerosing cholangitis (PSC). In this study, we investigated whether UDCA treatment is associated with improved liver transplantation (LT)-free survival in a cohort of Japanese patients with PSC.Journal instruction requires a city and country for affiliations; however, these are missing in affiliation [6]. Please verify if the provided city and country are correct and amend if necessary.'Tokyo, Japan' is correct.We used retrospective data from the Japanese PSC registry that included 435 patients with PSC. In this study, we enrolled patients with a complete dataset at diagnosis, along with the diagnosis year, treatment protocol, follow-up period, and outcome data. The association between UDCA treatment and all-cause death or LT was analyzed using Cox regression and inverse probability of UDCA treatment weighting (IPTW)-adjusted Cox regression models adjusted for covariates.Among 435 patients with PSC, 110 were excluded due to insufficient or missing data, and the remaining 325 patients (male, 187 (58%); mean age at diagnosis, 45.8 years) were enrolled. The mean follow-up period was 5.1 years, and 57 deaths and 24 LTs occurred during observation. UDCA was administered to 278 patients (86%). The Cox regression model demonstrated that UDCA treatment was associated with an improvement in LT-free survival [adjusted hazard ratio (aHR) 0.47, 95% confidence interval (CI) 0.28-0.78, p = 0.003]. In addition, the IPTW-adjusted model indicated a significant association between UDCA and LT-free survival (aHR 0.43, 95% CI 0.25-0.75, p = 0.020). Sensitivity analysis excluding patients treated with bezafibrate indicated a similarly significant association between UDCA treatment and LT-free survival.In this Japanese PSC cohort, UDCA treatment was significantly associated with improved LT-free survival.

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is essential for improving prognosis; however, diagnosing PDAC at an early stage is challenging. In patients with localized high-grade pancreatic intraepithelial neoplasia (HG-PanIN), whose tumorous lesion is undetectable on cross-sectional images such as computed tomography or magnetic resonance image, long-term survival is expected. Pancreatic cystic lesions or main pancreatic duct (MPD) dilatation are important indirect findings for the initial diagnosis of HG-PanIN. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) should play important roles in detecting abnormal image findings, such as local irregular MPD stenosis, caliber MPD changes, small cystic lesions, or branch duct dilatation. Additionally, EUS could detect hypoechoic areas around the MPD stenosis in some patients with HG-PanIN. Subsequently, endoscopic retrograde cholangiopancreatography (ERCP) and its associated pancreatic juice cytology, including serial pancreatic juice aspiration cytologic examination (SPACE) after placement of an endoscopic nasopancreatic drainage (ENPD) tube, may have high diagnostic accuracy for confirming the malignancy in HG-PanIN. Although ERCP and its associated pancreatic cytology, including SPACE, may be associated with post-ERCP pancreatitis (PEP), a recent randomized trial suggested that a 4-Fr ENPD tube may reduce the incidence of PEP. In the future, further prospective multicenter studies are required to establish a standard method of SPACE. Additionally, further studies for novel biomarkers could help to establish evolutionary methods with duodenal fluid and pancreatic juice for the early and accurate diagnosis of early-stage PDAC.

Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells. LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors. DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFβ. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC. Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFβ.

Background Pancreaticobiliary maljunction and intrahepatic gallstones are at a high risk for biliary malignancy. Lysophosphatidylcholine (LPC) is increased in the bile of these patients, and we have previously reported that LPC-induced cytotoxicity causes senescence-associated secretory phenotype (SASP) in cholangiocytes. We aimed to determine the protective effect of phosphatidylcholine (PC) on LPC-induced cholangiocyte cytotoxicity. Methods MMNK-1, a human immortalized cholangiocyte cell line was treated with LPC with or without PC. To assess the biological effects of SASP components on cholangiocarcinoma, HuH28 and HuCCT1 (human cholangiocarcinoma cell lines) were cultured in the conditioned media where MMNK-1 cells treated with LPC. Results The presence of PC reduced reactive oxygen species generation and oxidative DNA damage in MMNK-1 treated with LPC. Moreover, SA-β-gal activity was markedly downregulated by PC. The secretion of SASP components, including interleukin (IL)-8, IL-6, and C-C motif chemokine ligand 2 was also substantially reduced in the presence of PC. Cellular proliferation and migration were enhanced in HuCCT1 and HuH28 cells when cultured in the conditioned media, and these observations were suppressed by simultaneous addition of PC. Conclusion PC protects cholangiocytes against LPC-induced cytotoxicity and cellular senescence, suggesting its potential as a target for inhibiting LPC-related carcinogenesis and its promotion.

Here, we describe a case of giant cell arteritis (GCA) simultaneously diagnosed with chronic subdural hematoma. In this case, head to chest computed tomography angiography was useful for the diagnosis and treatment of GCA.

A 78-year-old woman with fever of unknown origin that had persisted for 3 months, systemic edema, and cervical lymphadenopathy was admitted to our hospital. Skin purpura and jaw claudication were subsequently observed. Histopathological examinations of the lymph nodes, skin, and temporal artery revealed findings characteristic of eosinophilic granulomatosis with polyangiitis (EGPA). However, she had no past medical history of asthma with modest eosinophilia. Although EGPA is a systemic vasculitis characterized by asthma and eosinophilia, various limited forms have been described. This was therefore considered to be an atypical form of non-asthmatic EGPA complicating with temporal arteritis (TA) diagnosed by tissue biopsy.

Early diagnosis is essential to improve the prognosis of patients with pancreatic cancer (PC). A long-term prognosis should be expected in patients with PC of

Background Several years have passed since the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012 were published. New findings and knowledge have accumulated since then. Methods The Research Committees for IgG4-related Diseases and for Intractable Diseases of the Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare of Japan and the Japan Biliary Association, have established a working group consisting of researchers specializing in IgG4-SC and have drawn up new clinical diagnostic criteria for IgG4-SC 2020. Results The diagnosis of IgG4-SC is based on a combination of the following six criteria: (1) narrowing of the intra- or extrahepatic bile duct, (2) thickening of the bile duct wall, (3) serological findings, (4) pathological findings, (5) other organ involvement, and (6) effectiveness of steroid therapy. Conclusion These new diagnostic criteria for IgG4-SC are useful in practice for general physicians and other non-specialists.

Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells.LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors.DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFβ. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC.Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFβ.

Background and aim Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, and hepatocellular injury with varying degrees of fibrosis. There are currently no established treatment approaches for NASH other than lifestyle interventions. Periostin, a matricellular protein required for tissue remodeling and fibrosis, plays an important role in hepatic steatosis and fibrosis and could be a potential target for NASH treatment. Advances in molecular biology and biochemical engineering have led to the development of antisense oligonucleotides (ASOs) that can inhibit target genes with no significant toxic effects. Herein, we investigated the therapeutic effects of periostin-targeting ASO (PNASO) in NASH. Methods C57BL/6J mice were fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with or without intraperitoneal injection of mouse PNASO. To explore the role of periostin in hepatocellular steatosis, Hc3716 cells, an immortalized human hepatocyte line, were treated with recombinant periostin in vitro. Results The induced periostin expression in the liver of CDAHFD-fed mice was significantly suppressed by PNASO. The deletion of hepatic periostin by PNASO significantly ameliorated hepatic steatosis while restoring the expression levels of peroxisome proliferator-activated receptor-alpha (PPAR-α) and its target genes. PNASO also inhibited hepatic fibrosis, reflected by the reduction of alpha-smooth muscle actin, collagen type I, and other fibrotic markers. In vitro experiments demonstrated that treatment with recombinant periostin increased cellular lipid accumulation in Hc3716 cells accompanied with the downregulation of PPAR-α. Conclusions Periostin-targeting ASO is a potential therapeutic approach for the efficient treatment of hepatic steatosis and fibrosis in NASH.

The liver dysfunction is a worldwide health problem. It has been suggested that an imbalance of gut microbiome is associated with a variety of diseases. The goal of the present clinical trial is to evaluate the effectiveness of Lactobacillus plantarum SN13T on hepatic function and fecal microbiota. This study enrolled 22 subjects, aged between 20 and 70 years, and who had any of the following conditions: 40

Familial Mediterranean fever (FMF) is the most common genetic autoinflammatory disease, but it has been considered a rare disease in Japan. We herein describe five patients with FMF who were diagnosed both clinically and genetically at a single Japanese institute. A genetic investigation of Mediterranean fever (MEFV) detected heterozygosity for the compound mutations L110P/E148Q (n=2) and L110P/148Q/P369S/R406Q (n=1), and heterozygosity for M694I (n=1) and S503C (n=1). Colchicine prevented febrile attacks and accompanying symptoms in four patients. One patient with an S503C mutation showed resistance. Physicians should be aware of the characteristic symptoms, as well as the more unusual symptoms such as headache, when diagnosing FMF.

ObjectiveTo identify the key diagnostic features and causes of fever of unknown origin (FUO) in Japanese patients.DesignMulticentre prospective study.SettingSixteen hospitals affiliated with the Japanese Society of Hospital General Medicine, covering the East and West regions of Japan.ParticipantsPatient aged ≥20 years diagnosed with classic FUO (axillary temperature≥38.0°C at least twice within a 3-week period, cause unknown after three outpatient visits or 3 days of hospitalisation). A total of 141 cases met the criteria and were recruited from January 2016 to December 2017.InterventionJapanese standard diagnostic examinations.Outcome measuresData collected include usual biochemical blood tests, inflammatory markers (erythrocyte sedimentation rate (ESR), C reactive (CRP) protein level, procalcitonin level), imaging results, autopsy findings (if performed) and final diagnosis.ResultsThe most frequent age group was 65–79 years old (mean: 58.6±9.1 years). The most frequent cause of FUO was non-infectious inflammatory disease. After a 6-month follow-up period, 21.3% of cases remained undiagnosed. The types of diseases causing FUO were significantly correlated with age and prognosis. Between patients with and without a final diagnosis, there was no difference in CRP level between patients with and without a final diagnosis (p=0.121). A significant difference in diagnosis of a causative disease was found between patients who did or did not receive an ESR test (p=0.041). Of the 35 patients with an abnormal ESR value, 28 (80%) had causative disease identified.ConclusionsAge may be a key factor in the differential diagnosis of FUO; the ESR test may be of value in the FUO evaluation process. These results may provide clinicians with insight into the management of FUO to allow adequate treatment according to the cause of the disease.

Background Geographical maldistribution of physicians, and their subsequent shortage in rural areas, has been a serious problem in Japan and in other countries. Family Medicine, a new board-certified specialty started 10 years ago in Japan by Japan Primary Care Association (JPCA), may be a solution to this problem. Methods We obtained the workplace information of 527 (78.4%) of the 672 JPCA-certified family physicians from an online database. From the national census data, we also obtained the workplace information of board-certified general internists, surgeons, obstetricians/gynaecologists and paediatricians and of all physicians as the same-generation comparison group (ages 30 to 49). Chi-squared test and residual analysis were conducted to compare the distribution between family physicians and other specialists. Results Five hundred nineteen JPCA-certified family physicians and 137,587 same-generation physicians were analysed. The distribution of family physicians was skewed to municipalities with a lower population density, which shows a sharp contrast to the urban-biased distribution of other specialists. The proportion of family physicians in non-metropolitan municipalities was significantly higher than that expected based on the distribution of all same-generation physicians (p Conclusions Family physicians distributed in favour of rural areas much more than any other specialists in Japan. The better balance of family physician distribution reported from countries with a strong primary care orientation seems to hold even in a country where primary care orientation is weak, physician distribution is not regulated, and patients have free access to healthcare. Family physicians comprise only 0.2% of all Japanese physicians. However, if their population grows, they can potentially rectify the imbalance of physician distribution. Government support is mandatory to promote family medicine in Japan.

Hepatolithiasis frequently results in severe complications. We conducted a cohort study to identify prognostic factors and to establish a hepatolithiasis severity classification system. The study cohort comprised 396 patients who were identified through a 1998 nationwide survey and followed up for 18 years or until death. Cox regression analysis was used to identify prognostic factors. Median survival time of the patients was 308 (range 0–462) months. Of the 396 patients enrolled in the study, 118 (29.8%) died, most frequently from intrahepatic cholangiocarcinoma (25 patients, 21.2%). Age of ≥ 65 years at the time of initial diagnosis [hazard ratio (HR) 3.410], jaundice for ≥ 1 week during follow-up (HR 2.442), intrahepatic cholangiocarcinoma (HR 3.674), and liver cirrhosis (HR 5.061) were shown to be significant risk factors for death from any therapeutic course. The data led to a 3-grade disease severity classification system that incorporates intrahepatic cholangiocarcinoma and liver cirrhosis as major factors and age of ≥ 65 years and jaundice for ≥ 1 week during follow-up as minor factors. Survival rates differed significantly between grades. The proposed hepatolithiasis severity classification system can be used to assess prognosis and thereby improve patient outcomes.

Background Fever of unknown origin (FUO) has many possible causes, so detailed history taking and physical examination are required. We identified key diagnostic features of medical history and physical findings for an efficient diagnosis of FUO. Methods A total of 42 consecutive patients (mean age: 50.6±20.3 years) with classic FUO were retrospectively recruited from January 2010 to March 2012. Key diagnostic features were identified from among diagnostic criteria for underlying diseases, indicators for diagnostic tests, and more useful factors for differential diagnosis. Results The mean number of abnormal findings per patient was 5.8 from taking the history and 2.0 from performing physical examination. In addition, the mean number of key diagnostic features identified was 0.7 (14.0%) from history taking and 0.6 (35.0%) from physical examination. The most relevant key diagnostic feature was arthritis, followed by cervical lymphadenopathy, dyspnea (with hypoxia), and ocular symptoms. Conclusion The usefulness of certain features of medical history and physical findings for diagnosing FUO was determined. Focusing on arthritis, cervical lymphadenopathy, dyspnea with hypoxia, and ocular symptoms might improve diagnostic efficiency in patients with FUO.

Background Several studies have demonstrated that elevated serum IgG4 levels are associated with poor outcomes of primary sclerosing cholangitis (PSC), but the impact of serum IgG4 levels on PSC remains controversial. In this study, we aimed to determine prognostic factors of patients with PSC and to investigate the association between serum IgG4 levels and the clinical features and prognosis of PSC in a Japanese cohort. Methods We retrospectively analyzed follow-up data for 435 patients with PSC (UMIN000018438). Patients with distinct etiologies of sclerosing cholangitis including IgG4-related sclerosing cholangitis (IgG4-SC) were excluded from this study. Results Serum IgG4 levels were tested at the time of diagnosis in 216 of 435 patients with PSC, and were elevated in 27 patients (>134 mg/dl, 12.5%). Clinical features at diagnosis were comparable between patients with normal and elevated serum IgG4 levels, with the exception of serum albumin. The overall and liver-transplantation free survival rate was comparable between the groups. Multivariate analysis indicated that age, albumin, and bilirubin, but not IgG4, at the time of diagnosis affected PSC prognosis. Conclusions The current study showed that serum IgG4 levels at diagnosis do not affect PSC prognosis in a Japanese cohort that excluded patients with IgG4-SC.

BACKGROUND Previous findings on hepatic bile acid compositions in nonalcoholic fatty liver disease (NAFLD) have been inconsistent and complicated. The aim of this study was to investigate the effects of steatosis on hepatic bile acid composition in a hypertensive NAFLD model without obesity and diabetes mellitus and compare hepatic bile acid composition between hypertensive rats with and without steatosis. METHODS Two groups of hypertensive rats were studied: spontaneously hypertensive rats (SHR) fed with a normal diet (SHR-N) or a choline-deficient diet (SHR-CD). Two groups of normotensive rats were studied: Wistar Kyoto rats (WKY) fed a normal diet (WKY-N) or a choline-deficient diet (WKY-CD). Hepatic bile acid analysis was performed using liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS Regarding bile acid composition, the hyodeoxycholic acid (HDCA) species in the SHR-CD group showed the largest change in bile acid composition, significantly decreasing to 21.9% of that found in the SHR-N group. In the WKY-CD group, no reduction of HDCA species was observed. CONCLUSIONS We demonstrated that the decrease in HDCA species was the main alteration in a hypertensive NAFLD model. It was suggested that the decrease in HDCA species in the SHR-CD group was caused by dysbiosis.

Purpose To show the practice location of graduates from two Japanese programs recruiting physicians to rural areas: a regional quota program of medical schools and a prefecture scholarship program (a prefecture is an administrative geographic division). Graduates of each program must work in a designated rural prefecture for a fixed period. Method A nationwide cohort study was conducted for three groups of participants graduating between 2014 and 2016: quota graduates without scholarship (quota alone), nonquota graduates with scholarship (scholarship alone), and quota graduates with scholarship. A questionnaire was sent via medical school or prefecture office to each potential subject to collect baseline individual data, including home prefecture and graduation year. Data were connected through physician identification number to the Physician Census 2016 of the Ministry of Health, Labour and Welfare to identify the subjects’ practice location and compared with data for other physicians in the census. Comparisons were conducted with Mann-Whitney and chi-square tests. Results The proportion of physicians working in nonmetropolitan municipalities for quota alone (185/244; 75.8%), scholarship alone (305/363; 84.0%), and quota with scholarship (341/384; 88.8%) was significantly higher than for other physicians (13,299/22,906; 58.1%). Median population density of the municipalities where subjects worked for quota alone (1,042.4 persons per square kilometer), scholarship alone (613.5), and quota with scholarship (547.4) was significantly lower than that for other physicians (3,214.0). These disparities increased with number of years since graduation. Conclusions The regional quota and prefecture scholarship programs succeeded in producing physicians who practiced in rural areas of Japan., This study was funded by the Japanese Ministry of Education, Culture, Sports, Science and Technology KAKENHI Grant-in-Aid for Scientific Research (C), Grant Number (25460803) and (18K10084).

A 37-year-old woman presented to our hospital with mild abdominal pain experienced for 2 months and hepatic nodules in segments 3 and 8. Peripheral blood eosinophilia was observed, and toxocariasis was serologically diagnosed. Seventeen days after the first imaging evaluation, a new lesion was found in segment 9 of the right lung, which was contiguous through the diaphragm to the hepatic nodule in segment 8. After treatment with albendazole, the liver and lung nodules disappeared. We suspect that larvae had directly invaded the lung from the liver, through the diaphragm.

Aim Primary sclerosing cholangitis (PSC) is very rare in Japan. Although a large-scale cohort study of 781 pediatric-onset PSC patients in Europe and North America showed that the 5-year survival with native liver was 88%, the long-term outcomes of pediatric-onset PSC in Japan are unknown. Here, we evaluated the clinical outcomes of pediatric-onset PSC in Japan. Methods We carried out a retrospective cohort study with a medical records review of pediatric PSC patients diagnosed between 1986 and 2017 at a single center. The PSC diagnoses were based on cholangiography, liver histology, and biochemical findings. The patients' survival was analyzed using the Kaplan-Meier method. Prognostic factors were determined by univariate and multivariate analyses using the Cox proportional hazards regression model. Results We identified 39 pediatric-onset PSC patients (22 boys, 17 girls). The median age at diagnosis was 9 years (interquartile range 6.0-13.5 years). The median follow-up period was 5.5 years (interquartile range 3.4-8.7 years). The phenotypes of PSC-autoimmune hepatitis, PSC-inflammatory bowel disease, and small-duct PSC were diagnosed in 13 (33.3%), 36 out of 38 (94.8%), and three (7.7%) patients, respectively. The 5-year liver transplantation-free survival of the whole cohort was 93.5%. Nine patients underwent liver transplantation, and four of these nine cases resulted in death. Both the univariate and multivariate analyses showed that the phenotype of "PSC-autoimmune hepatitis overlap" was an independent poor prognostic factor. Conclusions The overall survival of pediatric-onset PSC in Japan was comparable to those in Western countries. The phenotype of PSC-autoimmune hepatitis was identified as a prognostic factor associated with a poorer long-term outcome.

Aim Autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) impose a significant burden on public health, and it is important to estimate their prevalence. We carried out a nationwide, hospital-based, epidemiological survey of AIH, PBC, and PSC, and compared the results with those from previous surveys. Method We randomly selected health-care facilities used in the survey from a list of all facilities in Japan. The selection rate was determined according to a stratification based on the facility characteristics and scale. We sent questionnaires to the selected facilities enquiring about the number and sex of patients with AILD who visited the facility in 2016. An identical survey was undertaken for AIH/PBC in 2004 and for PSC in 2007; we carried out a comparative analysis of these data. Results We selected 1793 departments from health centers all over Japan. Of them, 1078 (60.1%) responded to the questionnaires. The number of reported patients with AIH, PBC, and PSC was 8505, 10 847, and 906, respectively, and point prevalence was 23.9 (95% confidence interval, 23.3-24.5) for AIH (8.7 in 2004), 33.8 (33.0-34.6) for PBC (11.6 in 2004), and 1.80 (1.75-1.85) for PSC (0.95 in 2007) per 100 000 population. Male-to-female patient ratio of AILD was 1:4.3 for AIH (1:6.9 in 2004), 1:3.9 for PBC (1:7.1 in 2004), and 1:0.88 for PSC (1:1.4 in 2007). Conclusion The current study indicates an increasing trend of prevalence as well as male-to-female patient ratio of AILD in Japan.

Background Wisteria floribunda agglutinin (WFA)-sialylated mucin core polypeptide 1 (MUC1) was investigated as a new glycoprotein marker for cholangiocarcinoma (CC) using glycoproteomics technologies. In this multicenter study, WFA-sialylated MUC1 levels in serum and bile samples were measured to determine their diagnostic capability in biliary tract carcinoma (BTC) and intrahepatic (Ih) CC. Methods The study included 244 patients with BTC, 59 patients with IhCC, 287 patients with benign biliary tract diseases, and 44 control subjects. Results Serum WFA-sialylated MUC1 levels were significantly higher in patients with either BTC or IhCC than in control subjects and those with benign biliary tract diseases. Patients with IhCC showed higher WFA-sialylated MUC1 levels than patients with tumors at other sites. No significant differences in WFA-sialylated MUC1 levels were found with regard to cancer stage or tissue type. Receiver operating characteristic curve analysis showed that WFA-sialylated MUC1 was superior to carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) for the diagnosis of benign biliary tract diseases, BTC, and IhCC, as well as for stage I and II carcinomas. Significantly higher levels of biliary WFA-sialylated MUC1 were observed in BTC/IhCC than in benign biliary tract diseases. The diagnostic capability of biliary WFA-sialylated MUC1 was also superior to that of CA19-9, and diagnostic sensitivity was higher than that of biliary cytology for BTC/IhCC. Conclusions WFA-sialylated MUC1 is a useful novel biomarker for BTC/IhCC. In the future, this measurement should be applied in the clinical setting.

Periostin is a matricellular protein that serves as a ligand for integrins and is required for tissue remodeling and fibrosis. We investigated the role of periostin in hepatic fibrosis and the mechanisms involved. Primary hepatic stellate cells (HSCs) and the HSC-immortalized cell line LX2 were used to study the profibrotic property of periostin and the interaction of periostin with integrins. Wild-type and periostin-deficient (periostin−/−) mice were subjected to two distinct models of liver fibrosis induced by hepatotoxic (carbon tetrachloride or thioacetamide) or cholestatic (3.5-diethoxycarbonyl-1.4-dihydrocollidine) injury. Periostin expression in HSCs and LX2 cells increased in association with their activation. Gene silencing of periostin resulted in a significant reduction in the levels of profibrotic markers. In addition to enhanced cell migration in response to periostin, LX2 cells incubated on periostin showed significant induction of α-smooth muscle actin and collagen, indicating a profibrotic property. An antibody targeting αvβ5 and αvβ3 integrins suppressed cell attachment to periostin by 60 and 30 % respectively, whereas anti-α5β1 antibody had no effect. Consistently, αv integrin-silenced LX2 cells exhibited decreased attachment to periostin, with a significant reduction in the levels of profibrotic markers. Moreover, these profibrotic effects of periostin were observed in the mouse models. In contrast to extensive collagen deposition in wild-type mice, periostin−/− mice developed less noticeable hepatic fibrosis induced by hepatotoxic and cholestatic liver injury. Accordingly, the profibrotic markers were significantly reduced in periostin−/− mice. Periostin exerts potent profibrotic activity mediated by αv integrin, suggesting the periostin–αv integrin axis as a novel therapeutic target for hepatic fibrosis.

Background Currently, no established pharmacologic treatment exists for the prevention of recurrent common bile duct (CBD) stones. Methods Here, we present a multi-center randomized trial that compared the CBD recurrence rate after bile duct stone removal between patients given ursodeoxycholic acid (UDCA) and the untreated group. A total of 36 patients were randomly assigned to either the UDCA (n = 15) or the untreated group (n = 21). The primary end-point was the recurrence rate of CBD stones. Results The recurrence rate of CBD stones was 6.6% in the UDCA group and 18.6% in the untreated group (P = 0.171). A multivariate analysis found that not receiving UDCA was an independent risk factor for stone recurrence. The recurrence rates of CBD stones did not differ by sex, past history of cholecystectomy, or the presence of gallstones. Conclusions Our findings indicate that UDCA may be a novel treatment strategy to prevent the recurrence of CBD stones. However, further evaluation of UDCA in a larger number of subjects will be required to confirm the applicability of these results.