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Background: Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case-control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case-control study to identify the environmental factors associated with the development of PBC in Japan., Methods: From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis., Results: The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01-2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07-1.92), ever smoking (OR, 1.70; 95% CI, 1.28-2.25), and hair dye use (OR, 1.57; 95% CI, 1.15-2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99-19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077-0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52-68.0) in the model for medical and familial factors., Conclusions: These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan., (© 2021. Japanese Society of Gastroenterology.)

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH., (© 2021. The Author(s).)

Background/purpose: Although ursodeoxycholic acid (UDCA) is a first-line treatment for primary biliary cholangitis (PBC), 20%-30% of patients with PBC exhibit an incomplete response to UDCA. Recently, the UDCA Response Score was proposed for predicting response to UDCA using pretreatment parameters in patients with PBC. We aimed to validate the UDCA Response Score in Japanese patients with PBC., Methods: Registry data of Japanese patients (n = 873) were collected. Patients with data on all clinical parameters required for calculating the UDCA Response Score were selected. The endpoint was UDCA response, defined as alkaline phosphatase <1.67 times the upper limit of the normal value after 12 months of UDCA treatment., Results: All parameters were available in 804 patients (male/female = 120/684, age 58.9 [interquartile range 51.1-66.9] years). Bezafibrate was commenced within 12 months of UDCA in 78 patients (9.7%) because of the lack of an early response. We found that the endpoint was not reached in these 78 patients, and the area under the receiver operating characteristic curve (AUROC) of the score was 0.74 (95% confidence interval [CI] 0.70-0.79). The AUROC was 0.77 (95% CI 0.70-0.83) in patients undergoing UDCA monotherapy (n = 726). Finally, the AUROC of the modified UDCA Response Score using only data from the treatment start date was 0.80 (95% CI 0.70-0.90) in patients receiving a combination therapy of UDCA and bezafibrate (n = 160)., Conclusion: The validity of the UDCA Response Score was acceptable in Japanese patients; this score will be informative in patients treated with a combination therapy of UDCA and bezafibrate., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective Liver injury is a notable complication of coronavirus disease 2019 (COVID-19). This study aimed to clarify the clinical features and liver injury in Japanese patients with COVID-19. Methods We conducted a multicenter retrospective cohort study. All consecutive patients with COVID-19 who visited or were admitted to our hospital before May 12, 2020, were enrolled. Their demographics, symptoms, laboratory findings, comorbidities, concomitant drugs, treatment, and clinical course were reviewed. We defined liver injury as alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) levels over the upper limit of normal. Results Twenty-two patients with COVID-19 (median age, 47 years old; men/women, 13/9) were enrolled. Two patients had underlying liver diseases, and two were diagnosed as having COVID-19 without any symptoms. Elevated ALT and GGT levels were found in 12 and 12 patients, respectively, and liver injury was observed in 15 patients (68.2%). Compared with the patients without liver injury, those with liver injury had a significantly higher fever during the clinical course (median, 37.5°C vs. 38.8°C, p=0.006). A significant correlation was found between the highest serum liver values and the highest body temperature in each patient. Among the 22 patients, 4 required artificial respiratory support, and 2 died thereafter. Liver injury was not associated with the severity or mortality of COVID-19. Conclusion Elevated levels of liver enzymes in the Japanese patients with COVID-19 were associated with the highest body temperature during the clinical course but not with the severity or mortality of COVID-19.

Background & Aims: It remains controversial whether direct-acting antivirals (DAAs) accelerate the recurrence of hepatitis C-related hepatocellular carcinoma (HCC) after curative therapy. This study aimed to evaluate HCC recurrence after DAA treatment of chronic hepatitis C., Methods: We enrolled patients with a history of successful radiofrequency ablation treatment for hepatitis C-related HCC who received antiviral therapy with DAAs (DAA group: 147 patients) or with interferon (IFN)-based therapy (IFN group: 156 patients). We assessed HCC recurrence rates from the initiation of antiviral therapy using the Kaplan-Meier method and evaluated risk factors for HCC recurrence by multivariate Cox proportional hazard regression analysis. The recurrence pattern was categorized as follows: intrahepatic recurrence with a single tumor <2 cm (stage 0), a single tumor or up to 3 tumors ≤3 cm (stage A), multinodular (stage B), and extrahepatic metastasis or macrovascular invasion (stage C)., Results: The recurrence rates at 1 and 2 years were 39% and 61% in the IFN group and 39% and 60% in the DAA group, respectively (p = 0.43). Multivariate analysis identified higher lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, a history of multiple HCC treatments, and a shorter interval between HCC treatment and initiation of antiviral therapy as independent risk factors for HCC recurrence. HCC recurrence in stage 0, A, B, and C was found in 56 (41%), 60 (44%), 19 (14%), and 1 (0.7%) patients in the IFN group and 35 (44%), 32 (40%), 11 (14%), and 2 (2.5%) patients in the DAA group, respectively (p = 0.70)., Conclusions: HCC recurrence rates and patterns after initiation of antiviral therapy did not differ between patients who received IFN-based therapy and DAA therapy., Lay Summary: We detected no significant difference in early hepatocellular carcinoma (HCC) recurrence rates and patterns between patients who received interferon-based and direct-acting antiviral therapy after HCC treatment. High lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, short recurrence-free period, and a history of multiple HCC treatments were independent risk factors for early HCC recurrence after the initiation of antiviral therapy., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to develop a Japanese version of hand-foot syndrome (HFS)-specific quality of life (QOL) questionnaire (HFS-14) to evaluate and monitor the QOL of patients with a possibility of HFS., Methods: The original English version of HFS-14 was translated and slightly modified into Japanese, and the Japanese HFS-14 was administered to 187 patients receiving chemotherapy with high risk of developing HFS as outpatients in four institutions in Japan. Factor validity, internal consistency, correlation with the Skindex-16 and Dermatology Life Quality Index (DLQI) scores, known group validity, and test-retest reliability were analyzed for 105 patients who developed HFS. Next, we compared HFS-14 with DLQI and Skindex-16., Results: Factor analysis confirmed the factor structure (one putative scale) of the Japanese HFS-14. Cronbach's alpha was over 0.90. The Japanese HFS-14 score was correlated with the Skindex-16 and DLQI score. Intra-class correlation coefficients were over 0.80. Patients with severe HFS reported significantly poorer HFS-14 score than those with mild HFS. The Skindex-16 and DLQI scores were also significantly different in patients with different Common Terminology Criteria for Adverse Events (CTCAE) grades, but with smaller effect sizes than those for the HFS-14 score., Conclusions: The Japanese HFS-14 provides a valid and reliable score for monitoring and evaluating HFS.

The liver micronucleus assay using young adult rats has the potential to detect liver carcinogens by repeated dosing, and could be expected to be integrated into repeated-dose toxicity studies using a hepatocyte isolation method without the traditional in situ collagenase perfusion. In this study, to assess the performance of the repeated-dose liver micronucleus assay, 2,4-dinitrotoluene (DNT), which is a rodent liver carcinogen, was administered orally to male rats at doses of 50, 100 and 200 mg/kg/day once daily for 14 or 28 consecutive days, and the frequencies of micronucleated hepatocytes (MNHEPs) and micronucleated immature erythrocytes (MNIMEs) were examined. Significant increases in the MNHEPs were observed at 50 mg/kg/day or more in the 14-day treatment, and 50 and 100 mg/kg/day in the 28-day treatment. These increases were dependent on both the dose and the number of administrations, which indicates the possibility that the MNHEPs accumulate as a result of repeated dosing. In contrast, no increase in the MNIMEs was observed. In conclusion, the repeated-dose liver micronucleus assay using young adult rats is sufficiently sensitive to detect the genotoxicity of 2,4-DNT at a low dose.

Objective: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. The aim of this study is to evaluate the efficacy of radiofrequency ablation (RFA) in elderly patients with HCC and to investigate cause-specific excess deaths associated with increasing number of elderly patients., Materials and Methods: We enrolled 1401 naive patients with HCC who were treated initially by RFA from 1999 to 2011. Patients below 75 years of age were categorized as 'younger' and those at least 75 as 'elderly'. Differences in the demographic and laboratory data of these patients were assessed, along with Kaplan-Meier analysis of survival using the log-rank test. In addition, we assessed the causes of death, defined as liver related and liver unrelated, by competing risk analysis and risk factors for respective causes of death by a proportional subdistribution model., Results: Overall, 353 patients were categorized as elderly. Elderly patients were more likely to be women, infected with hepatitis C virus, and score better in the Child-Pugh classification. The mortality at 5 years was lower in the elderly than in the younger patients (47.3 vs. 37.1%; P<0.001). Competing risk analysis showed a significant difference in liver-unrelated death (P<0.001) between the two groups, whereas there were no significant differences in liver-related death (P=0.64). By the proportional subdistribution model, age was a significant risk factor only for liver-unrelated death., Conclusion: RFA provided satisfactory 5-year survival rates in elderly patients with HCC. The elderly tended to die from liver-unrelated causes.

Background: In the treatment of hepatocellular carcinoma (HCC), hepatic resection has the advantage over radiofrequency ablation (RFA) in terms of systematic removal of a hepatic segment., Methods: We enrolled 303 consecutive patients of a single naïve HCC that had been treated by RFA at The University of Tokyo Hospital from 1999 to 2004. Recurrence was categorized as either intra- or extra-subsegmental as according to the Couinaud's segment of the original nodule. To assess the relationship between the subsegments of the original and recurrent nodules, we calculated the kappa coefficient. We assessed the risk factors for intra- and extra-subsegmental recurrence independently using univariate and multivariate Cox proportional hazard regression. We also assessed the impact of the mode of recurrence on the survival outcome., Results: During the follow-up period, 201 patients in our cohort showed tumor recurrence distributed in a total of 340 subsegments. Recurrence was categorized as exclusively intra-subsegmental, exclusively extra-subsegmental, and simultaneously intra- and extra-subsegmental in 40 (20%), 110 (55%), and 51 (25%) patients, respectively. The kappa coefficient was measured at 0.135 (95% CI, 0.079-0.190; P<0.001). Multivariate analysis revealed that of the tumor size, AFP value and platelet count were all risk factors for both intra- and extra-subsegmental recurrence. Of the patients in whom recurrent HCC was found to be exclusively intra-subsegmental, extra-subsegmental, and simultaneously intra- and extra-subsegmental, 37 (92.5%), 99 (90.8%) and 42 (82.3%), respectively, were treated using RFA. The survival outcomes after recurrence were similar between patients with an exclusively intra- or extra-subsegmental recurrence., Conclusions: The effectiveness of systematic subsegmentectomy may be limited in the patients with both HCC and chronic liver disease who frequently undergo multi-focal tumor recurrence.

Background: Percutaneous radiofrequency ablation (RFA) has been widely accepted as an alternative to surgery for small hepatocellular carcinoma (HCC). In RFA, a portion of liver tissue surrounding tumour is also ablated to achieve a safety margin. The intrahepatic bile duct may be injured and result in chronic bile duct dilatation upstream of the injured site. However, the impact of such an injury on the overall prognosis has been unclear., Methods: Patients who showed bile duct dilatation following RFA were identified by a retrospective review of imaging studies. Each dilatation was classified as mild (limited to one hepatic subsegment) or severe (affecting two or more subsegments). The relation between the incidence of intrahepatic bile duct dilatation and HCC recurrence or survival was analysed using proportional hazard models., Results: Among 589 consecutive HCC patients treated with RFA, 70 (11.9%) and 21 (3.6%) patients showed mild and severe bile duct dilatation respectively. Patients with severe dilatation, but not those with mild dilatation, had lower survival and higher HCC recurrence than patients without dilatation. Severe dilatation, but not mild dilatation, was significantly associated with death [hazard ratio (HR) 2.17, P=0.035] and recurrence (HR 2.89, P<0.001)., Conclusion: Whereas mild bile duct dilatation after RFA is clinically negligible, bile duct dilatation affecting two or more subsegments should be regarded as a complication that may affect the prognosis and should be observed carefully., (© 2010 John Wiley & Sons A/S.)

Sporadic outbreaks of fatal enteritis occurred among free-living wild crows ('large billed' or 'wok' crow; Corvus macrorhynchos) in an open-air park in Japan in 2002. Eight crows were found dead during February, followed by two more in September, and five of the eight were examined histopathologically. At necropsy, all cases showed a markedly dilated small intestine, especially the jejunum and ileum, with large amounts of gas, and dark red to greenish-brown soft content. The necrotic intestinal wall was markedly thickened with multifocal haemorrhages. All cases had multifocal white foci in the liver, and four cases showed marked splenomegaly. Histologically, there was severe necrotic enteritis characterized by extensive mucosal necrosis and multifocal haemorrhages, as well as inflammatory cell infiltrations. A prominent pseudo-membrane formation was noted in the affected intestine. Severe adhesive peritonitis was also observed in three cases. Gram-positive bacilli were present in large numbers in the lumen, and in and around necrotic lesions in the affected intestine. The bacilli were positive for Clostridium perfringens enterotoxin type A by immunohistochemistry, and were also positive for C. perfringens type A using the immunofluorescence method. C. perfringens was isolated by anaerobic culture from the intestinal contents. The present enteritis was thought to be induced by proliferated C. perfringens in the intestine, and to be the cause of death.