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Epidemiology and Management of Drug-induced Liver Injury: Importance of the Updated RUCAM

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Journal of Clinical and Translational Hepatology 2023年第5期11卷 1239-1245页

作者： Takashi Kobayashi Michihiro Iwaki Asako Nogami Masato Yoneda Department of Gastroenterology and Hepatology Yokohama City University Graduate School of MedicineYokohamaJapan

Drug-induced liver injury(DILI)is a major cause of acute liver injury,liver failure,and liver transplantation worldwide.In recent years,immune checkpoint inhibitors have become widely used.This has led to an increase in DILI,for which pathophysiology and management methods differ significantly from the past.As the number of cases of acute liver injury and liver transplantation due to DILI is expected to increase,information about a DILI is becoming more valuable.DILI is classified into two types according to its etiology:intrinsic DILI,in which the drug or its metabolites cause liver damage that is dose-dependent and predictable;and idiosyncratic DILI,in which liver damage is also dose-independent but unpredictable.In addition,depending on the course of the disease,chronic DILI or drug-induced autoimmune hepatitis may be present.The number of DILI cases caused by antimicrobial agents is decreasing,whereas that caused by drugs for malignant tumors and health foods is increasing.The Roussel Uclaf Causality Assessment Method is widely used to assess causality in DILI.Liver injury is a type of immune-related adverse event.The pattern of hepatic injury in immune-related adverse events is mostly hepatocellular,but mixed type and bile stasis have also been reported.Sclerosing cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of injury.Treatment mainly comprises withdrawal of immune checkpoint inhibitors and steroid administration;however,mycophenolate mofetil may be considered if the disease is refractory to steroids.

关键词： Drug-induced liver injury Immune-related adverse events Immune checkpoint inhibitor Updated RUCAM

COVID-19 vaccination and liver disease

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World Journal of Gastroenterology 2022年第48期28卷 6791-6810页

作者： Sotaro Ozaka Takashi Kobayashi Kazuhiro Mizukami Kazunari Murakami Department of Gastroenterology Faculty of MedicineOita UniversityYufu 879-5593OitaJapan Department of Infectious Disease Control Faculty of MedicineOita UniversityYufu 879-5593OitaJapan

Various vaccines against severe acute respiratory syndrome coronavirus 2 have been developed in response to the coronavirus disease 2019(COVID-19)global pandemic,several of which are highly effective in preventing COVID-19 in the general population.Patients with chronic liver diseases(CLDs),particularly those with liver cirrhosis,are considered to be at a high risk for severe COVID-19 and death.Given the increased rates of disease severity and mortality in patients with liver disease,there is an urgent need to understand the efficacy of vaccination in this population.However,the data regarding efficacy and safety of COVID-19 vaccination in patients with CLDs is limited.Indeed,several organ-specific or systemic immune-mediated side effects following COVID-19 vaccination,including liver injury similar to autoimmune hepatitis,have been recently reported.Although the number of cases of vaccine-related liver injury is increasing,its frequency,clinical course,and mechanism remain unclear.Here,we review the current findings on COVID-19 vaccination and liver disease,focusing on:(1)The impact of COVID-19 in patients with CLD;(2)The efficacy,safety,and risk-benefit profiles of COVID-19 vaccines in patients with CLD;and(3)Liver injury following COVID-19 vaccination.

关键词： COVID-19 vaccine Liver disease Side effect Liver injury Immune-related hepatitis Autoimmune hepatitis

The effect of basic fibroblast growth factor on regeneration in a surgical wound model of rat submandibular glands

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International Journal of Oral Science 2016年第1期8卷 16-23页

作者： Fumitaka kobayashi Kenichi Matsuzaka takashi Inoue Department of Clinical Pathophysiology Tokyo Dental CollegeTokyoJapan

This study developed an animal model of surgically wounded submandibular glands （SMGs） and investigated the effects of collagen gel with basic fibroblast growth factor （bFGF） on tissue regeneration of surgically wounded SMGs in vivo. The animal model was produced by creating a surgical wound using a 3-mm diameter biopsy punch in SMGs. The wound was filled with collagen gel with bFGF （bFGF group） or without bFGF （control group）. In the animal model of surgically wounded SMGs, salivary glands without scar tissue around the wound area were observed with smaller areas of collagen gel. Small round and spindle-shape cells invaded the collagen gel in both groups after operation day （AOD） 5, and this invasion dramatically increased at AOD 7. Host tissue completely replaced the collagen gel at AOD 21. The invading immune cells in the group treated with collagen gel with bFGF were positive for vimentin, g-smooth muscle actin （αSMA）, CD49f, c-kit and AQP5 at AOD 7. Similarly, the mRNA expression of vimentin, αSMA, CD49f, keratin 19 and AQP5 was also increased. This study suggests that the use of collagen gels with bFGF improves salivary gland regeneration.

关键词： animal model basic fibroblast growth factor collagen immunohistochemistry salivary gland wound healing

Pancreatolithiasis with an anatomic variant of Wirsung duct:a case report

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Gastroenterology Report 2023年第1期11卷 585-587页

作者： Satoshi Yamamoto Kazuo Inui Yoshiaki Katano Senju Hashimoto Hironao Miyoshi Takashi Kobayashi Yoshihiko Tachi Department of Gastroenterology Fujita Health University Bantane HospitalOtoubashiNakagawa-kuNagoyaAichiJapan Department of Gastroenterology Yamashita HospitalNakamachiIchinomiyaAichiJapan Board Chairman Geriatric Health Services Facility YukiMizuhomachiHandaAichiJapan Department of Gastroenterology Fujita Health University Okazaki Medical CenterHarisakichoOkazakiAichiJapan

Introduction In contrast to familiar developmental anomalies,such as pancreatobiliary maljunction and pancreas divisum,a double orifice of the ampulla of Vater is a much more rare congenital malformation.We encountered a patient with pancreatolithiasis associated with anatomic variation of Wirsung duct showing a single major duodenal papilla with a double orifice and no minor papilla.

关键词： Vater orifice congenital

Pan-peroxisome proliferator-activated receptor agonist lanifibranor as a dominant candidate pharmacological therapy for nonalcoholic fatty liver disease

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Hepatobiliary Surgery and Nutrition 2022年第3期11卷 433-435页

作者： Masato Yoneda Takashi Kobayashi Nogami Asako Michihiro Iwaki Satoru Saito Atsushi Nakajima Department of Gastroenterology and Hepatology Yokohama City University HospitalKanazawa-kuYokohamaJapan

As obesity incidence increases worldwide,nonalcoholic fatty liver disease(NAFLD)has become the most common form of liver disease,with a reported global prevalence of 25.2%(1).Nonalcoholic steatohepatitis(NASH)is a severe form of NAFLD.However,the precise natural history of NAFLD/NASH remains unclear.NASH is rapidly becoming the leading cause of end-stage liver disorders and liver transplants and is associated with increased cardiovascular disease risk(2).As a result,it poses critical health issues globally from both medical and socioeconomic perspectives.

关键词： NAFLD liver cardiovascular

Delayed immune-related sclerosing cholangitis after discontinuation of pembrolizumab:A case report

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World Journal of Gastroenterology 2022年第28期28卷 3732-3738页

作者： Takeshi Tanaka Arata Sakai Masahiro Tsujimae Yasutaka Yamada Takashi Kobayashi Atsuhiro Masuda Yuzo Kodama Division of Gastroenterology Department of Internal MedicineKobe University Graduate School of MedicineKobe 650-0017HyogoJapan

BACKGROUND Secondary sclerosing cholangitis,characterized by biliary obstruction,can be caused by drugs such as immune checkpoint inhibitors(ICIs).While there a few reports of sclerosing cholangitis after immune checkpoint inhibitor administration,no case has been reported after discontinuation of such drugs.CASE SUMMARY A 68-year-old man who underwent chemotherapy for lung adenocarcinoma with bone metastasis presented with abdominal pain and fever 4 mo after the final administration of pembrolizumab.Computed tomography revealed thickening of the gallbladder wall and dilatation of the common bile duct.Endoscopic retrograde cholangiopancreatography revealed an irregularly narrowed intrahepatic bile duct.Biopsy of the bile duct demonstrated that CD8+T cells were predominant over CD4+T cells.Liver biopsy showed dominant infiltration of CD8+T in the portal tract,but onion-skin lesions were not observed.The patient was diagnosed with immune-related sclerosing cholangitis induced by pembrolizumab.Administration of methylprednisolone and endoscopic nasobiliary drainage were performed,but the cholangiography and laboratory test findings did not improve.No further treatment was administered due to disease progression,and the patient was referred for palliative care.CONCLUSION Immune-related sclerosing cholangitis may have a late onset,and such cases occurring after discontinuation of ICIs should be carefully managed.

关键词： Immune-related adverse events Sclerosing cholangitis Delayed immunerelated events Case report

Tropifexor,a selective non-acid farnesoid X receptor agonist,improved nonalcoholic steatohepatitis in a phase 2 trial,but several issues remain to be resolved

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Hepatobiliary Surgery and Nutrition 2023年第5期12卷 759-762页

作者： Masato Yoneda Takashi Kobayashi Naohiro Wada Tomohiro Otani Asako Nogami Michihiro Iwaki Atsushi Nakajima Department of Gastroenterology and Hepatology Yokohama City University HospitalYokohamaJapan

As obesity continues to escalate worldwide,nonalcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of liver disease,with a reported global prevalence of 30.1%(1).The prevalence of NAFLD,which was around 25%in the 1990s,has been increasing year by year in recent years and has exceeded 35%in the past few years(1).The spectrum of disease includes nonalcoholic fatty liver(NAFL),characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation,and nonalcoholic steatohepatitis(NASH),which is additionally characterized by the presence of inflammation and cellular injury(2).

关键词： Nonalcoholic fatty liver disease(NAFLD) obesity nonalcoholic steatohepatitis(NASH) tropifexor selective non-acid farnesoid X receptor agonists(selective non-acid FXR agonists)

Clinical management for malignant afferent loop obstruction

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World Journal of Gastrointestinal Oncology 2021年第7期13卷 684-692页

作者： Arata Sakai Hideyuki Shiomi Atsuhiro Masuda Takashi Kobayashi Yasutaka Yamada Yuzo Kodama Division of Gastroenterology Department of Internal MedicineKobe University Graduate School of MedicineKobe 650-0017HyogoJapan

Afferent loop obstruction(ALO)is defined as duodenal or jejunal mechanical obstruction at the proximal anastomosis site of a gastrojejunostomy.With advances in chemotherapy,the incidence of malignant ALO is increasing.Malignant ALO can be complicated by ischemia,gangrenous bowel,pancreatitis,and ascending cholangitis.Moreover,the general condition of patients with recurrent cancer is often poor.Therefore,accurate and rapid diagnosis and minimally invasive treatments are required.However,no review articles on the diagnosis and treatment of malignant ALO have been published.Through literature searching,we reviewed related articles published between 1959 and 2020 in the PubMed database.Herein,we present recent advances in the diagnosis and treatment of malignant ALO and describe future perspectives.Endoscopic transluminal self-expandable metal stent(SEMS)placement is considered the standard treatment for malignant ALO,as this procedure is well established and less invasive.However,with the development of interventional endoscopic ultrasound(EUS)in recent years,the usefulness of EUS-guided gastrojejunostomy has been reported.Moreover,through indirect comparison,this approach has been reported to be superior to transluminal SEMS placement.It is expected that a safer and less invasive treatment method will be established through the continued advancement and innovation of interventional endoscopy techniques.

关键词： Malignant afferent loop obstruction Endoscopic self-expandable metal stent placement Endoscopic ultrasound guided gastrojejunostomy Lumen-apposing metal stent

KDM2B promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma

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Journal of Genetics and Genomics 2021年第7期48卷 618-630页

作者： Kevin Christian Montecillo Gulay Keisuke Aoshima Yuki Shibata Hironobu Yasui Qin Yan Atsushi kobayashi takashi Kimura Laboratory of Comparative Pathology Department of Clinical SciencesFaculty of Veterinary MedicineHokkaido UniversitySapporoHokkaido 060-0818 Japan Laboratory of Radiation Biology Department of Applied Veterinary SciencesFaculty of Veterinary MedicineHokkaido UniversitySapporoHokkaido 060-0818 Japan Department of Pathology Yale School of MedicineNew HavenCT 06510USA

Epigenetic regulators have been implicated in tumorigenesis of many types of cancer;however,their roles in endothelial cell cancers such as canine hemangiosarcoma(HSA)have not been studied.In this study,we find that lysine-specific demethylase 2 b(KDM2 B)is highly expressed in HSA cell lines compared with normal canine endothelial cells.Silencing of KDM2 B in HSA cells results in increased cell death in vitro compared with the scramble control by inducing apoptosis through the inactivation of the DNA repair pathways and accumulation of DNA damage.Similarly,doxycycline-induced KDM2 B silencing in tumor xenografts results in decreased tumor sizes compared with the control.Furthermore,KDM2 B is also highly expressed in clinical cases of HSA.We hypothesize that pharmacological KDM2 B inhibition can also induce HSA cell death and can be used as an alternative treatment for HSA.We treat HSA cells with GSK-J4,a histone demethylase inhibitor,and find that GSK-J4 treatment also induces apoptosis and cell death.In addition,GSK-J4 treatment decreases tumor size.Therefore,we demonstrate that KDM2 B acts as an oncogene in HSA by enhancing the DNA damage response.Moreover,we show that histone demethylase inhibitor GSK-J4 can be used as a therapeutic alternative to doxorubicin for HSA treatment.

关键词： DNA repair Epigenetics Hemangiosarcoma KDM2B Oncogene