Nobusuke Kishikawa

Spontaneously hypertensive rats develop pronounced hepatic steatosis induced by choline‐deficient diet: Evidence for hypertension as a potential enhancer in non‐alcoholic steatohepatitis

Aim:  Patients with non‐alcoholic steatohepatitis (NASH) frequently have many co‐morbidities including essential hypertension, which is reported to increase vascular production of reactive oxygen species (ROS) and alter the hepatic anti‐oxidant defense system. Since ROS play a role in the pathogenesis of NASH, it is hypothesized that hypertension modulates the hepatic oxidative status and influences the development of NASH. The aim of this study was to investigate the potential effects of hypertension on the progression of NASH.

Nutritional factors (nutritional aspects) in biliary disorders: bile acid and lipid metabolism in gallstone diseases and pancreaticobiliary maljunction.

Nutritional factors play a key role in the pathogenesis of biliary diseases such as gallstones and pancreaticobiliary maljunction. Gallstones are primarily classified into cholesterol stone and pigment stone according to the major composition. Cholesterol gallstone formation is very likely based upon supersaturated bile formation, and pigment stones are formed in bile rich in bilirubin. Thus, defects of hepatic metabolism of lipids and organic anions lead to biliary stones. Here, the recent understanding of cholesterol gallstone pathogenesis is elaborated. On the other hand, there is another important link of biliary lipid degradation to serious biliary disease, namely pancreaticobiliary maljunction. Lysophosphatidylcholine (lysoPC), a derivative of phosphatidylcholine hydrolysis by phospholipase A2, is a highly abundant bioactive lipid mediator present in circulation as well as in bile. Increases in bile of lysoPC and phospholipase A2 have been reported in pancreaticobiliary maljunction and considered to be the major risk factor for biliary tract cancers. Further, oxidized fatty acids have been established as a potent ligand for G2A, a member of G protein‐coupled receptor family that mediates a diverse array of biological processes including cell growth and apoptosis. Thus, both of lysoPC and free fatty acids are supposed to play an important role through G2A in biliary inflammation and carcinogenesis of pancreaticobiliary maljunction. Taken together, nutritional factors, especially lipid compounds, are seemingly crucial in the pathogenesis of biliary diseases, and such a causal relationship is reviewed by mainly authors’ previous publications.

Cholangiocyte senescence caused by lysophosphatidylcholine as a potential implication in carcinogenesis.

The incidence of biliary tract cancer in patients with pancreaticobiliary maljunction or intrahepatic cholelithiasis is markedly high with undefined mechanism. In these diseases, biliary lysophosphatidylcholine (LPC) level is reportedly increased. This study investigated the influence of LPC on cholangiocytes focusing on cellular senescence and its potential contribution to carcinogenesis.

Clinical evaluation of ezetimibe on bile lithogenicity in humans: Use of transnasal endoscopy for bile sampling.

Ezetimibe inhibits cholesterol absorption by blocking Niemann–Pick C1‐like 1 proteins (NPC1L1) expressed in the small intestine. Because NPC1L1 is also expressed in human liver, ezetimibe conceivably alters biliary lipid compositions. Here, we performed a clinical trial investigating the effect of ezetimibe on biliary lipids using transnasal endoscopy for bile collection.

Enhancing hepatic fibrosis in spontaneously hypertensive rats fed a choline‐deficient diet: a follow‐up report on long‐term effects of oxidative stress in non‐alcoholic fatty liver disease

We previously reported a model of non‐alcoholic fatty liver disease (NAFLD) using spontaneously hypertensive rats (SHRs), fed a choline‐deficient (CD) diet for 5 weeks, that hepatic steatosis but not fibrosis is developed through oxidative stress. To determine the relationship between hypertension and hepatic fibrosis in NAFLD, we examined whether long‐term CD diet leads to hepatic fibrosis through oxidative stress.

Key diagnostic features of fever of unknown origin: Medical history and physical findings

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.

Long -term administration of a Niemann -Pick C1 -like 1 inhibitor, ezetimibe, does not worsen bile lithogenicity in dyslipidemic patients with hepatobiliary diseases

Certain lipid‐lowering drugs increase bile lithogenicity. Here we investigated whether long‐term administration of ezetimibe, a new class of hypocholesterolemic agents designed to inhibit intestinal cholesterol absorption by inhibiting Niemann‐Pick C1‐like 1, alters bile lithogenicity in patients with hepatobiliary diseases.

Partial characterization of proapoptotic action of biliary deteriorated lipids on biliary epithelial cells in pancreaticobiliary diseases

Lysophosphatidylcholine (LPC), a derivative of phosphatidylcholine (PC) hydrolyzed by phospholipase A2 (PLA2), is reported to be increased in bile of the patients with pancreaticobiliary maljunction or intrahepatic cholelithiasis, both of which are major risk factors for biliary tract cancers with undefined etiology.

Five Cases of Familial Mediterranean Fever in Japan: The Relationship with MEFV Mutations

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.

Primary Signet Ring Cell Carcinoma of Rectum Diagnosed by Boring Biopsy in Combination with Endoscopic Mucosal Resection

A 46-year-old man with severe back pain visited our hospital. Magnetic resonance imaging revealed extensive bone metastasis and rectal wall thickness. Colonoscopy revealed circumferential stenosis with edematous mucosa, suggesting colon cancer. However, histological findings of biopsy specimens revealed inflammatory cells but no malignant cells. The patient underwent endoscopic ultrasound, which demonstrated edematous wall thickness without destruction of the normal layer structure. After unsuccessful detection of neoplastic cells by boring biopsies, we performed endoscopic mucosal resection followed by boring biopsies that finally revealed signet ring cell carcinoma. Herein, we present a case and provide a review of the literature.