Shinji Takashimizu

Current status of ectopic varices in Japan: Results of a survey by the Japan Society for Portal Hypertension

Aim:  The Clinical Research Committee of the Japan Society for Portal Hypertension has conducted a nationwide questionnaire survey to clarify the current status of ectopic varices in Japan.

Clinical and pathological features of a prolonged type of acute intrahepatic cholestasis.

Aim:  We examined the clinical and pathological features of drug‐induced acute intrahepatic cholestasis (AIC) to elucidate the pathogenesis of prolonged cases.

Immunohistochemical studies on the expression of P-glycoprotein and p53 in relation to histological differentiation and cell proliferation in hepatocellular carcinoma.

Localization of P-glycoprotein (P-gp) and p53 was immunohistochemically examined in 41 patients with hepatocellular carcinoma (HCC) in order to determine the relationship between the expression of P-gp and p53 and the degree of histological differentiation or cell proliferation in HCC. P-gp showed different patterns of expression between cancerous and cirrhotic liver hepatocytes, and the expression in cancerous tissue also varied according to the degree of histological differentiation. In cirrhotic liver hepatocytes, expression of P-gp was found on bile canalicular membranes. In the case of cancerous tissue, P-gp was localized on the canalicular membranes in well-differentiated HCC showing a trabecular pattern, as recognized cirrhotic liver hepatocytes. In moderately differentiated HCC showing pseudo-glandular patterns, predominant expression of P-gp was found on the luminal side of cell membranes of the glandular ducts. The P-gp expression rate was 87.5% in well-differentiated HCC, 84% in moderately differentiated HCC, and 37.5% in poorly differentiated HCC, indicating a marked decrease with decreasing degree of differentiation. On the other hand, the rate of mutation of p53, a tumor suppressor gene, was 12.5% in well-differentiated HCC, 52.0% in moderately differentiated HCC, and 85.5% in poorly differentiated HCC, showing a significant increase with decreasing degree of differentiation (P<0.005). The labeling index (LI) of proliferating cell nuclear antigen (PCNA) tended to increase with the progression of chronic liver disease, with a markedly high value of 24.0+/-1.5% in cases of HCC. The PCNA LI was 15.6+/-11.9% in well-differentiated HCC, 23.1+/-15.1% in moderately differentiated HCC, and 50.1+/-13.3% in poorly differentiated HCC, which indicated a significantly increase in poorly differentiated HCC (P<0.001). Thus, it became apparent that abnormal expressions of P-gp and p53 and the cell proliferation in HCC vary according to the degree of histological differentiation of the malignancy. This suggests that more effective chemotherapy for HCC can be potentially developed by considering the pattern and level of expression of P-gp as a mechanism of drug resistance and the extent of histological differentiation.

Balloon-occluded transarterial chemoembolization using a 1.8-French tip coaxial microballoon catheter for hepatocellular carcinoma: technical and safety considerations.

Abstract Objective: To evaluate the technical feasibility and safety considerations of balloon-occluded transarterial chemoembolization (B-TACE) using a newly developed 1.8-French (Fr) tip microballoon catheter for hepatocellular carcinoma (HCC). Material and methods: Between February 2013 and May 2013, 31 patients (20 males, 11 females; age range 56–85 years) underwent B-TACE using a 1.8-Fr tip microballoon catheter for unresectable HCC. The technical success rate, procedural complications, and adverse events of B-TACE were retrospectively investigated. Results: A total of 31 patients were subjected to 70 sessions of B-TACE using a 1.8-Fr tip microballoon catheter. The level of B-TACE was sub-subsegmental in 11, subsegmental in 35, segmental in 14, lobar in five, and right inferior phrenic artery in five sessions. The overall technical success rate was 99% (69 out of 70 sessions). As procedural complications, rupturing of the microballoon (n = 3) and aneurysmal dilatation at the site of balloon occlusion (n = 2) were encountered. There were no significant differences in any parameters between blood biochemical examination before and between two to four weeks after the procedure. Conclusion: A 1.8-Fr tip microballoon catheter enables selective catheterization in patients with HCC and B-TACE using the 1.8-Fr tip microballoon catheter is a safe procedure.

An endothelin A receptor antagonist induces dilatation of sinusoidal endothelial fenestrae: implications for endothelin-1 in hepatic microcirculation

BackgroundSinusoidal endothelial fenestrae (SEF) regulate the sinusoidal circulation by altering their diameter and number. This study documented the effects of endothelin (ET) receptor antagonists on SEF and hepatic microcirculation.MethodsThe portal pressure and hepatic tissue blood flow were measured with a hydromanometer and a laser Doppler blood flow meter, respectively. BQ-123 (ETA receptor antagonist) or BQ-788 (ETB receptor antagonist) was continuously infused into normal rats at the rate of 10 nmol/min for 10 min. The sinusoids were observed at 60 min after the infusion by scanning electron microscopy. The localization of ET-1 and ETA and ETB receptors was examined by the indirect immunoperoxidase method.ResultsWhen BQ-123 was infused, the portal pressure gradually decreased with time, and it showed a significant reduction compared with the control groups. On the other hand, a decrease in portal pressure was not evident in the BQ-788-infused groups. Hepatic tissue blood flow was maintained at the value prior to the infusion in both groups. BQ-123 also caused a marked dilatation of the SEF. The diameters of the SEF after BQ-123 infusion were almost three times those of normal SEF. ET-1 was evenly present along the sinusoidal walls, and the reaction products of the ETA receptors were recognized along the portal vein and in the sinusoidal cells, that is, the hepatic stellate cells and endothelial cells.ConclusionsAction of ET-1 via the ETA receptors may regulate the size of SEF in addition to hepatic microcirculation.

Differential expression of multidrug resistance (mdr) and canalicular multispecific organic anion transporter (cMOAT) genes following extrahepatic biliary obstruction in rats

The hepatic canalicular membrane has transporters that play an important role as efflux pumps in the excretion of endogenous bile constituents or xenobiotics into bile canaliculi. To elucidate functional significance of canalicular transporters in the mechanism of cholestasis, mRNA expression levels of multidrug resistance (mdr) lb, mdr2 and canalicular multispecific organic anion transporter (cMOAT) genes were analyzed by Southern blotting of reverse‐transcribed PCR products of liver mRNA obtained from cholestatic rats that had been subjected to bile duct ligation. Both mdr1b and mdr2 mRNA expression increased after ligation. Immunohistochemical study revealed that the products of both mdr1b and mdr2 were present on the canaliculi, and that their levels increased after ligation. In contrast, cMOAT mRNA expression was not increased, but rather attenuated by ligation. The expression of canalicular transporters was differentially regulated in extrahepatic biliary obstruction, indicating the different roles are played by mdr and cMOAT in the pathogenesis of cholestasis.

Clinical effects of infusing anti-Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes into patients with severe chronic active EBV infection

Immune cell therapy with autologous Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes (CTLs) or lymphokineactivated killer (LAK) cells was performed in 2 adults with severe chronic active EBV infection (SCAEBV). The patient in case 1, who had complications of pancytopenia, high fever, and massive splenomegaly, was treated with 13 doses of LAK cell infusion followed by 4 doses of autologous CTL infusion.The patient in case 2, who had liver dysfunction due to natural killer cell-type infection, was treated with 4 doses of autologous CTL infusion. In case 1, the LAK cell infusions were effective in lowering the viral load and improving several biochemical parameters (lactate dehydrogenase, soluble interleukin 2 receptor) and resulted in complete amelioration of the high fever. Subsequent infusions of autologous CTLs reduced the viral load only temporarily and were accompanied by an increase in frequency of EBV-specific T-cells in the blood. However, the patient’s main problem of pancytopenia was not resolved. In case 2, infusion of autologous CTLs did not improve the patient’s hepatic dysfunction or viral load but caused a significant increase in autoantibody levels. Thus the effect of auto-CTL treatment was limited or deteriorative in SCAEBV patients.

Initial site of bile regurgitation following extrahepatic biliary obstruction in living rats.

Background and Aim:  The precise mechanism of bile regurgitation from the biliary system to the blood stream still remains to be elucidated. The aim of this study was to examine the initial site of bile regurgitation in vivo after common bile duct (CBD) obstruction by digitally enhanced fluorescence microscopy.

Mechanisms of Hepatic Microcirculatory Disturbances Induced by Acute Ethanol Administration in Rats, With Special Reference to Alterations of Sinusoidal Endothelial Fenestrae

Elucidation of the hepatic hemodynamics in acute ethanol administration is an issue of clinical importance for better understanding of alcoholic liver diseases. The purpose of this study is to clarify the mechanism of hepatic microcirculatory disturbances after acute ethanol administration, especially regarding the effects of ethanol on alterations of sinusoidal endothelial fenestrae (SEF) and the involvement of endothelin-l (ET-1) in the mechanism of portal hypertension induced by ethanol. Ethanol was administrated into the portal vein via the mesenteric vein branch of rats as a continuous infusion (4 and 8 mg/min of ethanol) for 60 min. Hepatic tissue blood flow measured with a laser Doppler blood flowmeter was found to be remarkably decreased with time, whereas portal pressure began to increase at 10 min and showed a significant increase by ˜1.5 cm H2 O at 60 min. Ethanol concentrations in blood at 60 min after 4 and 8 mg/min of ethanol infusion were 0.75 mg/ml and 1.77 mg/ml, respectively. At this point, scanning electron microscopy revealed significant decreases in number and diameter of SEF both in zone 1 and zone 3, with the increase in ethanol level. These findings suggested that decreases in number and diameter of SEF, whether primary or secondary, may lead to the impairment of the transport of plasma substances from sinusoids to hepatocytes in acute ethanol administration. Furthermore, the pretreatment of BQ-123 inhibited a decrease in hepatic tissue blood flow and an increase in portal pressure caused by ethanol, indicating that ET-1 may be involved in the mechanism of hepatic circulatory disturbances in acute ethanol administration.

Balloon-occluded arterial stump pressure before balloon-occluded transarterial chemoembolization

Abstract Objective To evaluate balloon-occluded arterial stump pressure (BOASP), which is responsible for effective balloon-occluded transarterial chemoembolization (B-TACE), at each hepatic arterial level before B-TACE using a 1.8-French tip microballoon catheter for unresectable hepatocellular carcinoma (HCC). Material and methods The BOASP at various embolization portions was retrospectively investigated. “Selective” and “non-targeted” BOASP was defined as the BOASP at the subsegmental or segmental artery and the lobar artery, respectively. Results The measurement of the BOASP was carried out in 87 arteries in 47 patients. BOASP > 64 mmHg was revealed in the caudate lobe artery (A1) and the left medial segmental (A4), right anterior superior segmental (A8), anterior segmental, right and left hepatic arteries. Significant difference was noted in the incidence of BOASP above 64 mmHg between “non-targeted” and “selective” BOASP (p = 0.01). “Non-targeted” BOASP was significantly greater than “selective” BOASP (p = 0.0147). In addition, the BOASP in A1, 4, 8 and the anterior segmental arteries were significantly greater than in the other subsegmental and segmental arteries (p = 0.0007). Conclusion “Non-targeted” B-TACE should be avoided to perform effective B-TACE and “selective” B-TACE at A1, 4, 8 and the anterior segmental arteries may become less effective than at the other segmental or subsegmental arteries.