In cirrhosis, the circulation becomes hyperdynamic, characterized as increased baseline cardiac output with decreased arterial pressure and peripheral vascular resistance. Despite the increased basal cardiac output, the heart reacts subnormally when subjected to physiological or pharmacological stress such as exercise, drugs or surgery. This blunted responsiveness of ventricular contractility has been termed “cirrhotic cardiomyopathy, ” but its pathogenesis remains unclear. We aimed to clarify the pathogenic factors underlying this condition, in particular the role of membrane changes in autonomic receptors or their signal transduction pathway, in different rat models of chronic liver disease. The majority of studies were performed in the chronic (4-week) bile duct ligated cirrhotic rat (BDL), a model of biliary cirrhosis with deep jaundice. Other studies were also performed in 3 other models of portal hypertension / cirrhosis were studied : portal vein-stenosed rats with infrahepatic portal hypertension but no parenchymal liver disease (PVS); thioacetamide-induced cirrhotic rats (TA), bile duct ligated cirrhotic rats then subjected to choledochojejunostomy to reanastomose the bile flow and relieve biliary obstruction (BDR) Controls had sham operation. Isolated left ventricular papillary muscles from these groups were tested for β-adrenergic responsiveness by electrical stimulation at 1Hz, voltage 1.3 × threshold, with graded doses of the β-adrenergic agonist isoproterenol. Compared to the sham-controls, muscles from all 3 cirrhotic groups showed blunted isoproterenol responsiveness, while PVS was not different from shams. Cardiac sarcolemmal plasma membranes were prepared from the ventricles of BDL or control rats by sucrose gradient centrifugation. Static and dynamic components of membrane fluidity were assessed by using diphenylhexatriene and stearic acid labelled with a series of 9-anthroyloxy probes, respectively. ³H-dihydroalprenolol and ³H-methyl scopalamine were used as radioligands to respectively characterize the stimulatory β-adrenergic and inhibitory muscarinic (m2) receptors. G-proteins were assessed by fluoride stimulation and SDS-PAGE with western blots using rabbit antibodies to G-protein subtypes. Adenylyl cyclase activity measured by cAMP generation was measured at baseline and following stimulation with 3 compounds : isoproterenol to activate the receptor, NaF to stimulate Gs-protein directly, and forskolin which stimulates adenylyl cyclase independent of receptor activation. BDL and TA rats showed decreased cAMP generation with all 3 drugs, whereas the BDR rats only showed decreases with isoproterenol and NaF, but intact forskolin responses. Compared to controls, the BDL rats had a 15% decrease in the β-adrenoceptor density without any change in the binding affinity. The receptor density and binding affinity of the m2 receptors were unchanged from controls. Despite the unchanged m2 receptor characteristics, isolated left ventricular papillary muscles from BDL rats showed blunted carbacho-induced attenuation of isoproterenol-stimulated contractility, indicating blunting of muscarinic function. Moreover we found a 40% decrease in isoproterenol-stimulated AC activity, suggesting that postreceptor factors in the signal transduction pathway for the β-adrenoceptor are also involved. This was confirmed by the fluoride and forskolin studies which showed attenuated responses, indicating defective Gs and AC enzyme activity in BDL rats. The BDL menbrane content of Gas and Gia as determined by western blotting were decreased by 20% and 47%, while the G_{commob B} level was unchanged. Both static and dynamic membrane fluidity significantly decreased, and the membrane cholesterol content was increased in the BDL rats, with consequent increased cholesterol : phospholipid ratio.

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We investigated hemodynamic changes following endoscopic sclero-ligation therapy (ESL : EIS combined with EVL therapy) which was performed in six patients with esophageal varices due to liver cirrhosis. Angioraphy before ESL demonstrated that both of the left gastric artery (LGA) and the left gastric vein (LGV) were the feeding vessels for esophageal varices in five patients. Varices in the other patient was fed solely by LGA. Before ESL, flow direction of LGV was hepatoufugal in four, and “to and fro” in two. After ESL, esophageal varices were eradicated in five patients, endoscopically. Of these, flow direction of LGV changed from hepatofugal to hepatopetal in two, from hepatofugal to “to and fro” in two. And in one patient with “to and fro”, the flow of LGV was not demonstrated. The diameter of LGV decreased in three out of four patients with patent LGV after ESL. Esophageal varices were not eradicated in one patient whose varices were fed by LGA alone. ESL neither changed the flow direction nor the diameter of the LGV. It is suggested that ESL embolized LGV completely or imcompletely, and caused subsequent hemodynamic changes for patients for whom LGV was the feeder vessel to the varices.

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Eighty two patients with chronic liver disease, 41 with cirrhosis and 41 with chronic hepatitis, were studied. In patients with cirrhosis, total systemic vascular resistance (TSVR) and pulmonary vascular resistance (PVR) were significantly lower than that with chronic hepatitis. Cardiac index and hepatic venous pressure gradient (HVPG) were significantly higher in the former group than in the latter group. In patients with cirrhosis, PVR was significantly correlated with TSVR (r =0.57, p <0.05) and HVPG (r =-0.37, p <0.05). Moreover, PVR was significantly correlated with serum total bilirubin level (r =-0.35, p <0.05) and serum choline esterase level (r =0.55, p <0.001). These results suggest that in patients with portal hypertension, PVR reduces with the deterioration of liver function and as a part of systemic hemodynamic alteration.

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Among 17 patients with esophageal varices, Doppler endoscopic ultrasonography (CD-EUS) was performed to detect intramural blood flow and evaluate enlarged perforating veins (EPV) before/after endoscopic treatment. Before treatment, intramural blood flow was detected in all patients (100.0%). EPV was detected in 9 patients (52.9%), ranged from 1.9 to 6.2 mm in diameter (mean diameter 3.3 ± 1.5). Blood flow in EPV was toward in 7 patients, away in 2 patients. At the end of the treatment blood flow in EPV was disappeared in all 9 patients, however intramural blood flow was persisted in 4 patients. Early reccurrence rate of esophageal varices was not different between the patients with and without residual intramural blood flow, however higher in the patients with toward EPV (3 of 7) than the patients with away EPV (0 of 2) or without EPV (1 of 8). Toward EPV were significantly larger in diameter in the patients with early reccurence (mean diameter 5.3 ± 0.8 mm) than in those with long-term reccurence or without reccurence (mean diameter 2.3 ± 0.3mm). And we were able to observe blood flow re-appearing in EPV at the time of reccurence. We conclude that toward, markedly enlarged perforating veins (MEPV) may be an important factor of early reccurence of esophageal varices and strict follow up or intensed therapy is required in these patients. CD-EUS is usefull to detect EPV and make the decision in selecting endoscopic treatment for esophageal varices.

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This study was designed to provide direct evidence of arterio-venous anastomoses (A-V A) within the gastric wall under a condition of liver cirrhosis and portal hypertension, while applying intravital microscopy to cirrhotic rats that treated by an injection of CCl₄. The intravital microscope's objective stage was placed on the rat's exposed stomach followed by the administration of Monastral Blue B. Several direct shunting channels from an arteriole to a venule were clearly visualized in the submucosal layer in cirrhotic rats, whereas no channels were observed in non-cirrhotic rats. This is the first report that demonstrates a presence of A-V A within the gastric wall under a cirrhotic liver condition, suggesting that A-V A may play an essential role on the development of esophagogastric varices and portal hypertensive gastropathy

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To determine clinical characteristic of hemorrhage-prone Vascular Ectasia (VE) in patients with liver cirrhosis, an investigation was carried out in 2 groups of bleeding and non-bleeding patients who received colonoscopic examination between January 1989 and July 1996. Thirty-one patients, or 26.5% of the patients receiving colonoscopic examination, were diagnosed with VE, of whom 7 were in the bleeding group and 24 in the non-bleeding group. There were no differences in age, sex ratio, or rate of liver cancer or esophageal varicosis between the 2 groups. When red spots and vascular spiders were compared on the endoscopic study, the frequency of the latter was higher in both the bleeding and non-bleeding groups. In addition, a bleeding tendency was noted in the patients with diminished hepatic reserve. The results of this study indicate that it is important to locate the source of bleeding with VE in mind when the gastrointestinal tract bleeds in liver cirrhosis patients with diminished hepatic reserve.

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Of 360 patients who underwent non-shunt operation for esophago-gastric varices, 82 patients showed development of hepatocellular carcinoma (HCC) after the operation. The risk factors in HCC development were assessed in those 82 patients with liver cirrhosis by clinical parameters and immunohistochemical staining with anti-Ki-67 antibody (MIB-1) in biopsied liver tissue at the time for the non-shunt operation. Patients of ≥45 years old and patients of ≥21ng/ml of serum AFP level at the time for non-shunt operation showed a significantly high cumulative rate of HCC development (p<0.01). Ki-67 labeling index (L.I.) in patients with HCC development was 0.16±0.10%, white that in patients without HCC development was 0.07±0.06%, showing a significant difference (p<0.01). The cumulative rate of HCC development was significantly higher in moderate L.I. group (0.11-0.20) and high L.I. groups (p≥0.21) than in low L.I. group (≤0.10) (p<0.01). It was supposed the rise of Ki-67 L.I. effects acceleration of cell proliferating activity and a high possibility of HCC development. We conclude that Ki-67 L.I. is of great use in evaluating the risk factors of HCC development.

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[in Japanese]

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Balloon-occluded retrograde transvenous obliteration (B-RTO) has been aceepted as a new treatment for fundic gastric varices (FGV). But since the drainage of FGV sometimes not only involves a gastro-renal shunt but also several small veins, it is difficult to get stable results after B-RTO. To solve this problem, we injected a concentrated glucose solution into FGV before injecting 5% ethanolamine oleate (EO). We performed B-RTO with a concentrated glucose solution in 11 patients with FGV from 1993 to 1996. First we analyzed the hemodynamics of the varices by balloon-occluded retrograde transvenous venograpy. In all cases, the drainage of the varices was not only via a gastrorenal shunt but also other small veins. To decrease the blood flow in the draining veins, we injected 50% or 70% glucose solution into the varices before injecting 5%EO. With this method, the blood flow in the veins was decreased and the effect of B-RTO was facilitated. 10 of 11 patients were successfully treated without any major complications, and the varices disappeared completely 2 or 3 months after B-RTO. In conclusion, pretreatment with a concentreted glucose solution is a safe and effective way to make B-RTO more successful for FGV.

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Pathogenesis and clinical significance of solitary varix (SoV) or scattered varices (ScV) of the upper or middle esophagus, not contiguous to any varix of the lower esophagus, have not yet been fully clarified. We recently carried out endoscopic assessment of these varices. Routine endoscopic examinations of the upper gastrointestinal tract were carried out among 6660 individuals. Out of these individuals, 54 patients were found to have SoV or ScV (85 lesions in total). They often found to be 25-34 cm from incisors, and on the posterior wall. When accompanying lesions were checked by endoscopy, chronic gastritis was the most frequent. The ages of patients with Dome-shaped varix were significantly higher than those with “Quonset hut”-shaped varix, and than those who was carried out the routine endoscopic examinations. Underlying disease, which cause ordinary esophageal varices, were seen in only 13 patients (24.1%). It seems unlikely that the factors for ordinary esophageal varices are responsible for the onset of SoV or ScV. Dome-shaped varix seems to be attributable to dilatation of submucosal vessels due to local fragility by aging.

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[in Japanese]

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While performing endoscopic varicealography during injection sclerotherapy (EVIS) in patients with esophageal varices, we occasionally encounter cases in whom satisfactory EVIS can not be achieved because of leakage of the sclerosant containing contrast medium to an extra-esophageal shunt through huge perforating veins. Leakage of the sclerosant could cause severe complications such as pulmonary embolism or hemolysis. Therefore, to prevent leakage of the sclerosant and to form thrombs in the blood supply route of the varices, we developed a new therapeutic method of endoscopic injection sclerotherapy (EIS), combined with selective endoscopic variceal ligation (s-EVL) of perforating veins connecting to collaterals outside of esophageal wall constituting an extra-esophageal shunt. In performing s-EVL, one or two EVL rings were placed just on the connections of the esophageal varices to perforating veins which were identified by endoscopic ultrasonography (EUS) done prior to the EVL. We performed EIS combined with s-EVL in 3 cirrhotic patients with large extra-esophageal shunt and could successfully prevent the leakage of sclerosant containing contrast medium to the external aspect of the esophageal wall from the shunt in all patients. Therefore, we could fill up sclerosants to the blood supply routes of esophageal varices to make the thrombus sufficiently. EIS conbined with s-EVL is an effective and safety method for the treatment of the esophageal varices with a large extra-esophageal shunt.

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[in Japanese]

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[in Japanese]

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[in Japanese]

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