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The effect of long-term administration of nipradilol (NIP, Hypadil Kowa, CAS 81486-22-8), a beta-blocker with a vasodilatory action, on esophageal varices was studied in 66 patients with compensated liver cirrhosis. Administration of NIP (6-12 mg/d) for 3-12 months produced progressive improvement of endoscopic findings over time (30% for C, 25% for F, and 40% for the R-C sign after 12 months). At the last examination (mean: 9 +/- 4 months), the improvement rates were 16.7%, 16.7% and 22.7%, respectively. No significant relationship was found between endoscopic improvement and the Child-Pugh score or the dose of NIP. Gastrointestinal bleeding occurred in five patients: one had bleeding esophageal varices, three had bleeding gastric varices, and one had a bleeding gastric ulcer. The systolic blood pressure was decreased significantly (4.6-12.3%) at 2 weeks as well as 1 and 2 months, and the heart rate showed a significant decrease throughout the study (10-18.4%). With the exception of the patients who had gastrointestinal bleeding, no symptoms of decompensation appeared, and there was no deterioration of laboratory parameters including ammonia. Adverse effects occurred in about 10% of the patients, most of which were related to bradycardia and/or hypotension, and they improved when the drug was withdrawn or the dose reduced. These results suggest that long-term administration of NIP is useful in the treatment of esophageal varices.

Macroscopic and unitary currents through Ca(2+)-activated Cl- channels were examined in enzymatically isolated guinea-pig hepatocytes using whole-cell, excised outside-out and inside-out configurations of the patch-clamp technique. When K+ conductances were blocked and the intracellular Ca2+ concentration ([Ca2+]i) was set at 1 microM (pCa = 6), membrane currents were observed under whole-cell voltage-clamp conditions. The reversal potential of the current shifted by approximately 60 mV per 10-fold change in the external Cl- concentration. In addition, the current did not appear when Cl- was omitted from the internal and external solutions, indicating that the current was Cl- selective. The current was activated by increasing [Ca2+]i and was inactivated in Ca(2+)-free, 5 mM EGTA internal solution (pCa > 9). The current was inhibited by bath application of 9-anthracenecarboxylic acid (9-AC) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) in a voltage-dependent manner. In single channel recordings from outside-out patches, unitary current activity was observed, whose averaged slope conductance was 7.4 +/- 0.5 pS (n = 18). The single channel activity responded to extracellular Cl- changes as expected for a Cl- channel current. The open time distribution was best described by a single exponential function with mean open lifetime of 97.6 +/- 10.4 ms (n = 11), while at least two exponentials were required to fit the closed time distributions with a time constant for the fast component of 21.5 +/- 2.8 ms (n = 11) and that for the slow component of 411.9 +/- 52.0 ms (n = 11). In excised inside-out patch recordings, channel open probability was sensitive to [Ca2+]i. The relationship between [Ca2+]i and channel activity was fitted by the Hill equation with a Hill coefficient of 3.4 and the half-maximal activation was 0.48 microM. These results suggest that guinea-pig hepatocytes possess Ca(2+)-activated Cl- channels.

The voltage-dependent K+ channel was examined in enzymatically isolated guinea pig hepatocytes using whole-cell, excised outside-out and inside-out configurations of the patch-clamp technique. The resting membrane potential in isolated hepatocytes was -25.3 +/- 4.9 mV (n = 40). Under the whole-cell voltage-clamp, the time-dependent delayed rectifier outward current was observed at membrane potentials positive to -20 mV at physiological temperature (37 degrees C). The reversal potential of the current, as determined from tail current measurements, shifted by approximately 57 mV per 10-fold change in the external K+ concentration. In addition, the current did not appear when K+ was replaced with Cs+ in the internal and external solutions, indicating that the current was carried by K+ ions. The envelope test of the tails demonstrated that the growth of the tail current followed that of the current activation. The ratio between the activated current and the tail amplitude was constant during the depolarizing step. The time course of growth and deactivation of the tail current were best described by a double exponential function. The current was suppressed in Ca(2+)-free, 5 mM EGTA internal or external solution (pCa > 9). The activation curve (P infinity curve) was not shifted by changing the internal Ca2+ concentration ([Ca2+]i). The current was inhibited by bath application of 4-aminopyridine or apamin. alpha 1-Adrenergic stimulation with noradrenaline enhanced the current but beta-adrenergic stimulation with isoproterenol had no effect on the current. In single-channel recordings from outside-out patches, unitary current activity was observed by depolarizing voltage-clamp steps whose slope conductance was 9.5 +/- 2.2 pS (n = 10). The open time distribution was best described by a single exponential function with the mean open lifetime of 18.5 +/- 2.6 ms (n = 14), while at least two exponentials were required to fit the closed time distributions with a time constant for the fast component of 2.0 +/- 0.3 ms (n = 14) and that for the slow component of 47.7 +/- 5.9 ms (n = 14). Ensemble averaged current exhibited delayed rectifier nature which was consistent with whole-cell measurements. In excised inside-out patch recordings, channel open probability was sensitive to [Ca2+]i. The concentration of Ca2+ at the half-maximal activation was 0.031 microM. These results suggest that guinea pig hepatocytes possess voltage-gated delayed rectifier K+ channels which are modified by intracellular Ca2+.

As the incidence of cardiac cirrhosis at autopsy today is much lower than that from decades ago, true cardiac cirrhosis is a rare finding. With the decline in incidence of valvular disease, cardiomyopathy, in the etiology of congested liver, has increased. The pathophysiology of congestive heart failure consists of two components: forward failure with decreased hepatic blood flow and backward failure with congestive liver. Both lead to hepatocellular hypoxia. Increased serum transaminases and serum bilirubin correlate with reduction in cardiac output and elevation of venous pressure. Even when cardiac cirrhosis develops, it is difficult to diagnose clinically.

An association between autoimmune disease and malignancy, in particular lymphoproliferative neoplasms, has been reported, as has an increased incidence of extrahepatic malignancy in primary biliary cirrhosis (PBC). Monoclonal immunoglobulin elevations in PBC are rare, and there have been only three cases in the literature of PBC associated with multiple myeloma. We describe a patient who was concurrently diagnosed as having PBC and multiple myeloma, and emphasize the need to consider myeloma when evaluating monoclonal gammopathy in PBC. We also discuss the possible mechanisms for the association of the two conditions.

To elucidate pathophysiological characteristics of the peripheral circulation in liver cirrhosis, cutaneous microcirculation was analyzed at the finger, palm, toe, and arch of the foot using laser Doppler spectroscopy in 19 patients with liver cirrhosis, and the results were correlated with cardiovascular hemodynamics (n = 10) and plasma neurohormonal factors (n = 8). Cutaneous blood flow at each area was all significantly reduced (P < 0.001, < 0.05, < 0.01, < 0.001, respectively) in patients with liver cirrhosis compared to those in normals (n = 20). Cutaneous blood mass was also significantly reduced (P < 0.05, < 0.01, < 0.001, respectively) except at the arch of foot in patients with liver cirrhosis. There were significant correlations between finger cutaneous blood flow and systemic vascular resistance (r = -0.73, P < 0.05), plasma norepinephrine level (r = -0.84, P < 0.01), plasma renin activity (r = -0.77, P < 0.01), plasma concentrations of aldosterone (r = -0.76, P < 0.05) and angiotensin II (r = -0.76, P < 0.05), between palm blood flow and plasma vasoactive intestinal polypeptide concentration (r = 0.83, P < 0.05). From these results and our previous data demonstrating increased forearm muscular blood flow in patients with liver cirrhosis, increases in arteriovenous anastomotic flow and the contribution of neurohormonal factors will represent pathophysiological mechanisms for these changes.

The difference in response rate to interferon (IFN) among several treatment regimens was assessed retrospectively in 48 HCV-RNA positive patients with chronic hepatitis C. The study focused on patients' pretreatment profiles and response to treatment, histological findings before and after the treatment and the significance of HCV-RNA detection in evaluating the outcome. A complete response (CR) evaluated by the outcome of alanine aminotransferase (ALT) was obtained in 16 of 25 patients (64.0%) treated with IFN in doses of 3 to 6 million units daily for the first 4 or 8 wks and subsequent dosing twice or three times weekly for the following 8 to 146 wks. In contrast, CR was obtained in only 7 of 16 patients (43.8%) treated with the regimen in which patients received IFN in doses of 1 to 6 million units daily for 4 to 8 wks and no subsequent IFN. In comparing the responders to IFN (25 cases) and the non responders (19 cases), there were no significant differences regarding patients' age, sex, the presence or absence of history of blood transfusion, pretreatment ALT values or histological magnitude, or total doses of IFN administered. When the basal and final biopsy samples were compared, Knodell's index of histological activity had decreased significantly in the responders but not in the non responders. In 24 of the 25 responders, HCV-RNA had disappeared from their serum at the end of treatment, and in 23 it remained undetectable 6 months after treatment. In contrast, in 6 of the 19 non responders HCV-RNA had become negative at the end of treatment but was detectable in all cases 6 months after treatment. Thus, it is concluded that (1) a regimen of daily administration for the first 4 or 8 wks with subsequent dosing twice or three times weekly was preferable in terms of obtaining frequent CR, (2) response to IFN cannot be predicted by a patient's pretreatment profile, (3) in responders, histological activity decreases, and (4) in responders, HCV-RNA becomes undetectable not only at the end of treatment but also 6 months after treatment.

The effect of blood volume contraction induced by a 4-week regimen of spironolactone (100 mg/day) or furosemide (40 mg/day) on the hepatic venous pressure gradient (HVPG), an indicator of portal hypertension, was evaluated in patients with cirrhosis and no ascites. In the spironolactone group (n = 15), HVPG decreased significantly from 16.5 +/- 0.9 mmHg (mean +/- S.E.M.) to 12.9 +/- 1.0 mmHg (P < 0.005) and total blood volume contracted significantly from 4338 +/- 231 ml to 4006 +/- 203 ml (n = 14, P < 0.01). Although the HVPG changes did not correlate significantly with changes in measured total blood volume or in simultaneously determined systemic haemodynamics, a significant inverse correlation (r = -0.74, P < 0.01, n = 12) was found between the HVPG change and posttreatment plasma aldosterone levels, attesting to the effectiveness of spironolactone therapy in lowering HVPG. In the furosemide group (n = 10), neither HVPG (13.7 +/- 0.3 mmHg vs. 13.6 +/- 0.9 mmHg) nor total blood volume (4961 +/- 153 ml vs. 4964 +/- 162 ml) declined significantly. These results show that long-term administration of spironolactone to patients with cirrhosis and no ascites produced a significant reduction in HVPG that may have been due to gradual, sustained volume contraction. Thus, spironolactone may prove to be an effective treatment for portal hypertension in cirrhosis without ascites.

The effect of (D-Ala, D-Leu) enkephalin (DADLE) on the binding of GTP in hippocampal preparations was studied. It was observed that treatment of hippocampal slices with 10(-5) -5 x 10(-5) M DADLE followed by the preparation of membrane fractions reduced the binding of 35S-GTP-gamma-S. There was no change in the affinity of the binding. This decrease of 35S-GTP-gamma-S binding was reversed when 5 x 10(-5) M naltrindole was included. The effect was not observed when the membrane fractions were incubated with DADLE. Photoaffinity labeling with the use of 32P P3-(4-azidoanilido)-P1 5'-GTP followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography revealed the incorporation of radioactivity into molecular mass of the 43 kDa and 33-34 kDa proteins. 32P Photolabeling of both the 43 kDa and 33-34 kDa bands decreased following treatment of hippocampal slices with 10(-4) M DADLE. These results suggested that DADLE reduces the GDP-GTP exchange in hippocampal membranes.

A mixture of 100 mM creatinine and 100 mM L-phenylalanine was heated at 60 or 37 degrees C in the presence of sugar or aldehyde. A mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formed in the model system was determined by reversed-phase HPLC. Any sugars tested induced the formation of PhIP when heated at 60 degrees C, though PhIP was not detected in a mixture without sugar. Among the sugars tested, D-erythrose and D-glyceraldehyde were more productive than pentose (D-arabinose and D-ribose) and hexose (D-glucose and D-galactose) in the yield of PhIP. Moreover, PhIP was formed even when a mixture of creatinine, L-phenylalanine and D-glucose or D-ribose was incubated at 37 degrees C for a long time. Both formaldehyde and acetaldehyde also induced the formation of PhIP, though PhIP was not detected in a mixture without sugar or aldehyde even when heated at 100 degrees C. These results indicate that PhIP can be formed at low-temperature heating and that either sugar or aldehyde is essential for PhIP formation in the model system. Our data also suggest that aldehydes may be a key reactant in the formation of PhIP in aqueous heating of the mixture of creatinine and L-phenylalanine.

To study the long-term effects of pharmacological combination therapy, a comparison was made of the haemodynamic changes in patients with cirrhosis and portal hypertension following a 4-week treatment of propranolol or nipradilol, a new nonselective beta-blocker with nitrovasodilating effect. Nipradilol (12 mg/dag, n = 12) significantly diminished wedged hepatic venous pressure (WHVP, 25 +/- 16%), the hepatic venous pressure gradient (HVPG, 20 +/- 12%), and estimated hepatic blood flow (EHBF, 18 +/- 16%). Propranolol (30 mg/day, n = 11) also caused a significant reduction in WHVP (22 +/- 21%) and HVPG (24 +/- 21%), but not in EHBF. The percentage of portal pressure reduction and the frequency of nonresponders did not differ between the nipradilol and propranolol groups. Both agents reduced heart rate by approx. 20%. Nipradilol, however, did not cause a significant reduction in cardiac index (CI) versus a 14% reduction by propranolol. Pulmonary capillary wedge pressure and central venous pressure, an index of preload, were decreased slightly in the nipradilol group. When nonresponders were excluded, there was a significant correlation of the percentage of reduction between WHVP and CI or systemic vascular resistance, in the nipradilol group. These results indicate that nipradilol may have potent hypotensive effects on portal hypertension, similar but not superior to propranolol. Nipradilol, at the dosage used in the present study, did not appear to exert a nitrovasodilating effect to enhance the portal pressure reduction induced by beta-blocking action.

A decapping enzyme has been purified about 2400-fold from rat liver cytosol. The decapping enzyme was shown to be fairly homogeneous by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The enzyme had an apparent molecular weight of 110,000 and consisted of two equal subunits. The enzyme hydrolyzed m7Guo5'PPP5'Ado to m7GMP and ADP. Analysis of the products produced from radioactively capped oligonucleotides and intact mRNA having 3H-cap suggests that the enzyme can hydrolyze capped mono- to pentanucleotides (m7Guo5'PPP5'N (where N = 1-5 nucleotides)) but not intact mRNA. The existence of methyl group at the N7 position of guanosine moiety of cap structure was necessary for the action of the decapping enzyme. This was confirmed by the comparison of the rates of hydrolysis of m7Guo5'PPP5'Ado by the enzyme in the presence of various nucleotides. The activity of enzyme was slightly stimulated by Na+, K+, NH4+, Ca2+ and polyamines. Mg2+ and Mn2+ were without effect on the enzyme activity.

To evaluate the etiologic and pathophysiological characteristics of the aged cirrhotics, a total of 219 cirrhotic patients who admitted to our department between 1975 and 1989 was divided into the three age groups; less than or equal to 49 (Group A, n = 70), 50-59 (Group B, n = 77) and greater than or equal to 60 (Group C, n = 72) years and compared. The frequency of female patients was significantly higher in Group B and C than Group A, respectively. The age-related variation in etiologies of cirrhosis was analyzed among patients between 1975 and 1989, as well as those observed in 1990, when the assay for antibody to hepatitis C virus (anti-HCV) was available. Compared with Group A, patients with Group C had a lower incidence in HBsAg positive and alcoholic cases. The incidence in cases of unknown cause increased with age and in the elderly over 70 anti-HCV negative cases were found in approximately 45 per cent, the incidence being significantly higher than that of the 50-to-59 year age group. Of the Group C patients 10.6 per cent had gastrointestinal bleeding, which was significantly lower in frequency as compared with 28.6 per cent of Group A. In contrast, the frequency of the other symptoms including jaundice, ascites and encephalopathy did not differ with age. Among various liver function indices the value of gamma-GTP was significantly lower and that of cholesterol was significantly higher in Group C than in Group A, although albumin tended to decline with age. When the extent of endoscopic findings of esophageal varices were compared between the elderly over 60 and the under 60s, the former included the less advanced cases than the latter. The hemodynamic studies revealed that the portal pressure and hepatic blood flow did not differ among the three age groups, but the cardiac index reduced and total systemic vascular resistance increased with age. Regarding the cause of death, the frequency of gastrointestinal bleeding was lower in Group B and C than in Group A. From these results it may be concluded that an approximately half of cirrhosis of the elderly occurs for no known cause other than HBV, HCV and alcohol, and that the frequency of gastrointestinal bleeding as well as the extent of esophageal varices appear to decline with age.

A carcinogenic heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was measured in condensate of cigarette mainstream smoke by HPLC. PhIP was detected in all brands of filter-tipped cigarettes analyzed. The mean level of PhIP in the cigarette mainstream smoke was 16.4 ng/cig.

The interrelation between endoscopic findings in esophageal varices, and systemic and hepatic hemodynamic abnormalities was studied in 76 male patients with compensated cirrhosis. Observation of these patients revealed a hyperdynamic systemic circulation, represented by an increased cardiac output and reduced total systemic vascular resistance with an enlarged circulating plasma volume and without an increase in heart rate, in comparison with 23 male patients with chronic hepatitis. In patients with cirrhosis and esophageal varices, the hyperdynamic circulatory state was closely related to the condition of the varices, in which a progress in the form was accompanied by an advance in the degree of hyperdynamism with an increase in circulating plasma volume. Whereas the extent of the varices as indicated by the location was closely related to a rise in the wedged hepatic venous pressure. The shunt volume through the portal-systemic collaterals requires further study to elucidate the mechanism of hyperdynamic circulation.

We proposed a new experimental animal model for portal hypertension in the female Japanese white rabbit by an intraportal injection of DEAE-cross-linked dextran microspheres (100 +/- 25 microns in diameter). Histology of the liver revealed portal obstruction by the injected microspheres in almost all portal triads, resulting in a foreign body granuloma. A sustained elevation of the portal pressure by a mean of 36.7% as compared with the basal value was observed for at least eight weeks in association with the portal-systemic collateral circulation demonstrated by portography, the radioisotope labeled microsphere method and histological examination of the esophagus and the liver. The elevation in portal pressure in the eighth week was associated with an increase in the portal blood flow determined at the main portal trunk. This was in accordance with the forward theory of the pathogenesis of portal hypertension. Since this model appears to show the two main conditions characteristic of portal hypertension persistent elevation of portal pressure and both extra- and intrahepatic portal collaterals, mimicking those in humans, portal obstruction by injecting DEAE-cross-linked dextran microspheres into the portal vein of the rabbit could provide a versatile model for portal hypertension.

Unlabelled: The effect on the HBeAg/anti-HBe system of SSM (specific substance Maruyama), an extract from human tubercle bacilli, was evaluated in patients with HBeAg positive type B chronic hepatitis., Subjects and Methods: Twenty-five (25) HBeAg positive patients with biopsy-proven chronic hepatitis were injected subcutaneously with SSM solution twice a week for two years. Fifteen (15) comparable patients served as untreated controls for one year. HBeAg and anti-HBe were measured by the RIA method., Results: (1) In the group receiving SSM injections, HBeAg disappeared in 8 out of 25 patients (32.0%) one year after the treatment and in 15 out of 23 (65.2%) within two years. Seroconversion from HBeAg to anti-HBe occurred in 5 of the 25 patients (20.0%) after one year and in 7 out of 23 (30.4%) within two years. Of the 15 untreated controls, HBeAg disappeared in 3 patients (20%), and seroconversion from HBeAg to anti-HBe occurred in 1 (6.7%) within one year. (2) In the SSM group, the HBeAg cut off index decreased significantly (p less than 0.01), from 5.2 +/- 1.9 during the pretreatment period to 2.7 +/- 2.3 twelve months after the treatment. (3) In the SSM group, a transient rise in sGOT and sGPT was observed in some patients three to nine months after starting the treatment. HBeAg disappeared in all these patients. (4) No notable side effects were observed in any of the patients treated with SSM., Conclusion: These results indicate that SSM treatment improves the HBeAg/anti-HBe system in patients with HBeAg positive chronic hepatitis.

An attempt was made to estimate noninvasively portal pressure (PP) in patients with chronic liver disease, using the theory of quantification, a kind of multivariate analysis. Forty-one patients with liver cirrhosis and 22 patients with chronic hepatitis in whom hepatic venous catheterization had been performed were studied. Seventeen parameters (age, sex, mean blood pressure, red blood cell count, platelet count, prothrombin time, lactate dehydrogenase, alkaline phosphatase, total bilirubin, albumin, gamma-globulin, indocyanine green retention at 15 min, blood urea nitrogen, hepatomegaly, splenomegaly, ascites and edema) were selected for the estimation of PP. The estimated PP correlated significantly with the data obtained by hepatic venous catheterization with a high correlation coefficient of 0.835 (p less than 0.01). An investigation using the theory of quantification was also undertaken to determine which of the 17 parameters selected above was most useful in estimating PP. Among the 17 parameters indocyanine green retention at 15 min, red blood cell count, prothrombin time, hepatomegaly and splenomegaly seemed to contribute significantly to the estimation of PP. When the formula was applied to 31 successive patients with chronic liver disease (external samples), the correlation between the estimated and measured PP was 0.455 (p less than 0.01). These results indicate that the formula is clinically useful in estimating PP in patients with chronic liver disease.

The effect of plasma volume contraction induced by a 4-wk administration of spironolactone or furosemide on the hepatic venous pressure gradient was evaluated in consecutively allocated patients with cirrhosis and no ascites. In the spironolactone group (n = 15), the hepatic venous pressure gradient decreased significantly (p less than 0.005), by 21.8%, with a significant contraction of circulating plasma volume (p less than 0.01). Although there were no statistically significant correlations between the change in hepatic venous pressure gradient and changes in circulating plasma volume or in simultaneously determined systemic hemodynamics, a significant negative correlation (r = -0.74, p less than 0.01, n = 12) between the hepatic venous pressure gradient change and the post-treatment plasma aldosterone levels was found. However, in the furosemide group (n = 10), the hepatic venous pressure gradient and circulating plasma volume did not significantly decrease. Our data demonstrated a significant reduction in the hepatic venous pressure gradient on a chronic administration of spironolactone, which may have been due to volume contractions in patients with cirrhosis and no ascites.

In 42 patients with compensated cirrhosis and 31 control subjects, blood flow (BF) and vascular resistance (VR) were measured at the forearm and calf, using a pneumoplethysmograph. In some of the subjects deep-body temperature (DBT) was also measured by the zero heat flow method. In cirrhosis, BF and DBT were significantly higher and VR was significantly lower in the forearm than in the calf. Corresponding differences were not observed in control subjects. When these indices of the forearm were compared between cirrhosis and controls, BF and DBT were significantly higher and VR was significantly lower in cirrhosis than in controls. In cirrhotics in whom the gradient between forearm BF and calf BF was 1 ml.dl-1.min-1 or more (forearm greater than calf), the vascular response of the forearm to cold stimulation was reduced, whereas in the remaining patients and in controls the forearm BF and VR responded significantly. These results suggest that there is a regional difference in peripheral circulation in cirrhotics, partly with participation of impaired sympathetic nervous activity, which may account for the selective distribution observed in the clinical manifestations of vascular spider, palmar erythema, and warm hand, inclined toward the upper extremities or the upper part of the body.

The effect of changes in body posture on estimated hepatic blood flow (EHBF) and various hemodynamic parameters was examined in 15 patients with compensated cirrhosis. EHBF and various hemodynamic parameters were first measured with the patients in the supine position, and then again 10 min after tilting to 45 degrees. EHBF was 1089 +/- 315 ml/min at supine and 1065 +/- 328 after tilting; the difference was not significant. However, the patients were then divided into two groups according to the magnitude of the decrease in EHBF after tilting, with those showing a decrease of 10% of more assigned to group B, and those showing a decrease of less than 10% assigned to group A. It was found that ICG (R15) and BSP (R45) were significantly higher in group A. Meanwhile, among hepatic and systemic hemodynamics, wedged hepatic venous pressure, hepatic venous pressure gradient, free hepatic venous pressure, cardiac index, systolic blood pressure, systemic vascular resistance, and stroke volume were found to have changed significantly after tilting. These results suggest that posture change has no effect on EHBF in compensated cirrhotic patients.

Changes in portal pressure are regulated by changes in hepatic vascular resistance, which is normally under neurohumoral control, and portal tributary blood flow. Two theories on the pathophysiology of portal hypertension have been proposed: the 'backward flow' theory, in which portal hypertension is attributable to increased resistance to portal venous flow, and the 'forward flow' theory, in which increased splanchnic blood flow maintains portal hypertension despite extreme portal-systemic shunting. The sinusoidal abnormalities caused by an accumulation of collagen in the perisinusoidal space of Disse may induce increased resistance to blood flow in various pathological conditions of the liver. Non-cirrhotic portal hypertension results from not only relatively uncommon disorders prevalent mainly in Asia and tropical countries, but also from acute and chronic phases of relatively common liver diseases. Systemic hyperdynamic circulation, characterised by an increased cardiac output and a reduced peripheral vascular resistance, and splanchnic hyperaemia may develop as consequences of portal hypertension. Although the mechanisms of these changes are not clearly understood, portal-systemic shunting as well as some vasoactive substances, including prostaglandins, may be involved. The erosive and eruptive mechanisms are the two potential explanations for variceal bleeding. In the latter, pressure should not be viewed in isolation and other additive factors such as variceal size may be involved. Several new techniques of measuring variceal pressure and blood flow may improve understanding of the actual pathophysiology of variceal bleeding. Renal haemodynamic alterations secondary to the systemic circulatory changes produced by portal hypertension may occur. The geographical pattern of prevalence in disorders associated with portal hypertension is briefly described in this paper.

Ketoconazole is an imidazole derivative recently developed as an antifungal agent. There have been only a few established cases of hepatotoxicity in the literature. This report describes a case of presumed ketoconazole hepatotoxicity characterized by the development of severe hepatitis with marked centrilobular necrosis. The lack of hypersensitivity reactions in clinical findings and centrilobular location of necrosis suggested a host idiosyncrasy with metabolic abnormality as the effect of ketoconazole in the present case.

Portal hypertension is a rare complication in hepatic amyloidosis. We experienced a case of a 40-year-old man with primary amyloidosis and advanced esophageal varices. Angiographic procedures clearly demonstrated portal hypertension secondary to intrahepatic arterio-portal shunting. Hepatic arterial embolization brought about a disappearance of the A-P shunt and portal hypertension, though rebleeding occurred. To our knowledge, this is the first case report in which the pathogenesis of portal hypertension in hepatic amyloidosis was elucidated.

The effects of aging on the pigment metabolism in Rotor's syndrome were investigated in six cases examined at least twice at an average interval of 10.5 +/- 6.5 years and additional four cases examined only once. No significant increase was found in the total (TB) or direct (DB) bilirubin in serum. However, indirect bilirubin increased significantly from 1.21 +/- 0.72 mg/dl to 2.28 +/- 1.00 mg/dl (p less than 0.05) and DB/TB ratio (% Direct) decreased significantly from 77.3 +/- 6.6% to 64.4 +/- 8.7% (p less than 0.05). BSP retentions at 45 minutes increased significantly from 26.8 +/- 10.9% to 45.3 +/- 14.9% (p less than 0.05). A significant positive correlation between the values of BSP retained at 45 minutes and the age was also observed (p less than 0.01). These results suggest that the pigment metabolism in Rotor's syndrome deteriorates with the age.

A 65-year-old case diagnosed as primary biliary cirrhosis without definite signs of Sjögren's syndrome at age 62 developed interstitial lung disease, which was clinically, histologically, radiographically, and scintigraphically compatible with fibrosing alveolitis. Analysis of the cells in bronchoalveolar lavage fluid revealed, however, increased proportions of not only neutrophils but also lymphocytic cells, which were predominant. This case should focus attention on the association of primary biliary cirrhosis and fibrosing alveolitis.