The influence of vasoactive agents on metabolic activity of the liver in cirrhosis: a study of the effects of posterior pituitary extract, vasopressin, and somatostatin

We studied the influence of posterior pituitary extract, vasopressin, and somatostatin on hepatic elimination function. Hepatic clearance and its two biological determinants, hepatic blood flow and metabolic activity (clearance Vmax/Km), were determined from hepatic indocyanine green elimination at steady-state in cirrhotic patients. Intravenous infusion of posterior pituitary extract (oxytocin, 59%; vasopressin, 41%) at the constant rate of 0.3 unit per kg per hr decreased hepatic clearance (p less than 0.05) and Vmax/Km (p less than 0.05) but did not change hepatic blood flow. Intravenous infusion of vasopressin (0.3 unit per kg per hr) decreased hepatic clearance (p less than 0.05), Vmax/Km (p less than 0.05) and hepatic blood flow (p less than 0.05). Intravenous infusion of somatostatin (250 micrograms per hr following a bolus i.v. injection of 250 micrograms) decreased hepatic clearance (p less than 0.05), Vmax/Km (p less than 0.05), and hepatic blood flow (p less than 0.05). This study shows that the vasoactive agents used in the management of upper digestive bleeding in cirrhotic patients may have deleterious effects on the metabolic activity of the liver in addition to their effects on hemodynamics. The results suggest that the vasoactive substances either increased the fraction of total hepatic blood which bypassed intact hepatocytes or directly impaired metabolic activity of hepatocytes. Reduction in the metabolic activity of the liver produced by vasoactive agents may have important implications in therapy of portal hypertension.     

Effect of portacaval shunt on drug disposition in patients with cirrhosis

To examine the consequences of liver blood flow variations on drug disposition in cirrhosis, we studied the effects of portacaval shunt on drug clearance in 35 cirrhotic patients. Lidocaine clearance and bioavailability, indocyanine green (ICG) clearance, aminopyrine breath test, and hepatic blood flow were measured before and 18 months after surgery. The patients were divided into two groups according to severity of disease: 14 patients (group 1) had slight liver dysfunction (ICG extraction ratio greater than 0.25) and 21 patients (group 2) had severe liver disease (ICG extraction ratio less than 0.25). After portacaval shunt the decrease in hepatic blood flow was similar for both groups (-65%). In group 1, ICG systemic clearance decreased from 9.10 +/- 0.68 to 4.40 +/- 0.34 ml/min . kg (p less than 0.05), whereas ICG intrinsic clearance remained unchanged; lidocaine systemic clearance decreased from 7.93 +/- 0.93 to 5.09 +/- 0.33 ml/min . kg (p less than 0.05), whereas lidocaine intrinsic clearance remained unchanged; bioavailability increased from 0.601 +/- 0.076 to 1, resulting in an abrupt reduction of oral clearance from 18.01 +/- 4.90 to 5.09 +/- 0.33 ml/min . kg (p less than 0.05). In group 2, ICG systemic clearance decreased slightly from 3.90 +/- 0.39 to 2.28 +/- 0.16 ml/min . kg (p less than 0.01) and ICG intrinsic clearance was not modified; lidocaine systemic and intrinsic clearance remained unchanged; and bioavailability increased from 0.779 +/- 0.229 to 1, resulting in a decrease of oral clearance from 7.68 +/- 1.65 to 4.23 +/- 0.37 ml/min X kg (p less than 0.05). The aminopyrine breath test was not affected by surgery in either group. We conclude that reduction of hepatic blood flow after portacaval shunt has only minimal effects on drug disposition in patients with severe liver disease, but results in a notable reduction in the clearance of high-extraction drugs in cirrhotics with mild liver disease.     

Simultaneous measurement of effective hepatic blood flow and systemic circulation

BACKGROUND/AIMS: Because the disappearance rate of indocyanine green depends not only on hepatocyte function but also hepatic blood flow, the disappearance rate of indocyanine green is considered to be affected by the systemic circulation. Although the disappearance rate of indocyanine green is slower in cirrhotic patients, a hyperdynamic state is reported to be present. Purpose of this study was to evaluate hepatic function and systemic circulation simultaneously with reference to the hyperdynamic state of cirrhotic liver. METHODOLOGY: Forty-six patients were selected randomly for this study. Simultaneous measurement of effective hepatic blood flow and systemic circulation using an indocyanine green clearance meter was performed. We calculated the effective hepatic blood flow using the early disappearance rate of indocyanine green movement, cardiac output, and circulating time simultaneously with indocyanine green clearance meter. RESULTS: Hepatic function and hyperdynamic circulation could be evaluated quantitatively. The indocyanine green disappearance rate was dependent on cardiac index in normal subjects, whereas the indocyanine green disappearance rate was lower in cirrhotic patients, although the cardiac index was relatively high. CONCLUSIONS: Hepatic function and systemic circulation could be evaluated simultaneously with this indocyanine green clearance meter. Hyperdynamic circulation was suggested to compensate the impaired hepatic function of cirrhotic liver. Simultaneous measurement of hepatic function and systemic circulation may be essential to studying liver function.     

Hepatic metabolic function in patients receiving long-term methotrexate therapy: comparison with topically treated psoriatics, patient controls and cirrhotics

Standard biochemical liver function tests and the clearances of antipyrine and indocyanine green have been compared in psoriatic patients taking methotrexate, psoriatic patients on topical treatment, patient controls and patients with hepatic cirrhosis. The methotrexate-treated patients showed significant elevations in alkaline phosphatase (p less than 0.025) and gamma glutamyl transpeptidase activities (p less than 0.05) compared to topically treated psoriatics and patient controls. The clearance of antipyrine was reduced in the methotrexate treated group but not significantly (p less than 0.1 greater than 0.05). In contradistinction, the weight-adjusted clearance of indocyanine green was significantly impaired in the methotrexate group in comparison with the topically treated psoriatics (p less than 0.01). The clearance of both antipyrine and indocyanine green were markedly lowered in the cirrhotics (p less than 0.001 against all other groups). These data suggest that the serial measurement of alkaline phosphatase and indocyanine green clearance may provide a non-invasive indicator of the development and progression of methotrexate-related liver injury.     

The effect of age upon liver volume and apparent liver blood flow in healthy man

The aim of this study was to determine the effect of aging upon liver volume and apparent liver blood flow in healthy man. Sixty-five subjects between 24 and 91 years of age were recruited. Liver volume was quantitated by a gray scale B ultrasound scan method. Apparent liver blood flow was determined from the plasma clearance of indocyanine green, based on an assumption of no change in hepatic extraction of the dye with age. A significant negative correlation was observed between age and both liver volume and apparent liver blood flow (p less than 0.001), whether expressed in absolute terms or per unit body weight. Similarly, a significant negative correlation was observed between apparent liver blood flow per unit volume of liver (liver perfusion) and age (p less than 0.005). The reduction in liver volume, apparent liver blood flow and perfusion may at least partly account for the decline in the clearance of many drugs undergoing liver metabolism which has been noted to occur with aging in man.     

Renal sodium retention in cirrhosis: tubular site and relation to hepatic dysfunction

Renal sodium handling, assessed by the response to acute saline loading, was investigated in 14 well-compensated, nonascitic alcoholic cirrhotics and six normal controls. Urinary sodium excretion in cirrhotic patients (199 +/- 141 mumoles per min) was significantly lower than in controls (387 +/- 104 mumoles per min; p less than 0.01) at 3 hr postinfusion. In contrast to controls, renal plasma flow and glomerular filtration rate did not increase in the cirrhotics in response to acute saline loading. Proximal fractional reabsorption of sodium was estimated by clearance techniques in the presence of a hypotonic diuresis. Cirrhotic subjects with impaired functional liver cell mass as assessed by antipyrine clearance were unable to decrease proximal fractional reabsorption of sodium significantly in response to saline loading. Assessment in the cirrhotics included measurement of hepatic vein pressure gradient, indocyanine green extraction ratio, indocyanine green clearance, and antipyrine clearance as indices of portal pressure, intrahepatic shunting, hepatic blood flow and functional hepatocellular mass, respectively. Urinary sodium excretion in the cirrhotics correlated strongly with antipyrine clearance (r = 0.839, p less than 0.0001) and weakly with portal pressure (r = 0.562, p = 0.037). No correlation was seen with the other indices of hepatic blood flow and shunting. The findings of this study suggest that alcoholic cirrhosis is associated with a decline in hepatocellular function which results in either a decreased clearance of a salt-retaining hormone or decreased synthesis of a natriuretic hormone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic evaluation of molsidomine: a vasodilator with antianginal properties in patients with alcoholic cirrhosis

Organic nitrates were reported to reduce portohepatic venous pressure gradient in patients with cirrhosis. However, these drugs lower arterial pressure and are well known to induce tolerance. The aim of the present study was to assess the hemodynamic effects of molsidomine, an antianginal agent, which does not induce tolerance and has little effect on arterial pressure in patients with normal liver, in 13 patients with alcoholic cirrhosis. Wedged hepatic vein pressure (-11%, p less than 0.01), portohepatic venous pressure gradient (-15%, p less than 0.005), hepatic blood flow (-17.4%, p less than 0.005), mean arterial pressure (-13.5%, p less than 0.01) and cardiac output (-17%, p less than 0.001) were significantly reduced by molsidomine. Free hepatic vein pressure, intrinsic hepatic clearance indocyanine green, heart rate and systemic vascular resistances were not significantly modified. There was no correlation between the decrease in portohepatic venous pressure gradient and the reduction in mean arterial pressure on one hand and the decrease in cardiac output on the other hand. We therefore conclude that in patients with cirrhosis, molsidomine has effects similar to nitrates on systemic and splanchnic hemodynamics.     

Galactose clearance measurements and liver blood flow

Galactose clearance, measured during low galactose infusion and calculated as infusion rate divided by peripheral galactose concentration (systemic clearance), has been proposed as a measure of liver blood flow. This requires nearly complete hepatic extraction as well as negligible extrahepatic elimination. The purpose of the study was to examine if these assumptions are fulfilled in subjects with no liver disease, and to compare the galactose clearance measurement with an independent measurement of liver blood flow. Liver blood flow was measured in 6 subjects by means of a constant indocyanine green infusion, indocyanine green concentration measurements in a peripheral artery and a hepatic vein, and calculation according to Fick's principle. The mean (+/- SEM) blood flow rate was 1.2 +/- 0.1 L/min. Galactose was given at a constant infusion rate of 142 +/- 10 mumol/min, and steady-state concentrations were measured in the peripheral artery (A) and the hepatic vein (V). The hepatic extraction fraction [(A - V)/A] was 0.91 +/- 0.03. The hepatic galactose elimination rate [(A - V) X flow] was 101 +/- 12 mumol/min; this is about two-thirds of the total elimination rate (viz., infusion rate). Urinary excretion was negligible. This indicates an extrahepatic galactose elimination of approximately 41 mumol/min. Systemic galactose clearance, calculated as mentioned above, was 1.5 +/- 0.1 L blood/min. It was significantly higher than the liver blood flow in each subject (paired t-test, each p less than 0.02), on average 133% of the flow. Thus the systemic galactose clearance value overestimates liver blood flow, probably due to a small, but in this context quantitatively important, extrahepatic galactose elimination.     

Comparison of bolus and infusion methods for estimating hepatic blood flow in patients with liver disease using indocyanine green

A non-invasive method of estimating liver blood flow by a two-compartment pharmacokinetic model of the plasma clearance of indocyanine green has been previously described in normal animals and patients without liver disease. This non-invasive technique has been compared with the conventional method of measuring liver blood flow by hepatic vein catheterisation in 25 patients with liver disease. There was good correlation between the values for indocyanine green clearance, with the infusion method tending to produce slightly higher results. However, there was poor agreement in the measurement of liver blood flow, as the non-invasive technique over-estimated the hepatic extraction ratio and thus underestimated liver blood flow. Therefore, in patients with liver disease the non-invasive method cannot be relied upon or replace hepatic vein catheterisation for the measurement of liver blood flow.     

Effect of propranolol on metabolic activity of the liver in patients with alcoholic cirrhosis

Many studies have been performed to investigate the haemodynamic effects of propranolol. However, little is known of its actions on the metabolic activity of the liver. This study aimed to investigate the influence of propranolol on hepatic function as assessed by the galactose elimination capacity (GEC) and the intrinsic clearance of indocyanine green (ICG). 15 patients with biopsy-proven alcoholic cirrhosis and portal hypertension were studied. 10 had GEC and ICG clearance measured before and after the i.v. injection of 15 mg of propranolol (group P) and 5 had ICG clearance measurement before and after normal saline injection (group C). Propranolol significantly reduced heart rate (P less than 0.005) and the porto-hepatic pressure gradient (P less than 0.01). Hepatic blood flow was not changed. GEC was not altered by propranolol. Propranolol decreased the intrinsic hepatic clearance of ICG as determined by the 'sinusoidal' model by 12% (P less than 0.01). This suggests that propranolol may have an inhibitory action on the hepatic elimination of ICG that is independent of any effect on total liver blood flow or drug metabolism, since intrinsic clearance is not influenced by changes in blood flow and ICG is thought not to be metabolized.     

Effects of verapamil on estimated hepatic blood flow in patients with HBsAg-positive cirrhosis

Acute and chronic effect of verapamil on estimated hepatic blood flow were investigated in 12 patients with HBsAg-positive cirrhosis and portal hypertension. Acute administration of verapamil results in a significant increase (8%) in estimated hepatic blood flow (p less than 0.05). However, after chronic continued administration of verapamil, the mean value of estimated hepatic blood flow remains unchanged vis-a-vis basal values. Acute and chronic use of verapamil significantly reduced the hepatic venous pressure gradient for about an average of 20% at 1 hr after drug administration (p less than 0.05) and 18% 2 weeks later (p less than 0.05). This drop was associated with a significant reduction in hepatic vascular resistance by 39% at 1 hr later and by 37% 2 weeks later. Furthermore, the drop in hepatic vascular resistance was independent of any verapamil-induced changes in systemic hemodynamics. Verapamil significantly increased the indocyanine green plasma clearance and extraction ratio after acute or chronic use of the drug. We conclude that in patients with HBsAg-positive cirrhosis, the mechanism of verapamil in reducing the hepatic venous pressure gradient is predominantly by inducing a drop in hepatic portal vascular resistance.     

Effect of Triglycyl-Lysin-Vasopressin on Quantitative Liver Function Tests in Patients with Cirrhosis

The effects of vasopressin and of its analogues on liver function, and their possible mechanisms of action, are poorly understood. This study was designed to assess the effect of triglycyl-lysin-vasopressin on liver function, evaluated by two quantitative tests independent of liver blood flow, i.e., indocyanine green intrinsic hepatic clearance and galactose elimination capacity. Indocyanine green intrinsic hepatic clearance and galactose elimination capacity were determined before and after administration of 2 mg triglycyl-lysin-vasopressin to (respectively) 10 and 12 patients with cirrhosis. Eighteen additional patients with cirrhosis were studied before and after infusion of placebo. No significant variation in either test was observed in placebo-treated patients. A significant decrease in indocyanine green intrinsic hepatic clearance, averaging 22%, was observed in patients receiving the drug (p = 0.04). Conversely, galactose elimination capacity remained unchanged after the drug. These results are compatible with the hypothesis that the drug produced a preferential decrease in perfusion in functioning areas of the liver, with relative maintenance of blood flow in non-functioning areas.     

Hemodynamic and liver function predictors of serum hyaluronan in alcoholic liver disease.

To define hepatic predictors of serum hyaluronan in patients with chronic liver disease, 62 patients with alcoholic liver disease were evaluated. In group 1, 30 patients had concurrent assessment of serum hyaluronan, liver function tests, Pugh grade and hemodynamic indices. A second, overlapping group of 42 patients (group 2) also had antipyrine clearance measured but without hemodynamic assessment. All but six patients had elevated serum hyaluronan levels. In both groups, serum hyaluronan levels differed between Pugh grades and, in each group, was significantly greater in Pugh grade C compared with those in Pugh grade A (p less than 0.05, Kruskal-Wallis test). When analyzed by correlation, serum hyaluronan was significantly associated with several indices in group 1, but on multivariate linear regression only three statistically independent predictors of serum hyaluronan were identified: serum albumin (p = 0.008), indocyanine green clearance (p = 0.024) and indocyanine green extraction (p = 0.036). The overall R2 for these correlates was 65%. In the second group, antipyrine clearance was not significantly associated with serum hyaluronan (r = 0.29, p = 0.06), but other associations were similar to the first group. On multivariate analysis, only serum albumin predicted serum hyaluronan (p less than 0.001; R2 = 43%). In conclusion, indices of hepatocyte synthetic function, sinusoidal blood flow and degree of intrahepatic shunting are independent predictors of serum hyaluronan in alcoholic liver disease. These data show the unique nature of serum hyaluronan and suggest its potential application to the assessment of acute hemodynamic changes in patients with liver disease.     

Effects of chronic oral cimetidine on apparent liver blood flow and hepatic microsomal enzyme activity in man

Cimetidine 200 mg three times daily and 400 mg at night was given to 10 subjects for four weeks. Apparent liver blood flow was measured by indocyanine green clearance and microsomal enzyme activity by antipyrine clearance, before and after cimetidine. There was no reduction in indocyanine green clearance but antipyrine clearance, as expected, was significantly reduced by 15% at four weeks. Chronic cimetidine treatment does not reduce apparent liver blood flow and is therefore unlikely to be of use in the treatment of portal hypertension. The cimetidine associated hepatic enzyme inhibition appears to persist with prolonged treatment. Therefore patients on chronic cimetidine remain vulnerable to certain drug interactions.     

Effect of somatostatin on splanchnic hemodynamics in patients with cirrhosis of the liver and in normal subjects

The effect of somatostatin on splanchnic hemodynamics was determined in 8 patients with cirrhosis of the liver and in 18 normal subjects using arterial-hepatic-venous catheterization. Estimated hepatic blood flow determined by indocyanine green infusion was 1.36 +/- 0.23 L/min (+/- SEM) in patients with cirrhosis and remained unaffected during 30 min of somatostatin (250 microgram/h) administration. Wedged hepatic venous pressure which was elevated to 23 +/- 1.8 mmHg was also uninfluenced. In contrast to somatostatin, an infusion of vasopressin (12 U/h for 30 min) given to the same patients, lowered estimated blood flow by 28% (p < 0.05) and wedged hepatic venous pressure by 18% (p < 0.02). Arterial gastrin and insulin levels were lowered during somatostatin infusion by 33% (p < 0.02) and by 75% (p < 0.005), respectively. In contrast to the cirrhosis, infusion of 250 microgram/h somatostatin into normal subjects was associated with a decrease of estimated hepatic blood flow from 1.20 +/- 0.16 to 0.88 +/- 0.12 L/min (p < 0.01) representing a 27% decline. Arterial gastrin and insulin concentrations were lower (p < 0.01) than in cirrhosis, but the basal levels were lowered by somatostatin to a similar degree in both groups of patients. A higher dose of somatostatin (500 microgram/h) administered to normal subjects resulted in a similar decrease of gastrin and of estimated hepatic blood flow as that seen with 250 microgram/h, whereas a lower dose (125 microgram/h) decreased gastrin but failed to influence estimated hepatic blood flow. Thus, somatostatin at a dose which has been used in the treatment of acute peptic ulcer hemorrhage (250 microgram/h) failed to influence estimated hepatic blood flow and wegded hepatic venous pressure in patients with cirrhosis but lowered splanchnic blood flow in normal subjects. Assuming that this effect contributes to somatostatin's therapeutic efficacy, these results cast doubt on its potential value in the treatment of upper gastrointestinal bleeding of cirrhotics with portal hypertension.     

Long-term effects of distal splenorenal shunt on hepatic hemodynamics and liver function in patients with cirrhosis: importance of reversal of portal blood flow.

We studied 23 patients with cirrhosis who had undergone retroperitoneal distal splenorenal shunt without portal-azygos disconnection more than 2 yr earlier. We investigated the suitability of the Doppler technique (ultrasound + Doppler) to assess the patency and blood flow direction through the portal vein and the distal splenorenal shunt and its correlation with the continuous thermal dilution technique. The study also assessed the influence of the distal splenorenal shunt and time after surgery on portal perfusion and liver function. Ultrasound + Doppler distal splenorenal shunt thrombosis in two patients; however, none was confirmed by continuous thermal dilution. Ultrasound + Doppler flowmetry was possible in 19 patients (83%) (mean, 1.58 +/- 0.53 L/min). Distal splenorenal shunt continuous thermal dilution measurements were performed in all patients (100%), (mean, 1.65 +/- 0.5 L/min). Good correlation was seen between them (r = 0.66). Ultrasound + Doppler of the portal vein showed a hepatopetal flow in 16 patients (69.9%). Hepatic blood flow was significantly higher in patients with hepatopetal flow (p = 0.003). Hepatic clearance and intrinsic hepatic clearance of indocyanine green were significantly lower in patients with hepatofugal flow. Patients with hepatofugal flow had a higher incidence of chronic encephalopathy. None of the patients with a follow-up of less than 4 yr exhibited hepatofugal flow, whereas 7 of the 16 patients with a longer follow-up had hepatofugal flow (43.7%). The difference was statistically significant (p = 0.04). This study suggests that ultrasound + Doppler sonography may provide useful data in the evaluation of the patency and blood flow direction through the portal vein and the distal splenorenal shunt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence of the intact hepatocyte theory in alcoholic cirrhosis

To improve our understanding of the predominant operational model involved in the decreased clearance in cirrhosis, hepatic clearance, the extraction ratio of indocyanine green, and liver plasma flow were estimated in cirrhosis, either with a method based on the Fick principle or with a pharmacokinetic method assuming a bicompartmental plasma elimination of the dye. The two methods gave similar values for clearance. In contrast, the pharmacokinetic analysis gave significantly (p less than 0.01) lower hepatic plasma flow values and significantly (p less than 0.01) higher extraction values than those obtained with the reference (Fick principle) method. The main finding of this work is that in these cirrhotic patients, as in normal subjects, 'cellular' extraction estimated by the pharmacokinetic method is in the range of 0.60-0.80, whereas the extraction by the entire liver, assessed by the reference method, is low. In chronic liver diseases such as cirrhosis these data support the predominance of the intact hepatocyte theory, which assumes the existence of intrahepatic shunts associated with normally perfused and normally extracting hepatocytes. In acute liver disease, a cellular damage could be superadded.     

Liver haemodynamics and function in alcoholic cirrhosis. Relation to testosterone treatment and ethanol consumption

Liver haemodynamics and liver function were measured in 34 alcoholic cirrhotic men before entry and after 12 months (median) in a double-blind, placebo-controlled study on the effect of oral testosterone treatment (200 mg t.i.d.). Comparing data at entry with those at follow-up in the total patient group, a significant change in median values of portal pressure (-23%, n = 34, P less than 0.005), hepatic blood flow (-22%, n = 28, P less than 0.001), indocyanine green clearance (+16%, n = 29, P less than 0.01), and galactose elimination capacity (+8%, n = 31, P less than 0.05) was observed. However, testosterone-treated patients did not differ significantly from placebo-treated patients regarding any of the measured variables. No significant relationships could be demonstrated between ethanol consumption and liver haemodynamics and liver function, but the number of patients consuming more than 100 g ethanol per day decreased significantly (P less than 0.001) from 22 (65%) before entry to one (3%) during follow-up. In conclusion, oral testosterone treatment of men with alcoholic cirrhosis does not explain the significant improvement of liver haemodynamics and function observed in this study. However, the improvement may be due to reduced ethanol consumption.     

Pharmacokinetic Study on the Hepatic Uptake of Indocyanine Green in Cirrhotic Patients

The mechanism by which the mean blood clearance (CLtot,B) of indocyanine green (ICG) was reduced in cirrhotic patients was examined pharmacokinetically. It was demonstrated that the reduction in the CLtot,B of ICG in cirrhosis would be mainly due to the decrease in the hepatic uptake clearance and partly due to the increase in the efflux clearance from the liver to plasma. It is suggested that the decrease in the hepatic uptake clearance in cirrhosis mainly reflects the decrease in the intrinsic clearance of hepatic uptake rather than the decrease in hepatic blood flow.     

Hepatic hemodynamics in patients with chronic hepatitis or cirrhosis as assessed by organ-reflectance spectrophotometry

Hepatic hemodynamics in patients with chronic liver disease has been studied by reflectance spectrophotometry of the liver in situ during peritoneoscopy. An organ-reflectance spectrophotometer used in this study was equipped with a branched optic fiber bundle, which coupled the liver surface with the spectrophotometer. The spectrophotometry could measure qualitatively and quantitatively the absorption of hemoglobin in the liver in situ, thus estimating the regional hepatic tissue blood hemoglobin concentration and the saturation level of hemoglobin in the regional tissue blood. The analysis of 42 cases has shown that the estimated regional hepatic tissue blood hemoglobin concentration and saturation level of hemoglobin decreased in most cirrhotic livers, suggesting that even in cirrhotic livers the hepatic oxygen extraction increased, concomitant with a decrease in the regional hepatic tissue blood hemoglobin concentration. The hepatic blood hemoglobin concentration estimated on the surface layer of the liver was positively correlated with the regional hepatic blood flow measured by radioisotope clearance technique. The estimated hepatic blood hemoglobin concentration was also correlated positively with serum albumin level and prothrombin time, and negatively correlated with plasma retention of indocyanine green at 15 min. It is concluded that the hepatic tissue blood hemoglobin concentration decreases significantly with progress of chronic hepatitis to cirrhosis. This decrease in hepatic blood hemoglobin concentration and flow is concomitant with a decrease in metabolic functions, which is not compensated by an increased hepatic oxygen extraction.