ICG Clearance Research Articles

Glycerol metabolism in severe falciparum malaria

Gluconeogenesis and liver blood flow (LBF) in severe falciparum malaria were assessed from the clearance and metabolic response to intravenously administered glycerol (0.3 g/kg) and Indocyanine Green ([ICG] 0.4 mg/kg), respectively. Fasting baseline blood glycerol concentrations (mean ± SD) were significantly higher in acute malaria (133 ± 65 μmol/L, n = 14), than in convalescence (65 ± 31 μmol/L, n = 9, P = .01), but basal triacylglycerol concentrations were similar. Estimated glycerol turnover was also more than twice as high in acute malaria compared with convalescence (1.36 ± 0.87 v 0.54 ± 0.15 μmol · min −1 · kg −1, P = .015). The increment in plasma glucose (AUC 0–55 min) following glycerol infusion was greater during acute malaria compared with convalescence (median [range], +31.6 [−0.9 to + 107.6] v + 14.5 [−103 to +27.1] mmol · min · L −1, P < .05), but the insulin increments were similar ( P = .9), indicating reduced tissue insulin sensitivity. The increment in venous lactate (AUC 0–55 min) was higher in severely ill patients (17.2 [−7.8 to +53.4] mmol · min · L −1, n = 10) compared with patients with moderately severe malaria (−3.1 [−8.7 to 3.2] mmol · min · L −1, n = 4, P = .01). LBF estimated from ICG clearance was lower during acute illness than in convalescence (mean ± SD, 15.5 ± 2.3 v 18.6 ± 2.9 mL · min −1 · kg −1, P = .007) and correlated inversely with the basal venous lactate concentration ( r s = .53, P < .05). LBFs less than 15 mL · min −1 · kg −1 were associated with hyperlactatemia, and all four fatal cases had LBFs of less than 12 mL · min −1 · kg −1. Thus, despite the propensity to hypoglycemia in severe falciparum malaria, the clearance and metabolic responses to glycerol were relatively unaffected. These data also provide evidence of increased glycolysis and an association between reduced LBF and lactic acidosis in severe malaria.

フィンガーピース法で求めた血中ＩＣＧ消失曲線の波形が示す臨床的意義

フィンガーピース法で求めた血中ＩＣＧ消失曲線の波形が示す臨床的意義

Effects of vena caval banding in experimentally induced multiple portosystemic shunts in dogs

Summary Effects of vena caval banding on portal venous and vena caval hemodynamics were examined in 6 control dogs and in 10 dogs that had undergone attenuation (banding) of the abdominal part of the caudal vena cava and had dimethylnitrosamine-induced multiple portosystemic shunts (pss). Additionally, indocyanine green (icg) extraction and clearance after infusion to steady state were used to calculate hepatic plasma flow in these dogs. Sixteen dogs were randomly assigned to 2 groups: control (n = 6) or diseased(n= 10). Diseased dogs were administered dimethylnitrosamine (2 mg/kg, po, twice weekly) until multiple pss developed, as assessed by results of clinical laboratory tests, ultrasonography, and hepatic scintigraphy. Shunts were confirmed visually at celiotomy and by contrast portography. Venous pressures (caudal vena caval, portal, and hepatic) were recorded before and after vena caval banding for up to 7 days in dogs from both groups. Peritoneal cavity pressures were recorded in all dogs after closure of the body wall. To determine icg extraction and clearance, a bolus injection of icg (0.5 mg/kg, iv) was administered, followed by steady-state infusion of 0.097 mg/min. Extractions and clearances of icg were measured, and from these, hepatic plasma flow rates were determined immediately before and after banding and at 6 hours, 48 hours, and 7 days after banding. The gradient (caudal vena caval pressure within 1 to 2 mm of Hg of portal pressure) between caudal vena cava and portal venous pressures established at banding was maintained after the first hour in both groups. Caudal vena cava pressures established at banding were maintained throughout the study, with the exception of the first hour in diseased dogs. Extraction ratios were higher in control dogs at all times, except at 48 hours. Clearance was higher in control dogs at all times. Hepatic plasma flow did not differ between groups, except immediately after banding, when flow was greater in diseased dogs, and differences were not found over time in either group. This study indicated that vena caval banding in this model of experimentally induced multiple pss increases and maintains caudal vena cava pressure, relative to portal venous pressure (after the first hour) for 7 days, and that calculated hepatic plasma flow is not persistently improved by vena caval banding.

Present status of autoimmune hepatitis in Japan.

The clinical and biochemical features of patients with autoimmune hepatitis (AIH) in Japan during the 15-year period, 1975 to 1990, were evaluated by a nationwide survey using a questionnaire prepared by the Intractable Diseases Study Group organized by the Ministry of Health and Welfare. Data on a total of 866 cases with AIH were collected and analyzed, and of these, 632 cases underwent follow-up study. AIH was predominant in females, with a male:female ratio of approximately 2:19. Biochemical investigation on the occasion of the first examination showed abnormalities of liver function tests, including increased serum total bilirubin, transaminase activity and gamma-globulin levels. The main complications of autoimmune diseases were rheumatoid arthritis, Sjögren's syndrome and chronic thyroiditis. All patients with complications were female. Of 253 AIH patients, 50 were positive for anti-C100-3 antibody. ICG clearance and platelet count, which are stigmata of liver cirrhosis, were the main factors of prognostic importance in AIH. Therefore, early diagnosis prior to the development of liver cirrhosis is important to improve the prognosis of AIH.

ＩＣＧクリアランスメータ（ＲＫ‐１０００）を用いた手術室・ＩＣＵでのＩＣＧ薬物動態解析の有用性

ＩＣＧクリアランスメータ（ＲＫ‐１０００）を用いた手術室・ＩＣＵでのＩＣＧ薬物動態解析の有用性

｀９９ｍ´Ｔｃ‐Ｇａｌａｃｔｏｓｙｌ Ｈｕｍａｎ Ｓｅｒｕｍ Ａｌｂｕｍｉｎによる慢性肝疾患の肝機能評価

99mTc-Galactosyl human serum albumin (99mTc-GSA) is a new liver imaging radiopharmaceutical which specifically binds to the asialoglycoprotein-receptor on the liver cell membrane.We investigated the usefulness of99mTc-GSA for evaluation of the liver function in patients with chronic liver damage. We calculated LHL15 for the index of hepatic uptake and HH15 for the index of clearance. In patients with liver cirrhosis, LHL15 value was higher and HH15 value was lower than those of other groups. Both decrease in LHL15 value and increase in HH15 value were correlated with the severity of the liver damage. Significant correlation was also observed between the prolongation of ICG clearance and both decrease in LHL15 value and increase in HH15 value.In conclusion, these findings indicate that 99mTc-GSA can be a useful agent for evaluation of the liver function in patients with chronic liver damage.

Prognostic value of galactose elimination capacity, aminopyrine breath test, and ICG clearance in patients with cirrhosis

Seventy-eight patients with cirrhosis were prospectively followed for up to 20 months, on the average. At entry into the study, galactose elimination capacity, aminopyrine breath test, and ICG clearance were measured. At the end of the study, 27 patients had died. Univariate analysis using the Kaplan-Meier method showed that both quantitative liver function tests (galactose elimination capacity: P less than 0.025; aminopyrine breath test: P less than 0.001; ICG clearance: P less than 0.005) and common clinical and biochemical data (encephalopathy: P less than 0.001; ascites: P less than 0.001; serum bilirubin: P less than 0.005; serum albumin: P less than 0.001; prothrombin index: P less than 0.05) were significant predictors of survival. To investigate whether quantitative liver function tests could contribute to a better definition of the prognosis, once Pugh score had already been taken into account, a multiple regression analysis according to the Cox model was performed. Pugh score and galactose elimination capacity resulted in the only independent prognostic covariates. From them a prognostic index was calculated, and the model was validated in an additional sample of 70 patients investigated according to the same protocol. The contribution GEC gave to the assessment of overall prognosis over that obtained using the Pugh score was slight, as estimated by the statistical parameters of the Cox's model, but was significant as assessed by a ROC curve analysis (P = 0.05). These data show that all quantitative liver function tests were predictors of survival in cirrhosis, and that the galactose elimination capacity added some new prognostic information to those already available using the Child-Turcotte-Pugh classification.

Decreased proapolipoprotein A-I processing in liver disease: evidence for hepatic participation in proapolipoprotein A-I conversion

We evaluated the proapolipoprotein A-I (proapo A-I)-converting activity to clarify the pathogenesis of the high proapo A-I/apo A-I ratio in the high-density lipoprotein (HDL) from patients with acute hepatitis and liver cirrhosis. The serum proapo A-I-converting activities were measured using 3H-labeled proapo A-I. 3H-labeled proapo A-I was purified from the media of cultured Hep G2 cells by immunoaffinity chromatography. The serum proapo A-I-converting activities were found to be significantly reduced in the patient with liver cirrhosis (140 ± 53 dpm/ml per h) or acute hepatitis (140 ± 48 dpm/ml per h) compared to normal subjects (315 ± 32 dpm/ml per h). Serum proapo A-I-converting activity has a positive correlation with liver function tests such as serum albumin, choline esterase activity, ICG clearance and inverse correlation with proapo A-I/apo A-I ratio in HDL. These results suggest that the high proapo A-I/apo A-I ratio is due to the decreased proapo A-I-converting activity, and that the liver plays a significant role in the conversion of proapo A-I to apo A-I.

Effect of oral propranolol on circulating catecholamines in cirrhosis: relationship to severity of liver disease and splanchnic haemodynamics

Patients with cirrhosis, especially those with decompensated disease have enhanced sympathetic nervous activity. We have investigated the effect of a single oral dose of 80 mg propranolol on circulating catecholamines and related the effect to splanchnic and systemic haemodynamics in 22 patients with cirrhosis. Plasma noradrenaline (NA) was significantly above normal average (NA: 0.52 vs. 0.23 ng/ml, p < 0.01) and increased with the severity of the liver disease ( p < 0.01). NA was negatively correlated with liver function as estimated by ICG clearance ( r = −0.74, p < 0.01). Azygos blood flow was increased (0.75 l/min) and positively related to plasma NA ( r = 0.57, p = 0.05, n = 12). After propranolol intake, plasma NA increased from 0.52 to 0.59 ng/ml ( p < 0.01). This response was found in all Child-Turcotte classes (A: 0.37 to 0.43; B: 0.49 to 0.56; C: 0.78 to 0.88 ng/ml), and in patients with as well as without ascites. Plasma adrenaline increased in the same way ( p < 0.01). Hepatic blood flow (from 1.10 to 0.93 l/min, p < 0.01) and azygos blood flow (from 0.75 to 0.55 l/min, n = 9, p < 0.05) decreased significantly after oral propranolol. A borderline significant correlation was observed between the decrease in azygos blood flow and the increase in NA ( r = 0.64, p = 0.06). Our results suggest that besides a relationship to liver function and severity of disease, sympathetic nervous activity, as reflected by circulating NA, will further enhance during β-adrenergic blockade, probably by a compensatory mechanism. Catecholamines and their response to propranolol may have a substantial influence on splanchnic and collateral haemodynamics.

Haemodynamic and pharmacokinetic study of intravenous fenoldopam in patients with hepatic cirrhosis.

1. The effect of intravenous fenoldopam-an arterial vasodilator-was assessed in twelve patients with cirrhosis and portal hypertension. Six patients had compensated (Grade A or B Child-Pugh classification) and six decompensated (Grade C) liver disease. 2. A significant dose dependent reduction in systemic blood pressure with a concomitant fall in systemic vascular resistance and increase in cardiac index was observed. Estimated portal pressure (WHVP-FHVP) increased (15.4 +/- 3.2 to 19.3 +/- 3.7 mm Hg, P less than 0.05) due to a rise in wedged hepatic venous pressure (24.6 +/- 4.3 to 29.0 +/- 5.8 mm Hg, P less than 0.05). Hepatic blood flow did not change significantly. Similar haemodynamic effects were observed in both compensated and decompensated patients. 3. Fenoldopam plasma clearance and ICG clearance were found to decrease with increasing infusion concentration, indicating possible increase of the intrahepatic shunting. 4. With the observed rise in portal pressure there must be some concern with respect to the long-term use of this drug in patients with previous variceal bleeding.

Variability in the pharmacokinetics of nisoldipine as caused by differences in liver blood flow response.

We investigated whether the effect of nisoldipine on liver blood flow depends on its route of administration. Ten healthy subjects took nisoldipine I.V. (infusion) and orally (without and with sotalol pretreatment). Pharmacokinetics of nisoldipine was assessed and liver blood flow (ICG clearance) was measured before dosing and at the end of the infusion or during absorption. During I.V. infusion the ICG plasma clearance increased by only 14%, whereas the increase was 60% during absorption of nisoldipine. Nisoldipine increases liver blood flow considerably only during the absorption phase. A positive correlation was found between the increase in liver blood flow during absorption and the systemic availability of nisoldipine, suggesting that the differences in liver blood flow response to nisoldipine substantially contribute to the variability in pharmacokinetics of the drug.

Prognostic value of galactose elimination capacity, aminopyrine breath test, and ICG clearance in cirrhosis: Comparison with the push score

Prognostic value of galactose elimination capacity, aminopyrine breath test, and ICG clearance in cirrhosis: Comparison with the push score

Development and clinical application of ICG clearance meter

Development and clinical application of ICG clearance meter

Relationship between the diagnosis, preoperative evaluation, and prognosis after orthotopic liver transplantation.

The purpose of this study was to identify which of the biochemical, immunological, or functional parameters derived before surgery as part of a systemic evaluation were helpful in predicting the frequency of rejection episodes, the chance of survival, and the cause risk of death (should death occur) of patients after orthotopic liver transplantation (OLTx). Ninety-eight adult patients who had an extensive preoperative protocol evaluation were studied before OLTx. The biochemical parameters assessed were albumin, prothrombin time, bilirubin, and ICG clearance. The immunologic parameters assessed included total lymphocytes, T3 cells, T4 cells, T8 cells, and the T4/T8 ratio. The degree of histocompatibility antigen (HLA) matching between the donor and the recipient was also evaluated in 80 of the 98 patients studied. Most postoperative deaths occurred within 12 weeks of the procedure (24%; 24 of 98 patients); 13 patients (13%) died within the first 6 postoperative weeks, of either bacterial or fungal sepsis. An additional 14 patients (14%) died after the initial 6 postoperative weeks due, primarily of an acquired viral and/or protozoan infection (p less than 0.01). During the first 6 weeks, survival was better for patients with cholestatic liver disease (ChLD, 93%, n = 45) and miscellaneous liver diseases (MISC, 100%, n = 10) than it was for those with parenchymal liver diseases (PLD, 77%, n = 43). Although albumin, prothrombin time, T4/T8 ratios, and per cent T8 cells were statistically different in patients with PLD as compared with those with ChLD, these parameters, as well as the per cent T4 cells, serum bilirubin level, per cent retention of ICG at 15 minutes, and the plasma ICG disappearance rate were not found to be of substantial help in predicting patient survival or non-survival. Moreover, neither the degree of HLA matching nor the number of rejection episodes differed between surviving and nonsurviving patients. The results of this study suggest that patients with PLD are at increased risk of early postoperative death after OLTx because of bacterial and/or fungal sepsis, as compared with patients operated upon for ChLD. Better pre-, intra-, and postoperative predictors of risk of death and complications are needed to reduce the early mortality observed after orthotopic liver transplantation.

Long-term effect of nadolol on quantitative liver function tests in patients with cirrhosis.

Nadolol, a non-cardioselective beta adrenoreceptor blocking agent, has been reported to decrease portal pressure without affecting liver function in cirrhotic patients treated for 1 month. There were no data about the long-term effects of nadolol on liver function. In 11 patients with cirrhosis and portal hypertension galactose eliminating capacity, aminopyrine metabolic capacity, ICG clearance and IGC intrinsic hepatic clearance according to the "parallel tube" model were measured before and after 6 months of treatment with nadolol at a dose reducing resting heart rate by approximately 25%. No significant variation in any of these parameters was found. Thus 6 months of continuous oral administration of nadolol did not further impair liver function in cirrhotics.

残存予定肝領域の肝静脈血流量およびＩＣＧ除去量測定による肝予備能に関する研究

肝切除後の肝不全防止のためには術前に残存肝の予備能を測定して肝切除不適合を除外する必要がある. そこで肝切除例30例を対象として術前に持続的局所熱希釈法を用い残存予定肝領域の肝静脈血流量とICG除去量を測定し, 両測定値と術後肝不全との相関について検討した. 肝硬変非併存例では残存予定肝領域の肝静脈血流量が300ml/minでも術後経過良好であったが, 肝硬変併存例では600ml/min未満で肝不全に陥る傾向が大であり, 同領域のICG除去量が0.1mg/min未満の症例は全例肝不全で死亡した. したがって肝硬変併存例では残存予定肝領域の肝静脈血流量が600ml/min未満, ICG除去量が0.1mg/min末満の症例は肝切除の適応から除外すべきである.

Effects of ranitidine on plasma clearance of indocyanine green in patients with liver cirrhosis.

The effects of ranitidine on plasma clearance of ICG were investigated in 68 cirrhotic patients (9 were positive for HBsAg, 33 were alcoholics and 26 had cryptogenic cirrhosis). The ICG clearance test was performed before and after ranitidine administration. In 31 patients treated with ranitidine (150 mg perorally), the plasma ICG clearance were 233.6 +/- 20.4 ml/min (mean +/- S.E.) and 239.2 +/- 20.5 ml/min before and after ranitidine, respectively. In the 37 treated with intravenous ranitidine 50 mg, the corresponding values were 205.4 +/- 17.7 ml/min and 206.4 +/- 17.9 ml/min. There was no significant change in the plasma clearance of ICG or the elimination rate constant after ranitidine administration. Even in patients with decompensated liver cirrhosis, no significant change was demonstrated in the plasma ICG clearance after ranitidine. These results led to the conclusions that ranitidine does not reduce the hepatic blood flow and that it is a safe and useful drug for the treatment of gastrointestinal tract bleeding in patients with liver cirrhosis.

Methodological problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearance in man.

Liver blood flow (Q) is often measured by constant infusion of ICG (i), concentration measurements in an artery (A) and a hepatic vein (V): Q = (A-V)/A. Some authors use ICG clearance, Cl = i/A, as a measure of Q assuming complete hepatic extraction. During the infusion, the ICG concentration often increases. The importance of this for calculated values of Q and Cl was examined, and the use of Cl as a measure of Q was reevaluated. ICG was given as 0.06-0.20 mumol/min to 52 subjects with liver disease, and about 0.20 mumol/min to 86 subjects with no liver disease. ICG concentration increased steeply during the first 90 min after start of the infusion; thereafter the increment was constant as evaluated in successive 40-min periods in eleven 320-min studies (analysis of variance P greater than 0.5); on average, 6 +/- 1% per hour (+/- SD). Q was not time-dependent (P greater than 0.5). ICG clearance decreased significantly, on average 5 +/- 2% per hour (+/- SD). Hepatic extraction fraction, (A-V)/A, (measurement period 90-130 min) was 0.34 +/- 0.21 in liver patients (+/- SD) and 0.61 +/- 0.80 in controls. Cl and Q were positively correlated in both groups but with substantial scatter. Thus, not only is the calculated ICG clearance time-dependent but the extraction fraction is further so low and variable, that any use of ICG clearance as a measure of liver flow is not justified.

Effect of nadolol on liver haemodynamics and function in patients with cirrhosis.

Beta-adrenoceptor blockers used in the medical management of portal hypertension decrease liver blood flow. The sporadic onset of hepatic encephalopathy during propranolol treatment was ascribed to this decrease. The aim of the present study was to evaluate the effect of chronic treatment with nadolol on liver blood flow and liver function. Nadolol, a non-cardioselective beta-adrenoceptor blocker, has been reported to be as powerful as propranolol in decreasing portal pressure. Before and after 1 month of treatment with nadolol at a dose reducing heart rate by 25%, in 15 cirrhotic patients with portal hypertension, the following parameters were determined: hepatic venous pressure gradient, hepatic blood flow, galactose eliminating capacity, aminopyrine metabolic activity, ICG clearance and intrinsic hepatic clearance. Hepatic venous pressure gradient and hepatic blood flow were decreased by nadolol. However liver function was not affected by the drug. We conclude that, despite a lowered hepatic blood flow, liver function is not affected by 1 month of nadolol treatment.

Flow- and pressure-adapted portal arterialization in dogs.

The effects of portal arterialization after portacaval shunt were studied in dogs. Flow- and pressure-adapted portal arterialization was performed by mounting a Teflon cuff on an autogenous vein bypass graft between the hepatic stump of the portal vein and the right renal artery. Immediately following operation, the total hepatic blood flow and intrahepatic portal venous pressure were within normal range. Eight weeks after operation, the intrahepatic portal venous pressure remained within the preoperative range, while total hepatic blood flow had increased double or triple. However, structural change due to increased flow was absent in the liver, even sixteen months after operation. Body weight, liver enzyme chemistry, ICG clearance rate, and amino acid metabolism were well maintained for the entire period of investigation. These findings suggest that sequelae such as hepatic encephalopathy and impaired hepatic metabolism after portacaval shunt can be avoided by portal arterialization, in the presence of an appropriate flow and pressure.