Identifying a long standing error in single-bolus determination of the hepatic extraction ratio for indocyanine green

For approximately 50 years, hepatic clearance of indocyanine green (ICG) has been used to assess liver function. Steady-state infusion of ICG with simultaneous measurement of arterial and hepatic venous ICG concentrations provides unambiguous measures of the extraction ratio for ICG and the hepatic blood flow rate, but also requires cannulation of a hepatic vein. Transient clearance following injection of a single bolus of ICG, which typically involves only measurement of arterial ICG concentration, is a more commonly used procedure. Since drawing blood from a hepatic vein is often impossible, and, in any event can be difficult, there has been considerable interest in the claim by Grainger et al. (Clin Sci 64:207–212, 1983) that a single-bolus, two-compartment model “enabled the hepatic extraction ratio (ER_ss) of dye to be determined solely from the plasma disappearance curve”. The principal purpose of this paper is to show that the claim by Grainger et al. is not valid because it ignores the fact that a finite fraction of ICG entering the liver passes directly into hepatic veins without being sequestered in the liver. A valid relationship between ER_ss and parameters determined from single-bolus clearance data is derived in this paper. For individuals with normally functioning livers, the single-bolus method of Grainger et al. yields an extraction ratio approximately 20% too large, but in cirrhotic patients with extensive intrahepatic shunting, the extraction ratio evaluated using the single-bolus method of Grainger et al. may be too large by a factor of two.     

Influence of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis

The influence of intravenous somatostatin infusion (7.6 micrograms/min) on systemic and splanchnic haemodynamics was examined in 10 patients with liver cirrhosis and portal hypertension. The hepatic vein catheter technique was employed and indocyanine green dye was injected to evaluate hepatic blood flow. Mean wedged hepatic venous pressure fell from 24.9 +/- 2.8 in the basal state to 21.4 +/- 3.2 mmHg (P less than 0.2) at 60 min of infusion and the mean arterial pressure decreased from 87 +/- 5 to 80 +/- 6 mmHg (P less than 0.05). The rate of indocyanine green dye disappearance decreased from 8.7 +/- 1.9 to 6.6 +/- 1.7%/min (P less than 0.001) during the infusion, indicating decreased hepatic blood flow. Arterial-hepatic venous oxygen differences rose from 69 +/- 11 to 78 +/- 11 ml/l. Blood glucose levels fell from 4.84 +/- 0.31 to 3.79 +/- 0.33 mmol/l at 60 min of infusion (P less than 0.005). It is concluded that a continuous infusion of somatostatin in patients with liver cirrhosis and portal hypertension causes a decreased hepatic blood flow with augmented hepatic oxygen extraction and a modest reduction in mean wedged hepatic venous pressure. In view of the magnitude of the observed haemodynamic changes the findings do not suggest an important role for somatostatin in the treatment of patients with bleeding oesophageal varices.     

Effect of cimetidine on the hepatic extraction of indocyanine green,the portal pressure and the systemic circulation in patients with cirrhosis of the liver

Summary The effect-of cimetidine on hepatic and systemic haemodynamic parameters was studied in seven patients with portal hypertension due to alcohol-induced cirrhosis of the liver and in one patient with peliosis hepatis following oral contraceptive steroids. The intravenous administration of cimetidine (350 mg as bolus, followed by 2 mg/min over 60 min) reduced the hepatic extraction of continuously infused indocyanine green (ICG) by 27%; this was statistically significant (P<0.01). Since the ICG clearance, calculated independently of hepatic perfusion, was lowered by 19%, this effect seems to be mainly due to a reduced capacity of the liver to remove the dye from the blood, rather than due to changes in perfusion. Cimetidine did not influence the elevated portal pressure in the patients with cirrhosis, or the normal pressure in the patient with peliosis hepatis. No significant effect was observed on heart rate, mean arterial pressure, pulmonary artery pressure, pulmonary capillary pressure and cardiac output. These studies indicate that the reduction of the hepatic ICG extraction following cimetidine is more the result of an inhibited capacity of the liver to remove the dye than of changes in the hepatic perfusion or in the systemic circulation.This work was presented in part at the annual meeting of the American Association for the Study of Liver Diseases, November 1981, in Chicago, and appeared in abstract form in Hepatology (1981) 1:515, No. 25 B     

Evaluation of disorders of portal and total hepatic blood flow in patients with chronic diffuse liver diseases

The total hepatic blood flow measured with radioactive colloidal gold and the portal blood flow with the echo-Doppler method were investigated in 19 healthy examinees and 63 patients with chronic diffuse liver diseases. In the group of healthy examinees, the average values of the total hepatic blood flow was 1254 +/- 231 ml/min and of the portal one 1104 +/- 227 ml/min. The lowest blood flow values were obtained in patients with decompensated cirrhosis, especially in the hepatic (704 +/- 186 ml/min) and the portal blood flow (562 +/- 198 ml/min). In all the groups of examinees, registered values of the total hepatic blood flow were significantly higher than the values of the portal blood flow. The relations of the values obtained by both methods, among groups, were similar. By both methods decreased values are not obtained in liver steatosis and chronic persistent hepatitis in relation to the normal values. In patients with more serious forms of chronic diffuse liver diseases (cirrhosis and chronic active hepatitis) significantly lower blood flow values than the normal ones were obtained. Both methods contribute to the investigation of liver circulation disturbances, liver function damages, and to the follow-up of the liver disease course. The possibility of an indirect evaluation of the arterial hepatic blood flow from the difference of hepatic and portal blood flows may mean a new approach to the investigation of pathophysiological liver occurrences.     

Splanchnic clearance of plasma vasopressin in the dog: evidence for prehepatic extraction

It is generally considered that the liver is primarily responsible for the extraction of vasopressin from the circulating blood by the splanchnic viscera. To investigate this matter further, measurements were made in the anesthetized dog of the concentrations of vasopressin in arterial, portal venous, and hepatic venous plasma, and of total splanchnic plasma flow and hepatic arterial plasma flow. The total splanchnic vasopressin extraction ratio was 12.9 +/- 1.0%. However, the concentration of vasopressin in portal venous plasma was consistently lower than in arterial plasma, and there was a substantial prehepatic extraction of vasopressin, averaging 10.5 +/- 0.8%. A quantitative evaluation of the contribution of the "prehepatic" viscera, i.e., viscera with venous drainage into the portal vein, is provided by the relevant clearances of vasopressin. The prehepatic and total splanchnic vasopressin clearances were 1.58 +/- 0.20 and 3.04 +/- 0.31 ml X min-1 X kg-1, respectively. Thus, the splanchnic viscera other than the liver were responsible for approximately half of the splanchnic clearance of vasopressin; the remainder could be attributed to the liver. Immunoreactive vasopressin was not found in the bile. In splenectomized dogs, in which venous blood was collected from the superior mesenteric vein, the vasopressin extraction ratio was 14.6 +/- 2.3%, suggesting that the prehepatic clearance of vasopressin occurs largely in the mesenteric bed. A more specific localization of the prehepatic clearance sites has not as yet been made.     

Regional liver circulation and the scintigraphic representation of the portal circulation with 133Xe

Regional hepatic blood flow has been determined by 4 methods with the aid of the 133Xe washout technique: scintisplenoportography (direct application of 133Xe into the spleen by means of a thin needle); arterial method (133Xe is injected into the A. hepatica by means of a catheter); retrograde-venous method (133Xe administered by an occluding hepatic vein catheter); percutaneous intrahepatic method (133Xe administered directly into the parenchyma by means of a Chiba needle). Ad 1.: Scintisplenoportography (SSP) was executed with 97 patients: 8 patients with a healthy liver presented a hepatic blood flow of 103.37 +/- 11.5 ml/100 g/min. 4 patients with a chronic hepatitis showed a hepatic blood flow of 105.67 +/- 10.2 ml/100 g/min. In 38 patients with compensated cirrhosis, hepatic blood flow was determined with 58.15 +/- 11.5 ml/100 g/min and 19 patients with decompensated cirrhosis showed a blood flow of 34.54 +/- 7.2 ml/100 g/min. Of the 19 patients, who did not present any liver image, 2 patients suffered from a prehepatic block, 1 patient (female) from a posthepatic block, the rest were decompensated cirrhoses. In 5 patients suffering from steatosis only collateral circulation was determined and in 4 patients the spleen could not be punctured. In the patients with compensated and decompensated cirrhosis of the liver, hepatic blood flow differentiated significantly (p less than 0.001) from patients with healthy livers and chronic hepatitis. In the patients with bioptically assured steatosis only the washout constant was determined. Reproducibility of this method was tested in 4 patients and no statistical difference of hepatic blood flow values could be found and the correlation coefficient amounted to 0.9856. The advantage of SSP lies in the possibility of recording the portal vein circulation: cranial collaterals were found in 33 patients, 2 patients had caudal collaterals exclusively and 29 patients cranial and caudal collaterals. 33 cirrhosis patients presented evidence of hepatic shunts. In nearly all patients hepatic blood flow was higher in the right lobe than in the left. Ad 2.: Arterial method was executed in 26 patients: 2 patients with healthy livers had a hepatic blood flow of 89.85 +/- 2.9 ml/100 g/min, 19 compensated cirrhoses with 49.28 +/- 11 ml/100 g/min and 3 decompensated cirrhoses with 36.43 +/- 3.4 ml/100 g/min.(ABSTRACT TRUNCATED AT 400 WORDS)     

Oxygen supply and uptake in the liver and the intestine

The oxygen supply to the liver was found to be dependent on the total blood flow only and not on the ratio of arterial to portal contribution. The mean value of O2-uptake in the liver, related to a blood flow of 110 ml/min - 100 g liver, amounted to 6.08 +/- 0.2 ml O2/min - 100 g liver (mean +/- S.E.M.). O2-uptake of the intestine was found to be 1.95 +/- 0.13 ml O2/min - 100 g tissue, related to a normal blood flow of 50 ml/min - 100 g tissue. With low oxygen supply O2 extraction in the liver reaches values of 97%, whereas the intestinal extraction does not surpass 75%. A rise in oxygen supply surmounting normal values does not increase the O2-consumption. Contrary to the intestinal circulation the liver showed no postocclusive vasodilatation. The oxygen debt was payed back by a greater extraction. The portal oxygen supply to the liver can markedly increase due to intestinal metabolic hyperemia. High O2-extraction capacity, rather than vasodilatation, is the main mechanism for matching hepatic oxygen supply with requirements. The hepatic venous blood may leave the liver with an extremely low O2-content.     

肝硬化肝门静脉血流超声测定与肝纤维化指标的比较

目的：探讨肝门静脉血流和肝纤维化指标对诊断肝硬化的诊断价值。方法：50例肝硬化患者和20例正常对照组用肝门静脉超声和放免法分别测定肝门静脉血流和肝纤维化指标。结果：肝硬化肝门静脉血流动力学指标均高于正常对照组（P〈0．05），并随着肝功能Child Puph分级程度严重而下降；活动性肝纤维化指标明显高于静止性肝硬化（P〈0．05～0．01）；超声与血清判断肝硬化的符合率比较大致相同。结论：肝门静脉超声和肝纤维化指标能判断肝硬化损害的程度。     

The influence of conjugation of cholic acid on its uptake and secretion: hepatic extraction of taurocholate and cholate in the dog

1. Sodium taurocholate or cholate was administered systemically at a constant rate of about 2.9 mumole/min.kg body wt. to anaesthetized dogs in which the common bile duct had been cannulated. In steady-state conditions blood was sampled from systemic and hepatic veins and the fraction of bile salt removed in a single passage through the liver was determined. Total hepatic blood flow was estimated by application of the Fick principle.2. The hepatic extraction fraction for synthetic taurocholate in ten experiments was 92%+/-5% (S.D.) over the blood flow range encountered (1.1-2.8 ml./min.g liver). The extraction of cholate extensively conjugated in the liver before excretion into bile was 79%+/-8% (S.D.) (twenty-one observations, thirteen experiments). In circumstances of similar hepatic blood flow the extraction of cholate transferred to bile in the free form (after acute taurine depletion) was significantly less than that of either synthetic taurocholate or cholate which could be actively conjugated before excretion. These results, which are discussed and criticized, support previous work on the advantage of conjugation in the transfer of cholic acid from blood to bile.3. The hepatic clearance of bile salt decreases with increasing administration rate, but the values obtained may be influenced by changes in hepatic blood flow. With regard to taurocholate an increase in total hepatic flow was observed when its administration rate exceeded about 5 mumole/min.kg body wt.4. The secretory maximum for glycocholate, a bile salt not normally found in dog bile, was of the same order as that for taurocholate.     

Indocyanine green plasma clearance as a measure of changes in hepatic blood flow

The results from simultaneous measurements of indocyanine green (ICG) plasma clearance and hepatic blood flow (HBF) in subjects without hepatic dysfunction during changes in HBF induced pharmacologically or by food stimulation, are reported. A linear relation is established between the relative changes in HBF and that of ICG clearance (r = 0.94), but the changes are not identical, and therefore the changes in HBF cannot be accurately predicted from that of ICG plasma clearance. The reason behind the lack of identity of the changes lies in the complicated kinetics of dye removal by the liver. The hepatic venous catheterization technique is the only method when physiologically correct values for hepatic blood flow or changes therein are wanted.     

Zunahme des Leberblutflusses unter Nifedipin

Summary The hepatic hemodynamic effect of 20 mg sublingual nifedipine was evaluated in 15 patients (13 men, 2 women) during heart catheterization. The liver blood flow was measured 10 min after administration of nifedipine by continuous thermodilution (Baim coronary sinus flow analyzer). Nifedipine was associated with a decrease in systolic blood pressure (from 156+/–14 to 138+/–13 mmHg), an increase in heart rate from (73+/–13 to 81+/–8.6 beats/min), and increase in cardiac output (from 6.0+/–1.6 to 6.5+/–1.3 l/min). In 2/15 patients no significant change was derived. The liver blood flow increased in 13/15 patients from 218+/–171.7 to 336.7+/–247.7 ml/min (22%–194%,P<0.01). The study demonstrates that the vasodilation of nifedipine involves the hepatic circulation. If the hepatic clearance of drugs is high and flow dependent, nifedipine-induced increase of hepatic blood flow may impair drug clearance.

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Abkürzungsverzeichnis LBF Leberblutfluß - PC-Position Pulmonalcapillar-Position - T_M Temperatur der Mischung von Blut und Infusionslösung - T_I Temperatur der Infusionslösung - T_B Temperatur des Blutes vor Infusion - F_I Indikatorfluß - s.l. sublingual     

The Effect of Glucagon on Hepatosplanchnic Hemodynamics,Functional Capacity,and Metabolism of the Liver in Gats

Glucagon in doses of 0.1, 0.5, and 5.0, μg/kg/min infused i.v. caused a marked increase in portal blood flow (up to 300 %) due to a dose-dependent increase in conductance-of gastrointestinal vessels, and an increase in the conductance in the hepatic low pressure vessels (up to 30 %), but only slight changes in hepatic arterial conductance and flow. Glucagon caused a decrease in the hepatic extraction of Indocyanine Green (ICG), no change in ICG clearance, an increase in bile acid secretion, but only minor changes in bile flow and ICG excretion. The splanchnic glucose output and ketone production were increased by glucagon. The cytoplasmic redox level was not affected, but the mitochondrial redox level was changed to a more oxidized state together with a 30 % rise in hepatic oxygen consumption and a correlated increase in ethanol elimination. These last effects were not dose-dependent. It is concluded that the marked changes in splanchnic hemodynamics found during glucagon infusions, are not a consequence of the metabolic effects of the hormone on the liver, but rather a direct effect of non-physiological concentrations of glucagon on gastrointestinal vessels. The results exclude any marked influence of glucagon on the intrahepatic distribution of blood flow and functional liver mass.     

Reassessment of monoethylglycinexylidide as preoperative liver function test in a rat model of liver cirrhosis and man

It is known that lidocaine is rapidly metabolized by the hepatic cytochrome P-450 system to form monoethylglycinexylidide (MEGX), its primary metabolite. We analyzed serum MEGX levels experimentally and clinically by fluorescent polatization immunoassay to reassess preoperative liver microsome functions. Experimental study: Liver cirrhosis was produced in rats by intra-abdominal injection of thioacetamide. MEGX, indocyanine green test (ICG), and liver biochemical variables were measured periodically. Then, survival rates were assessed after the rats received a 70% hepatectomy. Clinical study: MEGX levels were measured in various human patients with chronic hepatitis or liver cirrhosis who underwent hepatectomy. Serum MEGX levels significantly dropped and ICG levels significantly rose with macroscopic and histologic progression of liver cirrhosis in rats. The MEGX levels correlated closely with albumin levels and ICG. Preoperative MEGX and ICG levels of the mortal group of rats differed significantly from those of the survival group with 70% hepatectomy. Furthermore, 100% of the rats with MEGX levels above 40 ng/ml and ICG levels below 1.0%. In the clinical study, MEGX levels were significantly lower in patients with chronic hepatitis or liver cirrhosis than in healthy volunteers and correlated significantly with liver function tests such as albumin, Fischer's ratio, prothrombin time, hepaplastin and ICG. A significant difference was found in MEGX levels between patients receiving lobectomy and those receiving subsegmentectomy or partial hepatectomy. All patients tolerated their operations. Our data indicate that the MEGX test combined with ICG test and Child-Pugh classification is a better predictor of residual liver reserve capacity, and the analysis of hepatic MEGX formation might prove useful for rapid and reliable assessment liver function and choice of surgical treatment. Received: 22 May 2000 / Accepted: 3 November 2000     

The inhibition of drug metabolism by cimetidine in patients with liver cirrhosis

Summary The effect of cimetidine treatment, 1 g daily over 6 days, on the disposition of theophylline was studied in nine patients with liver cirrhosis and in nine patients without liver disease. Plasma elimination half-life tended to increase from 14.6±8.2 h to 24.3±14.1 h in the cirrhotic patients (P>0.05) and from 8.3±4.2 h to 10.3±4.1 h in the control patients (P<0.05). Total plasma clearance decreased from 0.50±0.23 ml/kg/min to 0.41±0.21 ml/kg/min (P<0.05) in the cirrhotics and from 0.77±0.34 ml/kg/min to 0.58±0.18 ml/kg/min (P<0.05) in the controls. Pretreatment clearance values were also significantly reduced in the cirrhosis group. No change was observed in the volume of distribution of theophylline. The degree of inhibition of theophylline metabolism did not depend on whether the patients were smokers, or whether they had low pretreatment clearance values. In liver cirrhosis, inhibition of drug metabolism by cimetidine varies widely and is unpredictable in the individual patient.Supported by the Deutsche Forschungsgemeinschaft (Gu 86/8-3)     

Serum hyaluronan: a marker of liver fibrosis in patients with chronic liver disease

The aim of this study was to evaluate the clinical significance of serum hyaluronan (HA) as a marker of liver fibrosis in patients with chronic liver disease. Serum HA was measured by an ELISA-based method in 28 patients with chronic hepatitis (CH), 43 patients with liver cirrhosis (LC), 57 patients with hepatocellular carcinoma (HCC) and 60 healthy controls. Mean serum HA concentration in patients with LC was 1,376.80 +/- 2,568.85 ng/ml which was significantly higher than those in patients with CH, HCC and the controls (575.93 +/- 732.58, and 426.36 +/- 687.33, and 117.86 +/- 311.11 ng/ml, respectively). Based on a ROC curve analysis, a cut-off point of 354 ng/ml discriminated between LC and other groups with a sensitivity, specificity and accuracy of 82.4%, 78.2%, and 80.2%, respectively. Mean HA concentrations were correlated with the degree of liver fibrosis, but not the grade of necroinflammatory activity. In patients with LC, the mean serum HA level was significantly increased in the Child C group (3,977.96 +/- 4,906.21 ng/ml) in comparison with the Child B and A groups (1,002.63 +/- 448.55, and 537.90 +/- 424.16 ng/ml, respectively). We conclude that serum HA concentrations reflect the extent of liver fibrosis and severity of cirrhosis. Thus, serum HA can be a diagnostic marker of liver fibrosis and cirrhosis in patients with chronic liver disease.     

阻塞性黄疸降低靛氰绿的大鼠肝胆转运过程

采用结扎胆总管的方法复制阻塞性黄疸(OJ)大鼠模型,研究靛氰绿在OJ大鼠的肝胆内转运过程。实验观察了OJ大鼠模型下列变化：各器官病理学的变化;肝血流量和靛氰绿肝清除率的改变;靛氰绿的药代动力学参数。结果表明,靛氰绿在OJ大鼠体内的消除减慢,肝清除率下降,肝血流量也明显减少。靛氰绿在OJ大鼠的清除率下降。药代动力学分析结果提示靛氰绿通过肝细胞膜转运至肝细胞内、在肝细胞内的滞留以及自肝细胞向胆管的转运等过程均出现损害。     

Lidocaine kinetics predicted by indocyanine green clearance

To evaluate the importance of hepatic blood flow in lidocaine kinetics, we compared indocyanine green clearance, an estimate of hepatic plasma flow, to lidocaine clearance in 26 patients, half with and half without congestive heart failure, who received a lidocaine infusion for 24 hours as clinically indicated. The results demonstrated that patients with congestive heart failure had significantly higher steady-state lidocaine levels (6.8 +/- 3.6(S.D.) vs. 2.9 +/- 0.9 microgram per milliliter, P less than 0.005) and reduced lidocaine clearance (3.8 +/- 1.4 vs. 10.9 +/- 3.1 ml per minute per kilogram, P less than 0.005) than patients without heart failure. Potentially subtherapeutic or toxic lidocaine levels were found in 10 patients. The regression line (y = 0.3 + 1.07 x) relating clearance of lidocaine to that of indocyanine green was linear (r = 0.95, P less than 0.001). Since indocyanine green clearance can be determined rapidly and noninvasively, it offers the potential of predicting lidocaine dosage requirements with avoidance of toxicity or suboptimum therapy.     

Evaluation of T and B lymphocytes in liver infiltrates of patients with chronic active hepatitis.

The proportions of T and B lymphocytes in the liver infiltrates of 23 patients with chronic active hepatitis have been determined. The results were compared with the values obtained from peripheral blood and with the presence of HB virus markers and alpha-fetoprotein in liver tissue. A group of patients with chronic liver disease other than chronic active hepatitis were studied as controls. In chronic active hepatitis the percentage of hepatic T cells was 49 +/- 8 SD (control patients 61 +/- 8) (P less than 0.01), whereas the percentage of B cells was 40 +/- 10 (control patients 18 +/- 8) (P less than 0.01). No correlation was observed between hepatic T and B cells and the presence of HB virus. The numbers of T cells in liver tissue was significantly higher, the numbers of B cells lower, in patients whose biopsies were positive for alpha-fetoprotein than in those whose biopsies were negative. In peripheral blood, only the patients with chronic active hepatitis and established cirrhosis presented lower absolute values of T cells, whereas surface immunoglobulin-positive lymphocytes were within the normal range.     

Mesocaval and distal splenorenal shunts: Effect on hepatic function,hepatic hemodynamics,and portal systemic encephalopathy

Summary The effect of the mesocaval interposition shunt (n=12) and the distal splenorenal shunt (n=9) on the wedged hepatic venous pressure, the estimated hepatic blood flow, quantitative hepatic function, and the rate of portal systemic encephalopathy was evaluated in 21 patients who had bled from esophageal varices. After mesocaval shunt the wedged hepatic venous pressure was significantly reduced by 42% (from 26±3 mm Hg to 15±5 mm Hg,P<0.001) compared to 16% only (from 25±3 mm Hg to 21±2 mm Hg,P<0.005) after distal splenorenal shunt. The estimated hepatic blood flow also decreased significantly after mesocaval shunt by 61% (from 1.45±0.46 l/min to 0.56±0.25 l/min,P<0.001) compared to 29% (from 1.29±0.32 l/min to 0.91±0.39 l/min,P<0.05) after distal splenorenal shunt. Despite significantly different influences of both types of shunt operations on wedged hepatic venous pressure and estimated hepatic blood flow (P<0.001), postoperative changes of hepatic function were comparable in both groups of patients. The galactose elimination capacity, the initial plasma disappearance rate of Bromsulphalein, and the plasma ratio of valine, leucine, and isoleucine to phenylalanine and tyrosine were reduced by 13%, 26%, and 29%, respectively, after mesocaval shunt, compared to 12%, 25%, and 17% after distal splenorenal shunt. Only two patients of the mesocaval shunt group with the largest decrease in estimated hepatic blood flow developed portal systemic encephalopathy postoperatively, and the distal splenorenal shunt patients with their minor hemodynamic sequelae remained free of portal systemic encephalopathy.Abbreviations AP Serum alkaline phosphatase - BSP Bromsulphalein - BSP-k_i Initial plasma disappearance rate constant of BSP - BSP-45 min Plasma retention of BSP 45 min after i.v. injection - C_a Concentration of ICG in arterial blood - C_hv Concentration of ICG in hepatic venous blood - ChE Serum cholinesterase - DSRS Distal splenorenal shunt - EHBF Estimated hepatic blood flow - E-ICG Hepatic extraction of ICG - FHVP Free hepatic venous pressure - GEC Galactose elimination capacity - GPT Serum glutamic pyruvic transaminase - HCT Hematocrit - ICG Indocyanine green - MCS Mesocaval shunt - MRUS Maximal rate of urea synthesis - NCT Number-connection test - PHG Portohepatic gradient - PSE Portal systemic encephalopathy - PT Prothrombin time - PVP Portal venous pressure - R Removal of ICG - V + L + I/P + T Molar ratio of valine + leucine + isoleucine/phenylalanine + tyrosine - WHVP Wedged hepatic venous pressure     

Correlation of caffeine elimination and child's classification in liver cirrhosis

Summary Apparent pharmacokinetic parameters of caffeine elimination from the circulation were determined in 27 patients with histologically confirmed liver cirrhosis, 8 patients with miscellaneous liver disease, and 8 patients with other than liver disease. The usefullness of this quantitative test to assess the severity of liver cirrhosis was compared to the Child-Turcotte or Child-Pugh classification score as well as to the galactose elimination capacity of these patients. Using reversed-phase high pressure liquid chromatography caffeine, paraxanthine, theophylline, and theobromine were analysed in blood plasma collected before and after an oral dose of caffeine. Compared to apparent caffeine pharmacokinetics in patients with normal livers or miscellaneous liver disease, cirrhosis was characterized by a statistically significant reduction in apparent caffeine clearance and prolongation in half-life. The reduced apparent plasma disappearance rate of caffeine in cirrhotics was related to the retarded formation of paraxanthine which was the main metabolite of caffeine in blood plasma both in the absence or presence of liver disease. The apparent caffeine clearance in cirrhosis decreased with increasing Child-Turcotte classification score: Child's class A patients differed significantly from Child's class B or Child's class C patients, whereas the difference between Child's class B and C patients did not reach statistical significance (Wilcoxon's rank test). In addition there was a strong correlation between the Child-Pugh classification score and apparent caffeine clearance (P<0.001). However, no correlation existed between Child's classification and galactose elimination capacity. Our data emphasize the value of the Child-Turcotte or Child-Pugh classification in assessing the severity of liver cirrhosis in a simpler and less time-consuming way than using quantitative liver function tests.Abbreviations AUC Area under curve - Cl apparent caffeine clearance - GEC galactose elimination capacity - V₀ distribution volume Dedicated to Prof. G.-W. Löhr on the occasion of his 65th birthdaySupported by SFB 154 Klinische und experimentelle Hepatologie