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Intrinsic hepatic clearance and child-turcotte classification for assessment of liver function in cirrhosis
Journal of Hepatology, 1985; 1: 253-259
253
Elsevier HEP 0027
Intrinsic Hepatic Clearance and Child-Turcotte Classification for Assessment of Liver Function in Cirrhosis
J. C. Barbare 1, R. E. Poupon 2, P. Jaillon 3, S. P r o d ' h o m m e 2, F. Darnis 1, R. Y. Poupon 1 tService d'H~patologie, H@ital Saint-Antoine, Paris, 21NSERM U21, Unit# de Recherches Statistiques, 94807 Ville]uif Cedex, and 3Servicede Pharraacologie et d'Exploration Fonctionnelle Cardiovasculaire, Unitdde Pharmacologie Clinique, H@ital Saint-Antoine, Paris (France) (Received 29 June, 1984) (Accepted 4 October, 1984)
Summary Child-Turcotte classification (CTC) is an empirical but widely accepted approach for assessment of severity of cirrhosis. However, it is not known to what extent CTC reflects accurately the degree of impairment of hepatic function. In this study we compared CTC, standard liver tests and intrinsic hepatic clearance (IHC) of indocyanine green as means of assessing hepatic function in 63 cirrhotic patients. As compared to 10 control patients, IHC was significantly decreased in the cirrhotic group: (mean + SD) 0.270 + 0.141 l/min vs 1.227 + 0.312 l/min (P < 0.001). Serum bilirubin (SB), prothrombin time (PT) and serum albumin were significantly correlated with the degree of IHC impairment while alkaline phosphatase, ALAT and clinical criteria of CTC were not. Multivariate analysis showed that SB and PT were the only 2 variables that significantly explained the impairment of IHC. The model which best explained IHC impairment was Z = 21.77 + 4.78 PT-1.25 SB. The rate of IHC variance explained by this model, as determined by multiple correlation coefficient square (R2), was 42.6%. These results suggest that CTC provides only gross information about the degree of impairment of liver function in cirrhosis. Correspondence to: R.Y. Poupon, Service d'H6patologie, H6pital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. T61.: 344 33 33 poste 25 08. 0168-8278/85/$03.30© 1985 Elsevier Science Publishers B.V. (Biomedical Division)
254
J . c . B A R B A R E et al.
To evaluate the role of liver function in the prognosis or in the response to treatments, it should therefore be preferable to employ direct measurement of liver function using a clearance technique.
Introduction
In patients with cirrhosis a quantitative expression of severity of liver disease is required for at least the following reasons: to assess the prognosis of individual patients, to permit a better selection of patients of homogeneous risk entering clinical controlled trials and to better evaluate the effects of treatments on survival as well as on liver function. Since 1964, the Child-Turcotte classification (CTC) [1] has been widely used for these purposes. This method has been found to provide a good index of long term prognosis after portosystemic shunt [2,3] and more recently in medically treated cirrhosis [4]. For these reasons CTC, although empirical and subjective, is widely accepted as an approach to evaluate cirrhosis. However, it is not known to what extent CTC reflects accurately the degree of impairment of hepatic function. One way to assess the severity of liver disease is to measure hepatic function using clearance principles [5,6]. Intrinsic hepatic clearance (IHC) is one of the most advanced physiological clearance concepts currently used to measure changes in hepatic elimination function in experimental condition as well as in liver diseases [6-8]. IHC provides a quantitative index of the metabolic activity of all the hepatocytes in contact with the blood perfusing the liver [5,8]. In order to better define the information provided by CTC, we have examined in this study the relationships between impaired IHC and CTC using unidimensional and multidimensional statistical analysis in 63 cirrhotic patients. Material and Methods
Patients Sixty-three patients (50 men, 13 women) with biopsy-proven cirrhosis were studied for the evaluation of portal hypertension. In all patients, portal hypertension was demonstrated either by the presence of esophageal varices or by a gradient between wedged and free hepatic venous pressure higher than 10 mm Hg. The clinical and biochemical data of the patients are given in Tables 1 and 2. The patients were classified according to CTC as modified by Campbell et al. [3]; each of the 5 factors described by Child and Turcotte is assigned a unit value (1 for an A classification; 2 for a B classification; and 3 for a C classification). Patients with a total of 5-8 are classified as A, 9-11 as B, 12-15 as C. Assessment of the 63 patients is given in Table 1. Cirrhotic patients were compared with 10 control patients (7 men, 3 women; 53 _ SD 12 years) without portal hypertension and having a biopsy-proven normal or fatty liver.
INTRINSIC CLEARANCE, CHILD-TURCOTFE CLASSIFICATIONAND LIVER FUNCTION
255
TABLE 1 CLINICAL AND BIOCHEMICAL D A T A FOR THE 63 CIRRHOSIS PATIENTS STUDIED Age (years) Cirrhosis (number of patients) Alcoholic Posthepatitic Cryptogenetic Serum bilirubin ~mol/l) Alkaline phosphatase (UI/I) (N b < 210) ALAT (UI/l) (N b < 27) Prothrombin time (% of N b) Serum albumin (g/dl) Child-Turcotte classification (number of patients) Class A Class B Class C
50 + 10" 49 3 11 32 + 23 a 270 + 141. 41 +- 31. 60 + 17" 3.6 + 0.6. 43 18 2
" Mean + SD. b N means normal.
Protocol Measurements of IHC and hepatic blood flow were performed after an overnight fast within 3 days before or after the clinical and biochemical evaluation of the patients as previously described [8]. Under fluoroscopic control, a no. 7F Cournand catheter was inserted in the main right hepatic vein. Indocyanine green (ICG) (vert d'indocyanine, Laboratoire Serb, Paris, France) was infused through an antecubital vein at a rate of 2.4 mg/min for 2 min and then at a constant rate of 0.48 mg/min. Simultaneous blood samples were drawn from a peripheral vein and from the hepatic vein before ICG infusion and after a dye equilibration period of 30 min, at 2-min intervals over a 10-min period. Determinations of ICG were performed immediately at the end of the investigation according to the method of Nielsen [9]. Calculations All calculations were performed from steady-state plasma concentrations of ICG. In all the patients a satisfactory steady state was achieved. The steady state approximated with the relative change in concentration (dc/dt)/dc, was always less TABLE 2 C H I L D - T U R C O T r E CRITERIA AND THEIR DISTRIBUTION IN THE PATIENTS Group designation (grading)
A (1)
B (2)
C (3)
Serum bilirubin (rag%) Serum albumin (g%) Ascites Neurological disorder Nutrition status
< 2.0 (64%) > 3.5 (52%) None (59%) None (90%) Excellent (49%)
2.0-3.0 (25%) > 3.0 (11%) 3.0-3.5 (30%) < 3.0 (18%) Easily controlled (35%) Poorly controlled (6%) Minimal (10%) Advanced coma (0%) Good (36%) Poor (15%)
256
J . c . BAR.BARE et al.
TABLE 3 COMPARISON OF IHC VALUES IN CONTROLS AND IN SUBGROUPS A AND B OF CIRRHOTIC PATIENTS BY ONE-WAY ANALYSIS OF V A R I A N C E (F = 95.3, P < 0.001)
Controls Cirrhotic patients Class A Class B
No. of subjects
IHC (ml/min) (mean + SD)
10
1227 + 312
43 18
304 + 133 195 + 136
than 1% per min. Hepatic plasma flow (HPF) was calculated as HPF = v/cp-ch, v being the rate of infusion of ICG (0.48 mg/min) and cp and ch being the plasma concentration of ICG in the peripheral venous blood and in the hepatic venous blood respectively. Hepatic blood flow was calculated as: HPF/l-hematocrit. IHC was determined according to the sinusoidal perfusion model of hepatic elimination [6,10] and was expressed as plasma clearance. IHC was then calculated as IHC = HPF'In cp/ch. Statistics Unidimensional comparisons and correlations were respectively made by Student's t-test and by a linear regression analysis. It was verified that the distribution of IHC in normal and cirrhotic groups may be considered as normal. For the correlation analysis, qualitative variables, i.e., ascites, encephalopathy and nutrition status, were quantitated as binary variables. Differences between control patients and subgroups A and B of cirrhotic patients, classified according to CTC, were made by one-way analysis of variance. Since subgroup C included only 2 patients, it was. omitted from the analysis of variance. In the 3 subgroups of cirrhotic patients, a stepwise multiple regression has been employed to identify, among the clinical and biochemical data, those variables which were significantly correlated with IHC. The combination of these variables which best explained IHC impairment was exTABLE 4 CORRELATIONS BETWEEN INTRINSIC HEPATIC C L E A R A N C E (IHC) AND CLINICAL AND BIOCHEMICAL D A T A IN 63 PATIENTS WITH CIRRHOSIS IHC vs
r value
P value
Prothrombin time Serum albumin Serum bilirubin Alkaline phosphatase ALAT Encephalopathy Ascites Nutritional status Hepatic blood flow
0.653 0.442 -0.388 -0.158 0.026 -0.233 -0.326 -0.227 0.006
<0.001 <0.001 <0.01 N.S. N.S. N.S. N.S. N.S. N.S.
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257
pressed as a multiple regression model Z. The rate of IHC variance explained by Z was assessed by multip!e correlation coefficient square (R2). Results
In cirrhotic patients, a significant correlation was found between prothrombin time and serum albumin (r = 0.497, P < 0.01) and between prothrombin time and serum bilirubin (r = -0.313, P < 0.05). Unidimensional comparison of standard liver tests showed no other significant correlation. IHC was significantly decreased in the cirrhotic group as compared with control patients (mean + SD): 0.270 + 0.141 1/min vs 1.227 + 0.312 l/min (P < 0.001). Hepatic blood flow was not significantly different in cirrhotic patients than in controis: 0.875 + 0.469 1/min vs 0.952 + 0.222 1/min. The values of IHC in controls and in subgroups A and B of cirrhotic patients are shown in Table 3. One-way analysis of variance revealed that the severity of liver disease as assessed by CTC was associated with a progressive impairment of IHC (F = 95.3, P < 0.001). The correlations observed in cirrhotic patients between IHC and clinical and biochemical data are given in Table 4. Serum albumin, serum bilirubin and prothrombin time were significantly correlated with the degree of impairment of IHC. Hepatic blood flow showed no significant correlation with available data including IHC. Multiple regression revealed that among clinical and biochemical data, prothrombin time and serum bilirubin were the only 2 variables which were related to the impairment of IHC. The model which best explained IHC impairment was: Z = 21.77 + 4.78 prothrombin time-1.25 serum bilirubin The 95% confidence intervals of the slope were respectively equal to (3.15, 6.39) for prothrombin time and (-2.47, -0.03) for serum bilirubin. The rate of IHC variance explained by this model was R 2 = 42.6%. Discussion
Hepatic function may easily be assessed from elimination of substances which are removed from the blood solely by the liver [6]. Hepatic elimination kinetics is determined by the rate at which the substance is delivered to the liver (i.e., hepatic blood flow) and the metabolic activity of all hepatocytes in contact with the blood perfusing the liver. According to current models of hepatic elimination, IHC [7,10] provides a quantitative index of the metabolic activity of the liver. In the present study, IHC was measured using ICG as the test substance. ICG elimination provides simultaneous estimation of hepatic blood flow and IHC [7,8]. Changes in ICG elimination parallel those of other substances which are removed by the liver such as propranolol, lidocaine or aminopyrine [12-14]. The results of IHC obtained in cirrhotics included in the present study confirm that IHC impairment is a salient lea-
258
J.c. BARBARE et al.
ture of cirrhosis [12,14]. Impaired IHC in cirrhosis may either be related to a decrease in the mass of normally functioning hepatocytes or to intrahepatic shunting of blood escaping the removal process [5]. Our finding that patients with cirrhosis and controls had a similar total hepatic blood flow should not be taken as evidence against the role of disturbed intrahepatic hemodynamics in the reduced IHC. This finding rather suggests that a major part of the hepatic blood flow circulated through intrahepatic shunts. In this study, the one-way analysis of variance showed that CTC score impairment was associated with similar changes of IHC, a finding which suggests that CTC reflects, at least in part, hepatic function in cirrhosis and therefore the importance of the reduction of hepatocyte mass and/or the development of intrahepatic shunts. To determine which variables were significantly and independently related to the impairment of IHC in cirrhotic patients a multivariate analysis was performed. This analysis revealed that only two biochemical tests, namely prothrombin time and serum bilirubin, explained the impairment of IHC. The percentage of the variance of IHC explained by the best combination of these two variables was only 42.6%. These results therefore suggest that CTC provides only gross and not sufficiently precise information on the degree of impairment of liver function. To evaluate the role of liver function in the prognosis of cirrhosis or in the response to medical or surgical treatments of portal hypertension, it should be preferable to have a direct measurement of liver function using a clearance technique rather than an empirical score, such as provided by CTC. Our study was performed mainly in patients having mild to moderately advanced cirrhosis (class A and B patients represented the major part of the patients studied). Therefore the results could have been different if patients in worse conditions had been included. As a matter of fact, the absence of a significant relationship between liver function tests and encephalopathy could possibly be explained by the small number of patients with encephalopathy. To conclude, our study shows lack of independent correlation, between four of the components of CTC, namely serum albumin, ascites, nutritional status and encephalopathy, and IHC. Our study also shows that CTC does not accurately reflect hepatocellular function as measured by IHC, at least in mild to moderate advanced cirrhosis.
Acknowledgement The authors wish to thank Edith Garat for her secretarial assistance.
References 1 Child, III, C. G. and Turcotte, J. G., Surgery and portal hypertension. In: C. G. Child, III (Ed.), The Liver and Portal Hypertension, Saunders, Philadelphia, PA, 1964: 1-85. 2 Turcotte, J. G., Wallin, Jr., V. W. and Child, III, C. G., End-to-side versus side-to-side portacaval shunts in patients with hepatic cirrhosis, Amer. J. Surg., 1969; 117: 108-116. 3 Campbell, D. P., Parker, D. E. and Anagnostopoulos, C. E., Survival prediction in portacaval
INTRINSIC CLEARANCE, CHILD-TURCO'Iq'E CLASSIFICATION AND LIVER FUNCTION
259
s h u n t s - - A computerized statistical analysis, Amer. J. Surg., 1973; 126: 748-751. 4 Christensen, E., Schlichting, P., Fauerholdt, L., Gluud, C., et al., Prognostic value of Child-Turcotte criteria in medically treated cirrhosis, Hepatology, 1984; 4: 430-435. 5 Branch, R. A., Drugs as indicators of hepatic function, Hepatology, 1982; 2: 97-105. 6 Winkler, K., Bass, L., Keiding, S. and Tygstrup, N., The physiologic basis for clearance measurements in hepatology, Scand. J. Gastroenterol., 1979; 14: 439-448. 7 Wilkinson, G. R. and Shand, D. G., A physiological approach to hepatic drug clearance, Clin. Pharmacol. Ther., 1975; 18: 377-390. 8 Barbare, J. C., Poupon, R., Jaillon, P., Bories, P., et al., 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, Hepatology, 1984; 4: 59-62. 9 Nielsen, N. C., Spectrophotometric determination of indocyanine green in plasma especially with a view to an improved correction for blank density, Stand. J. Clin. Lab. Invest., 1963; 15: 613-621. 10 Bass, L., Keiding, S., Winkler, K. and Tygstrup, N., Enzymatic elimination of substrates flowing through the intact liver, J. Theor. Biol., 1976; 61: 393-410. 11 Caesar, J., Shaldon, S., Chiandussi, L., Guevara, L., et al., The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function, Clin. Sci., 1961; 21: 43-57. 12 Pessayre, D., Lebrec, D., Descatoire, V., Peignoux, M., et al., Mechanism for reduced drug clearance in patients with cirrhosis, Gastroenterology, 1978; 74: 566-571. 13 Villeneuve, J. P., Arsene, D. and Huet, P. M., Assessment of liver function by the aminopyrine breath test, Clin. Invest. Med., 1983; 6: 5-9. 14 Huet, P. M. and Villeneuve, J. P., Determinants of drug disposition in patients with cirrhosis, Hepatology, 1983; 3: 913-918.
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Elsevier HEP 0027
Intrinsic Hepatic Clearance and Child-Turcotte Classification for Assessment of Liver Function in Cirrhosis
J. C. Barbare 1, R. E. Poupon 2, P. Jaillon 3, S. P r o d ' h o m m e 2, F. Darnis 1, R. Y. Poupon 1 tService d'H~patologie, H@ital Saint-Antoine, Paris, 21NSERM U21, Unit# de Recherches Statistiques, 94807 Ville]uif Cedex, and 3Servicede Pharraacologie et d'Exploration Fonctionnelle Cardiovasculaire, Unitdde Pharmacologie Clinique, H@ital Saint-Antoine, Paris (France) (Received 29 June, 1984) (Accepted 4 October, 1984)
Summary Child-Turcotte classification (CTC) is an empirical but widely accepted approach for assessment of severity of cirrhosis. However, it is not known to what extent CTC reflects accurately the degree of impairment of hepatic function. In this study we compared CTC, standard liver tests and intrinsic hepatic clearance (IHC) of indocyanine green as means of assessing hepatic function in 63 cirrhotic patients. As compared to 10 control patients, IHC was significantly decreased in the cirrhotic group: (mean + SD) 0.270 + 0.141 l/min vs 1.227 + 0.312 l/min (P < 0.001). Serum bilirubin (SB), prothrombin time (PT) and serum albumin were significantly correlated with the degree of IHC impairment while alkaline phosphatase, ALAT and clinical criteria of CTC were not. Multivariate analysis showed that SB and PT were the only 2 variables that significantly explained the impairment of IHC. The model which best explained IHC impairment was Z = 21.77 + 4.78 PT-1.25 SB. The rate of IHC variance explained by this model, as determined by multiple correlation coefficient square (R2), was 42.6%. These results suggest that CTC provides only gross information about the degree of impairment of liver function in cirrhosis. Correspondence to: R.Y. Poupon, Service d'H6patologie, H6pital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. T61.: 344 33 33 poste 25 08. 0168-8278/85/$03.30© 1985 Elsevier Science Publishers B.V. (Biomedical Division)
254
J . c . B A R B A R E et al.
To evaluate the role of liver function in the prognosis or in the response to treatments, it should therefore be preferable to employ direct measurement of liver function using a clearance technique.
Introduction
In patients with cirrhosis a quantitative expression of severity of liver disease is required for at least the following reasons: to assess the prognosis of individual patients, to permit a better selection of patients of homogeneous risk entering clinical controlled trials and to better evaluate the effects of treatments on survival as well as on liver function. Since 1964, the Child-Turcotte classification (CTC) [1] has been widely used for these purposes. This method has been found to provide a good index of long term prognosis after portosystemic shunt [2,3] and more recently in medically treated cirrhosis [4]. For these reasons CTC, although empirical and subjective, is widely accepted as an approach to evaluate cirrhosis. However, it is not known to what extent CTC reflects accurately the degree of impairment of hepatic function. One way to assess the severity of liver disease is to measure hepatic function using clearance principles [5,6]. Intrinsic hepatic clearance (IHC) is one of the most advanced physiological clearance concepts currently used to measure changes in hepatic elimination function in experimental condition as well as in liver diseases [6-8]. IHC provides a quantitative index of the metabolic activity of all the hepatocytes in contact with the blood perfusing the liver [5,8]. In order to better define the information provided by CTC, we have examined in this study the relationships between impaired IHC and CTC using unidimensional and multidimensional statistical analysis in 63 cirrhotic patients. Material and Methods
Patients Sixty-three patients (50 men, 13 women) with biopsy-proven cirrhosis were studied for the evaluation of portal hypertension. In all patients, portal hypertension was demonstrated either by the presence of esophageal varices or by a gradient between wedged and free hepatic venous pressure higher than 10 mm Hg. The clinical and biochemical data of the patients are given in Tables 1 and 2. The patients were classified according to CTC as modified by Campbell et al. [3]; each of the 5 factors described by Child and Turcotte is assigned a unit value (1 for an A classification; 2 for a B classification; and 3 for a C classification). Patients with a total of 5-8 are classified as A, 9-11 as B, 12-15 as C. Assessment of the 63 patients is given in Table 1. Cirrhotic patients were compared with 10 control patients (7 men, 3 women; 53 _ SD 12 years) without portal hypertension and having a biopsy-proven normal or fatty liver.
INTRINSIC CLEARANCE, CHILD-TURCOTFE CLASSIFICATIONAND LIVER FUNCTION
255
TABLE 1 CLINICAL AND BIOCHEMICAL D A T A FOR THE 63 CIRRHOSIS PATIENTS STUDIED Age (years) Cirrhosis (number of patients) Alcoholic Posthepatitic Cryptogenetic Serum bilirubin ~mol/l) Alkaline phosphatase (UI/I) (N b < 210) ALAT (UI/l) (N b < 27) Prothrombin time (% of N b) Serum albumin (g/dl) Child-Turcotte classification (number of patients) Class A Class B Class C
50 + 10" 49 3 11 32 + 23 a 270 + 141. 41 +- 31. 60 + 17" 3.6 + 0.6. 43 18 2
" Mean + SD. b N means normal.
Protocol Measurements of IHC and hepatic blood flow were performed after an overnight fast within 3 days before or after the clinical and biochemical evaluation of the patients as previously described [8]. Under fluoroscopic control, a no. 7F Cournand catheter was inserted in the main right hepatic vein. Indocyanine green (ICG) (vert d'indocyanine, Laboratoire Serb, Paris, France) was infused through an antecubital vein at a rate of 2.4 mg/min for 2 min and then at a constant rate of 0.48 mg/min. Simultaneous blood samples were drawn from a peripheral vein and from the hepatic vein before ICG infusion and after a dye equilibration period of 30 min, at 2-min intervals over a 10-min period. Determinations of ICG were performed immediately at the end of the investigation according to the method of Nielsen [9]. Calculations All calculations were performed from steady-state plasma concentrations of ICG. In all the patients a satisfactory steady state was achieved. The steady state approximated with the relative change in concentration (dc/dt)/dc, was always less TABLE 2 C H I L D - T U R C O T r E CRITERIA AND THEIR DISTRIBUTION IN THE PATIENTS Group designation (grading)
A (1)
B (2)
C (3)
Serum bilirubin (rag%) Serum albumin (g%) Ascites Neurological disorder Nutrition status
< 2.0 (64%) > 3.5 (52%) None (59%) None (90%) Excellent (49%)
2.0-3.0 (25%) > 3.0 (11%) 3.0-3.5 (30%) < 3.0 (18%) Easily controlled (35%) Poorly controlled (6%) Minimal (10%) Advanced coma (0%) Good (36%) Poor (15%)
256
J . c . BAR.BARE et al.
TABLE 3 COMPARISON OF IHC VALUES IN CONTROLS AND IN SUBGROUPS A AND B OF CIRRHOTIC PATIENTS BY ONE-WAY ANALYSIS OF V A R I A N C E (F = 95.3, P < 0.001)
Controls Cirrhotic patients Class A Class B
No. of subjects
IHC (ml/min) (mean + SD)
10
1227 + 312
43 18
304 + 133 195 + 136
than 1% per min. Hepatic plasma flow (HPF) was calculated as HPF = v/cp-ch, v being the rate of infusion of ICG (0.48 mg/min) and cp and ch being the plasma concentration of ICG in the peripheral venous blood and in the hepatic venous blood respectively. Hepatic blood flow was calculated as: HPF/l-hematocrit. IHC was determined according to the sinusoidal perfusion model of hepatic elimination [6,10] and was expressed as plasma clearance. IHC was then calculated as IHC = HPF'In cp/ch. Statistics Unidimensional comparisons and correlations were respectively made by Student's t-test and by a linear regression analysis. It was verified that the distribution of IHC in normal and cirrhotic groups may be considered as normal. For the correlation analysis, qualitative variables, i.e., ascites, encephalopathy and nutrition status, were quantitated as binary variables. Differences between control patients and subgroups A and B of cirrhotic patients, classified according to CTC, were made by one-way analysis of variance. Since subgroup C included only 2 patients, it was. omitted from the analysis of variance. In the 3 subgroups of cirrhotic patients, a stepwise multiple regression has been employed to identify, among the clinical and biochemical data, those variables which were significantly correlated with IHC. The combination of these variables which best explained IHC impairment was exTABLE 4 CORRELATIONS BETWEEN INTRINSIC HEPATIC C L E A R A N C E (IHC) AND CLINICAL AND BIOCHEMICAL D A T A IN 63 PATIENTS WITH CIRRHOSIS IHC vs
r value
P value
Prothrombin time Serum albumin Serum bilirubin Alkaline phosphatase ALAT Encephalopathy Ascites Nutritional status Hepatic blood flow
0.653 0.442 -0.388 -0.158 0.026 -0.233 -0.326 -0.227 0.006
<0.001 <0.001 <0.01 N.S. N.S. N.S. N.S. N.S. N.S.
INTRINSIC CLEARANCE, CH/LD-TURCOTI'E CLASSIFICATION AND LIVER FUNCTION
257
pressed as a multiple regression model Z. The rate of IHC variance explained by Z was assessed by multip!e correlation coefficient square (R2). Results
In cirrhotic patients, a significant correlation was found between prothrombin time and serum albumin (r = 0.497, P < 0.01) and between prothrombin time and serum bilirubin (r = -0.313, P < 0.05). Unidimensional comparison of standard liver tests showed no other significant correlation. IHC was significantly decreased in the cirrhotic group as compared with control patients (mean + SD): 0.270 + 0.141 1/min vs 1.227 + 0.312 l/min (P < 0.001). Hepatic blood flow was not significantly different in cirrhotic patients than in controis: 0.875 + 0.469 1/min vs 0.952 + 0.222 1/min. The values of IHC in controls and in subgroups A and B of cirrhotic patients are shown in Table 3. One-way analysis of variance revealed that the severity of liver disease as assessed by CTC was associated with a progressive impairment of IHC (F = 95.3, P < 0.001). The correlations observed in cirrhotic patients between IHC and clinical and biochemical data are given in Table 4. Serum albumin, serum bilirubin and prothrombin time were significantly correlated with the degree of impairment of IHC. Hepatic blood flow showed no significant correlation with available data including IHC. Multiple regression revealed that among clinical and biochemical data, prothrombin time and serum bilirubin were the only 2 variables which were related to the impairment of IHC. The model which best explained IHC impairment was: Z = 21.77 + 4.78 prothrombin time-1.25 serum bilirubin The 95% confidence intervals of the slope were respectively equal to (3.15, 6.39) for prothrombin time and (-2.47, -0.03) for serum bilirubin. The rate of IHC variance explained by this model was R 2 = 42.6%. Discussion
Hepatic function may easily be assessed from elimination of substances which are removed from the blood solely by the liver [6]. Hepatic elimination kinetics is determined by the rate at which the substance is delivered to the liver (i.e., hepatic blood flow) and the metabolic activity of all hepatocytes in contact with the blood perfusing the liver. According to current models of hepatic elimination, IHC [7,10] provides a quantitative index of the metabolic activity of the liver. In the present study, IHC was measured using ICG as the test substance. ICG elimination provides simultaneous estimation of hepatic blood flow and IHC [7,8]. Changes in ICG elimination parallel those of other substances which are removed by the liver such as propranolol, lidocaine or aminopyrine [12-14]. The results of IHC obtained in cirrhotics included in the present study confirm that IHC impairment is a salient lea-
258
J.c. BARBARE et al.
ture of cirrhosis [12,14]. Impaired IHC in cirrhosis may either be related to a decrease in the mass of normally functioning hepatocytes or to intrahepatic shunting of blood escaping the removal process [5]. Our finding that patients with cirrhosis and controls had a similar total hepatic blood flow should not be taken as evidence against the role of disturbed intrahepatic hemodynamics in the reduced IHC. This finding rather suggests that a major part of the hepatic blood flow circulated through intrahepatic shunts. In this study, the one-way analysis of variance showed that CTC score impairment was associated with similar changes of IHC, a finding which suggests that CTC reflects, at least in part, hepatic function in cirrhosis and therefore the importance of the reduction of hepatocyte mass and/or the development of intrahepatic shunts. To determine which variables were significantly and independently related to the impairment of IHC in cirrhotic patients a multivariate analysis was performed. This analysis revealed that only two biochemical tests, namely prothrombin time and serum bilirubin, explained the impairment of IHC. The percentage of the variance of IHC explained by the best combination of these two variables was only 42.6%. These results therefore suggest that CTC provides only gross and not sufficiently precise information on the degree of impairment of liver function. To evaluate the role of liver function in the prognosis of cirrhosis or in the response to medical or surgical treatments of portal hypertension, it should be preferable to have a direct measurement of liver function using a clearance technique rather than an empirical score, such as provided by CTC. Our study was performed mainly in patients having mild to moderately advanced cirrhosis (class A and B patients represented the major part of the patients studied). Therefore the results could have been different if patients in worse conditions had been included. As a matter of fact, the absence of a significant relationship between liver function tests and encephalopathy could possibly be explained by the small number of patients with encephalopathy. To conclude, our study shows lack of independent correlation, between four of the components of CTC, namely serum albumin, ascites, nutritional status and encephalopathy, and IHC. Our study also shows that CTC does not accurately reflect hepatocellular function as measured by IHC, at least in mild to moderate advanced cirrhosis.
Acknowledgement The authors wish to thank Edith Garat for her secretarial assistance.
References 1 Child, III, C. G. and Turcotte, J. G., Surgery and portal hypertension. In: C. G. Child, III (Ed.), The Liver and Portal Hypertension, Saunders, Philadelphia, PA, 1964: 1-85. 2 Turcotte, J. G., Wallin, Jr., V. W. and Child, III, C. G., End-to-side versus side-to-side portacaval shunts in patients with hepatic cirrhosis, Amer. J. Surg., 1969; 117: 108-116. 3 Campbell, D. P., Parker, D. E. and Anagnostopoulos, C. E., Survival prediction in portacaval
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