- Email: [email protected]
MEGX test in hepatology: The long-sought ultimate quantitative liver function test?
4
Journal of Hepatology. 1993; 19:4-7 © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0168-8278/93/$06.00
HEPAT 01491
Leader
MEGX test in hepatology: The long-sought ultimate quantitative liver function test?
J/irg Reichen Department of Clinical Pharmacology, University of Berne. Berne. Switzerland
Two papers in this issue of the Journal of Hepatology evaluate the formation of mono-ethyi-glycine-xylidide (MEGX) from lidocaine as a quantitative test of liver function (1,2). Meyer-Wyss et al. (1) compare the MEGX test with others, namely galactose elimination capacity and the aminopyrine breath test in 111 patients with chronic liver disease of different etiologies and histologic severity. As reported by many previous investigators these authors report a large variability of all three tests within and between groups of histologic severity. In their study the MEGX test was inferior to both the aminopyrine breath test and the galactose elimination capacity in differentiating mild from severe histologic lesions (1). Unlike the second paper, the sensitivity and specificity of the different tests were not calculated and Figs. 1-3 are not convincing evidence of the separating power of any of the tests evaluated. Huang et al. compared the MEGX test in 71 patients with chronic liver disease with 26 normal controls. They also evaluated it against indocyanine green retention, galactose elimination capacity and the Pugh score (2). Using receiver-operator characterization these authors found an accuracy of 86% for the MEGX test at a cutoff value of 54 ng/ml (MEGX serum level at 15 minutes after administration of lidocaine) for differentiating between liver disease and healthy controls and - - more im-
Correspondence to:
portantly - - that a value of less than 30 ng/ml was associated with lower survival probability (Fig. 4 of Ref. 2). Unfortunately, the prognostic value of the other tests was not similarly evaluated. While lidocaine clearance was used as a quantitative liver function test in the past with variable success (3-5), its use never gained widespread acceptance. The MEGX test was proposed by Oellerich and colleagues as another quantitative liver function test (6). This group has repeatedly reported that it gives an accurate prediction of graft survival determination of MEGX formation in the donor (7-8) and short-term survival in adult and pediatric liver transplantation candidates (9-11). Independent confirmation of the prognostic value of the MEGX test has been established by comparing it with an accepted score of end-stage liver disease in children (12) and by the study of Huang et al. in the present issue (2). The studies showing the favorable prognostic accuracy of the MEGX test have been performed on a limited number of patients. Thus, Oellerich et al. repeatedly report on their prospective study (9-11) and it is difficult to assess the number studied since the numbers diverge. The two most recent publications of these authors reported to have performed the test on 101 patients 28 of whom died (10) and on 164 patients 26 of whom died (11); Huang et al. add 71 patients (9 died
Prof. J. Reichen, Dept. Clinical Pharmacology,Murtenstrasse 35, CH 3010 Berne, Switzerland.
MEGX TEST IN HEPATOLOGY from their disease) to this number. The higher mortality in the Hanover studies reflects the investigation of liver transplant candidates while in the study from Taiwan, patients which chronic liver disease with and without decompensation were included. The discriminating power of the MEGX test according to histologic severity, in particular cirrhotic versus non-cirrhotic disease, appears to be inferior to other quantitative liver function tests (1,13). The reasons for the maintained quantitative function in patients with established cirrhosis remain unclear. However, animal studies have suggested that liver cell mass and thus function is maintained in the early stages of cirrhosis (14). There is circumstantial evidence that the same may be true in patients (15). Thus, in end-stage cirrhosis (Child C patients) the MEGX test may permit further refinement of the prognosis as suggested by the data from Taiwan and Hanover (2,9-11) while early in the disease other tests may be more effective in discriminating power (1,13). In contrast to the use of this test in children with chronic liver disease (12) a direct extrapolation to pediatric liver donors requires further investigation since normal values were higher in children than previously reported in adults (16). In this study it was unclear whether this discrepancy represented developmental changes or - - more likely - - the effects of enzyme induction. As described by Oellerich's group the MEGX test appears attractive, since it is simple to perform: 1 mg/kg lidocaine is injected as a bolus i.v., a plasma sample obtained at 15 min after injection and MEGX concentration determined by a commercially available kit using a fluorescence polarization immunossay (6). Test results may thus be obtained within 20 minutes (6), an important issue when evaluating organ donors. The MEGX test also appears attractive for children; indeed, Gremse et al. found that the MEGX test correlated with a validated composite score in 28 children with chronic liver disease and detected deterioration earlier than clinical signs and symptoms (12). Is this then the panacea that true believers in quantitative function testing have been waiting for? Before addressing this question one must first consider the processes which lead to MEGX formation. Although MEGX formation has been found to correlate with lidocaine clearance (6), the processes governing this metabolic clearance are quite complex. Lidocaine is a drug with a high first-pass extraction (17); therefore, any intervention altering hepatic perfusion will interfere with its clearance (17) and thereby
with MEGX formation. Oellerich et al. felt that since only ICG retention and MEGX formation predicted survival in their cirrhotic patients (9-11), the flowdependence of lidocaine clearance was an important advantage of the test and the impairment observed in liver transplant candidates was mainly due to portosystemic shunting (11). However, the concept of flow- and enzyme-limited hepatic clearance (18) loses its meaning in liver disease. Thus, in patients with advanced liver disease, lidocaine clearance is independent of blood flow (19), and, comparison of mild and severe liver disease may measure different processes. This could explain the disappointing performance of the test in populations including patients with mild and severe liver disease (1,13). Second, lidocaine is transported in blood bound to c~l-acid glycoprotein, an acute phase reactant, u l-Acid glycoprotein and - - therefore protein binding of lidocaine - - is reduced in cirrhosis (20); a situation which could be altered by infections and stress, however, thus potentially affecting test results even when there is no change in liver function. Furthermore, the tissue distribution of lidocaine is a complex process which varies with serum levels (17), and the extent to which altered body composition of cirrhotic patients alters distribution phenomena remains largely unexp.lored. The de-ethylation of lidocaine to MEGX is a cytochrome P-450-dependent process. The cytochrome P-450 isozymes responsible for MEGX formation are susceptible to enzyme-inducing and -inhibiting agents (17) which indeed, has been shown to have a possible effect of MEGX formation in pediatric liver donors (16). Smoking increases the clearance of lidocaine (21) but does not appear to affect MEGX formation at 15 min (9). A formal analysis of MEGX formation and disposition in smokers and non-smokers has not yet been presented, however, and it remains unclear whether separate normal values must be established for smokers and non-smokers. Cytochrome P-450IIIA4 is the main isozyme responsible for MEGX formation in man (22) and widely varying values (over a 9-fold range) were found in human microsomes. At present it is unclear whether this is due to environmental and/or genetic influences. Cytochrome P-450IIIA4 is also largely responsible for cyciosporine A metabolism, which could be of particular interest in transplant candidates and organ donors if the MEGX test were shown to predict cyclosporin clearance like the erythromycin breath test (23). Finally, when evaluating quantitative liver function tests the safety must be considered. This is particularly important for the MEGX test since it has been proposed
6
J. REICHEN
TABLE I Properties of different quantitative liver function tests according to the five criteria (Ease of performance, kinetic properties, potential for interactions, safety and prognostic value) discussed in the text
Test
Ease of performance
MEGX GECa ABTa 1CGa Antipyrine Coffeine
Patient
Analysis
Kinetics
Interactions
Safety
Prognostic value
simple complex simple complex simple simple
simple simple complex simple complex simple
complex simple complex simple simple simple
many none many few many many
?b yes ?b ?h ?h yes
insufficient data 4-c 4-(' 4-(' insufficient data insufficient data
aGEC, galactose elimination capacity; ABT, aminopyrine breath test: ICG, indocyanine green clearance or retention. bThe safety of these compounds has not been fully established: for details on MEGX, please refer to the text. Aminopyrine and antipyrine have been reported to induce agranulocytosis after prolonged use but no adverse effects have ever been observed in the test situation. Dose-dependent pseudoallergy has been reported after indocyanine green administration (25) but this occurrency appears extremely rare. cA prognostic value either alone or as part of a score has been found by some but not all investigators.
as a quantitative liver function test in pediatrics (12). Fatal adverse reactions to lidocaine have occurred but are almost always d o s e - d e p e n d e n t (17); serum levels leading to respiratory arrest, convulsions or cardiac/ circulatory c o m p r o m i s e should not be attained by the dose (1 mg/kg) currently used. Fatal allergic reactions to lidocaine have been described but are exceedingly rare (24). Mild side effects were noted in some o f the published studies (2,13) and a 'severe" adverse reaction was reported by Stremmel et al. but details were not given (13). F r o m the above discussion, several desirable p r o p e r ties for a quantitative liver function test emerge: 1.
2.
3.
4. 5.
The test should be easy to perform both for the patients (number o f samples, need for venous access, etc.) and with analysis. The kinetics o f the test c o m p o u n d should be well characterized, not too complex and preferably be determined by only one process. There should be no interactions with concomitant medications, no m a j o r other environmental (diet, nutritional state, etc.) influences and no m a j o r genetic heterogeneity in the p o p u l a t i o n studied. The test substance should be safe. The test should provide prognostic information.
The properties o f some o f the most p o p u l a r q u a n t i t a tive liver function tests these four criteria are listed in Table 1. A l t h o u g h this review c a n n o t c o m p a r e the merits o f scores with those o f quantitative testing, Table 1 appears to answer the question o f whether this new test is the panacea h o p e d for; the answer is clearly no.
The M E G X test may a l r e a d y have some merits in children and in organ donors. However, the unresolved questions addressed a b o v e require a d d i t i o n a l studies which should address the following questions: 1.
2.
3.
W h a t is the clearance o f M E G X alone? C o u l d a d m i n i s t r a t i o n o f M E G X instead o f its precursor lidocaine simplify the unresolved kinetic issues? W h y is there m a r k e d heterogeneity in M E G X f o r m a t i o n o f h u m a n microsomes? Does this affect the M E G X test? Finally, large, prospective multicenter studies with a p p r o p r i a t e statistical analysis are needed to answer the basic question o f all quantitative liver function tests, namely whether they are superior to scores with respect to p r o g n o s t i c a t i o n in endstage liver disease.
Acknowledgments S u p p o r t e d by a grant from the Swiss N a t i o n a l F o u n dation for Scientific Research (32.30168.90).
References I
Meyer-WyssB, Renner E. Luo H. Scholer A. Assessment of lidocaine metabolite formation in comparison with other liver function tests. J Hepatol 1993; 19: . 2 Huang YS, Lee SD, Deng .IF, et al. Measuring lidocaine metabolite - - monoethylglycinexylidide as a quantitative index of hepatic function in adults with chronic hepatitis and cirrhosis. J Hepatol 1993; 19:. 3 Forrest JAH, Finlayson NDC, Adjepon-Yamoah KK, Prescott LF. Antipyrine, paracetamol and lignocaine elimination in chronic liver disease. Br Med J 1977: i: 1384-7. 4 Colli A, Buccino G, Cocciolo M, Parravicini R, Scaltrini G. Dis-
7
MEGX TEST IN HEPATOLOGY position of a flow-limited drug (lidocaine) and a metabolic capacity-limited drug Itheophylline) in liver cirrhosis. Clin Pharmacol Ther 1988: 44: 642-9. 5 Pomier-Layrargues G. Huet PM, Infante-Rivard C. et al. Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic encephulopathy in cirrhotic patients following elective end-to-side portacaval shunt. Hepatology 1988: 8: 1506-10. 6 Oellerich M, Raude E, Burdelski M. et al. Monoethylglycinexylidide formation kinetics: A novel approach to assessment of liver function. J Clin Chem Biochem 1987: 25: 845-53. 7 Oellerich M. Ringe B. Gubernatis G. et al. Lignocaine metabolitc formation as a measure of pre-transplant liver function. Lancet 1989: i: 640-2. 8 Burdelski M, Oellerich M, Lamesch P, et al. Evaluation ofquantitative liver function tests in liver donors. Transplant Proc 1987: 19: 3838-9. 9 Oellerich M, Burdelski M. Lautz H-U. Schulz M, Schmidt F-W. Herrmann h. Lidocaine metabolite formation as a measure of liver function in patients with cirrhosis. Ther Drug Monit 1990: 12: 219-26. 10 Oellerich M, Burdelski M. Lautz H-U, Binder L, Pichlmayr R. Predictors of one-year pretransplant survival in patients with cirrhosis. Heptalogy 1991: 14: 1029-34. 11 Oellerich M. Burdelski M, Lautz H-U, et al. Assessment of pretransplant prognosis in patients with cirrhosis. Transplantation 1991: 51: 801-6. 12 Gremse AD, A-Kader HH, Schroeder TJ. Balistreri WF. Assessment of lidocaine metabolite formation as a quantitative liver function test in children. Hepatology 1990: 12: 565-9. 13 Stremmel W, Wojdat R, Groteguth M. et al. Leberfunktionstests im klinischen Vergleich. Z Gastroenterol 1992: 30: 784-90. 14 Gross JB, Reichen J, Zelmer T, Zihamermann A. The evolution of changes in quantitative liver function tests in a rat model of
15
16 17 18 19 20
21 22 23
24 25
cirrhosis: Correlation with morphometric measurement of hepatocyte mass. Hepatology 1987', 7: 457-63. Reichen J, Widmer T, Cotting J. Accurate prediction of death by serial determination of the galactose elimination capacity in primary biliary cirrhosis - - A comparison with the Mayo model. Hepatology 199[; 14: 504-10. Rossi SJ, Schroeder TJ, Vine WH. et al. Monoethylg[ycinexylide formation in assesing pediatric donor liver function. Ther Drug Mon 1992; 14: 452-6. Benowtiz NL, Meister W. Clinical pharmacokinetics of lignocaine. Clin Pharmacokin 1978; 3: 177-201. Wilkinson Gr, Shand DG. A physiologic approach to hepatic drug clearance. Clin Pharmacol Ther 1975: 18: 377-90. Huet PM, Villeneuve JP. Determinants ofdrug disposition in patients with cirrhosis. Hepatology 1983: 3: 913-8. Barry M, Keeling PWN, Weir D, Feely J. Severity of cirrhosis and the relationship ofalpahl-acid glycorpotein concentration to plasma protein binding of lidocaine. Clin Pharmacol Ther 1990: 47: 366-70. Huet PM, Lelorier J. Effects ofsmoking and chronic hepatitis B on lidocaine and indocyanine green kinetics. Clin Pharmacol Ther 1980: 20: 208-15. Bargetzi MJ, Aoyama T, Gonzalez F J, Meyer UA. Lidocaine metabolism in human liver microsomes by cytochrome P450111A4. Clin Pharmacol Ther 1989; 46: 521-7. Turgeon DK, Normolle DP, Leichtman AB, Annesley TM, Smith DE, Watkins PB. Erythromycin breath test predicts oral clearance of cyclosporine in kidney transplant recipients. Clin Pharmacol Ther 1992: 52: 471-8. Strunin L. Local Anesthetics. Meyler's side effects of drugs. Amsterdam: Excerpta Medica 1975. 256-61. Speich R, Saesseli B, Hoffmann U. Neflel K, Reichen J. Anaphylactoid reactions after indocyanine-green administration. Ann lnt Med 1988: 109: 345-6.
Journal of Hepatology. 1993; 19:4-7 © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0168-8278/93/$06.00
HEPAT 01491
Leader
MEGX test in hepatology: The long-sought ultimate quantitative liver function test?
J/irg Reichen Department of Clinical Pharmacology, University of Berne. Berne. Switzerland
Two papers in this issue of the Journal of Hepatology evaluate the formation of mono-ethyi-glycine-xylidide (MEGX) from lidocaine as a quantitative test of liver function (1,2). Meyer-Wyss et al. (1) compare the MEGX test with others, namely galactose elimination capacity and the aminopyrine breath test in 111 patients with chronic liver disease of different etiologies and histologic severity. As reported by many previous investigators these authors report a large variability of all three tests within and between groups of histologic severity. In their study the MEGX test was inferior to both the aminopyrine breath test and the galactose elimination capacity in differentiating mild from severe histologic lesions (1). Unlike the second paper, the sensitivity and specificity of the different tests were not calculated and Figs. 1-3 are not convincing evidence of the separating power of any of the tests evaluated. Huang et al. compared the MEGX test in 71 patients with chronic liver disease with 26 normal controls. They also evaluated it against indocyanine green retention, galactose elimination capacity and the Pugh score (2). Using receiver-operator characterization these authors found an accuracy of 86% for the MEGX test at a cutoff value of 54 ng/ml (MEGX serum level at 15 minutes after administration of lidocaine) for differentiating between liver disease and healthy controls and - - more im-
Correspondence to:
portantly - - that a value of less than 30 ng/ml was associated with lower survival probability (Fig. 4 of Ref. 2). Unfortunately, the prognostic value of the other tests was not similarly evaluated. While lidocaine clearance was used as a quantitative liver function test in the past with variable success (3-5), its use never gained widespread acceptance. The MEGX test was proposed by Oellerich and colleagues as another quantitative liver function test (6). This group has repeatedly reported that it gives an accurate prediction of graft survival determination of MEGX formation in the donor (7-8) and short-term survival in adult and pediatric liver transplantation candidates (9-11). Independent confirmation of the prognostic value of the MEGX test has been established by comparing it with an accepted score of end-stage liver disease in children (12) and by the study of Huang et al. in the present issue (2). The studies showing the favorable prognostic accuracy of the MEGX test have been performed on a limited number of patients. Thus, Oellerich et al. repeatedly report on their prospective study (9-11) and it is difficult to assess the number studied since the numbers diverge. The two most recent publications of these authors reported to have performed the test on 101 patients 28 of whom died (10) and on 164 patients 26 of whom died (11); Huang et al. add 71 patients (9 died
Prof. J. Reichen, Dept. Clinical Pharmacology,Murtenstrasse 35, CH 3010 Berne, Switzerland.
MEGX TEST IN HEPATOLOGY from their disease) to this number. The higher mortality in the Hanover studies reflects the investigation of liver transplant candidates while in the study from Taiwan, patients which chronic liver disease with and without decompensation were included. The discriminating power of the MEGX test according to histologic severity, in particular cirrhotic versus non-cirrhotic disease, appears to be inferior to other quantitative liver function tests (1,13). The reasons for the maintained quantitative function in patients with established cirrhosis remain unclear. However, animal studies have suggested that liver cell mass and thus function is maintained in the early stages of cirrhosis (14). There is circumstantial evidence that the same may be true in patients (15). Thus, in end-stage cirrhosis (Child C patients) the MEGX test may permit further refinement of the prognosis as suggested by the data from Taiwan and Hanover (2,9-11) while early in the disease other tests may be more effective in discriminating power (1,13). In contrast to the use of this test in children with chronic liver disease (12) a direct extrapolation to pediatric liver donors requires further investigation since normal values were higher in children than previously reported in adults (16). In this study it was unclear whether this discrepancy represented developmental changes or - - more likely - - the effects of enzyme induction. As described by Oellerich's group the MEGX test appears attractive, since it is simple to perform: 1 mg/kg lidocaine is injected as a bolus i.v., a plasma sample obtained at 15 min after injection and MEGX concentration determined by a commercially available kit using a fluorescence polarization immunossay (6). Test results may thus be obtained within 20 minutes (6), an important issue when evaluating organ donors. The MEGX test also appears attractive for children; indeed, Gremse et al. found that the MEGX test correlated with a validated composite score in 28 children with chronic liver disease and detected deterioration earlier than clinical signs and symptoms (12). Is this then the panacea that true believers in quantitative function testing have been waiting for? Before addressing this question one must first consider the processes which lead to MEGX formation. Although MEGX formation has been found to correlate with lidocaine clearance (6), the processes governing this metabolic clearance are quite complex. Lidocaine is a drug with a high first-pass extraction (17); therefore, any intervention altering hepatic perfusion will interfere with its clearance (17) and thereby
with MEGX formation. Oellerich et al. felt that since only ICG retention and MEGX formation predicted survival in their cirrhotic patients (9-11), the flowdependence of lidocaine clearance was an important advantage of the test and the impairment observed in liver transplant candidates was mainly due to portosystemic shunting (11). However, the concept of flow- and enzyme-limited hepatic clearance (18) loses its meaning in liver disease. Thus, in patients with advanced liver disease, lidocaine clearance is independent of blood flow (19), and, comparison of mild and severe liver disease may measure different processes. This could explain the disappointing performance of the test in populations including patients with mild and severe liver disease (1,13). Second, lidocaine is transported in blood bound to c~l-acid glycoprotein, an acute phase reactant, u l-Acid glycoprotein and - - therefore protein binding of lidocaine - - is reduced in cirrhosis (20); a situation which could be altered by infections and stress, however, thus potentially affecting test results even when there is no change in liver function. Furthermore, the tissue distribution of lidocaine is a complex process which varies with serum levels (17), and the extent to which altered body composition of cirrhotic patients alters distribution phenomena remains largely unexp.lored. The de-ethylation of lidocaine to MEGX is a cytochrome P-450-dependent process. The cytochrome P-450 isozymes responsible for MEGX formation are susceptible to enzyme-inducing and -inhibiting agents (17) which indeed, has been shown to have a possible effect of MEGX formation in pediatric liver donors (16). Smoking increases the clearance of lidocaine (21) but does not appear to affect MEGX formation at 15 min (9). A formal analysis of MEGX formation and disposition in smokers and non-smokers has not yet been presented, however, and it remains unclear whether separate normal values must be established for smokers and non-smokers. Cytochrome P-450IIIA4 is the main isozyme responsible for MEGX formation in man (22) and widely varying values (over a 9-fold range) were found in human microsomes. At present it is unclear whether this is due to environmental and/or genetic influences. Cytochrome P-450IIIA4 is also largely responsible for cyciosporine A metabolism, which could be of particular interest in transplant candidates and organ donors if the MEGX test were shown to predict cyclosporin clearance like the erythromycin breath test (23). Finally, when evaluating quantitative liver function tests the safety must be considered. This is particularly important for the MEGX test since it has been proposed
6
J. REICHEN
TABLE I Properties of different quantitative liver function tests according to the five criteria (Ease of performance, kinetic properties, potential for interactions, safety and prognostic value) discussed in the text
Test
Ease of performance
MEGX GECa ABTa 1CGa Antipyrine Coffeine
Patient
Analysis
Kinetics
Interactions
Safety
Prognostic value
simple complex simple complex simple simple
simple simple complex simple complex simple
complex simple complex simple simple simple
many none many few many many
?b yes ?b ?h ?h yes
insufficient data 4-c 4-(' 4-(' insufficient data insufficient data
aGEC, galactose elimination capacity; ABT, aminopyrine breath test: ICG, indocyanine green clearance or retention. bThe safety of these compounds has not been fully established: for details on MEGX, please refer to the text. Aminopyrine and antipyrine have been reported to induce agranulocytosis after prolonged use but no adverse effects have ever been observed in the test situation. Dose-dependent pseudoallergy has been reported after indocyanine green administration (25) but this occurrency appears extremely rare. cA prognostic value either alone or as part of a score has been found by some but not all investigators.
as a quantitative liver function test in pediatrics (12). Fatal adverse reactions to lidocaine have occurred but are almost always d o s e - d e p e n d e n t (17); serum levels leading to respiratory arrest, convulsions or cardiac/ circulatory c o m p r o m i s e should not be attained by the dose (1 mg/kg) currently used. Fatal allergic reactions to lidocaine have been described but are exceedingly rare (24). Mild side effects were noted in some o f the published studies (2,13) and a 'severe" adverse reaction was reported by Stremmel et al. but details were not given (13). F r o m the above discussion, several desirable p r o p e r ties for a quantitative liver function test emerge: 1.
2.
3.
4. 5.
The test should be easy to perform both for the patients (number o f samples, need for venous access, etc.) and with analysis. The kinetics o f the test c o m p o u n d should be well characterized, not too complex and preferably be determined by only one process. There should be no interactions with concomitant medications, no m a j o r other environmental (diet, nutritional state, etc.) influences and no m a j o r genetic heterogeneity in the p o p u l a t i o n studied. The test substance should be safe. The test should provide prognostic information.
The properties o f some o f the most p o p u l a r q u a n t i t a tive liver function tests these four criteria are listed in Table 1. A l t h o u g h this review c a n n o t c o m p a r e the merits o f scores with those o f quantitative testing, Table 1 appears to answer the question o f whether this new test is the panacea h o p e d for; the answer is clearly no.
The M E G X test may a l r e a d y have some merits in children and in organ donors. However, the unresolved questions addressed a b o v e require a d d i t i o n a l studies which should address the following questions: 1.
2.
3.
W h a t is the clearance o f M E G X alone? C o u l d a d m i n i s t r a t i o n o f M E G X instead o f its precursor lidocaine simplify the unresolved kinetic issues? W h y is there m a r k e d heterogeneity in M E G X f o r m a t i o n o f h u m a n microsomes? Does this affect the M E G X test? Finally, large, prospective multicenter studies with a p p r o p r i a t e statistical analysis are needed to answer the basic question o f all quantitative liver function tests, namely whether they are superior to scores with respect to p r o g n o s t i c a t i o n in endstage liver disease.
Acknowledgments S u p p o r t e d by a grant from the Swiss N a t i o n a l F o u n dation for Scientific Research (32.30168.90).
References I
Meyer-WyssB, Renner E. Luo H. Scholer A. Assessment of lidocaine metabolite formation in comparison with other liver function tests. J Hepatol 1993; 19: . 2 Huang YS, Lee SD, Deng .IF, et al. Measuring lidocaine metabolite - - monoethylglycinexylidide as a quantitative index of hepatic function in adults with chronic hepatitis and cirrhosis. J Hepatol 1993; 19:. 3 Forrest JAH, Finlayson NDC, Adjepon-Yamoah KK, Prescott LF. Antipyrine, paracetamol and lignocaine elimination in chronic liver disease. Br Med J 1977: i: 1384-7. 4 Colli A, Buccino G, Cocciolo M, Parravicini R, Scaltrini G. Dis-
7
MEGX TEST IN HEPATOLOGY position of a flow-limited drug (lidocaine) and a metabolic capacity-limited drug Itheophylline) in liver cirrhosis. Clin Pharmacol Ther 1988: 44: 642-9. 5 Pomier-Layrargues G. Huet PM, Infante-Rivard C. et al. Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic encephulopathy in cirrhotic patients following elective end-to-side portacaval shunt. Hepatology 1988: 8: 1506-10. 6 Oellerich M, Raude E, Burdelski M. et al. Monoethylglycinexylidide formation kinetics: A novel approach to assessment of liver function. J Clin Chem Biochem 1987: 25: 845-53. 7 Oellerich M. Ringe B. Gubernatis G. et al. Lignocaine metabolitc formation as a measure of pre-transplant liver function. Lancet 1989: i: 640-2. 8 Burdelski M, Oellerich M, Lamesch P, et al. Evaluation ofquantitative liver function tests in liver donors. Transplant Proc 1987: 19: 3838-9. 9 Oellerich M, Burdelski M. Lautz H-U. Schulz M, Schmidt F-W. Herrmann h. Lidocaine metabolite formation as a measure of liver function in patients with cirrhosis. Ther Drug Monit 1990: 12: 219-26. 10 Oellerich M, Burdelski M. Lautz H-U, Binder L, Pichlmayr R. Predictors of one-year pretransplant survival in patients with cirrhosis. Heptalogy 1991: 14: 1029-34. 11 Oellerich M. Burdelski M, Lautz H-U, et al. Assessment of pretransplant prognosis in patients with cirrhosis. Transplantation 1991: 51: 801-6. 12 Gremse AD, A-Kader HH, Schroeder TJ. Balistreri WF. Assessment of lidocaine metabolite formation as a quantitative liver function test in children. Hepatology 1990: 12: 565-9. 13 Stremmel W, Wojdat R, Groteguth M. et al. Leberfunktionstests im klinischen Vergleich. Z Gastroenterol 1992: 30: 784-90. 14 Gross JB, Reichen J, Zelmer T, Zihamermann A. The evolution of changes in quantitative liver function tests in a rat model of
15
16 17 18 19 20
21 22 23
24 25
cirrhosis: Correlation with morphometric measurement of hepatocyte mass. Hepatology 1987', 7: 457-63. Reichen J, Widmer T, Cotting J. Accurate prediction of death by serial determination of the galactose elimination capacity in primary biliary cirrhosis - - A comparison with the Mayo model. Hepatology 199[; 14: 504-10. Rossi SJ, Schroeder TJ, Vine WH. et al. Monoethylg[ycinexylide formation in assesing pediatric donor liver function. Ther Drug Mon 1992; 14: 452-6. Benowtiz NL, Meister W. Clinical pharmacokinetics of lignocaine. Clin Pharmacokin 1978; 3: 177-201. Wilkinson Gr, Shand DG. A physiologic approach to hepatic drug clearance. Clin Pharmacol Ther 1975: 18: 377-90. Huet PM, Villeneuve JP. Determinants ofdrug disposition in patients with cirrhosis. Hepatology 1983: 3: 913-8. Barry M, Keeling PWN, Weir D, Feely J. Severity of cirrhosis and the relationship ofalpahl-acid glycorpotein concentration to plasma protein binding of lidocaine. Clin Pharmacol Ther 1990: 47: 366-70. Huet PM, Lelorier J. Effects ofsmoking and chronic hepatitis B on lidocaine and indocyanine green kinetics. Clin Pharmacol Ther 1980: 20: 208-15. Bargetzi MJ, Aoyama T, Gonzalez F J, Meyer UA. Lidocaine metabolism in human liver microsomes by cytochrome P450111A4. Clin Pharmacol Ther 1989; 46: 521-7. Turgeon DK, Normolle DP, Leichtman AB, Annesley TM, Smith DE, Watkins PB. Erythromycin breath test predicts oral clearance of cyclosporine in kidney transplant recipients. Clin Pharmacol Ther 1992: 52: 471-8. Strunin L. Local Anesthetics. Meyler's side effects of drugs. Amsterdam: Excerpta Medica 1975. 256-61. Speich R, Saesseli B, Hoffmann U. Neflel K, Reichen J. Anaphylactoid reactions after indocyanine-green administration. Ann lnt Med 1988: 109: 345-6.