Clinical Chemistry 43: 1952-1957, 1997;
(Clinical Chemistry. 1997;43:1952-1957.)
© 1997 American Association for Clinical Chemistry, Inc.
Assessment of monoethylglycinexylidide as measure of liver function for patients with chronic viral hepatitis
Ronald J. Elin1,a,
Michael W. Fried2,4,
Maureen Sampson1,
Mark Ruddel1,
David E. Kleiner3 and
Adrian M. DiBisceglie2,5
1
Clinical Pathology Department, Warren Grant Magnuson Clinical Center,
2
Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and
3
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
4
Current address: Robert W. Woodruff Health Sciences
Center, Emory University School of Medicine, Atlanta, GA 30322.
5
Current address: Department of Internal Medicine, St.
Louis University Health Sciences Center, 1402 South Grand Blvd., St.
Louis, MO 63104.
a Author for correspondence: National Institutes of Health, Bldg. 10, Rm. 2C-306, 10 Center Dr.—MSC 1508, Bethesda, MD 20892-1508. Fax 301-402-1612; e-mail relin{at}nih.gov
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Abstract
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The liver metabolizes lidocaine by oxidative deethylation to form
monoethylglycinexylidide (MEGX), an analyte proposed as an index of
liver function. We determined MEGX and lidocaine serum concentrations
with the TDx (Abbott Laboratories) at baseline and 15, 30, 60, and 90
min after the intravenous administration of lidocaine (1 mg/kg),
analyzing specimens from 12 apparently healthy volunteers and 40
patients with chronic viral hepatitis diagnosed by liver biopsy and
serum tests. The patients were grouped on the basis of the histology
activity index. The following laboratory tests were performed on serum
specimens from all subjects: albumin (ALB), alanine aminotransferase
(ALT), aspartate aminotransferase (AST), alkaline phosphatase, total
bilirubin, and prothrombin time. The results showed no significant
difference among the four groups for the concentrations of MEGX,
lidocaine, and lidocaine/MEGX at the four time points. However, the
concentrations of ALB, ALT, AST, AST/ALT, and prothrombin time were
substantially different among the four groups. Thus, we conclude that
assay of MEGX in our patients with chronic viral hepatitis did not
contribute to the assessment of liver function when compared with
apparently healthy volunteers and traditional tests of liver
function.
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Introduction
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Chronic viral hepatitis, which results from chronic infection with
hepatitis B, hepatitis C, or delta hepatitis, is often a progressive
disease that can lead to cirrhosis and its attendant complications of
liver failure and portal hypertension. In clinical practice, a liver
biopsy in conjunction with biochemical variables is used to determine
the degree of liver injury and the prognosis related to these diseases.
However, to what extent these variables estimate the true functional
hepatic reserve at any time is controversial. In addition, evidence of
hepatic synthetic dysfunction, such as decreased serum albumin
(ALB)1
concentration and prolonged prothrombin time, occurs only late in the
course of chronic liver disease, when the hope for improvement from any
antiviral therapy is limited. Thus, a test that measures more subtle
degrees of hepatic dysfunction that are present before the onset of
decompensated cirrhosis may be useful clinically.
Numerous tests of functional hepatic reserve, such as galactose
elimination capacity (1), antipyrine breath test
(2), and indocyanine green clearance (3),
that utilize the role of the liver as an organ for detoxifying
xenobiotics via the cytochrome P-450 mixed-function oxidase system,
have been investigated previously although their clinical utility has
been limited. Lidocaine, a commonly used local anesthetic and
antiarrythmic agent, is eliminated from the body primarily by hepatic
metabolism to monoethylglycinexylidide (MEGX) (4).
Lidocaine exhibits a first-dash pass effect because it is rapidly taken
up and metabolized by the microsomal cytochrome P-450 enzyme system
(5). Patients with chronic liver disease show a reduced
plasma clearance and prolongation of the plasma half-life of lidocaine
(6). Thus, after the intravenous administration of
lidocaine, the rate of decrease of the serum lidocaine concentration or
the rate of increase of the major metabolite, MEGX, may serve as a test
of liver function. Determination of the formation of MEGX may be useful
as a predictor of short-term survival in cirrhotics before
transplantation and may predict donor organ viability
(7)(8)(9)(10)(11)(12)(13). Recently, the determination of MEGX has been
proposed as a quantitative test of liver function in patients with
chronic hepatitis and cirrhosis (9)(10)(11). To evaluate the
clinical value of this proposed test for liver function, we determined
the MEGX concentration in apparently healthy volunteers and patients
with chronic viral hepatitis and compared the results with liver
biopsies and established clinical laboratory tests of liver disease in
patients.
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Materials and Methods
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patients
We studied 40 patients with chronic viral hepatitis (mean age 42
years, range 23–62 years, 9 women and 31 men); 23 patients were
chronically infected with hepatitis B, 14 with hepatitis C, and 3 with
delta hepatitis. The diagnosis of chronic viral hepatitis was based on
an increase in the serum alanine aminotransferase (ALT, EC 2.6.1.2)
concentration for the previous 6 months and serological testing.
Patients with a long history of alcohol use or taking medication that
might induce microsomal enzymes were excluded from the study. The
control group for the study consisted of 12 apparently healthy
volunteers (mean age 31 years, range 18–55 years, 2 women and 10 men).
Informed consent was obtained from all patients and apparently healthy
volunteers before participation in the study. The protocol for the
study was approved by the Institutional Review Board of the National
Institute of Diabetes and Digestive and Kidney Diseases.
histological analysis
All hepatitis patients in the study had a percutaneous liver
biopsy within 1 week of MEGX testing. Each biopsy specimen was reviewed
and scored by an investigator (M.W.F.) and a pathologist (D.E.K.) with
the scoring system established by Knodell et al. (14) and
referred to as the histology activity index (HAI): periportal injury,
piecemeal necrosis (0–10, PP score), portal inflammation (0–4, P
score), lobular injury (0–4, L score), and fibrosis (0–4, F score).
The maximum total score is 22 (sum of the maximum four individual
scores), but the maximum score found in this study was 18. Patients
were grouped on the basis of their HAI score: mild (HAI 0–6, mean age
41 years, range 27–59 years, 1 woman and 4 men), moderate (HAI 7–12,
mean age 39 years, range 23–54 years, 6 women and 15 men), and severe
(HAI 13–22, mean age 46 years, range 28–62 years, 2 women and 12
men).
megx testing and laboratory analyses
MEGX testing was performed on all patients after an overnight
fast. Patients in the supine position were given a dose of 1 mg/kg of
20 g/L lidocaine-HCl injected slowly into a peripheral vein over a
period of ~1 min. Blood samples anticoagulated with EDTA were
obtained just before injection and at 15, 30, 60, and 90 min after
lidocaine administration. The plasma lidocaine and MEGX concentrations
were measured by fluorescence polarization immunoassay with an Abbott
TDx analyzer (Abbott Laboratories). The among-day CV for MEGX at a
concentration of 98.7 µg/L (n = 22) was 7.7%; for lidocaine at
730 µg/L it was 2.6%. The concentration of MEGX before injection
(background) was undetectable in all individuals.
Before the injection of lidocaine, the following tests were performed
on a serum specimen from each patient and apparently healthy volunteer
with the Hitachi 736 (Boehringer Mannheim): ALT, aspartate
aminotransferase (AST, EC 2.6.1.1), ALB, alkaline phosphatase (EC
3.1.3.1), and total bilirubin. Further, the prothrombin time was
determined by photo-optical clot detection with the Coag-A-Mate X2
(Organon Technika).
statistics
The results for MEGX and lidocaine concentrations and the
lidocaine/MEGX ratio are expressed as the mean ± SEM (Table 1
). We calculated MEGX and lidocaine indices on the basis of the
area under the curve (MEGX or lidocaine concentration at four time
points) for each patient and apparently healthy volunteer. Further,
analysis of variance (ANOVA) was used to compare four groups with the
MEGX and lidocaine concentrations, the lidocaine/MEGX ratio at 15 min,
and the indices (Table 1
) and with traditional liver function tests
(Table 2
). Log transformation was used on all chemical tests except ALB
and the lidocaine/MEGX ratio to normalize the data. If the ANOVA was
significant (P <0.05), we used Duncan Multiple Range Test
(15) to determine differences between groups. Groups shown
with the same letter are not significantly different from each other
(Table 2
). We compared the HAI and the four-component biopsy scores
comprising the HAI with the MEGX concentration at each time interval
and the index by pairwise regression analysis (Table 3
). A power analysis also was performed for the experimental
design to determine the probability of detecting a difference in the
concentration of MEGX, lidocaine, and the ratio at 15 min
(16).
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Table 1. Comparison of lidocaine and MEGX concentrations and their
ratio (mean ± SEM) among three groups with chronic viral
hepatitis on the basis of severity and apparently healthy
volunteers.
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Table 2. Comparison of traditional liver tests among three groups
with chronic active hepatitis on the basis of severity and apparently
healthy volunteers.
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Results
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There were no significant differences (P >0.05) among
the four groups (apparently healthy volunteers and patients with mild,
moderate, and severe hepatitis) for the MEGX and lidocaine
concentrations and lidocaine/MEGX results at all time intervals and
their indices (Table 1
). The mean and SEM of the MEGX concentration for
the three groups of hepatitis patients and apparently healthy
volunteers are shown in Fig. 1
. There was a progressive lowering of the curve for
hepatitis patients, going from mild to severe injury. The curve for
apparently healthy volunteers was similar to that for patients with
moderate hepatic injury, with all points for mild hepatic injury above
and severe hepatic injury below that of apparently healthy volunteers.
The power analysis with 80% power to find a difference among groups
indicated that a 20% difference in the mean is required for lidocaine,
a 50% difference for MEGX, and 70% difference in the ratio for
results at 15 min. Four (ALB, ALT, AST, and prothrombin time) of the
six traditional laboratory tests to assess liver function and the
AST/ALT ratio show a significant difference (P <0.01)
among the four groups (Table 2
). The best tests were ALB, ALT, AST, and
the AST/ALT ratio, which showed no overlap between apparently healthy
volunteers and the three groups of hepatic injury. The prothrombin time
results for apparently healthy volunteers overlapped with patients with
mild and moderate chronic hepatitis but did differ from patients with
chronic severe hepatitis. Two of the tests, total bilirubin and
alkaline phosphatase, did not differ significantly among the four
groups.
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Figure 1. The mean ± SEM of the MEGX concentration at 15, 30,
60, and 90 min after intravenous injection of 1 mg/kg lidocaine in
apparently healthy volunteers (triangle) and patients with
chronic viral hepatitis grouped on the basis of their HAI biopsy score:
mild (square), moderate (diamond), and severe
(circle).
The open symbols indicate individual values, the solid
symbols indicate the mean, and the bars indicate the
SEM.
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The MEGX concentration at the four sampling times and the index was
compared with the composite HAI biopsy score and its four components
(Table 3
). There was a significant correlation (P <0.04)
between the composite HAI biopsy score and the MEGX concentration at 15
and 60 min and the index. Four of the five MEGX variables correlated
significantly with either fibrosis or periportal injury and piecemeal
necrosis. Portal inflammation correlated with the MEGX concentration
only at 15 min, and there was no correlation of any of the MEGX
variables with lobular injury.
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Discussion
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For 70 years, the metabolism and excretion of several xenobiotics
have been used as a measurement of liver function with limited success.
One of the most widely used xenobiotics in the past,
bromsulfophthalein, is not used today because of the risk of fatal
hypersensitivity reactions. Several other xenobiotics (aminopyrine,
antipyrine, caffeine, galactose, indocyanine green, etc.) have been
evaluated but proven not to be superior to conventional clinical
laboratory tests (10)(11)(17). One
of the more recent xenobiotics proposed to assess liver function is
lidocaine and its metabolite MEGX. Do the properties of lidocaine and
MEGX differ from these other xenobiotics in such a way that the
metabolism and excretion of this compound by the liver will provide
useful clinical information about the function of this organ?
The use of lidocaine and MEGX to assess liver function was first
proposed by Oellerich et al. in 1987 (7). These authors
reported that the MEGX concentration obtained 15 min after lidocaine
injection was substantially lower in patients with liver cirrhosis and
correctly predicted success or failure of transplanted livers in the
majority of cases. Since that report, several studies, which had
inconsistent findings, have assessed the value of this test in
determining the suitability of the donor liver for transplantation
(5)(8)(12)(13)(18)(19).
The results of studies vary for the use of the MEGX test for the
assessment of liver function. Several studies of patients with
cirrhosis and viral hepatitis and children with liver disease have
found some value in the MEGX test for assessing liver function
(4)(5)(7)(9)(11)(20).
On the one hand, a study by Meyer-Wyss et al. (10)
concluded that the MEGX test "quantitates a very particular enzymatic
reaction which may not be representative for the functional reserve of
the entire organ." The results of the current study would support
this statement because we found no significant differences in MEGX and
lidocaine concentrations and lidocaine/MEGX ratio among the three
groups with progressive hepatitis based on the HAI and apparently
healthy individuals.
Why should the results of the current study and that by Meyer-Wyss et
al. (10) differ from several other studies? The important
factors that relate to this difference are the metabolism of lidocaine
and the classification and extent of liver impairment. The rate of
conversion of lidocaine to MEGX is related directly to the mass of
cytochrome P-450 in the liver. However, the mass of cytochrome P-450
varies among individuals on the basis of genetic heterogeneity
(21). Also several medications are known to induce the
cytochrome P-450 system, which will increase the rate of MEGX
production (21)(22). Gender is also a factor;
women have a lower concentration of MEGX at 15 min than men
(23)(24). Woman taking oral contraceptives
have a further reduction of their MEGX production (23).
The individual variables given above for the metabolism of lidocaine to
MEGX are the major factors relating to the broad range for the MEGX
concentration at 15 min in apparently healthy individuals found in the
current study, 18–137 µg/L (Fig. 1
). However, our findings were
similar to those of Oellerich et al. (7), who found that
the MEGX concentration in apparently healthy individuals at 15 min
varied between 15 and 130 µg/L (7). Many factors
independent of the disease process affect the rate of conversion of
lidocaine to MEGX by the liver. These nondisease factors erode the
accuracy and precision of this test to assess impaired liver function.
The calibrator for comparison of MEGX results varies among the studies
in the literature. Six of the studies
(4)(5)(9)(10)(11)(20) use
the Child–Pugh score (25) to grade the extent of the
liver disease (cirrhosis) for comparison with MEGX results. This
classification is based on a clinical component (ascites and
encephalopathy) and a laboratory component (total bilirubin, ALB, and
prothrombin time) and is used primarily in patients with cirrhosis. The
study by Gremse et al. (20)(26) used a
classification for pediatric patients based on a history of ascites and
laboratory tests (cholesterol, indirect bilirubin, and partial
thromboplastin time). Four of the studies
(7)(10)(11)(20)
documented the liver disease with a liver biopsy, but only the study by
Shiffman et al. (11) used the HAI for comparison with MEGX
results. However, these authors found that a given 15-min MEGX
concentration predicted the hepatic histology with the HAI, with a
sensitivity of only 55–60% and a specificity of only 18–46%
(11)(27). Thus, different variables (clinical
evaluation, laboratory tests, or liver biopsy) have been used as
calibrators to compare MEGX results. Few studies have used liver
histology to assess MEGX results; only one study used the HAI and found
poor detectability and specificity.
The type and extent of liver impairment are factors that affect the
clinical application of the MEGX test. Steatosis, the degree of hepatic
inflammation, and fibrosis may affect MEGX production independently
(27). The mean MEGX concentration in our patients with
severe hepatitis was 41.5 µg/L. In the study by Meyer-Wyss et al.
(10) with results similar to the current study, patients
were grouped on the basis of the Child–Pugh grading system into five
categories of increasing clinical severity of liver disease. For the
first three groups, the mean MEGX concentration was >40 µg/L, and
the last two groups had mean MEGX concentrations ~20 µg/L. However,
several of the other studies that found value in the MEGX test had
groups with severe liver disease in which the mean MEGX concentration
was <20 µg/L
(4)(5)(9)(11).
Shiffman et al. (11) found that severe life-threatening
complications of cirrhosis were observed only in patients with a MEGX
concentration <20 µg/L; at concentrations <10 µg/L, the 1-year
survival rate was only 50%. In our study five of our seven tests of
traditional liver function were able to discriminate between apparently
healthy volunteers and one or more of the three categories of patients
with hepatic injury when the MEGX test showed no difference. Thus, the
MEGX test may have value in the assessment of liver function in
patients with cirrhosis, but it is of little value in quantifying liver
function in patients who do not have end-stage liver disease.
The MEGX test at some time points does correlate with the HAI and
components of the HAI in our patients with chronic viral hepatitis. The
MEGX concentration at 15 min shows a significant inverse correlation
with the composite HAI and two of the components, portal inflammation
and periportal injury and piecemeal necrosis. Interestingly, the
fibrosis score did not show a correlation with the MEGX concentration
at 15 min (the usual time point for this test), but did at all other
time points. It may be that the lack of correlation with the fibrosis
score at 15 min was a result of nondisease factors in view of the
relatively mild degree of liver impairment of our patients. Schiffman
et al. (11) found a significant inverse correlation
(r = -0.72, P <0.005) for the change in
the 15-min MEGX concentration and the change in the HAI in 35 patients
studied before and after treatment. However, about half of their
patient population had cirrhosis with a mean MEGX concentration of
~20 µg/L. Thus, the MEGX concentration may relate to the HAI in
patients with advanced liver disease.
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Acknowledgments
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We thank Steven Banks for his assistance with the statistics for
this study.
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Footnotes
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1 Nonstandard abbreviations: MEGX, monoethylglycinexylidide; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; HAI, histology activity index; ANOVA, analysis of variance. 
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Top
Abstract
Introduction
