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Vol. 162 No. 19, October 28, 2002 |
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Original Investigation |
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Racial and Ethnic Differences in Alcohol-Associated Aspartate Aminotransferase and  -Glutamyltransferase Elevation
Scott H. Stewart, MD, MS
Arch Intern Med. 2002;162:2236-2239.
ABSTRACT
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Background Recent analyses have confirmed that Hispanic and black non-Hispanic
Americans are at an increased risk for death from liver cirrhosis. The reasons
for this are unknown. As a common cause of cirrhosis, differing sensitivities
to alcohol-related hepatocellular injury may play a role. This study compared
racial and ethnic aspartate aminotransferase and  -glutamyltransferase
level elevations within alcohol-drinking categories.
Methods A cross-sectional analysis of adult subjects from the Third National
Health and Nutrition Examination Survey. Logistic regression models were used
to estimate the risk for elevation of aspartate aminotransferase and -glutamyltransferase
levels among Mexican American and black non-Hispanic subjects compared with
white non-Hispanic subjects within categories of alcohol use. Adjustment was
made for age, sex, exposure to hepatitis C and B, and body mass index.
Results Among current drinkers, black non-Hispanic and Mexican Americans were
more likely to have a 2-fold elevation in aspartate aminotransferase levels
when compared with white non-Hispanic Americans. This was most pronounced
in the highest-frequency drinkers (Mexican Americans: odds ratio, 9.1 [95%
confidence interval, 3.9-21.0]; and black non-Hispanic Americans: odds ratio,
3.1 [95% confidence interval, 1.4-6.8]). No racial and ethnic differences
were apparent among current abstainers. A similar pattern was found for 2-fold -glutamyltransferase
level elevations.
Conclusions Among current drinkers, Mexican and black non-Hispanic Americans may
have an increased risk for hepatocellular injury. These results require confirmation
in other study populations for whom validated measures of quantity and pattern
of drinking exist.
INTRODUCTION
RECENT ANALYSES1-2 of death
certificate data have demonstrated that age-adjusted cirrhosis-related mortality
is higher in Hispanic and black non-Hispanic Americans compared with white
non-Hispanic Americans. The reason for this is not known, and may include
differences in alcohol consumption, differences in access to care, or other
causes. However, to significantly influence population-based estimates for
death rates, the cause or causes must be prevalent in the population. The
most common causative agent is alcohol, but reliable data from the National
Longitudinal Alcohol Epidemiologic Study3 have
demonstrated that the prevalence of heavy drinking in the population is similar
among various racial and ethnic groups. If alcohol were a cause of the observed
differences in cirrhosis-related mortality, then alcohol use would have to
represent a higher risk for cirrhosis in Hispanic and black non-Hispanic Americans.
This study estimates the potential contribution of alcohol sensitivity to
cirrhosis-related mortality disparities by evaluating racial and ethnic differences
in the likelihood of hepatocellular injury associated with various levels
of alcohol use. Aspartate aminotransferase (AST) was chosen as the primary
marker for hepatocellular injury because it is relatively more specific than
other liver enzymes for detecting alcohol-induced hepatocyte necrosis.4 -Glutamyltransferase (GGT) was also analyzed
as an additional marker for alcohol-induced hepatotoxicity. If racial and
ethnic differences exist, sensitivity to the hepatotoxic effects of alcohol
would be supported as a possible independent contributor to cirrhosis-related
mortality disparities.
PARTICIPANTS AND METHODS
This study was an analysis of survey data from the Third National Health
and Nutrition Examination Survey (NHANES III). NHANES III was conducted by
the National Center for Health Statistics in 2 phases, from October 18, 1988,
through October 24, 1991, and from September 20, 1991, through October 15,
1994. Data were collected during several sessions, including interview, examination,
and laboratory components. The complex sampling design allows estimates for
the noninstitutionalized, civilian, US population and for white non-Hispanic,
black non-Hispanic, and Mexican Americans. Full details of the NHANES III
design have been discussed elsewhere.5 For
the AST analysis, subjects were restricted to adults (aged  17 years) for
whom alcohol use data, AST measurement, and covariate data were available.
The final sample size was 15 774 persons. The GGT measurement was initiated
in the later stages of NHANES III, and the sample size for this analysis was
smaller as a result (n = 12 288).
The outcome of primary interest was the probability of having an elevated
AST level. This was defined as greater than the race- and ethnicity-adjusted
95th percentile, and greater than 2 times the adjusted 95th percentile. The
2-fold elevation was chosen because this would likely correlate more strongly
with hepatic inflammation,6-7 whereas
the 95th percentile cutoff may overemphasize clinically insignificant differences
in race- and ethnicity-specific alcohol and AST associations. Separate analyses
were conducted for each definition of AST elevation. Adjusting the 95th percentile
for race and ethnicity was necessary, because black non-Hispanic, white non-Hispanic,
and Mexican Americans had significantly different AST distributions (by 1-way
analysis of variance on the normally distributed natural logarithm of AST).
These different distributions have been detected in other study populations.8 Mean differences, however, were quite small (1-2 U/L
after exponentiation of the mean logarithme values).
The 95th percentile values were determined in the unweighted samples, because
the weighting is intended to estimate means rather than medians. These differed
more substantially (34, 41, and 46 U/L for white non-Hispanic, black non-Hispanic,
and Mexican Americans, respectively). This may merely reflect different sample
sizes, which were smaller for black non-Hispanic Americans (n = 4261) and
Mexican Americans (n = 4419) than for white non-Hispanic Americans (n = 6471)
(the remaining 623 subjects were members of other ethnic groups for whom results
are not reported because of small sample sizes). Subjects were classified
as having an elevated AST level if their measured levels were greater than
1 and 2 times their specific racial and ethnic group 95th percentiles, respectively.
The main predictor for AST elevation was race and ethnicity, and analyses
were stratified by alcohol use categories. Adjustment was made for age, sex,
hepatitis C antibody positivity, hepatitis B surface antigen positivity, and
body mass index.9 Racial and ethnic groups
included black non-Hispanic, Mexican, and white non-Hispanic Americans. For
all risk estimates, the white non-Hispanic group was used as a reference.
Alcohol use categories were frequency measures determined from a simple summation
from the response to 3 questions in the NHANES III household interview. These
questions determined how many times in the past 30 days the following had
been consumed: (1) beer or lite beer; (2) wine, wine coolers, sangria, or
champagne; and (3) hard liquor, such as tequila, gin, vodka, scotch, rum,
whiskey, and liqueurs. To make population estimates for categories of alcohol
use, several classifications were constructed. These included abstainers and
frequencies of 1 to 9, 10 to 29, and 30 or greater drinking episodes. Age
and body mass index (calculated as the weight in kilograms divided by the
square of height in meters) were approximately normally distributed and were
included as continuous variables. Hepatitis C antibody and hepatitis B surface
antigen were considered positive for positive and indeterminate results.
Multivariate logistic regression models were analyzed to provide odds
ratios (ORs) for AST level elevation for the racial and ethnic groups, adjusting
for the remaining covariates. Analyses were stratified by alcohol use category.
Interactions of race and ethnicity with the remaining covariates were analyzed
and were largely insignificant (race and ethnicity with sex, P = .95; race and ethnicity with body mass index, P = .59; and race and ethnicity with hepatitis C antibody, P = .86). The exception was the interaction of race and ethnicity with
hepatitis B surface antigen (P = .01). On closer
inspection, this was because few Mexican Americans were positive for the hepatitis
B surface antigen, none of whom had a 2-fold AST level elevation. This interaction
was not included in the analyses.
An AST level elevation is not a specific marker for alcohol-induced
hepatitis. However, more specific markers, such as the AST–alanine aminotransferase
ratio, would not be sufficiently sensitive for use in this population-based
sample. For example, of 15 774 subjects, only 24 had an alanine aminotransferase
level greater than the 95th percentile coupled with an AST–alanine aminotransferase
ratio of at least 2. To provide additional epidemiologic evidence for or against
racial and ethnic differences in sensitivity to the hepatotoxic effects of
alcohol, an additional analysis was performed on the odds for a 2-fold or
greater elevation in GGT level. For the overall sample, a wide racial and
ethnic variation in the distribution of GGT levels was found (95th percentile:
68 U/L in white non-Hispanic Americans, 94 U/L in Mexican Americans, and 107
U/L in black non-Hispanic Americans). Because of this large variation, GGT
elevation was not adjusted for racial and ethnic differences in enzyme distribution,
and was defined as a level of 2 times the overall population 95th percentile.
The 95th percentile was equal to 88 U/L. While this decision increased the
overall probability for a GGT elevation among non-Hispanic black and Mexican
Americans, the pattern of GGT elevation within alcohol strata was of greater
interest than the actual magnitude of the increased risk. A pattern of increasing
risk for black non-Hispanic and Mexican Americans in more frequent drinking
strata would support the hypothesis of racial and ethnic differences in alcohol
sensitivity, and the absence of such a pattern would provide evidence against
differences in hepatic sensitivity to alcohol. The GGT level was not measured
at the start of NHANES III, and was only available for a portion of the adult
population. This incomplete sampling resulted in multiple NHANES III strata
containing data on GGT from only one primary sampling unit. To complete the
analysis, the first observations from such strata were collapsed into a second
primary sampling unit. For this reason, the confidence intervals resulting
from the GGT analysis may not accurately reflect the range of possible values
in the population, and should be considered exploratory. The point estimates,
however, were valid for the US population. Logistic regression was used to
measure ORs for elevated GGT level using the same approach and same covariates
as described for AST level elevation.
Intercooled Stata, version 7 (Stata Corp, College Station, Tex), was
used for all analyses, with appropriate person-level weighting and adjustment
for the complex survey design.
RESULTS
Sample characteristics from the analysis of AST differences are listed
in Table 1. Demographically, white
non-Hispanic subjects were older and Mexican Americans had a slightly higher
proportion of men. Racial and ethnic representation within the various drinking
categories differed statistically but was clinically similar, although among
current drinkers, Mexican Americans were somewhat less likely to drink frequently.
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Table 1. Sample Characteristics*
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The results of the stratified regression analyses for AST differences
are shown in Table 2. The ORs
for AST level at the 95th percentile or greater were not significantly different
from 1.0, except in the highest drinking frequency category. At this level
of drinking, Mexican Americans had a significantly elevated risk for AST level
elevation compared with white non-Hispanic Americans, and black and white
non-Hispanic Americans had a statistically similar risk. For 2-fold AST elevation,
there was a consistent trend toward increased risk for black non-Hispanic
and Mexican Americans that was proportional to the frequency of alcohol drinking.
This was statistically significant for black non-Hispanic Americans in the
highest frequency category, and significant for Mexican Americans in all current
drinking categories. No increased risk was seen for abstainers. The ORs in
all current drinking categories were highest for Mexican Americans, intermediate
for black non-Hispanic Americans, and lowest for white non-Hispanic Americans.
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Table 2. Odds Ratios for AST Level Elevation by Race and Ethnicity
Within Alcohol Use Categories*
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Results for the GGT analysis are shown in Table 3. Similar to the AST analysis, this also demonstrated increased
risks for 2-fold GGT level elevation for Mexican Americans and black non-Hispanic
Americans compared with white non-Hispanic Americans among current drinkers.
The relative risk increased with increasing frequency of alcohol consumption.
No increased risk was seen among abstainers. This result was surprising because
of the operationalization of elevated GGT level as 2 times the overall sample
95th percentile, an approach that was anticipated to result in elevated odds
for black non-Hispanic and Mexican Americans regardless of drinking status.
This suggests that the differences in enzyme distribution for the overall
sample are due to or strongly associated with alcohol use. As a consequence
of the partial sampling of GGT in NHANES III and the analysis method, the
confidence intervals provided in the table should be regarded as exploratory
rather than firm and the statistical significance of the GGT differences is
difficult to comment on.
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Table 3. Odds Ratios for 2-Fold GGT Level Elevation by Race and Ethnicity
Within Alcohol Use Categories*
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COMMENT
This study evaluated racial and ethnic differences in the probability
of AST and GGT level elevations in the US population stratified by categories
of alcohol use. The results suggest that among current drinkers, Mexican Americans
and black non-Hispanic Americans may have a higher risk for hepatocellular
injury when compared with white non-Hispanic Americans who drink a similar
amount of alcohol. This pattern is consistent with the observed racial and
ethnic differences in liver cirrhosis–related mortality in the United
States.
The hypothesis that the same degree of alcohol consumption may carry
a higher risk for liver injury based on an individual's racial and ethnic
heritage is not new, and may be due to genetic determinants. Such a possibility
is consistent with many findings regarding genetically determined susceptibility
to alcohol-related morbidity and cardiovascular benefits. A recent report,10 for example, has demonstrated that genetic differences
in alcohol dehydrogenase and aldehyde dehydrogenase levels were associated
with different patterns of liver injury, pancreatitis, and esophageal cancer
susceptibility. Other studies have associated alcoholic cirrhosis with HLA
subtypes11 and protection from myocardial infarction
with alcohol dehydrogenase polymorphisms.12 A
comparison of Japanese and US persons who abuse alcohol demonstrated different
susceptibilities to liver injury.13 Racial
differences in alcohol-associated AST levels may be due to variations in alcohol
dehydrogenase, acetaldehyde dehydrogenase, or other enzymes for which race
serves as a marker.14 Alcohol dehydrogenase
and acetaldehyde dehydrogenase polymorphisms differ between black non-Hispanic
and white non-Hispanic Americans15-16;
however, Mexican Americans have not been similarly examined. From an ethnic
perspective, environmental factors such as diet or other culturally shared
exposures might also contribute to differences in sensitivities to alcohol
toxicity.
Several limitations of this analysis need to be addressed. The point
estimates for 2-fold enzyme elevations have fairly wide confidence intervals.
Although the estimated ORs suggest racial and ethnic differences, the true
magnitude may be negligible or large. An additional limitation is the nature
of the alcohol measure. This is a frequency measure rather than a quantity
measure, because the serving size was not estimated. While frequency is likely
correlated with quantity, it is possible that the average quantity consumed
per drinking episode differs between racial and ethnic groups. If this were
true, the OR estimates would be biased. The pattern of drinking is also not
accurately measured. If drinking pattern affects the risk of disease and systematically
differed between racial and ethnic groups, the OR estimates may again be biased.
An additional source of error may lie in the differing baseline AST distributions
among the groups. While statistically significant, this may not be clinically
significant, amounting to mean differences of 1 to 2 U/L. The 95th percentiles
differed by up to 12 U/L, which may merely reflect sample size differences
between the racial and ethnic groups rather than the true distributions. If
this were the case, this analysis would underestimate the ORs by erroneously
assigning higher values for elevated AST level to black non-Hispanic and Mexican
Americans. The GGT distributions were also higher in black non-Hispanic and
Mexican Americans compared with white non-Hispanic Americans. This may have
contributed to the higher odds for 2-fold GGT elevations through another mechanism,
but the absence of increased risk among abstainers and the increasing odds
among more frequent drinkers suggest that alcohol contributes to these differences.
Finally, as with any cross-sectional study, confounding from unmeasured factors
is possible. The frequency of alcohol use may be serving as a marker for an
associated, but independent, cause of enzyme elevation.
In conclusion, this study supports the hypothesis that, on average,
Mexican and black non-Hispanic Americans may be more susceptible to alcohol-induced
hepatocellular injury than white non-Hispanic Americans. Because frequent
alcohol use is prevalent in the United States, such racial and ethnic differences
may contribute to disparities in cirrhosis-related mortality rates. Findings
from this study require duplication in additional study populations, preferably
with valid measurement of quantity and pattern of consumption.
AUTHOR INFORMATION
Accepted for publication April 3, 2002.
Corresponding author: Scott H. Stewart, MD, MS, Department of Medicine,
Erie County Medical Center, 462 Grider St, Buffalo, NY 14215 (e-mail: ss243{at}buffalo.edu).
From the Division of General Internal Medicine, School of Medicine
and Biomedical Sciences, State University of New York at Buffalo.
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