Serum aminotransferase activity and mortality risk in a United States community

Authors


  • Potential conflict of interest: Nothing to report.

Abstract

Serum aminotransferase [such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] is commonly used as an indicator of liver disease. The aim of the study was to determine the degree to which aminotransferase results are associated with increased mortality at the population level. All adult residents of Olmsted County, Minnesota, who had a health care encounter at Mayo Clinic, Rochester, in 1995 were identified and their AST or ALT results extracted from a laboratory database. These subjects were followed forward from January 1995 to April 2006 and their survival determined. To exclude patients with abnormal results because of a terminal illness, deaths within the first 2 years were excluded. The main outcome measure was survival. Standardized mortality ratios (SMRs) were calculated, based on Minnesota White death rates. During 1995, AST was measured at least once in 18,401 community residents, of whom 2,350 (13%) had results greater than the upper limit of normal (ULN). Of 6,823 subjects who had their ALT measured, 911 (13%) had results higher than ULN. Abnormal AST was associated with a significantly increased SMR (1.32 for 1–2× ULN and 1.78 for >2× ULN). SMR was also higher for abnormal ALT (SMR = 1.21 for 1–2× ULN and 1.51 for >2× ULN). In contrast, normal AST or ALT was associated with a risk of death lower than expected (SMR 0.95 for AST, 0.61 for ALT). Conclusion: Serum levels of AST and ALT obtained in a routine medical care setting are associated with future mortality in community residents. (HEPATOLOGY 2008;47:880–887.)

Serum aminotransferase activities, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), are commonly referred to as “liver enzymes,” because they are abundantly present within hepatocytes, catalyzing transfer of amino groups to generate products in gluconeogenesis and amino acid metabolism. Because these enzymes are released from damaged hepatocytes into the blood, their activities measured in the serum have been widely recognized as a tool to detect liver disease.1–3 Although used routinely in clinical practice for decades, their role as a predictor of mortality has not been examined until recently. A German study of male construction workers found that elevated AST was associated with increased mortality from all causes.4 Likewise, in a large population-based study from South Korea, serum ALT activity measured at baseline was correlated with subsequent mortality, and it was shown that elevated serum ALT was associated with a marked increase in mortality from liver disease.5 However, that particular study was conducted in an area endemic for hepatitis B virus and yet lacked information about hepatitis B virus in the study participants. Whether these data are applicable to the United States may be questionable.

This is important because data from the National Health and Nutrition Examination Survey (1999–2002) showed that the prevalence of elevated serum of AST or ALT in the United States was 9.8%, most of which could not be explained on the basis of easily identifiable liver disease such as hepatitis C or excessive alcohol consumption.6 Presumably, many Americans with abnormal aminotransferases have nonalcoholic fatty liver disease (NAFLD).7 Whereas NAFLD is an important source of morbidity and mortality from liver disease, it also may be an important indicator of increased cardiovascular risk mediated through metabolic consequences of insulin resistance.8, 9 Thus, aminotransferases may be an important indicator of health, yet the magnitude of their impact on mortality in the general population of the United States has not been established.

In this work, we use unique data resources available in Olmsted County, Minnesota, to evaluate the relation between serum aminotransferase activities and subsequent mortality. The aims of the study were (1) to describe the utilization of serum aminotransferase assessments in the community; (2) to determine whether abnormal aminotransferase results are associated with increased mortality; and (3) to explore correlation between aminotransferase results and causes of death.

Abbreviations

ALT, alanine aminotransferase; AST, aspartate aminotransferase; NAFLD, nonalcoholic fatty liver disease; REP, Rochester Epidemiology Project; SMR, standardized mortality ratios; ULN, upper limit of normal.

Patients and Methods

Data Sources and Elements.

Population-based epidemiologic research can be conducted in Olmsted County, Minnesota, because medical care is virtually self-contained within the community, and there are only a few providers. In fact, just 2 major health care providers serve the population, namely, the Mayo Medical Center and Olmsted Medical Center. Moreover, each of these providers uses a unit medical record whereby all (inpatient and outpatient) medical information for each individual resident of Olmsted County is accumulated in a single record. These distinct features of the health care environment in Olmsted County led to a creation of a unified medical index system (the Rochester Epidemiology Project, REP) by which the details of the medical care provided to Olmsted County residents can be studied.10 Thus, REP makes it possible to identify a group of patients with certain characteristics and follow them forward, assessing long-term outcomes such as mortality and causes of death.

Based on the REP database, all adult (age >18) Olmstead County residents were identified who had at least one healthcare encounter at any of the Mayo Clinic facilities in Olmsted County in calendar year 1995. Although Mayo has a well-established reputation as a quaternary referral center for a variety specialty and subspecialty conditions, it also delivers the majority of primary care to the local population: each year, approximately half the population of Olmsted Country is seen at one of the Mayo Clinic facilities for reasons such as pre-employment examinations, minor illnesses, sports physicals, and routine medical care.

The year 1995 was chosen to ensure at least 10 years of follow-up. These subjects' demographic information (age, sex, and race) was extracted from the database. Mayo's laboratory database (“Laboratory Information System”) was then queried to extract all AST and ALT data on the same individuals. In 1995, AST and ALT activities in the serum were assayed by colorimetric methods using commercial kits (Roche Diagnostics, Indianapolis, IN). The upper limit of normal (ULN) of AST was 31 IU/L for both men and women, whereas that for ALT was 45 IU/L for men and 29 IU/L for women. Based on the AST and ALT data, subjects were divided into 4 groups: (1) those who did not have their aminotransferases tested in 1995; (2) those whose results were less than the ULN; (3) those with results between 1 and 2 times the ULN; and (4) those with results higher than 2 times the ULN.

Survival Analysis.

Community residents thus characterized were followed forward in time for death. Because the study objective was to assess the correlation between aminotransferase results and long-term survival, subjects who died or were lost to follow-up within first 2 years were excluded, a priori, from further analysis. For example, because AST is also one of the “cardiac enzymes” that increases acutely in the setting of myocardial infarction, it is likely to be associated with high short-term mortality. In subjects who survived at least 2 years, the last day of known follow-up in the REP database was used to assess survival. Thus, survival analysis was conducted based on the date of death in those who died and the date of last follow-up in those who survived. In those who died, several sources of information, including institutional registration file, death certificates, and medical records, were used to ascertain the date of death and to determine the cause. Causes of death were classified into hepatobiliary (International Classification of Diseases version 9 codes: 006.3, 070.0–070.9, 155–156, 275.0–275.1, 277.3, 331.81, 452, 453.0, 456.2, 570–576, 751.6, 782.4, 789.1), cardiovascular (International Classification of Diseases version 9 codes: 390–459, 745–747, except 452, 453.0, 456.2, 572.1), and all others. Follow-up was ended as of April 2006.

The Kaplan-Meier method was used to estimate survival of community residents in the 4 groups according to the aminotransferase data. Standardized mortality ratios (SMRs) were calculated to determine the association between aminotransferase data and subsequent mortality, independent of age and sex. Mortality data of the reference population (that is, Minnesota whites) were obtained from the Minnesota State Department of Health.11 Based on these data, expected numbers of deaths were derived for age-specific and sex-specific strata. SMRs were calculated by the ratio between observed and expected numbers of deaths. Ninety-five percent confidence intervals were calculated assuming a Poisson error structure. To assess the overall relation between aminotransferase values and subsequent risk of mortality, generalized additive models were used to model a smooth but potentially nonlinear conformation.12, 13 Again, relative risk was calculated using the expected mortality based on the age-specific and sex-specific mortality rates for the Minnesota white population.

Results

During 1995, 54,586 residents (49% of community residents) had at least one healthcare encounter at any Mayo Clinic facility in Olmsted County. Of those, 7,404 residents who died or who moved from the community within the following 2 years were excluded according to the a priori inclusion criteria. Of the remaining 47,182 community residents, 18,401 (39.0%) had their AST measured and 6,823 (14.5%) had an ALT assessment. In 22,448 residents, either of the aminotransferases was measured, and 2,776 (5.9%) had both AST and ALT (Fig. 1).

Figure 1.

Study population.

Table 1 compares the characteristics of Olmsted County residents with respect to AST and ALT data. Individuals who did not have their AST measured were younger than those who did (P < 0.001), whereas the reverse was true with ALT (P < 0.001). Overall, there was female preponderance, except in those with abnormal AST results. Most of our study subjects were of a white race, although race data were not always available.

Table 1. Characteristics of Residents of Olmsted County, MN, According to Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) Results
 ASTALT
<ULN1–2× ULN>2× ULNNo Test<ULN1–2× ULN>2× ULNNo Test
  • *

    P < 0.05 compared with the respective <ULN group (Wilcoxon rank sum test).

  • P < 0.05 compared with the respective <ULN group (χ2 test).

  • % excluding missing race.

No.16,051 (34.0%)1,897 (4.0%)453 (1.0%)28,781 (61.0%)5,912 (12.5%)670 (1.4%)241 (0.5%)40,359 (85.5%)
Age (mean, SD)54.0 (18.6)56.2 (18.5)*50.7 (18.6)*41.2 (15.8)*43.5 (12.5)43.6 (13.1)46.0 (17.1)46.7 (18.7)*
Sex (% male)40.253.352.042.245.747.042.441.9
Race (%)        
 Caucasian96.594.390.695.798.295.792.595.6
 Asian/Pacific Is1.52.63.81.80.51.32.51.9
 African American0.81.02.10.90.31.10.51.0
 Native Am/Alaskan0.30.60.80.30.20.41.50.3
 Hispanic0.20.31.30.30.30.40.00.3
 Other0.71.21.31.00.51.13.00.9
Unknown/missing (n)27333438065101446133408047

Of the 18,401 residents with AST data, 16,051 (87.2%) had results within normal limits, 1897 (10.3%) between ULN and 2 times ULN, and 453 (2.5%) higher than 2 times ULN. The distribution of AST was skewed to the right, with a mean of 25.7 (±37.2) and median of 21.0 (range, 4–1860; interquartile range, 17–26). Individuals with the highest AST results were younger than the other AST groups. The proportion of nonwhites was higher among those with abnormal AST than among those with normal AST.

With regard to ALT, the result was within normal limits in 5912 (86.6%), whereas 911 (13.4%) had abnormal ALT values. Of those, 241 (3.5%) had ALT that was greater than twice normal. The distribution of ALT was also skewed, with a mean of 29.4 (±80.9) U/L and median of 21.0 (range, 4–4860; interquartile range, 15–29). In contrast to the AST data, those with ALT greater than 2 times ULN were older and more likely to be female than those with lower ALT results, although these differences were not statistically significant. Similar to AST results, the proportion of whites was smaller among those with abnormal ALT than among those with normal ALT.

When the study population was followed forward in time, 4639 deaths were observed. The median duration of follow-up among the survivors was 10.9 years (interquartile range: 10.1–11.2 years). Figure 2 shows the survival of Olmsted County residents by their AST and ALT results without adjustment for age and sex. For both AST and ALT, abnormal results were associated with progressive decreases in survival. Survival of those who were not tested differed between AST and ALT. The group whose AST was not tested had better survival than those with AST results. In contrast, survival in those without ALT result was better than those with ALT greater than 2 times ULN but poorer than those with ALT between 1 and 2 times the ULN. This observation could be accounted for by the differences in the age distribution between groups. For example, those without AST were much younger than those with AST data, whereas those without ALT were the oldest of the group (Table 1).

Figure 2.

Kaplan Meier survival of Olmsted County residents by AST and ALT results. * Indicates P < 0.01 in comparison with the <ULN group in each panel.

Standardized mortality ratios were calculated to exclude confounding effects of age and sex (Table 2). Community residents who did not have their aminotransferase determined had better survival than expected (SMR = 0.79 for AST and 0.93 for ALT). Those whose results were normal also had better survival than expected (SMR = 0.95 for AST and 0.61 for ALT). For both AST and ALT, abnormal results were associated with an increased risk of death. For AST, abnormal AST up to 2 times ULN was associated with a 32% increase in the risk of death, and more than 2 times ULN with a 78% increase, compared with the reference population. Similarly, abnormal ALT up to 2 times ULN was associated with a 21% increase in the risk of death, and more than 2 times ULN, with a 59% increase, compared with the reference population.

Table 2. Standardized Mortality Ratios (SMR) Among Residents of Olmsted County, MN, According to Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) Results
 Total Number of SubjectsNumber of Observed DeathsNumber of Expected DeathsSMR (95% CI)P
  1. NOTE. SMR based on Minnesota whites as the reference population. 141 (AST) and 202 (ALT) results were excluded from this analysis because of missing sex or birth date, or because their laboratory tests were performed on different dates: therefore, although they had >2 years of follow-up for 1 test, they did not for the other.

AST     
 Not done28,7581,4611,8500.79 (0.75–0.83)<0.001
 < ULN15,9912,6712,8250.95 (0.91–0.98)0.004
 1–2× ULN1,8853742831.32 (1.19–1.46)<0.001
 > 2× ULN452102571.78 (1.45–2.16)<0.001
ALT     
 Not done40,2354,2924,6170.93 (0.90–0.96)<0.001
 <ULN5,8851933150.61 (0.53–0.71)<0.001
 1–2× ULN66739321.21 (0.86–1.66)0.228
 > 2× ULN24032201.51 (1.04–2.14)0.018

Figure 3 illustrates the relation between aminotransferase results and the likelihood of subsequent death. In both sexes, there was a progressive rise in mortality as AST increased. This tendency was also observed within the normal range and the AST value that corresponded to a relative risk of 1 (in other words, that of the reference population) was 22 IU/L in women and 32 IU/L in men. A similar trend was seen with ALT; however, because of the smaller sample size, the estimates are not as precise. For example, the downward trend above an ALT of 100 IU/L in women is probably an artifact because of the relatively few observations in that range of ALT (n = 52).

Figure 3.

Relative risk of death according to the amnotransferase level.

Seventy-three subjects (1.6% of the 4639 decedents, out of the 47,182 study subjects) died of liver disease (including hepatobiliary malignancies);1559 (33.6%), of cardiovascular causes, 1,015 (21.9%), of malignancy (exclusive of hepatobiliary neoplasms); leaving 1,992 (42.3%) who died of other or undetermined causes. The age at death was much younger in decedents from hepatobiliary causes (69.6 ± 5.8) than others (82.3 ± 12.0 for cardiovascular, 74.0 ±13.5 for nonliver malignancies and 80.4 ± 15.2 for other/unknown causes). There was a strong male preponderance among decedents from liver causes (58.9%), whereas those from other causes were more likely to be women (45.5% male for cardiovascular, 45.7% for non-liver malignancies and 40.8% for other/unknown causes). Of decedents with available data, AST was significantly higher among those who died of hepatobiliary causes (Fig. 4). The proportion of decedents who had their ALT measured was higher among those with hepatobiliary causes of death, although the proportions with ALT data were much smaller in general than those with AST data. Of those with available data, decedents from hepatobiliary causes had higher ALT than those with other causes of death.

Figure 4.

Comparison of aminotransferase levels by the cause of death.

Discussion

In this work, we demonstrate that serum AST and ALT activities are associated with increased risk of mortality in the ensuing decade. The relation between the aminotransferase results at the outset and the subsequent risk of death (excluding the first 2 years) was almost linear. It is clearly shown that these simple, inexpensive blood tests may represent valuable indicators of long-term outcome. One of the main reasons why AST was measured much more commonly than ALT (40% versus 15%) is that AST was a part of an automated multi-channel chemistry panel commonly ordered by clinicians before a change in the Medicare reimbursement policy in 1998. Because the panel became unbundled since, it is likely that AST is ordered less commonly now compared with 1995. Our data raises a question whether aminotransferase must be considered as a screening tool to be applied more widely.

The SMRs we found in association with abnormal aminotransferases range between 1.21 and 1.78. SMRs of a similar magnitude have been reported in association with conditions well established to have a substantial public health impact. Thus, Bender et al.14 estimated that body mass indices higher than 25kg/m2 were associated with SMRs of 1.73 in male and 1.46 in female. Similarly, Ringbaek et al.15 showed an SMR of 1.54 in men and 1.91 in women with asthma after 15 years of follow-up. In addition to these comparisons, the high proportion (13%) of abnormal aminotransferase results among community residents seen in our practice makes our results important. As expected, we found that normal aminotransferase values are “protective”; once subjects with abnormal results and thus higher risk of death are removed from the population, the remainder will have survival better than average.

There may be several mechanisms by which serum AST and ALT may be associated with an increased risk of death. First, as Fig. 4 suggests, AST and ALT, being markers of serious liver diseases, increase the risk of mortality from liver disease.3, 5, 16, 17 Although that association may be self-evident, it is less certain what level of aminotransferase best distinguishes the presence and absence of liver disease. Prati et al.18 found that when asymptomatic individuals with hepatitis C and those at high risk of NAFLD were removed, the ULN may defined as ALT of 30 IU/L in men and 19 IU/L in women, much lower than conventional ULN (40 IU/L and 30 IU/L, respectively). Piton et al.19 proposed that, in addition to sex, body mass index be taken into account in the definition of the ULN for ALT. Although these data are helpful in identifying patients who may have clinically relevant liver disease, they do not necessarily indicate that these normal values are helpful in estimating the risk of mortality. In our data, Fig. 3 suggests that the risk of death (from all causes) increased as AST/ALT levels increase even within the normal range. However, the level of risk did increase beyond 1 (average risk of death in this study population). For example, in women, in whom the ULN for ALT was 30, the risk of death is higher for ALT of 30 compared with ALT of 20, but the risk of death at 30 is about that of an average woman included in this study.

Second, aminotransferases, particularly ALT, might also be a marker of cardiovascular diseases, and this may add to the risk of death. According to a study based on the Third National Health and Nutrition Examination Survey, ALT was associated with the risk of coronary heart disease among nonobese participants without viral hepatitis or excessive alcohol consumption.9 The link between ALT and coronary artery disease risk is thought to be via the metabolic syndrome, which creates a biochemical milieu to facilitate atherosclerosis, as well as NAFLD.8, 20 AST also may become elevated in patients with acute myocardial injury or congestive heart failure.21 By the intent of our study design, deaths within the first 2 years of observation were eliminated to exclude many of these patients with advanced end organ damage.

Third, aminotransferase elevations may reflect another serious comorbid condition that increases the risk of death. For example, chronic alcohol consumption or abuse is one of the common causes of AST/ALT elevation. The increased risk of death in that population not only may stem from alcohol-induced end organ damage (such as alcoholic liver disease) but also may be related to morbidity associated with concurrent depression, polysubstance use including tobacco products, and accidents.22–26 Similarly, although hepatitis C virus infection is an important source of morbidity and mortality from liver disease, it also may be a marker of injection drug use and its associated physical, psychological, and social consequences.27 Finally, aminotransferases can be elevated in various kinds of chronic nonhepatic disease such as muscle and thyroid disease.28

A unique feature of our data is that they are derived from a self-contained healthcare setting in Olmsted County, Minnesota.10, 29 The well-established infrastructure and proven track record of the REP help us be confident of the quality and completeness of the follow-up in our large number of community residents. In addition, we would like to point out that the subjects included in this study were seen at Mayo Clinic, which principally functioned as a primary care health provider to the local residents, rather than as the specialty referral center it is reputed to be.

It is also important to underline the limitations to this study. First, we point out that our data were obtained in a routine medical care setting, as opposed to screening of random individuals in the community. Obviously, there is a selection process embedded in our data that insofar as to be captured in this study, the community resident must have been seen for healthcare and the provider must have ordered AST/ALT. When the prevalence of aminotransferase elevation in this study (13%) is compared against that in the US population in general (10%, National Health and Nutrition Examination Survey 1999–2002), the degree of oversampling of those with abnormal aminotransferase in this study appear rather minor.6 Our data did show that physicians' decisions to order AST/ALT have a demonstrable correlation with the subsequent risk of death in that lack of AST/ALT data was associated with small yet significant decrease in mortality. Thus, our results apply to individuals seen in healthcare setting rather than population at large. Second, along the same vein, only a minority of community residents had their AST/ALT measured. This reduced the sample size in specific subgroups. For example, the proportion with AST/ALT data was quite small among decedents, which prevented more meaningful analysis of cause-specific mortality. Third, this study was based on a single aminotransferase result. According to a study based on blood donors, aminotransferase elevation was found to be persistent in 28%, intermittent in 36%, and singular in 33%.30 Incorporation of follow-up laboratory results may further refine our understanding of the relation between aminotransferase and subsequent morbidity and mortality. Furthermore, given the long lag time between asymptomatic aminotransferase elevation and death of liver disease, a study with longer follow-up may find a stronger association between the two. Lastly, the large proportion of whites in our study may reduce the generalizability of the data. Although there may be differences in the prevalence of elevated ALT between races, they may be more indicative of disparities in liver disease prevalence. Further investigation is needed as to whether there are inherent biological differences in the distribution of ALT or the significance of abnormal values among difference races.

Serum aminotransferases levels are not recommended as a routine preventive service by the US Preventive Services Task Force.31 The US Preventive Services Task Force emphasizes instead the role of individual physicians in ordering screening tests according to their judgment of benefits and risks. Our data lend some support to the US Preventive Services Task Force recommendation, because community residents in whom AST/ALT were not ordered had a lower risk of death than expected. Conversely, liver disease is generally asymptomatic until complications of advanced disease occur. Measurement of aminotransferases may allow early detection and treatment of conditions that could lead to significant morbidity and mortality in the future. Although our data are not able to answer these questions, we believe they contribute to understanding the role of these simple blood tests in improving the health of the population in general. In conclusion, these data, based on a large number of residents in a US community, suggest that serum levels of AST and ALT obtained in a routine medical care setting are associated with future mortality.

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