Potential conflict of interest: Nothing to report.
Given the accumulating evidence that gamma-glutamyltransferase (γ-GT) is not merely a sensitive marker for liver and bile disorders but also a risk marker for a multiplicity of other chronic diseases, γ-GT may represent a promising risk indicator for occupational disability, which has emerged as an important public health problem. The association between γ-GT and disability pension was examined in a cohort of 16,520 male construction workers in Württemberg, Germany, who participated in routine occupational health examinations from 1986 to 1992 and who were followed until 2005. Using the Cox proportional hazards model, hazard ratios were calculated with γ-GT concentrations in the lowest quartile (1 to 24 U/L) as reference category after adjustment for age and further adjustment for potential confounding factors such as nationality, type of occupation, smoking, alcohol consumption, cholesterol, and body mass index (BMI). Overall, a monotonically increasing association of γ-GT with all-cause disability pension (total number: n = 2,998 cases) was observed, with the steepest increase at lower levels of γ-GT. Particularly strong associations were observed for participants in the highest quartile (>67 U/L) and disability pension due to musculoskeletal disorders, diseases of the digestive system, and cardiovascular as well as mental diseases (age-adjusted hazard ratios with 95% confidence intervals: 1.53, 1.27–1.85; 9.68, 3.10–30.21; 1.76, 1.28–2.42; and 1.83, 1.23–2.72, respectively). Conclusion: γ-GT is a strong risk indicator of all-cause occupational disability even at levels of γ-GT in the “normal range” and is in particular associated with disability pension due to diseases of the digestive system, musculoskeletal disorders, cardiovascular, and mental diseases. (HEPATOLOGY 2009.)
Serum gamma-glutamyl transferase (γ-GT) has long been recognized as a biomarker of hepatobiliary disease and excessive alcohol consumption.1, 2 In recent years our knowledge of γ-GT's physiological functions has expanded and evidence has accumulated that γ-GT is not merely a sensitive marker for liver and bile disorders, but that it may also serve as a risk marker for a multiplicity of other chronic diseases. For example, several population studies have shown strong positive associations between γ-GT and cardiovascular risk factors such as smoking, components of the metabolic syndrome (namely, obesity, hypertension, lipid metabolism, and in particular type 2 diabetes),3–9 resulting in γ-GT as a predictor for cardiovascular diseases. Elevated γ-GT was also recently found to be associated with chronic kidney disease independently of baseline confounding factors such as alcohol consumption.10
Permanent disability pension, which is a great burden to the individual, has emerged as an important public health problem globally and causes high costs at the population level.11 According to the Survey of Income and Program Participation (SIPP), 32.1 million working-age people (or 18.7% of the population age 15 to 64) in the United States have a disability: 14.9 million reported as severe.12 In Germany, almost 1.6 million people receive a disability pension compensation from the German pension fund (6.4% of all pensions), of whom over 160,000 were granted in 2007 (13% of all incident pensions).13 Several chronic diseases such as cardiovascular diseases, musculoskeletal disorders, mental disorders, neoplasms, diabetes, and lung and gastrointestinal disorders account for the vast majority of disability pensioning in many countries with an established social security system.14
Given the accumulating evidence that γ-GT is not merely a sensitive marker for liver and bile disorders, but also a risk marker for a multiplicity of other chronic diseases, γ-GT may represent a promising risk marker to identify workers at risk of occupational disability and who may benefit from targeted intervention. A study from Sweden indicated elevated values of γ-GT among middle-aged men before as well as after receiving a disability pension, which was ascribed in this study to overconsumption of alcohol.15 In a previous cohort study from Germany the risk of occupational disability was found to be significantly increased with elevated γ-GT levels compared to those with γ-GT levels in the normal range.16 However, in that former analysis, the size and follow-up time of the cohort were too small to assess dose-response patterns or the associations of γ-GT with disability due to different causes in detail. Therefore, we enlarged the cohort and extended follow-up in order to assess dose-response patterns with respect to overall and cause-specific disability.
BMI: body mass index; γ-GT: gamma-glutamyltransferase; ICD-9: International Classification of Diseases (9th revision).
Patients and Methods
The study cohort at baseline comprised 19,421 male employees from the German construction industry, age 25 to 59 years, belonging to one of the following occupations: bricklayers (n = 6,204), painters (n = 2,947), laborers (n = 2,874), plumbers (n = 2,804), carpenters (n = 2,594), and plasterers (n = 1,998). They participated in a routine occupational health examination by the Workmen's Compensation Board for construction workers in Württemberg (in the south of Germany) between August 1986 and December 1992. This occupational health surveillance is based on legislation on health and safety at work and regular examinations are offered to all construction workers. In the period of recruitment, over 75% of all invited employees participated in the medical examination and were eligible for follow-up. All participants were members of the statutory pension fund and did not receive a disability pension at baseline examination. They were representative for the underlying population of all construction workers with respect to age, nationality, and type of occupation. All patients gave informed consent regarding analysis of the health data. The retrospective follow-up study was approved by the Ethics Committees of the medical faculties of the University Clinics of Heidelberg and Ulm, by the data protection officer of Baden-Württemberg, and by the Baden-Württemberg State Ministry of Social Affairs.
The health examination at baseline was part of the routine occupational health surveillance and included a physician-explored work history (including drinking and smoking habits), a self-reported occupational and medical history, a physical exam (including measurements of weight, height, and blood pressure), functional measurements such as blood and serum analysis, lung function, electrocardiogram, audiometry, and a test of visual acuity. The examinations were conducted by experienced occupational health physicians and documented according to a standardized protocol. γ-GT levels in this study were measured at 25°C with a Hitachi 705/717 system. Measures of γ-GT were missing in 818 cases because some workers either rejected providing a blood sample or provided external laboratory-analyzed findings from a recent blood analysis, which were not included in the medical records used for our study.
Information on date and cause of disability pension was obtained from the German pension fund in March 2006. The pension register of the German Pension Fund Baden-Württemberg provided information regarding vital status and whether the individual was still working, had retired due to age, was unemployed or under rehabilitation, or whether a disability pension (permanent or temporary) was granted. In case of missing data with respect to actual employment or pension status, which occurred mainly due to remigration of some foreign workers as well as due to a high occupational fluctuation in the construction industry, we also included the information from previous follow-up rounds performed from 1992–1994 and 1998–2000.17, 18
The criteria for being work-disabled and receiving disability pension are under repeated revision. Up to the year 2000, a disability pension was granted in Germany when the ability to earn a living (i.e., working hours) has been permanently reduced by at least 50% due to injury, illness, or impairment—irrespective of whether the injury was caused by work or not—and whether the worker could not be referred to another adequate occupation. In the year 2001 the threshold was set to 3 and 6 hours of work ability per day for complete and partial work disability. Irrespective of these changes, disability pensions were granted throughout the entire follow-up, contingent on thorough medical examination by the pension fund's medical service. Causes of disability pension were coded according to the International Classification of Diseases (ICD-9) and validated by trained medical officers from the pension fund.
Regarding the 818 men with missing measures of γ-GT at baseline (4.2%), we used multiple imputation to fill in the pertinent missing baseline data for γ-GT according to subject age. Another 2,083 men (10.7%) had to be excluded who had either moved to a different region or had changed employment, and for whom no information from previous follow-up rounds were available. The very strict confidentiality rules in Germany did not allow us to follow these people further. Hence, the final study population for this analysis comprised 16,520 construction workers who could be successfully linked with the pension register.
Because nowadays serum activity of γ-GT is measured at 37°C in general, we converted γ-GT values to the current measure as previously described.19 γ-GT concentrations were classified into five groups with cut points at 24, 36, 66, and 132 U/L, which correspond to the 25th, 50th, 75th, and 90th percentiles computed over the entire sample. For men the normal range of this measure is now defined as all values below 55 U/L.19
Average daily amount of alcohol was calculated from frequency and type of beverage and categorized as none, occasional, 1–30, 31–60, 61–90, and more than 90 g alcohol per day. Smoking status was classified as never, former, or current smoking. Body mass index (BMI; kg/m2) was categorized as lower than 24.9, 25.0 to 29.9, 30.0 or higher, which corresponds to the WHO classification scheme20 for normal (including underweight), overweight, and obesity.
Techniques of survival analysis were employed to assess the association of γ-GT with the occurrence of disability pension with the date of baseline examination as inception of follow-up time. We defined the onset of occupational disability as the point of time from which a disability pension was granted—irrespective of the date of ascertainment of disability pension. In case of transient or multiple temporary disability pensions, the first occurrence of disability was taken as endpoint for the analysis. A person was denoted as censored in case of being known not to be granted a disability pension according to pension fund records, or termination of pension fund insurance due to other reasons, such as retirement pension, 65th birthday, death, or change to another insurer, or (in analyses of cause-specific disabilities only) disability pension due to another cause.
Relative hazards of occupational disability according to levels of γ-GT were calculated using Cox's proportional hazards model. After crude analysis, we first included age as a covariate in the model. Adjustment for further potential confounding factors such as nationality, type of occupation, BMI, smoking, cholesterol, and alcohol consumption was done in multivariate analysis. For age, linear and quadratic age terms were simultaneously entered into the model, whereas index variables were created for the other, categorical variables.
Additional analyses were carried out in subgroups according to the presence or absence of defined types of comorbidity at baseline (prevalence of cardiovascular diseases [ICD-9: 390–459], diseases of the liver, bile and pancreas [ICD-9: 570–577] as well as diabetes mellitus [ICD-9: 250]) and with respect to cause-specific disability pension. Within these subgroup specific analyses we combined the two highest groups to the highest quartile in order to prevent too imprecise effect estimates.
To explore potential differences in the predictive value of γ-GT in the short and long run, additional specific analyses were conducted for the initial 3 and subsequent years of follow-up.
To prevent statistical drawbacks caused by categorization, γ-GT was also entered as a continuous variable with 18 U/L as the reference value in supplementary regression models using fractional polynomials as described by Royston et al. and Sauerbrei et al.21, 22 All statistical analyses were performed with the SAS statistical software package, release 9.1 (SAS Institute, Cary, NC). The proportional hazards assumption was checked by log (−log) survival plots.
Characteristics of the study population (overall and grouped by γ-GT) are shown in Table 1. At baseline, the 16,520 study participants had a mean age of 42 years and 76% of the cohort members were of German nationality. With over 30%, bricklayers constituted the largest professional group in our sample. A considerable share of about 63% of the study population was overweight or obese (BMI ≥25 kg/m2). Smoking and alcohol consumption were also very common in our study, with a proportion of 58% current smokers and 52% moderate and heavy drinkers (≥30 g/day).
Table 1. Characteristics of the Study Population at the Baseline Examination by Category of Gamma-Glutamyltransferase (γ-GT)
γ-GT Categories (U/L at 37°C)
Total (n = 16,520)
≤ 24 (n = 4,502)
25 to 36 (n = 3,806)
37 to 66 (n = 4,109)
67 to 132 (n = 2,481)
> 132 (n = 1,622)
Information regarding BMI was missing in 273 cases (2%), regarding alcohol consumption in 2,197 cases (13%), regarding cholesterol in three cases and regarding smoking in 2,658 cases (16%).
Prevalence adjusted to the age distribution in the entire cohort by the direct method: Cardiovascular disease, ICD-9: 390–459; diabetes mellitus, ICD-9: 250; musculoskeletal disorders, ICD-9: 710–739; respiratory diseases, ICD-9: 460–519; diseases of the digestive system, ICD-9: 520–579; mental disorders, ICD-9: 290–319.
Increased γ-GT activity was associated with old age and German nationality. The proportion of regular alcohol consumers, the prevalence of obesity (BMI ≥30 kg/m2), and high cholesterol levels (>254 mg/dL) were strongly increased with elevated γ-GT concentrations (P-values for trend tests: <0.001). Regarding types of occupation, no substantial differences of γ-GT concentrations could be observed. Baseline prevalences of cardiovascular diseases, diseases of the digestive system, mental disorders, and diabetes mellitus were strongly associated with increased γ-GT levels, whereas the prevalence of musculoskeletal disorders and respiratory diseases were nearly constant across all γ-GT categories. In contrast, the proportion of healthy persons without any recorded comorbidity strongly decreased with increasing γ-GT.
All-Cause Disability Pension According to γ-GT.
A total of 2,998 incident cases of disability pension occurred over the mean follow-up time of 10.9 years. Table 2 presents the association between γ-GT levels and all-cause disability pension with the lowest quartile of γ-GT concentration as the reference category. The results of the regression analysis based on the imputed data of γ-GT values were consistent with results using either only complete cases or adding index variables to indicate subjects with missing information. Crude analysis revealed a strong monotonically increasing association between γ-GT levels and all-cause disability pension (P-value for trend test: <0.001) with a significantly increased risk in all groups, which was over 3-fold elevated in the highest group compared to the reference group. After adjustment for age, the association of γ-GT concentration with disability pension was reduced but a clear monotonic trend persisted (P < 0.001). Relative risks were further reduced to some extent by adjustment for BMI, nationality, type of occupation, smoking status, cholesterol, and alcohol consumption, but there still remained a clear dose-response relation between γ-GT levels and all-cause disability pension, with an almost 2-fold elevated risk in the highest γ-GT group. Risk of occupational disability was significantly increased even in the second-lowest group (25 to 36 U/L).
Table 2. All-Cause Pension Disability by Category of Gamma-Glutamyltransferase (γ-GT)
γ-GT Categories (U/L at 37°C)
25 to 36
37 to 66
67 to 132
Per 100,000 person years.
Adjusted for age.
Adjusted for age, body mass index, nationality, smoking status, cholesterol, type of occupation and alcohol consumption.
Of the 2,998 cases of disability pension, 500 (17%) occurred during the first 3 years of the follow-up period. Relative risk of occupational disability within the first 3 years of follow-up was even more strongly associated with γ-GT than within the entire follow-up period.
After exclusion of the first 3 years of follow-up, the results did not materially change compared to the analysis without left truncation. Again, risk of occupational disability was significantly increased at all γ-GT levels compared to the lowest group.
The monotonically increasing association of γ-GT with disability pension could also be observed in dose-response analyses using γ-GT as a continuous variable (Fig. 1). The increase in hazard ratios was steeper at lower γ-GT concentrations than at higher levels. Additional analyses with stratification by the presence or absence of cardiovascular diseases, diabetes mellitus, and diseases of the liver, bile, and pancreas, which all might cause elevations of γ-GT levels, did not indicate any relevant confounding or interaction by these conditions (data not shown).
Disability Pension According to γ-GT and Cause of Disability.
Information on cause of disability could be obtained for 2,713 out of 2,998 (90.5%) cases of disability pension. With 1,244 (45.9%) cases, musculoskeletal disorders represented the most common cause of disability pension, with half of them being due to dorsopathies. The second most common cause was cardiovascular diseases (17.3%), followed by mental disorders (8.9%), and cancer (8.0%). Frequencies and hazard ratios (multiple adjusted) of cause-specific disability pension are shown in Table 3.
Table 3. Cause-Specific Pension Disability by Category of Gamma-Glutamyltransferase (γ-GT)
Total n = 16,520
γ-GT Categories (U/L at 37°C)
≤ 24 n = 4,502
25 to 36 n = 3,806
37 to 66 n = 4,109
> 67 n = 4,103
Per 100,000 person years.
Adjusted for age, body mass index, nationality, smoking status, cholesterol, type of occupation, and alcohol consumption.
Risk of disability monotonically increased with γ-GT activity for cardiovascular diseases, respiratory diseases, as well as musculoskeletal disorders, with significant increased risks for the two highest γ-GT categories. For the latter, the relative risk was even significantly elevated at all γ-GT categories compared with the reference group. This pattern did not change when separately considering disability pension due to dorsopathy as well as due to osteoarthritis, the two most predominant musculoskeletal causes of disability in our cohort (data not shown). Increased risks of occupational disability due to all of the assessed causes were observed in the highest quartile of γ-GT concentration. With an age-adjusted hazard ratio of 9.86 (95% confidence limits: 3.10; 30.21), the strongest risk elevation was observed for occupational disability due to diseases of the digestive system, which were predominantly diseases of the liver, bile, and pancreas. The significant increase of occupational disability due to other causes among men with γ-GT concentrations in the highest quartile was mainly due to diabetes.
Serum γ-GT is not merely a sensitive marker for liver and bile disorders, but also a risk marker for a multiplicity of other chronic diseases. Our analyses showed that serum γ-GT is positively associated with risk of all-cause occupational disability even at levels in the range of normal γ-GT concentrations. Furthermore, a consistent risk increase was found for mental and cardiovascular diseases and diseases of the digestive system and musculoskeletal disorders, which represent the major causes of disability in this occupational group.
The results of the association of γ-GT on all-cause disability pension are consistent with those from a previous analysis of our cohort, where a modest but significant increase in risk of occupational disability was seen at γ-GT levels above 28 U/L (measured at 25°C, corresponding to a γ-GT threshold level of 55 U/L measured at 37°C).16 However, our previous analysis was confined to all-cause disability as the sole endpoint. Although the association of γ-GT with all-cause disability pension was partly explained in our cohort by factors related to enzyme activity, such as alcohol consumption, obesity, smoking, cholesterol and cardiovascular diseases, diabetes mellitus, and diseases of the liver, bile, and pancreas, controlling for these factors or exclusion of persons with these diseases only slightly reduced the prognostic impact of γ-GT on occupational disability. This indicates that the relationship of elevated γ-GT activity on disability pension was not merely explained by these confounding factors. Further possible causes of increased γ-GT levels could be hepatotoxic agents and other nonhepatic factors such as renal, pulmonary, and myogenic (including cardiac) disorders, which may also account for some of the increased risk of occupational disability.
The positive association between γ-GT and disability due to cardiovascular diseases is consistent, albeit somewhat weaker, than corresponding results from epidemiological studies assessing the association between γ-GT and mortality. This difference in quantity may be explained by the relatively low mortality and disability rates due to cardiovascular diseases in construction workers.23, 24 However, in our cohort the increase in disability risk remained significant in the two top quartiles of γ-GT.
The relationship of γ-GT with disability due to the digestive system was particularly pronounced by hepatic diseases, whose associations with elevated γ-GT levels are likewise well established.1 Our findings, that γ-GT predicts disability pension due to diseases of the digestive system, are in line with these findings.
The positive association of γ-GT with increased risk of disability due to mental diseases in the highest quartile in our study is more difficult to interpret. A possible explanation could be residual confounding due to solvents, which were in widespread use in the construction industry. It has been reported that the combined effect of occupational solvent exposure and alcohol intake could be an important cause of organic brain damage, which is responsible for several mental diseases such as dementia and cerebral atrophy.25 Another recent study revealed that γ-GT levels were increased significantly in patients with Alzheimer's disease and therefore may be an independent marker for oxidative stress in Alzheimer's disease.26
An increased risk of occupational disability due to cancer was likewise reported for the highest γ-GT category only. Experimental evidence has elucidated the ability of cellular γ-GT to modulate crucial redox-sensitive functions, such as cellular proliferative/apoptotic balance as well as antioxidant/antitoxic defenses, and its role in tumor progression, invasion, and drug resistance has repeatedly been suggested.27–29 γ-GT is constitutively expressed in several organs and is often significantly increased in malignant or premalignant lesions, where it is considered a factor conferring growth and survival advantages for the rapidly dividing neoplastic cells.30 However, there remains some uncertainty on the association of γ-GT with cancer as a health outcome. Although two epidemiologic investigations failed to detect an association between γ-GT and cancer mortality in middle-aged men,4, 31 a strong significant relationship between γ-GT and risk of cancer incidence was found in a recent analysis from an Austrian prospective study.32
The most novel finding of the present study was the strong association of γ-GT levels with disability pension due to musculoskeletal disorders, which was seen among cases due to osteoarthritis as well as dorsopathy even at levels in the normal range of γ-GT. Few studies have focused on the association of γ-GT with musculoskeletal disorders. A study of middle-aged men found that men with somatic back pain experienced more stress at work and had higher serum levels of γ-GT, possibly due to a higher intake of alcohol and/or painkillers compared with men who had nonsomatic pain.33 However, associations of γ-GT with disability pension due to musculoskeletal disorders persisted in our cohort even after control for alcohol consumption.
A number of limitations require careful discussion in the interpretation of our study. Although we controlled for major potential confounders including BMI, smoking, and alcohol consumption there remains a potential for residual confounding. This particularly applies to potential confounding by smoking and alcohol consumption, which tend to be imperfectly reported. Information regarding socioeconomic factors as well as dietary factors that are known to affect disability risk34, 35 were not available. However, the strong association of γ-GT with disability pension did not materially change after adjustment for type of occupation, which might be used as a proxy measure for socioeconomic status. Furthermore, our study was restricted to a male occupational cohort, and our results may not necessarily be generalizable to other populations.
A further potential limitation of the cause-specific disability analysis is the fact that only information regarding the primary cause of disability was available. No information regarding auxiliary causes of disability pensioning was provided. Furthermore, we cannot rule out the possibility that unmeasured comorbidity at time of ascertainment of disability pension may mask the true association of γ-GT with cause-specific disability pension. However, such comorbidity would be more relevant for absolute measures of the occurrence of disability (such as incidence rate and incidence rate difference) rather than relative measures unless under-ascertainment of comorbidity would vary across γ-GT categories. In addition, all diagnoses responsible for work disability were defined by trained medical officers from the pension fund.
Our study also has particular strengths, including the size of the study population, the length and completeness of follow-up, as well as a broad range of γ-GT values. The large case number of disability pensions allowed us to assess the γ-GT-disability association in great detail, in particular with respect to dose-response relationships. In contrast to alcohol consumption and smoking, γ-GT is not affected by reporting problems and could be almost completely ascertained in the entire cohort by a simple laboratory test.
In conclusion, γ-GT was found to be a strong risk indicator of all-cause occupational disability even at levels of γ-GT in the normal range among construction workers, which persisted after adjustment for age and other confounding factors. Besides the established association of γ-GT with diseases of the digestive system and cardiovascular diseases, γ-GT was found to be a major risk indicator of occupational disability due to mental and musculoskeletal disorders, the most common causes of disability pension in our cohort.
The results of our study expand our knowledge regarding the prognostic relevance of gamma-glutamyltransferase beyond the clinical setting even at γ-GT levels in the normal range.
We thank the German Pension Fund Baden Württemberg for providing the follow-up data and Claudia El-Idrissi Lamghari (German Cancer Research Center, Division of Clinical Epidemiology and Aging Research, Heidelberg) and Jürgen Banzhaf (Workmen's Compensation Board for Construction Workers, Germany) for technical assistance over the course of this study.