Association between different patterns of shift work and liver function tests: A cross-sectional analysis of Shahedieh PERSIAN cohort data,Iran,2020

Abstract

BACKGROUND:

Recent studies suggest that shift work may cause liver dysfunction.

OBJECTIVE:

This study aimed to examine the relationship between different patterns of shift work and elevated level of liver enzymes.

METHODS:

In this cross-sectional study, 1910 workers aged 35 to 70 years were selected with simple random sampling from 9978 participants of the recruitment phase of Shahedieh PERSIAN cohort study. Level of serum liver enzymes (ALT, AST, ALP, and GGT) and ALT/AST ratio was compared between shift workers and non-shift workers, and among employees working in different patterns of shift work. Data were analyzed by SPSS (version 21.0) using Student’s T test, Mann-Whitney U test, chi-square test, Kruskal Wallis test, and logistic regression.

RESULTS:

Among 1347 males (71%) and 563 females (29%) with a mean age of 40.4±7.4 years, 469 were shift workers. Fixed evening type shift was the most common (30.3%) and fixed night-shift was the least common (0.9%) type of shift work. The mean blood levels of liver enzymes was not significantly different between shift workers and non-shift workers. In comparison between different patterns of shift work, the mean serum level of GGT was significantly higher in individuals with slow rotating shifts than those with fixed evening shifts, rapid rotating, split and fixed 24 hour shifts (p≤0.001). After adjusting for confounding factors only elevated AST was significantly higher in shift workers.

CONCLUSION:

There was only a significant association between shift work and elevated AST, and no relationship was found with ALT, ALP, GGT, and ALT/AST ratio.

Keywords

Liver enzymes Shahedieh cohort study aminotransferase

1 Introduction

Shift work is defined as working out of the normal daily working hours [1]. Today, the need for shift work as a necessity to meet the demands of industrialization, globalization and 24-hour society has increased [2]. There are different patterns of shift work, including fixed shifts in which a person typically works in one constant shift (such as night work), rotating shifts in which a person works in a schedule of different shifts, and unplanned working shifts [1].

The effects of shift work on workers’ health have been widely assessed and proved in many previous studies. Some adverse health effects of shift work include sleep problems, circadian rhythm disorders, psychological disorders, gastrointestinal problems, cardiovascular diseases, metabolic disorders, etc. [3 –5]. A relationship between shift work and higher expression of some genes related to cancer or metabolic disorders has also been found in some studies. Ledda et al. found a significant relationship between shift work and insulin resistance in health care workers [6]. Bracci et al. in two different studies showed a higher expression of some genes related to breast cancer and metabolism in shift workers [7, 8].

Recently, the possible effect of shift work on liver function has raised concern. Liver injury and especially, chronic liver disease is an important problem in different countries [9]. Liver transferase enzymes such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are the most common enzymes used for screening of liver injury. Alkaline phosphatase (ALP) and γ-Glutamyl transferase (GGT) are other enzymes used to monitor liver damage; although these enzymes are also produced in some organs other than liver [10]. Liver enzyme tests have been commonly used in some occupational settings to screen for such liver diseases as non-alcoholic fatty liver disease (NAFLD) and hepatitis, especially in early stages [11].

Some evidence shows that liver enzymes synthesis may follow a circadian pattern. Shift work may thus affect the level of liver enzymes by this mechanism, although some other mechanisms such as changes in the metabolism in shift workers due to sleep disturbances or lifestyle change have been considered as well [12, 13]. The results of studies on the relationship between shift work and elevated liver enzymes are controversial. Most previous studies have assessed the effect of one pattern of shift work (especially night shift work) on one or two liver enzymes, mostly ALT and AST. Some studies have found an association between shift work and elevation of some liver enzymes, in night shift workers [11 , 15]. Khosravipour et al. found an association between 12 h rotating night shift work and elevated ALP [14]. Wang et al. similarly found an association between night shift work and elevated ALT [15]; but Balakrishnan et al. did not find any association between rotating or night shift work with elevated ALT or AST [16]; similarly Choi et al. could not find a relationship between shift work and elevated ALT [17]. No studies were found in the literature on the association between different patterns of shift work and four liver enzymes, i.e. ALT, AST, ALP and GGT.

Due to inconclusive data about the effect of shift work on liver enzymes and lack of evidence about the effect of different patterns of shift work on all four enzymes in the previous studies, this study was conducted to assess the association between shift work and blood level of four liver enzymes among individuals working in different patterns of shift work.

2 Materials and methods

This was a cross-sectional study on 1910 middle-aged individuals (including 1347 males and 563 females) as a cross-sectional analysis of recruitment phase of the Shahedieh PERSIAN cohort study in Yazd, Iran. This study was performed in 2020 after completion of enrollment phase, data cleaning, and final quality control of data. Shahedieh cohort study is a branch of a national multi-center cohort study (PERSIAN cohort) on adult population (age range: 35–70 years) started in Shahedieh, Zarch and Ashkezar (in Yazd province in the center of Iran) from 2015 and the follow-up and repeated measurements phases are continuing [18]. The participants were randomly selected from Shahedieh cohort participants, and were divided into shift workers and non-shift workers. Those with a second job, previous shift work experience, history of viral hepatitis, cancer and renal failure were excluded from the study. The study was approved by the ethics committee of Shahid Sadoughi University of Medical Sciences (code: IR.SSU.MEDICINE.REC.1398.231). Informed consent was obtained from each participant at the enrollment phase of the study.

The information about history of fatty liver and other diseases was extracted from cohort database in which there was a questionnaire about chronic diseases and only the diseases with documented diagnosis were considered. Data on exercise level and sleep were also extracted from cohort database in which two questionnaires were used to collect data about exercise level and sleep [18].

2.1 History of shift work

An occupational history questionnaire (designed by the researchers) was completed for each participant during their first visit by a trained occupational hygienist. The questionnaire included a detailed lifetime working history, consisting of company name, job title, time schedule of work, years of shift work and daily working hours for each job. Shift workers were categorized according to their shift pattern into the following groups: fixed night (working between 7 P.M. and 7 A.M.), fixed evening (working between 2 P.M. and 10 P.M.), scattered or split shifts (working at different times of the day and night, but not continuously), fast rotating (a shift schedule including one to four consecutive shifts of the same type), slow rotating (a schedule including at least five consecutive shifts of the same type), and fixed 24 hours [17, 19], considering our country work schedules.

The selected participants were from various industries with different jobs. The jobs/industries in shift workers were as following: driving (18.6%), farming (13.2%), office work (12.6%), textile industry (12.6%), metal industry (8.6%), tile and ceramic industry (7.7%), plastic industry (4.9%), car mechanic (4.3%), food industry (3.8%), and others (13.7%). Non-shift workers were employed in the aforementioned jobs besides clerical works, military jobs, and service works.

2.2 Measurements

Demographic information (i.e. age, gender, and work experience), smoking status, history of diseases and the results of para-clinical measurements were extracted from the cohort database. The measurements were done immediately after registration in the morning in fasting condition (between 8 A.M. and 9 A.M.). For each participant 25cc of blood was collected using vacutainers (Greiner Bio-One International GmbH, Kremsmunster, Austria), and then was centrifuged and fractioned into different aliquots for laboratory tests and storing [18]. The measurements which were used in this study included: Serum ALT, AST, ALP and GGT level measured by an automatic biochemical analyzer (BT 1500, Biotechnica, Italy). ALT/AST ratio was also calculated. Elevated liver enzymes were defined as ALT > 36U/L, AST > 33U/L, ALP > 306U/L, and GGT > 40U/L [20]. In this study, we considered the same maximum normal levels of enzymes for men and women according to McPherson [20]. Standing height was measured by a standard stadiometer and weight was measured by a digital scale (Seca, China). Height (in m) and body weight (in Kg) were used to calculate body mass index (BMI).

2.3 Statistical analysis

Data were analyzed by SPSS (version 21.0), using Kolmogorov-Smirnov test, Student’s T test, Mann-Whitney U test, chi-square test, Kruskal Wallis test, and logistic regression. A p < 0.05 was considered as statistically significant. Kolmogorov-Smirnov test showed that level of liver enzymes in different groups were not normally distributed, so non-parametric tests were used for comparison of liver enzymes in different shift work patterns. Due to various job titles in both groups, job title was not considered as a variable in data analysis.

The data used in this study were all collected in PERSIAN cohort study in which data collection was regularly controlled by quality control and quality assurance methods by a central and a local team. A smart central server was used to minimize the errors during data entry followed by regular inspections of the field by local and central teams [18]. All data were cleaned after the enrollment phase and all analyses were done after data cleaning phase.

3 Results

Among 1910 participants in the study, 1347 were males (71%) and 563 were females (29%). Totally, 469 participants (25%) were shift workers. The mean age of the participants was 44.2±7.4 years and it was not significantly different between shift workers and non-shift workers (p = 0.95). Also, marital status, average work experience and BMI did not differ between two groups. However, gender distribution (p < 0.001) and smoking rate (p = 0.003) was significantly different between two groups. Table 1 compares demographic data and history of some diseases between shift workers and non-shift workers.

Table 1
Comparison of demographic data and history of some diseases among shift workers and non-shift workers of the Shahedieh cohort 2015–16

Parameter Shift workers Non-shift workers P value

Number of people 469 1441 –

Gender:

Female 85(18.12%) 478(33.17%) <0.001

Male 384(81.87%) 963(66.82%) <0.001

Smoking 103 (21.96%) 226 (15.68%) 0.003

Marital status (married) 99.35% 98.68% 0.13

History of diseases:

Diabetes 50(10.6%) 127(8.8%) 0.15

Fatty liver 35(7.46%) 122(8.46%) 0.28

Mean±SD

Age (yrs) 44.2±7.8 44.2±7.2 0.95

Work experience (yrs) 15.24±9.66 15.22±9.37 0.24

BMI (Kg/m²) 27.01±4.66 27.38±4.56 0.96

Total sleep (h/day) 6.45±1.46 6.64±1.24 0.009

Exercise (h/day) 0.09±0.25 0.09±0.26 0.98

Parameter	Shift workers	Non-shift workers	P value
Number of people	469	1441	–
Gender:
Female	85(18.12%)	478(33.17%)	<0.001
Male	384(81.87%)	963(66.82%)	<0.001
Smoking	103 (21.96%)	226 (15.68%)	0.003
Marital status (married)	99.35%	98.68%	0.13
History of diseases:
Diabetes	50(10.6%)	127(8.8%)	0.15
Fatty liver	35(7.46%)	122(8.46%)	0.28
Mean±SD
Age (yrs)	44.2±7.8	44.2±7.2	0.95
Work experience (yrs)	15.24±9.66	15.22±9.37	0.24
BMI (Kg/m²)	27.01±4.66	27.38±4.56	0.96
Total sleep (h/day)	6.45±1.46	6.64±1.24	0.009
Exercise (h/day)	0.09±0.25	0.09±0.26	0.98

The Mann-Whitney U test showed that the mean serum level of AST, ALT, ALP, GGT and ALT/AST ratio was not significantly different between two groups of shift workers and non-shift workers (Table 2).

Table 2

Comparison of mean liver enzymes between shift workers and non-shift workers of the Shahedieh cohort 2015–16

Liver enzyme	Normal values	Shift workers	Non-shift workers	P value
AST (U/Lit)	<33 U/Lit	18.83±8.79	18.77±7.41	0.88
ALT (U/Lit)	<36 U/Lit	22.11±14.34	23.01±15.59	0.29
ALP (U/Lit)	<306 U/Lit	187.08±60.09	190.67±55.86	0.26
GGT (U/Lit)	<40 U/Lit	26.44±20.38	28.01±22.34	0.13
ALT/AST	–	1.15±0.38	1.18±0.52	0.21

Among different patterns of shift work, fixed evening shift (N = 141, 30.1%) and split shift (N = 141, 30.1%) were the most common and fixed night shift (N = 4, 0.9%) was the least common shift pattern. Table 3 shows the distribution of various shift patterns and average liver enzymes in each group.

Table 3

Mean age, BMI and liver enzymes in different shift patterns of the participants*

Shift pattern
	Non-shift workers	Fast rotating	Slow rotating	Night	Evening	Split	Fixed 24h	Total
Number (%)	1441 (75.4%)	94 (4.6%)	78 (4.1%)	4 (0.2%)	141 (7.4%)	141 (7.4%)	11 (0.6%)	1910 (100%)
Age (yrs)	44.21±7.22	40.23±4.39	41.14±5.77	47.50±7.32	43.04±6.71	49.45±8.61	45.73±7.52	44.21±7.35
BMI (Kg/m²)	27.38±4.56	26.42±3.75	26.56±4.27	30.35 ± 6.72	27.01±4.91	27.55±5.16	26.77±2.78	27.29±4.59
AST (U/lit)	18.77±7.41	18.68±11.70	19.55 ± 8.71	18.25±5.31	18.41±7.35	19.23±8.28	15.81±5.82	18.79±7.77
ALT (U/lit)	23.01±15.59	21.85±17.68	24.16±14.63	24.25 ± 12.63	21.54±13.99	21.85±12.00	20.00±15.36	22.79±15.29
ALP (U/lit)	190.67±55.86	187.11±64.72	196.05±71.19	197.25 ± 39.18	182.67±55.92	185.51±55.16	197.09±59.02	189.80±56.92
GGT (U/lit)	28.01±23.34	24.69±22.34	32.75 ± 34.11	29.50±8.50	25.60±14.50	24.97±18.47	25.63±19.77	27.63±21.89
ALT/AST	1.18±0.52	1.14±0.40	1.24±0.45	1.28 ± 0.33	1.13±0.39	1.13±0.36	1.15±0.41	1.17±0.49

*Bold digits show the highest level.

The highest AST and GGT was observed in slow rotating shift workers and the highest ALT, ALP, and ALT/AST ratio in the night shift workers, although only the level of GGT in slow rotating shift workers was significantly different with fast rotating, evening, split and fixed 24 hours shifts (p = 0.008). After omitting night shift workers from the analysis, the results did not change.

There was no significant relationship between duration of shift work experience and mean liver enzymes in shift workers (p = 0.82, 0.15, 0.79, and 0.95 for AST, ALT, ALP and GGT, respectively).

The mean of liver enzymes in men was lower than women, which was significant for ALP and ALT, and the gender distribution was different between shift workers and non-shift workers as well. However, logistic regression showed no association between elevated level of liver enzymes and gender.

Considering the difference in smoking between two groups, uni-variate regression model showed that only the independent effect of smoking on GGT was significant, and bivariate regression did not show a significant association between shift work and elevated levels of liver enzymes after adjusting for cigarette smoking (p = 0.28 for ALT, p = 0.08 for AST, p = 0.34 for ALP, and p = 0.09 for GGT).

Among all participants, 3.2% of shift workers and 6.2% of non-shift workers had thyroid disease, but after excluding these participants, the results (relationship between shift work and mean levels of liver enzymes) did not change. Due to existence of some confounding factors, multi-variate regression model was used and the results showed that shift work was significantly associated only with elevated level of AST (Table 4).

Table 4

The relationship between shift work and elevated level of liver enzymes after adjusting for confounding factors

Variables	ALT			AST			ALP			GGT
	β	Exp (β) (95% CI)	P value	β	Exp (β) (95% CI)	P value	β	Exp (β) (95% CI)	P value	B	Exp (β) (95% CI)	P value
Shift work (ref*: non-shift worker)	–0.13	0.88 (0.59–1.30)	0.52	0.79	2.21 (1.05–4.73)	0.04	–0.18	0.83 (0.59–1.16)	0.18	–0.31	0.74 (0.52–1.04)	0.09
Gender (ref: male)	0.12	1.13 (0.79–1.60)	0.49	0.31	1.36 (0.61–2.94)	0.44	–0.15	0.85 (0.62–1.18)	0.36	–0.05	0.95 (0.70–1.29)	0.75
BMI	0.005	1.005 (0.97–1.04)	0.79	0.33	1.03 (0.96–1.11)	0.37	0.03	1.03 (0.99–1.06)	0.06	0.04	1.03 (1.00–1.06)	0.02
Smoking (ref: no smoking)	0.14	1.15 (0.75–1.74)	0.52	0.17	1.18 (0.47–2.93)	0.72	0.23	1.26 (0.83–1.88)	0.27	–0.44	0.65 (0.42–0.98)	0.04
Thyroid disease (ref: no disease)	0.09	1.09 (0.55–2.16)	0.79	–0.42	0.65 (0.08–4.91)	0.68	0.49	1.63 (0.77–3.43)	0.19	–0.14	0.87 (0.46–1.62)	0.66

*Ref: reference group.

4 Discussion

In this study, the mean level of liver enzymes (ALT, AST, ALP, and GGT) was compared between two groups of shift workers and non-shift workers in the general population and no relationship was observed between them. No significant dose-response relationship was observed as well between the number of shift work years and mean liver enzymes among shift workers. The frequency of elevated liver function tests was not significantly different between those working in a shift work schedule and other participants, but when adjusting for some possible confounding factors (gender, BMI, smoking, and thyroid disease), the frequency of elevated AST was significantly higher in shift workers comparing non-shift workers.

Shift work is a common pattern of work in many industries and jobs. Working as a shift worker leads to a change in circadian rhythm and biological clock which may affect the worker’s health. Recently, the effect of shift work on liver enzymes has raised concern. Liver enzymes may show liver dysfunction in an early stage. Some evidence shows that circadian rhythm affects the synthesis and blood level of liver enzymes by a peripheral internal clock which causes a diurnal variation in liver enzymes [21, 22]. Shift work causes a dysfunction in the internal biologic clock and circadian rhythm, and chronic exposure to shift work may affect the expression of some genes in hepatocytes and cause hepatic dysfunction [23].

Previous studies about the relationship between shift work and liver dysfunction have reached contradictory results. Balakrishnan et al. in a study on 8,159 employees aged 20 to 69 years in the general population found no association between non-alcoholic fatty liver disease and shift work [16], which was consistent with the results of the current study, although their population age range was wider than the population of the current study. Some studies have shown an association between shift work and liver dysfunction, including elevated liver enzymes [24 –26]. Choi et al. found a significant effect of shift work on ALT only in female workers, but the effect was not significant for AST in females and for ALT and AST in males [17]. They also could not find a significant difference between different patterns of shift work and abnormal liver enzymes as well, which was consistent with the results of the current study. Khosravipour et al. assessed the effect of shift work on ALP and found a significant difference in ALP level between 12 hour rotating night and 12 hour fixed day shift workers [14], which was against the results of the current study; although the pattern of shift work in this study was almost unique and was completely different from shift patterns in the current study, and also all of their participants were males selected from one industry, but in the current study people were selected from general population with different jobs. Wang et al. assessed the effect of night shift work on ALT and found a significant independent effect for shift work on ALT of night shift workers [15], which was inconsistent with the results of the current study. Their study population was selected from a cohort on night shift workers who were all males which was different from our population and the night shift workers were only 4 individuals in the present study, and also we assessed different patterns of shift work but they assessed only night shift work.

Previous studies mostly have compared ALT, AST or ALP between day and rotating shift workers or day and night shift workers, but in this study, the mean level of ALT, AST, ALP, GGT, and ALT/AST ratio and the frequency of individuals with elevated level of enzymes were compared between six different patterns of shift work and there was no significant difference between the groups; Only GGT was significantly higher in slow rotating shift workers in comparison to other groups. ALP and GGT usually show cholestatic liver disease, but recent studies suggest that elevated GGT, even in normal amounts, may be associated with an increase in cardiovascular and hepatic disease risk [10]. We did not find a study in the literature on the relationship between shift work and GGT level and ALT/AST ratio.

Shift work can reduce the opportunity to participate in exercise activities. In addition, the biological response to exercise may be different in shift workers [27]. Exercise may lead to changes in the level of liver enzymes besides level of blood lipids [28]. In the current study, the amount of time spent on aerobic exercise per day was not significantly different between shift workers and non-shift workers. Some studies have linked sleep deprivation to liver dysfunction [29]. However, the average of total sleep in 24 hours among shift workers was lower than day workers and the difference was statistically significant, which was consistent with the findings of previous studies [30].

Regarding the effects of smoking on liver enzymes, studies show contradictory results and there is insufficient evidence. There is a consensus that smoking exacerbates the process of alcohol-induced liver fibrosis [31]. Cigarette smoking was more frequent in shift workers than day workers, which was consistent with previous studies [32], but by comparing the mean of liver enzymes between smokers and non-smokers, we did not find a significant difference, and after adjusting the results for smoking, the results did not change.

In this study, comparisons were made between individuals with various occupations, so their physical and chemical exposures were probably different, which could affect liver function. However, due to the high variability of the jobs in shift workers and non-shift workers, this variable was not considered in the analysis in this study.

There may be a relationship between shift work and BMI, and BMI and liver enzymes. The association of BMI and liver enzymes has been proven in some previous studies [31]. A systematic review showed a positive relationship between night shift work and different types of obesity [33]. Peplosnka et al. found a significant relationship between rotating night shift work and obesity [34]. Liu et al. found a relationship between BMI and ALT, but GGT and ALP were not related to adiposity [35]. In this study, BMI was not significantly different between two groups of shift workers and non-shift workers. Multivariate logistic regression showed a slight relationship between BMI and GGT, and there was no significant relationship with other enzymes.

The results of the current study did not show a significant effect of work experience on liver enzymes among shift workers; although this study was cross-sectional and the duration of shift work could not be assessed in detail due to recall bias. Few studies have assessed dose-response relationship between shift work duration and liver enzymes. Wang et al. found a dose-response relationship between shift work and elevated ALT in night shift workers. The authors of the study declared that their study was the first one to assess this relationship [15]. Lin et al. in a cohort study also found that 5-year exposure to shift work aggravated elevated ALT [25].

In the present study, despite the sufficient sample size to compare between two groups of shift workers and non-shift workers, the sample size to compare among six different patterns of shift work was probably not enough, especially in night shift workers who were only four individuals, although after omitting night shift workers from the analysis, the results did not change.

4.1 Strengths and limitations

To the best of our knowledge, this is the first study that assessed the relationship between different patterns of shift work on four liver enzymes and ALT/AST ratio. However, the study is not without limitations. First of all, this was a cross-sectional study, so it suffers from integral limitations of the design, especially in showing cause-effect relationship. Also, we could not consider job title as a variable in the analyses due to the high variability of the jobs among the participants. The study may also suffer from recall bias about the history of shift work.

5 Conclusion

This study provides limited support for the hypothesis of the relationship between shift work and mean level of ALT, AST, ALP, GGT, and ALT/AST ratio in adult general population, but it can offer some evidence in favor of the idea that elevated AST may be related to shift work in this population after adjusting for some confounding factors; Although the results should be interpreted cautiously due to the limitations of the study. Studies with a larger sample size in each shift work pattern and longitudinal studies for assessing the possible trend of elevated liver enzymes after a period of shift work are recommended.

Ethical approval

The study was approved by the ethics committee of Shahid Sadoughi University of Medical Sciences (code: IR.SSU.MEDICINE.REC.1398.231).

Informed consent

Informed consent was obtained from each participant at the enrollment phase of the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Footnotes

Acknowledgments

The authors are grateful to the central team of the PERSIAN cohort, especially Prof. Reza Malekzadeh and Dr. Hossein Poustchi, and the local team of the Shahedieh cohort, especially Ms. Atefe Zare and Ms. Ameneh Mojibian and all participants of the Shahedieh cohort study, with special thanks to Dr. Mohammad Javad Zare for his kind collaborations.

Funding

None to report.

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