Objectively measured sedentary time, physical activity, and liver enzyme elevations in US Hispanics/Latinos

Abstract

Background & Aims

Sedentariness and physical inactiveness are associated with deleterious health outcomes, but their associations with liver enzyme elevations remain uncertain.

Methods

In 10 385 US Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos, we examined associations of sedentary time and moderate-to-vigorous physical activity (MVPA) measured by accelerometers with liver enzyme elevations. Elevated alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyltransferase (GGT) were defined as the highest sex-specific deciles. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated using weighted Poisson regressions.

Results

After adjusting for demographic/socioeconomic factors and MVPA, increasing quartiles of sedentary time were associated with a higher prevalence of elevated ALT (PRs [95% CI] = 1.0, 1.17 [0.92–1.47], 1.21 [0.96, 1.53], and 1.51 [1.13–2.02]; P-trend=0.007) and elevated GGT (PRs [95% CI] =1.0, 1.06 [0.82–1.36], 1.35 [1.06–1.73], and 1.66 [1.27–2.16]; P-trend=0.0001). These associations were attenuated but remained significant after further adjustment for cardiometabolic traits including body-mass index, waist-hip-ratio, lipids, and homeostatic model assessment of insulin resistance. In contrast, increasing quartiles of MVPA were associated with a lower prevalence of elevated ALT (PRs [95% CI] =1.0, 0.97 [0.77–1.23], 0.84 [0.66–1.06], and 0.72 [0.54–0.96]; P-trend=0.01) after adjusting for demographic/socioeconomic factors and sedentary time, but this association became non-significant after further adjustment for cardiometabolic traits. Notably, the association of sedentary time with GGT elevation was significant both in individuals meeting the US Physical Activity Guidelines for Americans (MVPA≥150 minutes/week) and in those who did not (both P-trend≤0.003).

Conclusions

Our findings suggest that objectively measured sedentary time is independently associated with elevated ALT and GGT in US Hispanics/Latinos.

Lay summary

Sedentariness and physical inactiveness are associated with deleterious health outcomes, but their relationships with liver enzyme elevations remain unclear. In a cross-sectional analysis of population-based study of US Hispanics/Latinos, we found that prolonged sedentary time was associated with a higher prevalence of elevated ALT and elevated GGT, and the associations were not fully explained by demographic/socioeconomic factors or traditional cardiometabolic risk factors. The potentially detrimental association of sedentariness appeared not diminished by increasing levels of physical activity.

Introduction

Non-alcoholic fatty liver disease (NAFLD), encompassing liver conditions ranging from steatosis to steatohepatitis that may progress to fibrosis, cirrhosis, or hepatocellular carcinoma,¹ is the most common liver disease in the US and the second leading indication for liver-transplantation.² Circulating levels of liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyltransferase (GGT), are recognized as biomarkers of potential NAFLD.^3–5 The prevalence of liver enzyme elevations has been used as valid surrogate indices of liver disease in epidemiological studies.⁶ A large proportion of patients with unexplained elevated aminotransferases (in absence of viral hepatitis or excessive alcohol intake) were found to have NAFLD on liver biopsy.^7,8 Furthermore, evidence from prospective cohort studies has revealed that elevated ALT and AST are associated with higher liver-related mortality risk, while elevated GGT is associated with a higher risk of mortality, not only from liver-related cause, but also in some studies, from all-causes, cardiovascular disease, cancer, and diabetes.^6,9–12

As a major component of treatment for NAFLD,³ physical activity (PA) has been shown to improve NAFLD severity by reducing weight, fat mass, intrahepatic triglycerides, and insulin resistance.^13,14 Sedentary behavior, in contrast, has been associated with NAFLD risk factors including obesity, hypertriglyceridemia, and insulin resistance, independent of physical activeness.^15,16 Prolonged sedentary time is also reported to be associated with a higher NAFLD prevalence regardless of the time engaged in PA in a Korean population and a small European population.^17,18 The increases in sedentary behavior in many populations during the past several decades are particularly striking.¹⁹ Understanding the interplay between sedentary time and PA in relation to liver enzyme elevations in diverse global populations is therefore crucial to inform clinical and public health interventions for NAFLD.

US Hispanics/Latinos have a high prevalence of NAFLD risk factors²⁰ (e.g., obesity and insulin resistance) and a 2-fold higher prevalence of aminotransferase elevation compared with non-Hispanic populations.²¹ However, data on PA and sedentary time in relation to NAFLD or liver enzyme elevation in such a high-risk population are scarce. Moreover, a majority of the current data on PA and sedentary time has been based on self-report that is subject to reporting bias. ^13,14,17,22 We therefore examined the association of objectively measured sedentary time and moderate-to-vigorous physical activity (MVPA) with the prevalence of elevations in ALT, AST and GGT in 10,385 US Hispanics/Latinos with diverse backgrounds in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Materials and methods

Study population

The HCHS/SOL is a multi-center prospective study of 16,415 self-identified Hispanic/Latino adults aged 18–74 years with Mexican, Puerto Rican, Dominican, Cuban, Central American, and South American background. Participants were recruited from 4 US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA) using a 2-stage probability sampling design. Detailed information on sampling methods and study designs has been introduced previously.^23,24 During the baseline visit (2008–2011), we conducted comprehensive in-person interviews to collect participants’ demographic characteristics, health status, and information on lifestyles and diet; and performed clinical examinations and collected biospecimens. The study was approved by the institutional review boards at all participating institutions. All participants gave written informed consent prior to the enrollment.

We excluded individuals suspected of having chronic HCV or HBV (N=270) based on positive HCV antibody, confirmed by viral load test or recombinant immunoblot assay, and positive HBV surface antigen. ^25,26 We further excluded individuals with elevated transferrin saturation (>50 %; N=655), had excess alcohol consumption (>7 drinks/week for women or >14 drinks/week for men; N=753), were not adherent to the accelerometer protocol (<10 hours of wear time for more than 3 days; N=3226), did not donate fasting blood samples (N=119), or had incomplete data on liver enzymes or other variables of interest (N=1007). A total of 10,385 participants were retained in the analyses after exclusions.

Assessment of sedentary behavior and physical activity

Detailed information on objectively measured sedentary behavior and physical activity in HCHS/SOL has been described in previous publications.^15,27 At the baseline examination, participants were instructed to wear an omnidirectional accelerometer (Actical version B-1, model 198–0200-03; Respironics Co. Inc., Bend, OR) above the iliac crest for 7 days. The accelerometer, programmed to measure acceleration in counts and steps in 1-minute epochs, was only supposed to be removed if the participants were swimming, showering, or sleeping. Non-wear time, determined by the Choi algorithm, was defined as over 90 consecutive minutes of 0 counts, with allowance for 1–2 minutes of non-0 counts if no counts were detected in a 30 minute window up- and downstream. An adherent day was defined as >10 hours of wear time. Only the participants with at least 3 adherent days were included in the analysis. Sedentary behavior was defined as <100 counts/minute, and MVPA was defined as >1535 counts/minute.^28,29 Time spent in each intensity was averaged across adherent days. Due to the high correlation between sedentary time and wear time (r²=0.83), all sedentary time was standardized to 16 hours of wear time per day using a residual method previously reported.¹⁵ Meeting the 2008 PA Guidelines for Americans (PAGA) was defined as having at least 150 minutes/week moderate-intensity activity, 75 minutes/week vigorous-intensity activity, or ≥150 minutes/week for a combination of the two.³⁰

Assessment of plasma liver enzymes and the definition of liver enzyme elevation

Plasma concentrations of ALT, AST, and GGT were measured using an α-ketoglutaratic enzymatic method on a Roche Modular P chemistry analyzer (Roche Diagnostics, Indianapolis, IN) in the Advanced Research and Diagnostics Laboratory at the University of Minnesota following standard protocols.³¹ At present, there are no standardized thresholds for defining AST, ALT, or GGT elevations. We therefore defined liver enzyme elevations as the highest sex-specific decile in our study population, according to prior studies in which elevated ALT, AST, and GGT based on the sex-specific deciles were associated with higher risk of liver-related and total mortality.⁶ More specifically, elevated ALT in HCHS/SOL was defined as ALT >59 IU/mL for men or >36 IU/mL for women; elevated AST was defined as AST >39 IU/mL for men or >30 IU/mL for women; and elevated GGT defined as GGT >72 IU/mL for men or >44 IU/mL for women. In a sensitivity analysis, we defined ALT and AST elevations using the NHANES threshold (AST >37 IU/mL or ALT >40 IU/mL for men; AST or ALT >31 IU/mL for women),²¹ which was not defined in Hispanics/Latinos but has been used to define suspected NAFLD in the US populations.

Assessment of covariates

Interviewer-administrated questionnaires were used to obtain information on age, sex, household income, education, employment status, health insurance status, Hispanic/Latino background, history of cigarette smoking and alcohol use, self-reported physical and mental health, and number of doctor visits in the past year. Participants were asked to bring all prescribed and non-prescribed medications that they took in the past 4 weeks to record medication uses and dose. Waist and hip circumference, and height were measured to the nearest 0.01 meter, and weight to the nearest 0.1 kg. Body-mass index (BMI) was calculated as weight in kilograms divided by square of height in meters. Waist-to-hip ratio (WHR) was calculated as waist circumference divided by hip circumference. Dietary intake was assessed with two 24-hour dietary recalls, and dietary quality was estimated using the alternate healthy eating index-2010 (AHEI). Levels of fasting triglycerides (TG) and high-density lipoprotein cholesterol (HDLC), as well as fasting and 2-hour glucose and insulin, were measured by the HCHS/SOL Central Laboratory in the Advanced Research and Diagnostics Laboratory at the University of Minnesota.¹⁵ Baseline diabetes and prediabetes were defined according to criteria from the American Diabetes Association.³² Homeostatic assessment of insulin resistance (HOMA-IR) was calculated as fasting insulin levels (mU/L) multiplied by glucose levels (mmol/L) and divided by 22.5.

Statistical analyses

Because sampling design of the HCHS/SOL, a sampling weight was calculated, non-response adjusted, trimmed, and calibrated based on 2010 US Census characteristics, to account for non-responses and oversampling of specific population groups.^23,27 An inverse probability weight (IPW) was calculated to account for incomplete accelerometer data (19.7%) as previously described.³³ The final weights used in the association analyses were the combined weights of IPW and the sampling weight. Analyses were conducted in SAS v9.3 (SAS Institute, Cary, NC) and SUDAAN release 11.0.1 (RTI International, Research Triangle Park, NC). A two-sided P values of <0.05 were considered statistically significant.

The cut-points for sedentary time quartiles were 10.9 hours/day, 12.1 hours/day and 13.1 hours/day. The cut-points for MVPA quartiles were 5.5 minutes/day, 14.3 minutes/day and 29.3 minutes/day. We compared the demographic and clinical characteristics across quartiles of sedentary time using ANOVA or chi-square tests. Poisson regression with robust variance estimators were used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) of liver enzyme elevations (ALT, AST, or GGT) comparing participants in higher quartiles to the lowest quartile of sedentary time or MVPA. To test for a linear trend, we assigned the median values of sedentary time or MVPA within each quartile and model this variable continuously. We adjusted for age, age-squared, sex, income, education, employment, smoking, alcohol use, AHEI-2010, health insurance status, healthcare utilization, self-reported health, medication intake, Hispanic/Latino background and field center. To examine the independence of sedentary time or MVPA in associations with elevated liver enzymes, we further built a model that included both sedentary time and MVPA. As previous studies suggested that associations of activeness or sedentariness with NAFLD might be mediated by weight, adiposity, insulin resistance, and blood lipids,^13,17 we further adjusted for BMI, WHR, HOMA-IR, TG, and HDLC to investigate the potential mediating effect of these variables.

Three sensitivity analyses were performed using the aforementioned analysis models: (i) excluding participants who self-reported a diagnosis of cardiovascular disease (CVD, including coronary heart disease, stroke, or heart failure), type 2 diabetes (T2D), or cancer before blood collection (remaining N=8333), (ii) excluding participants with incomplete HBV/HCV testing data (remaining N=7728), and (iii) defining elevations in ALT and AST based on thresholds used previously in the NHANES and by our group in the HCHS/SOL.

We performed stratified analyses by Hispanic/Latino background (Mainland: Mexican, Central, and South American; Caribbean: Cuban, Dominican, and Puerto Rican),³⁴ MVPA levels (meeting the US PAGA or not; only for analysis of sedentary time), and by subgroups of age, gender, BMI, prevalent diabetes, and prevalent hyperlipidemia. The interaction effects of the risk strata with sedentary time or MVPA were examined using the Wald test.

Results

In this Hispanic/Latino population, the average time spent in sedentary was 11.9 hours/day and in MVPA, was 21.1 minutes/day. Participants who spent more time in sedentary behavior were older, had higher BMI and HOMA-IR, and lower HDL-C; meanwhile, they were less likely to meet the US PAGA and had a lower AHEI. Participants with liver enzyme elevations spent longer time in sedentary, less time in MVPA, and are more likely to have an unfavorable metabolic risk profile (i.e., higher BMI, HOMA-IR, and triglycerides, and lower HDL-C; Table 1). With respect to Hispanic/Latino background, individuals of Dominican and Puerto Rican backgrounds spent more time in sedentary behavior, while those of Mexican background spent less. Consistent with our previous findings,³⁴ individuals of Mexican background had a higher prevalence of ALT elevation compared to those of Caribbean backgrounds (Tables 1 and S1).

Table 1.

Age- and sex-adjusted characteristics of the target population (n=10 385) by quartile of sedentary behavior

Characteristic	Quartiles of sedentary time				P
	Quartile 1 (n=2596)	Quartile 2 (n=2596)	Quartile 3 (n=2597)	Quartile 4 (n=2596)
Sedentary hours/day, mean (range) *	9.6 ( 0.8, 10.9)	11.6 (10.9, 12.1)	12.6 (12.1, 13.1)	13.8 (13.1, 16.0)	-
MVPA minutes/day, mean (95% CI) *	42.8 (39.7, 45.9)	24.4 (23.0, 25.8)	17.9 (16.8, 19.0)	12.2 (11.3, 13.1)	-
2008 US physical activity guidelines, n (%) *					-
Does not meet guidelines	959 (33.9)	1496 (54.0)	1817 (66.0)	2164 (78.8)
Meets guidelines	1637 (66.1)	1100 (46.0)	780 (34.0)	432 (21.2)
DEMOGRAPHIC CHARACTERISTICS
Age years, mean (95% CI)	39.1 (38.3, 39.9)	39.7 (38.8, 40.6)	41.5 (40.6, 42.3)	44.7 (43.5, 45.8)	<0.0001
Sex, % male (95% CI)	54.1 (51.0, 57.2)	43.5 (40.7, 46.3)	39.0 (36.3, 41.8)	43.2 (40.1, 46.4)	<0.0001
Annual household income, % (95% CI)					<0.0001
$20 000 or less	44.9 (41.2, 48.7)	43.8 (40.4, 47.3)	44.6 (41.1, 48.3)	49.7 (45.5, 53.9)
$20 001 - $50 000	45.3 (41.9, 48.8)	40.1 (37.4, 42.9)	40.2 (36.8, 43.7)	38.9 (34.8, 43.1)
More than $50 000	9.8 ( 7.7, 12.3)	16.1 (13.6, 18.9)	15.2 (12.7, 18.0)	11.4 ( 9.2, 14.2)
Education level, % (95% CI)					0.0006
Less than 9th grade	21.0 (18.8, 23.4)	16.7 (14.8, 18.8)	15.1 (13.5, 17.0)	17.5 (15.6, 19.5)
Some high school	13.6 (11.6, 15.8)	14.3 (12.3, 16.5)	12.9 (11.2, 14.7)	15.6 (13.1, 18.5)
High school graduate/equivalent	29.5 (27.0, 32.2)	26.0 (23.4, 28.8)	28.8 (26.4, 31.4)	27.3 (23.5, 31.5)
More than high school	35.9 (32.8, 39.0)	43.0 (40.2, 45.8)	43.1 (40.3, 46.0)	39.6 (35.8, 43.4)
Hispanic/Latino background, % (95% CI)					<0.0001
Dominican	5.6 ( 4.1, 7.7)	7.0 ( 5.6, 8.7)	8.8 ( 7.1, 11.0)	18.9 (15.1, 23.4)
Central American	7.6 ( 6.0, 9.5)	7.4 ( 5.9, 9.2)	8.1 ( 6.7, 9.7)	8.0 ( 6.6, 9.7)
Cuban	18.1 (14.6, 22.3)	21.9 (18.0, 26.5)	23.7 (19.6, 28.3)	19.4 (15.8, 23.5)
Mexican	49.5 (44.9, 54.2)	40.7 (36.6, 44.9)	36.4 (32.1, 40.9)	24.7 (21.3, 28.5)
Puerto Rican	10.8 ( 8.7, 13.3)	13.4 (11.4, 15.8)	15.0 (12.8, 17.5)	19.2 (16.6, 22.1)
South American	4.7 ( 3.7, 5.8)	6.2 ( 4.9, 7.9)	5.5 ( 4.4, 6.8)	5.2 ( 4.1, 6.5)
Other/more than one	3.7 ( 2.6, 5.3)	3.3 ( 2.3, 4.7)	2.5 ( 1.7, 3.8)	4.6 ( 2.8, 7.5)
Employment status, % (95% CI)					<0.0001
Retired and not currently employed	5.4 ( 4.3, 6.7)	6.4 ( 5.2, 7.7)	7.8 ( 6.8, 9.0)	9.8 ( 8.7, 11.1)
Not retired and not currently employed	26.6 (23.7, 29.7)	39.4 (36.5, 42.2)	47.5 (44.7, 50.4)	54.9 (51.5, 58.2)
Employed part-time (≤35 hours/week)	22.1 (19.5, 25.0)	20.5 (18.2, 23.0)	15.9 (13.9, 18.3)	11.5 ( 9.4, 14.1)
Employed full-time (>35 hours/week)	45.9 (42.9, 49.0)	33.8 (31.2, 36.5)	28.7 (26.4, 31.2)	23.7 (20.9, 26.8)
Health insurance, % (95% CI)	45.4 (42.0, 49.0)	48.1 (44.8, 51.4)	50.5 (47.2, 53.8)	57.5 (53.5, 61.4)	<0.0001
HEALTH STATUS
Body mass index kg/m2 (BMI), mean (95% CI)	28.8 (28.5, 29.2)	29.3 (28.9, 29.6)	29.2 (28.8, 29.6)	30.4 (29.9, 30.8)	<0.0001
Waist-to-hip ratio (WHR), mean (95% CI)	0.9 ( 0.9, 0.9)	0.9 ( 0.9, 0.9)	0.9 ( 0.9, 0.9)	0.9 ( 0.9, 0.9)	0.028
HOMA-IR, geometric mean (95% CI)	2.3 ( 2.1, 2.4)	2.5 ( 2.4, 2.6)	2.5 ( 2.4, 2.6)	2.9 ( 2.7, 3.0)	<0.0001
Triglycerides mg/dL, geometric mean (95% CI)	106 ( 102, 109)	110 ( 107, 114)	111 ( 107, 115)	117 ( 113, 121)	0.0006
HDL-cholesterol mg/dL, mean (95% CI)	49.6 (48.8, 50.4)	48.7 (47.9, 49.5)	48.1 (47.5, 48.7)	47.5 (46.7, 48.4)	0.002
Hyperlipidemia, % (95% CI)	42.0 (39.3, 44.8)	43.6 (40.8, 46.5)	45.0 (42.3, 47.8)	45.8 (42.3, 49.2)	0.29
Self-report physical health score, mean (95% CI)	50.7 (50.2, 51.3)	51.0 (50.6, 51.5)	50.2 (49.7, 50.7)	48.5 (47.9, 49.1)	<0.0001
Self-report mental health score, mean (95% CI)	50.0 (49.3, 50.8)	50.0 (49.4, 50.6)	49.6 (49.0, 50.2)	48.6 (47.8, 49.4)	0.05
Smoking status, % (95% CI)					0.14
Never	64.7 (61.7, 67.6)	64.6 (61.5, 67.5)	62.8 (60.0, 65.4)	66.6 (63.6, 69.5)
Former	17.7 (15.6, 20.0)	18.5 (16.4, 20.9)	18.1 (16.2, 20.2)	15.3 (13.6, 17.0)
Current	17.6 (15.2, 20.3)	16.9 (14.6, 19.4)	19.1 (16.8, 21.7)	18.1 (15.4, 21.2)
Alcohol use history, % (95% CI)					0.61
Never	20.0 (17.3, 23.0)	20.6 (18.1, 23.4)	21.3 (18.9, 23.9)	18.7 (16.2, 21.4)
Former, quit for health reasons	6.1 ( 4.8, 7.7)	6.2 ( 4.8, 7.9)	5.9 ( 4.8, 7.3)	7.0 ( 5.7, 8.6)
Former, quit for other reasons	24.5 (21.7, 27.4)	23.6 (21.1, 26.2)	23.7 (21.6, 26.0)	27.3 (23.9, 30.9)
Current moderate use	49.4 (46.2, 52.7)	49.7 (46.1, 53.3)	49.0 (46.1, 51.9)	47.0 (43.3, 50.8)
Doctor visits in past 12 months, % (95% CI)					<0.0001
Zero	35.4 (32.5, 38.4)	33.2 (30.2, 36.3)	28.5 (25.8, 31.2)	29.0 (25.4, 33.0)
One	17.0 (14.8, 19.5)	16.0 (13.9, 18.4)	15.7 (13.8, 17.9)	13.5 (11.6, 15.7)
Two or more	47.6 (44.5, 50.7)	50.8 (47.7, 53.9)	55.8 (53.0, 58.6)	57.5 (53.8, 61.1)
Alternative healthy eating index, mean (95% CI)	48.3 (47.8, 48.8)	47.8 (47.3, 48.3)	47.2 (46.7, 47.7)	46.7 (46.2, 47.1)	<0.0001
Antidiabetic medications, % (95% CI)	6.7 ( 5.5, 8.2)	6.0 ( 4.9, 7.3)	8.6 ( 7.3, 10.0)	11.1 ( 9.9, 12.5)	<0.0001
Antihypertensive medications, % (95% CI)	10.6 ( 9.2, 12.2)	10.7 ( 9.2, 12.3)	12.7 (11.2, 14.4)	15.5 (14.0, 17.3)	<0.0001
Lipid-lowering medications, % (95% CI)	9.1 ( 7.2, 11.5)	7.6 ( 6.3, 9.1)	9.4 ( 8.1, 10.9)	11.0 ( 9.8, 12.3)	0.004
NSAID use, % (95% CI)	14.9 (13.1, 16.8)	16.1 (14.2, 18.2)	16.4 (14.5, 18.4)	15.6 (13.5, 17.9)	0.72

All variables are presented as mean/percentage (95% confidence intervals) unless otherwise stated. All numbers and analyses have accounted for the sampling strategies of the HCHS/SOL and were adjusted for 10-year age groups. CI, confidence interval; HCHS/SOL, Hispanic Community Health Study/Study of Latinos; and MVPA, moderate to vigorous physical activity.

^*Sedentary time, MVPA, and whether met the 2008 Physical Activity Guidelines were not adjusted for age and sex.

After multivariable adjustment including demographic and social-economic characteristics, smoking, alcohol use, AHEI-2010 score, and medication use, more sedentary time and less MVPA both were significantly associated with a higher prevalence of elevated ALT, AST, and GGT (P-trend=0.02 to <0.0001; Table 2 Model 2). After further adjustment for MVPA, higher sedentary time remained significantly associated with elevated ALT and GGT. The PRs (95% CI) comparing higher to the lowest quartiles of sedentary time were 1.17 (0.92–1.47), 1.21 (0.96–1.53), and 1.51 (1.13–2.02) for ALT elevation (P-trend=0.007), and 1.06 (0.82–1.36), 1.35 (1.06–1.73), and 1.66 (1.27–2.16) for GGT elevation (P-trend<0.001; Table 2 Model 3). After additional adjustment for sedentary time, MVPA was inversely associated with the prevalence of ALT elevation; PRs (95% CI) comparing higher to the lowest quartiles were 0.97 (0.77–1.23), 0.84 (0.66–1.06), and 0.72 (0.54–0.96) (P-trend=0.01; Table 2 Model 3). When further adjusting for potential mediating variables including indicators of obesity (BMI and WHR), insulin resistance (HOMA-IR), and lipids (TG and HDL-C), the associations of sedentary time with ALT and GGT elevations attenuated but remained significant (P-trend<0.05), whereas the association between MVPA and ALT elevation attenuated and became non-significant (P-trend=0.30) (Table 2 Model 4 and Table S2).

Table 2.

Prevalence ratios (95% CIs) of liver enzyme elevations according to quartile of sedentary time or MVPA

Outcomes and models	Quartiles of sedentary time or MVPA				P for trend
	Quartile 1	Quartile 2	Quartile 3	Quartile 4
Sedentary time
PR of elevated ALT (95% CIs) †
No. of subjects with elevated ALT	234	288	281	277
Model 1	1.00 (ref)	1.17(0.93,1.46)	1.23(1.00,1.52)	1.50(1.18,1.92)	0.001
Model 2	1.00 (ref)	1.25(1.00,1.57)	1.34(1.08,1.67)	1.77(1.37,2.28)	<0.0001
Model 3 (M2 + MVPA)	1.00 (ref)	1.17(0.92,1.47)	1.21(0.96,1.53)	1.51(1.13,2.02)	0.007
Model 4 (M3 + BMI+WHR+HOMA-IR+TG+HDL-C)	1.00 (ref)	1.13(0.90,1.42)	1.18(0.94,1.49)	1.34(1.02,1.76)	0.035
PR of elevated AST (95% CIs) ‡
No. of subjects with elevated AST	224	264	293	295
Model 1	1.00 (ref)	1.05(0.82,1.35)	1.19(0.94,1.51)	1.37(1.05,1.80)	0.017
Model 2	1.00 (ref)	1.11(0.86,1.44)	1.26(0.98,1.63)	1.45(1.09,1.93)	0.01
Model 3 (M2 + MVPA)	1.00 (ref)	1.07(0.82,1.39)	1.19(0.90,1.56)	1.32(0.96,1.82)	0.08
Model 4 (M3 + BMI+WHR+HOMA-IR+TG+HDL-C)	1.00 (ref)	1.04(0.80,1.36)	1.17(0.89,1.55)	1.20(0.88,1.63)	0.20
PR of elevated GGT (95% CIs) §
No. of subjects with elevated GGT	243	277	292	361
Model 1	1.00 (ref)	1.05(0.81,1.35)	1.41(1.12,1.78)	1.74(1.39,2.18)	<0.0001
Model 2	1.00 (ref)	1.10(0.86,1.41)	1.43(1.14,1.80)	1.80(1.43,2.27)	<0.0001
Model 3 (M2 + MVPA)	1.00 (ref)	1.06(0.82,1.36)	1.35(1.06,1.73)	1.66(1.27,2.16)	0.0001
Model 4 (M3 + BMI+WHR+HOMA-IR+TG+HDL-C)	1.00 (ref)	1.04(0.81,1.33)	1.33(1.05,1.68)	1.50(1.16,1.94)	0.0008
MVPA
PR of elevated ALT (95% CIs) †
No. of subjects with elevated ALT	311	308	252	209
Model 1	1.00 (ref)	0.87(0.69,1.09)	0.72(0.57,0.90)	0.54(0.41,0.71)	<0.0001
Model 2	1.00 (ref)	0.92(0.73,1.15)	0.75(0.59,0.95)	0.58(0.45,0.76)	<0.0001
Model 3 (M2 + Sedentary time)	1.00 (ref)	0.97(0.77,1.23)	0.84(0.66,1.06)	0.72(0.54,0.96)	0.014
Model 4 (M3 + BMI+WHR+HOMA-IR+TG+HDL-C)	1.00 (ref)	0.99(0.79,1.25)	0.89(0.70,1.13)	0.88(0.67,1.16)	0.30
PR of elevated AST (95% CIs) ‡
No. of subjects with elevated AST	319	280	245	232
Model 1	1.00 (ref)	0.85(0.65,1.10)	0.90(0.68,1.18)	0.74(0.56,0.96)	0.04
Model 2	1.00 (ref)	0.86(0.66,1.11)	0.88(0.66,1.17)	0.71(0.54,0.95)	0.02
Model 3 (M2 + Sedentary time)	1.00 (ref)	0.89(0.69,1.16)	0.94(0.71,1.24)	0.82(0.60,1.12)	0.25
Model 4 (M3 + BMI+WHR+HOMA-IR+TG+HDL-C)	1.00 (ref)	0.92(0.71,1.19)	1.00(0.75,1.33)	0.96(0.71,1.31)	0.99
PR of elevated GGT (95% CIs) §
No. of subjects with elevated GGT	392	301	264	216
Model 1	1.00 (ref)	0.77(0.61,0.96)	0.70(0.56,0.87)	0.62(0.48,0.79)	0.001
Model 2	1.00 (ref)	0.80(0.64,1.00)	0.72(0.57,0.90)	0.64(0.50,0.82)	0.001
Model 3 (M2 + Sedentary time)	1.00 (ref)	0.86(0.69,1.08)	0.83(0.66,1.04)	0.84(0.65,1.09)	0.34
Model 4 (M3 + BMI+WHR+HOMA-IR+TG+HDL-C)	1.00 (ref)	0.90(0.73,1.11)	0.89(0.72,1.11)	1.01(0.78,1.31)	0.71

Model 1: weighted Poisson regressions to obtain prevalence ratio (PR) and 95% confidence intervals (CI), adjusting for age, age-squared, sex

Model 2: further adjusted for household income, education, employment status, Hispanic/Latino background, field center, smoking, alcohol use history, health insurance status, healthcare utilization, self-reported health, alternative healthy eating index, and the following medications within the last 4 weeks prior to the baseline visit, according to scanned medication inventory: antidiabetic, antihypertensive, lipid-lowering, and non-steroidal anti-inflammatory drugs.Model 3: further adjusted for sedentary behavior or MVPA, as appropriate, treated as continuous variables;Model 4: further adjusted for body mass index, waist to hip ratio, homeostasis model assessment of insulin resistance, fasting triglycerides, and fasting HDL cholesterol.

^†Elevated ALT defined as above the sex-specific 90th percentile (≥59 IU/mL for men and ≥36 IU/mL for women).

^‡Elevated AST defined as above the sex-specific 90th percentile (≥39 IU/mL for men and ≥30 IU/mL for women).

^§Elevated GGT defined as above the sex-specific 90th percentile (≥72 IU/mL for men and ≥44 IU/mL for women).

MVPA, moderate to vigorous physical activity; ALT, alanine aminotransferase; AST, aspartate aminotransferase; and GGT, gamma-glutamyl transferase.

A sensitivity analysis excluding participants who reported having CVD, T2D, or cancer yielded similar results with respect to all associations (Table S3). When excluding participants missing HBV/HCV testing data, the associations of sedentary time with elevated ALT and GGT remained significant (P-trend<0.05), whereas the association between MVPA and elevated ALT was attenuated and became non-significant (P-trend=0.1) (Table S4). When using the NHANES thresholds to define ALT and AST elevations,^21,34 we noted that the prevalence of ALT elevation were doubled while the prevalence of AST elevation were halved; more time spent in sedentary and less in MVPA were significantly associated with a higher prevalence of ALT elevation in Model 2, but such associations did not survive after further adjustments in Model 3 (Table S5).

When stratifying the analysis by physical activity sub-groups, we observed an significant positive association of sedentary time with ALT and AST elevations among individuals who did not met the 2008 US PAGA recommendations (P-trend≤0.01); although such an association was weaker and statistically nonsignificant in individuals who met the PAGA recommendations (P-trend>0.05), no significant effect modification by MVPA was found (P-interaction>0.4; Figure 1). In contrast, we noted significant positive association between sedentary time and GGT elevation among individuals meeting the PAGA and those who did not with highly comparable effect sizes: PRs for increasing quartiles were 1 [reference], 1.08, 1.47 and 1.96 among those who met the PAGA (P-trend=0.003), and were 1.14, 1.21, 1.52, and 1.88 among those who did not (P-trend<0.001; Figure 1).

Figure 1.

Multivariable-adjusted prevalence ratio (PR) and 95% confidence intervals (CI) of elevated ALT (A), AST (B), and GGT (C) by quartiles of sedentary time, stratified by whether or not meeting the 2008 Physical Activity Guidelines.

Results were adjusted for covariates listed for model 1 of Table 2.

When stratifying by Hispanic/Latino background, we observed a significant positive association of sedentary time with ALT and AST elevations in participants of Mainland backgrounds (P-trend≤0.02) but not in those of Caribbean backgrounds (P-trend≥0.33), though no significant effect modification was found (P-interaction>0.05; Figure 2). The association between sedentary time and GGT elevation was significant and consistent in Mainland and Caribbean groups (both P-trend≤0.02, P-interaction=0.67). The association between MVPA and liver enzyme elevations was similar by Hispanic/Latino backgrounds (P-interaction>0.5; Figure 2).

Figure 2.

Multivariable-adjusted prevalence ratio (PR) and 95% confidence intervals (CI) of ALT, AST and GGT elevations by quartiles of sedentary time (A, B, and C) or MVPA (D, E, and F), stratified by Hispanic/Latino background.

Results were adjusted for covariates listed for model 1 of Table 2.

Stratified analyses by other risk factors suggested that the associations of sedentary time and MVPA with liver enzyme elevations were generally consistent across subgroups of age, sex, BMI, and prevalent diabetes or hyperlipidemia (Figure 3). Nominally significant interactions were observed between diabetic status with sedentary time and MVPA on ALT elevation, and between sex and sedentary time, hyperlipidemia and MVPA, on GGT elevation (P-interaction<0.05; Figure 3).

Figure 3.

Multivariable-adjusted prevalence ratio (PR) and 95% confidence intervals (CI) of liver enzyme elevations associated with sedentary time (A) or MVPA (B), stratified by age group, sex, BMI, and prevalence of diabetes or hyperlipidemia.

Results were adjusted for covariates listed for model 1 of Table 2. PRs represent risks of liver enzyme elevations per hour increase in sedentary time or per 30 minutes increase in MVPA.

Discussion

Leveraging objectively measured data on sedentary time and physical activity in a large, diverse US Hispanic/Latino population, our data revealed that prolonged sedentary time was associated with a higher prevalence of ALT and GGT elevations, independent of time engaged in MVPA, obesity, insulin resistance, and blood lipids. In contrast, more time spent in MVPA was associated with a lower prevalence of ALT elevation, independent of sedentary time, but the association was abolished after further accounting for obesity, insulin resistance, and blood lipids.

Our findings are consistent with recent cross-sectional evidence in which self-reported sitting time was positively associated with prevalence of ultrasonographically-identified NAFLD in non-Hispanic white and Asian adults independent of physical activity levels.^17,18,35 The robust association between sedentary behavior and ALT elevation rather than AST elevation may reflect the slightly different physiology of these two biomarkers: ALT is primarily secreted by damaged liver and kidney cells, while AST is secreted in the setting of liver, kidney, and muscle cell damage.³⁶ Of note, in the present study, the increasing prevalence of ALT and GGT elevations with sedentary time was consistent among individuals who met the US PAGA and those who did not. This supported the conclusion that sedentary behavior potentially has an independent influence on liver enzyme elevations apart from MVPA.

The strong association between prolonged sedentary time and GGT elevation observed in our study has not been previously reported. GGT is predominantly located in the cell membrane and critical for the maintenance of the intracellular reduced glutathione – a major antioxidant agent.³⁶ Although GGT exists in many tissues, its serum activity originates primarily in the hepatobiliary system and it is a sensitive marker for many hepatobiliary diseases.³⁶Accumulating evidence supports a strong positive association of GGT with liver-related mortality, all-cause mortality and – in some but not all studies – death from other causes including cardiovascular disease, cancer and diabetes.^6,9–12 Prolonged sedentary time has been associated with increased mortality risk.¹⁶ Whether GGT elevation indicates any biological mechanisms underlying the association of sedentary behavior with mortality requires further investigation.

The American Gastroenterological Association and American College of Gastroenterology recommend increasing physical activity as a part of NAFLD management.³ Previous studies supported physical activity as beneficial for reducing risk of NAFLD, possibly through its beneficial effect in weight loss, and changes in adiposity, blood lipids, glucose, and insulin resistance.^14,15,17,22 Consistently, our study in US Hispanics/Latinos also suggested that the inverse association between MVPA and liver enzyme elevation might be partially mediated by variations in indicators of obesity, insulin resistance, and blood lipid. However, using objective data derived from multi-day activity monitoring, we found that the association between MVPA and liver enzyme elevations was largely attenuated (for ALT) or even abolished (for AST and GGT) after further adjusting for sedentary time, suggesting a potentially large contribution from sedentariness in the association analysis of MVPA if not well controlled for.

A previous study in Korean population suggested that the association between sitting time and NAFLD were only slightly attenuated after adjusted for BMI, but could be fully explained by percent fat mass.¹⁷ In the current study, we found that adiposity measured by BMI and WHR can only partially explain the association between sedentary behavior and liver enzyme elevation, which may reflect the limitation of BMI and WHR in measuring obesity. In addition, our study did not measure NAFLD directly, which may also explain the discrepancy between our and previous study. We found that the associations of sedentary behavior with liver enzyme elevation could not be fully explained by adiposity measures (BMI, WHR), insulin resistance (HOMA-IR) and blood lipids (triglycerides, HDL-cholesterol), suggesting additional potential mediators, such as visceral fat and liver fat, which were not measured in the current study. ^37–39 Visceral fat, which has been associated with sedentary time,^37,40 plays an important role in the development of NAFLD.^38,41 In addition, liver fat has been found to be reduced through exercise without significant weight loss or improvement in glucose and insulin sensitivity.^37,42,43

Key strengths of the current study include the measurement by accelerometry of sedentary time and MVPA, and a unique population with diverse Hispanic/Latino backgrounds. Although self-reported sedentary behaviors and physical activities have been frequently used in large-scale studies of NAFLD, objective measurements, which are more precise and may be less biased, have only been used in an NHANES study (N=3056 with 10% Mexican Americans)⁴⁴ and a few small cross-sectional studies (<800 non-Hispanic whites).^18,45,46 The relationship of sedentary behavior and MVPA with liver enzyme elevations has never been reported in US Hispanics/Latinos, who have a higher prevalence of aminotransferase elevation²¹ and different lifestyles regarding sedentary behavior and physical activities⁴⁷ compared with other US populations. US Hispanics/Latinos of different backgrounds also exhibit diversity with respect to NAFLD prevalence and lifestyles.^15,34. In our study, we did not observe significant effect modifications by Hispanic/Latino backgrounds, suggesting that decreasing sedentary time and increasing MVPA may exhibit beneficial impact on liver enzymes regardless of the Hispanic/Latino heritage.

Several limitations of our study warrant discussion. First, the placement of accelerometers or body habitus may influence the measures, and some standing time may be treated as sitting time. Second, the study did not include a direct assessment of clinically proven NAFLD. Nevertheless, liver enzyme elevations used in the current study represent surrogate biomarkers of suspected NAFLD,²¹ and elevations of ALT and AST have been associated with liver-related mortality while GGT has been associated with liver-related mortality and all-cause mortality.^6,9–12 Third, the current study only included BMI and WHR as obesity measures, and thus was unable to examine the potential involvement of body fat and body composition (e.g., body fat percent, skeletal muscle mass)¹⁷ in the relationship between sedentary behavior and liver enzyme elevation. A fourth limitation is the cross-sectional study design. However, our analyses were focused on the subclinical markers (i.e., liver enzyme elevations) of which the levels are unaware to the study participants and thus reduce the impact of reverse causation.

In summary, we found significant associations between objectively measured sedentary time and ALT and GGT elevations, regardless of time engaged in MVPA, in a US Hispanic/Latino population. Our data, together with previous evidence,^16,17 highlight that increasing PA alone may not diminish the detrimental association of sedentary behavior with liver enzyme elevations. If these findings are confirmed in other populations, a promising avenue for clinical and public health intervention to prevent or treat NAFLD may be to promote reduction in sedentary behaviors.

Abbreviations

AHEI

alternate Healthy Eating Index

ALT

alanine aminotransferase

AST

aspartate aminotransferase

BMI

body-mass index

CI

confidence interval

CVD

cardiovascular disease

GGT

γ-glutamyltransferase

NAFLD

non-alcoholic fatty liver disease

HBsAg

HBV surface antigen

HBV

hepatitis B virus

HCHS/SOL

Hispanic Community Health Study/Study of Latinos

HCV

hepatitis C virus

HDL-C

high-density lipoprotein cholesterol

HOMA-IR

homeostatic assessment of insulin resistance

MVPA

moderate-to-vigorous physical activity

NHANES

National Health and Nutrition Examination Survey

PA

physical activity

PAGA

Physical Activity Guidelines for Americans

PR

prevalence ratio

TG

triglycerides

T2D

type 2 diabetes

US

United States

WHR

waist-to-hip ratio