Environmental Research 132 (2014) 264–268

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Secondhand tobacco exposure is associated with nonalcoholic fatty liver disease in children Connie Lin a, Carl B. Rountree b,c, Sosamma Methratta b,d, Salvatore LaRusso d, Allen R. Kunselman e, Adam J. Spanier b,e,n a

College of Medicine, Penn State University Hershey Medical Center, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, USA Department of Pediatrics, Penn State University Hershey Medical Center, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, USA c Department of Pediatrics, Bon Secour St. Mary's Hospital, 5801 Bremo Rd, Richmond, VA 23226, USA d Department of Radiology, Penn State University Hershey Medical Center, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, USA e Department of Public Health Sciences, Penn State University Hershey Medical Center, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, USA b

art ic l e i nf o

a b s t r a c t

Article history: Received 22 August 2013 Received in revised form 8 April 2014 Accepted 9 April 2014

Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in children in the United States, and prevalence rates are rising. Smoking is associated with NAFLD, but the association of secondhand smoke exposure with NAFLD is unknown. Aims: To investigate the association of secondhand tobacco exposure with NAFLD in children. Methods: We surveyed parents/guardians of 304 children aged 3–12 years who had received an abdominal ultrasound at Penn State Hershey Medical Center. The survey addressed demographics, medical history, secondhand tobacco exposure, activity level, screen viewing time and other environmental exposures. A pediatric radiologist and sonographer reviewed the ultrasounds to grade the presence of bight liver compatible with NAFLD. We conducted logistic regression analysis to assess the association of secondhand tobacco exposure and NAFLD. Results: 54% of eligible potential participants responded to the survey. Fatty liver was present in 3% of the children. Increasing child age was associated with increased odds of NAFLD (OR 1.63 95% CI 1.1, 2.4). Reported child obesity was associated with increased odds of NAFLD (OR 44.5 95% CI 5.3, 371.7). The rate of NAFLD was higher in the smoke exposed group (6.7% vs. 1.7%). For every extra pack per day smoked at home, the odds of a child having NAFLD increased 1.8 times (AOR 1.8, 95% CI 1.2, 2.8), and any exposure increased a child's odds of NAFLD four-fold (AOR 4.0, 95% CI 1.02, 15.8). Conclusion: We found an association of secondhand smoke exposure and NAFLD in children. This may represent an area for future prevention efforts. & 2014 Elsevier Inc. All rights reserved.

Keywords: Nonalcoholic fatty liver Children Ultrasonongraphy Steatohepatitis Secondhand smoke

1. Introduction Nonalcoholic fatty liver disease (NAFLD) is the number one cause of liver disease in children and adults in the United States (Schwimmer et al., 2006). NAFLD is being recognized increasingly in the pediatric population with prevalence ranging from 2.6 to 9.6% for suspected NAFLD among children and adolescents in the USA and Asia (Franzese et al., 1997; Schwimmer et al., 2006;

Abbreviations: AOR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio n Corresponding author at: Department of Pediatrics, Mail Code HS83, Penn State University, Hershey Medical Center, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, USA. Fax: þ717 531 0869. E-mail address: [email protected] (A.J. Spanier). http://dx.doi.org/10.1016/j.envres.2014.04.005 0013-9351/& 2014 Elsevier Inc. All rights reserved.

Strauss et al., 2000; Tominaga et al., 1995; Park et al., 2005; Bellentani and Marino, 2009; Alavian et al., 2009). Exposure to secondhand smoke (SHS) has been linked to numerous adverse health outcomes in both adults and children (U.S. Department of Health and Human Services, 2006). Despite the decline in SHS exposure among children in the past decade, 20–25% of children and adolescents live in a household with at least one smoker (U.S. Department of Health and Human Services, 2006). The home is the primary source of SHS exposure for children, and while smoke exposure rates have declined over time, 50.2% of nonsmoking children have measurable exposure (Ashley and Ferrence, 1998; Kaufmann et al., 2010; U.S. Department of Health and Human Services, 2006). Adult smokers have higher rates of NAFLD (Hamabe et al., 2011). Additionally, there is experimental evidence suggesting that secondhand tobacco exposure may be associated with the development of NAFLD. Second hand smoke can stimulate lipid accumulation in

C. Lin et al. / Environmental Research 132 (2014) 264–268

hepatocytes, and results in inactivation of 50 -AMP-activated protein kinase which ultimately leads to accumulation of triglycerides in hepatocytes (Yuan et al., 2009). Lipid and triglyceride accumulation are the primary components of NAFLD (Chalasani et al., 2004). To our knowledge, no studies have evaluated the association of secondhand tobacco exposure with NAFLD in children. With the rise in NAFLD and high rates of secondhand smoke exposure among children, our aim was to evaluate the association between secondhand tobacco exposure and NAFLD based on ultrasound evaluation.

2. Methods 2.1. Study design We enrolled a cohort of children who had an abdominal ultrasound at our medical center. We obtained the contact information for families of children (n¼ 716) aged 3 to 12 years who had previously had an abdominal ultrasound in Penn State Hershey Medical Center during the period of July, 2003–July, 2010. Informed consent was implied by response to the mailed survey invitation and review of accompanying study information. This study was approved by the Penn State College of Medicine Institutional Review Board. Children ages 3–12 years were eligible for enrollment. Children were excluded if they had other established liver disease diagnoses noted in their electronic medical record. We excluded children over 12 years to reduce the risk of including child smokers. We sent letters of explanation and an invitation to participate to the parent or guardian of the children who were in the enrollment age range. We were not able to pre-screen for any of the other enrollment criteria prior to the mailing; therefore, some families receiving letters may have had a child who was not eligible for participation. Families could opt out, return our survey via self-addressed stamped envelope, or participate via phone. Thus, we collected all exposure and demographic data by written survey response or phone survey conducted by a trained surveyor.

2.2. Secondhand tobacco exposure We determined secondhand tobacco exposure using survey data. A telephone surveyor who was blinded to ultrasound results asked the parent or guardian questions, based on a validated questionnaire, to assess whether they, other family members who live in the house, or other individuals who do not live in the house but spend time with the child smoke cigarettes (Coghlin et al., 1989). We also recorded the reported number of cigarettes smoked per day by each individual. We created several variables to classify children as exposed or not exposed based on this report. First, we created a dichotomous variable of any reported exposure (reported smoking by the parent, guardian, or any other individual). Second, we calculated the total number of cigarettes smoked per day by anyone and log transformed this variable because it had a right-skewed distribution. Third, we divided the total number of cigarettes smoked per day by 20 to approximate the number of packs per day to which the child might be exposed.

2.3. Potential covariates We obtained social, demographic, and health information via survey for consideration as potential covariates. We surveyed the parent or guardian to obtain information about their age, education, Pennsylvania county of residence, type of housing, occupation, water source, medical history, and weight category (ideal weight or below vs. above ideal weight). We also obtained information about their child's race, ethnicity, reported weight category, reported physical activity, television viewing, computer use and video game playing data. We recorded the child age, sex, height, weight, and body mass index (BMI) from medical records. BMI was not available for all children (n¼ 138) because the radiology department is a referral site rather than the site of primary care.

2.4. NAFLD diagnosis Two readers (a pediatric radiologist and a pediatric sonographer) retrospectively reviewed the abdominal ultrasounds to grade the presence of bight liver compatible with NAFLD. Following the definitions of other investigators, each reviewer graded the liver on a scale of 0–2: no steatosis (0), mild steatosis (1), or moderate to severe steatosis (2), respectively (Alavian et al., 2009; Shannon et al., 2011). We blinded the radiologist and sonographer to survey results and to the

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scores of the other reader. We assigned a diagnosis of NAFLD if an ultrasound received a score of 2 by both reviewers.

2.5. Statistical analysis We used arithmetic means and 95% confidence intervals to describe central tendency and dispersion for exposures and demographics. We employed the standard 2-sided 5% level to determine statistical significance for our analyses. We conducted logistic regression analysis of the dichotomous NAFLD outcome. First we conducted bivariate analyses to evaluate the association of secondhand smoke exposure, as well as other potential covariates, with NAFLD. Next, we conducted a stepwise, forward-selection multivariable logistic regression analysis using standard techniques. We explored the interactions of covariates with secondhand smoke exposure. In initial multivariable analysis, we excluded obesity because of documented associations between smoke exposure and obesity as well as obesity and NAFLD (Tominaga et al., 1995; U.S. Department of Health and Human Services, 2006; Weitzman et al., 2005). In secondary analyses, we evaluated the association of tobacco exposure (number of cigarettes smoked per day around the home and packs per day) with NAFLD only among those with reported smoke exposure to reduce the influence of a large proportion of zero or no exposure. SAS Version 9.3 (SAS Institute, Inc., Cary, NC) was used for all data analyses.

3. Results 3.1. Characteristics of the study population Of the 716 ultrasounds, 662 had valid addresses in our system. We reached 462 by mail or phone, and 200 did not return calls or respond to the mailing. Of the 462 we reached 355 participated (144 by paper and 211 by phone). Because we did not pre-screen for eligibility, 51 of the 355 participants (14.4%) did not meet all inclusion criteria (most due to preexisting liver disease); thus, the total sample was 304. Applying the proportion that were eligible among participants (85.6%) to the non-responder and nonparticipant totals (200 and 105) yields 171 likely eligible non-responders and 90 likely eligible nonparticipants. Thus the total possible eligible population could have been 565, yielding an eligible participant response rate of 54%. Of the 304 study participants, 75% were white, 51% male, and the mean age was 7.7 years (Table 1). The reported frequency of overweight was 15.1%. BMI was not available on all children to verify parent report; however, all children with BMI based obesity, had parent reported obesity. There were 75 children (24.7%) for whom smoke exposure was reported (Table 2). Only 9 of the participants (3%) met our criteria for diagnosis of NAFLD; 8 of these children were white, and 1 was Hispanic. If we had expanded the NAFLD definition to include children who scored a 2 by one reviewer and a 1 by the other reviewer, the number with NAFLD would have increased to 11 (3.6%).

3.2. Covariates We evaluated the association of potential parent or guardian covariates with NAFLD including demographics, Pennsylvania county of residence, type of housing, occupation, water source, medical history, and weight category, and none of the associations was significant. We also evaluated the association of potential child covariates with NAFLD including race, ethnicity, reported physical activity, television viewing, computer use, video game playing time, sex, and body mass index, and none of the associations was significant. Only child age and reported child weight category were associated with NAFLD. Increased child age was associated with increased odds of NAFLD (OR 1.63, 95% CI 1.1, 2.4). Reported child overweight (classified dichotomously) was associated with increased odds of NAFLD (OR 44.5, 95% CI 5.3, 371.7).

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Table 1 Characteristics of study participants.

Table 3 Association of reported secondhand tobacco exposure and fatty liver adjusted for child age. N (%)

Number of participants Gender Male Female Ethnicity Non-Hispanic White Non-Hispanic Black Hispanic Other Obese (reported) Not Obese Age, years (mean7 standard deviation)

304 155 (51.0) 149 (49.0) 229 (75.3) 33 (10.9) 13 (4.3) 29 (9.5) 46 (15.1) 258 (84.9) 7.7 7 2.7

Table 2 Reported secondhand tobacco exposure rates.

Any reported smoke exposure, N (%) Number of Cigarettes Per day mean (95% CI) Packs per day Mean (95% CI)

Overall sample N ¼304

Children with ANY reported smoke exposure

75 (24.7)

75 (100)

4.5 (3.3, 5.7) 0.4 (0.3, 0.5)

18.4 (15.2, 21.7) 1.7 (1.3, 2.0)

3.3. Smoke exposure and NALFD The rate of NAFLD was higher in the smoke exposed group (6.7% vs. 1.7%, p ¼0.04). In bivariate logistic regression analysis each of the smoking categorizations was associated with increased odds of NAFLD: log of the number of cigarettes smoked per day OR¼ 1.25 (95% CI 1.04, 1.5), any smoke exposure dichotomized OR¼ 4.02 (95% CI 1.05, 15.4), and the number of packs per day OR¼ 1.63 (95% CI 1.1, 2.3). In analyses adjusted for age (Table 3), each of the smoking categorizations was associated with increased odds of NAFLD: log of the number of cigarettes smoked per day AOR¼1.2 (95% CI 1.03, 1.5), any smoke exposure dichotomized AOR ¼4.0 (95% CI 1.02, 15.8), and the number of packs per day AOR¼1.8 (95% CI 1.2, 2.8). For every extra pack per day smoked at home, the odds of a child having NAFLD were increased 1.8 times, and simply having any exposure increased a child's odds of NAFLD four times. There was no significant interaction of the log of the number of cigarettes smoked per day or any smoke exposure dichotomized with age (p ¼0.1 and p¼ 0.12 respectively). There was an interaction of age with packs per day (p ¼0.02), increasing pack per day exposure and increasing age increased the odds of NAFLD (AOR 2.2, 95% CI 1.1, 4.2). We conduced secondary analysis of smoke exposure with NAFLD among only those with reported exposure (n ¼75) and found an association. Accounting for child age, the log of the number of cigarettes smoked per day was associated with NAFLD, AOR¼ 14.4 (95% CI 1.0, 207.2), and the number of packs per day was associated with NAFLD, AOR ¼1.9 (95% CI 1.0, 3.9). 3.4. Obesity and smoke exposure and NALFD In bivariate logistic regression analysis, each of the smoking categorizations was associated with increased odds of reported child overweight: log of the number of cigarettes smoked per day OR¼ 1.1 (95% CI 1.02, 1.2), any smoke exposure dichotomized

Tobacco exposure measure (by report)

Adjusted odds ratio

Any smoke exposure 4.0 Log of the number of cigarettes per 1.2 day Cigarette packs per day 1.8

95% Confidence interval 1.02, 15.8 1.03, 1.5 1.2, 2.8

OR¼2.1 (95% CI 1.1, 4.0), and the number of packs per day OR¼1.4 (95% CI 1.1, 1.9). In the initial multivariable (adjusted) analyses of NAFLD, we excluded weight variables (reported child weight category and BMI) as noted in the methods. When parent reported child overweight status was added to the adjusted analyses of NAFLD, the smoke and NAFLD association was attenuated: log of the number of cigarettes smoked per day AOR¼ 1.1 (95% CI 0.92, 1.39), any smoke exposure dichotomized AOR¼ 2.1 (95% CI 0.4, 9.8), and the number of packs per day AOR ¼1.5 (95% CI 0.9, 2.4). In each of these analyses report of child being overweight was associated with increased odds of NAFLD. There was no significant interaction of reported child overweight status with the log of the number of cigarettes smoked per day, any smoke exposure dichotomized, or packs per day in these analyses (p ¼0.32, p ¼0.95 and p ¼0.42 respectively). The association of reported child overweight status with NAFLD was of borderline significance when limited to the smoke exposed children AOR ¼10.1 (95% CI 0.9, 119.9).

4. Discussion Here we report an association of secondhand tobacco smoke exposure and NAFLD in children. The association was not as strong as the association of parent reported child overweight status and NAFLD, but without accounting for weight, being exposed to any smoke at home was associated with a four-fold increase in odds of NAFLD. Secondhand smoke exposure rates among children vary depending on how the exposure is measured. In a study using biologic markers of exposure, 50.2% of nonsmoking children were noted to have measurable exposure (Kaufmann et al., 2010). In a study evaluating reported smoke exposure Singh et al. (2010), reported that in 2007, on a national level 26.2% of children lived in a household with a smoker. Our participant exposure rate (24.7%) was similar to the nationally reported rates. Active smoking has been associated with increased risk of NAFLD, but to our knowledge associations of secondhand smoke exposure and pediatric NAFLD have not been evaluated. In a retrospective study Hamabe et al. (2011), reported that cigarette smoking is an independent risk factor for NAFLD, in addition to age, obesity, dyslipidemia, and the total number of metabolic syndrome risk factors. While the mechanism for this association is unclear, several investigators have reported potential pathways. Hongwei et al. noted that cigarette smoking inactivates 50 adenosine monophosphate-activated protein kinase (AMPK) by dephosphorylation and promoted triglyceride accumulation in hepatocytes via activation of sterol regulatory element binding protein-1 (SREBP-1), inducing fatty liver in mice fed a high fat diet (Yuan et al., 2009). In obese rats, cigarette smoking elevated ALT and caused hepatocellular ballooning and lobular inflammation (Azzalini et al., 2010). Smoking also promotes the production of inflammatory cytokines and hepatic fibrosis-associated molecules

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(Azzalini et al., 2010). Further investigation is needed to evaluate the mechanism of smoking in the development of NAFLD. We noted that odds of NAFLD increased with increasing child age (OR 1.63 95% CI 1.1, 2.4). Alavian et al. (2009) also found NAFLD to be significantly more common among older children (12.5 against 3.5% po 0.0001). This finding could be related to higher abdominal obesity and BMI measurement in older children, which is in agreement with the results in Schwimmer et al. (2006). It could also be related to increased duration of exposure to disease risk factors. Investigators have noted an epidemic of childhood obesity and a combination of poor diet and sedentary lifestyle, and parallel to that, the prevalence of pediatric NAFLD has been rising ranging from 2.6 to 10% (Nobili et al., 2009). Similarly, we documented NAFLD in 3% of our study participants. Consistent with other studies, we noted an association of obesity with increased odds of NAFLD. In an ultrasound-based study of obese Italian children, fatty liver was present in 38 (53%) children, and elevated serum aminotransferease were present in 25% (Franzese et al., 1997). In a study of school-aged children in northern Japan, overall prevalence of fatty liver was 2.6% by sonography with male dominancy and increasing to 10%–35% in obese children (Marion et al., 2004). In another study from Turkey, the prevalence of fatty liver detected by sonography was 11.8% and elevated ALT and AST levels were found in 4.6% (Arslan et al., 2005). In terms of smoke exposure and NAFLD, for every extra pack per day smoked at home, the odds of a child having NAFLD were increased 1.8 times, and having any exposure increased a child's odds of NAFLD four-fold. Studies have shown that smoking is associated with increased insulin resistance in adults and may be a primary defect leading to endothelial dysfunction, abnormal lipid metabolism, and accelerated cardiovascular disease (Marion et al., 2004). Because both tobacco smoke and the metabolic syndrome are individually associated with insulin resistance, these two may be linked through this common pathophysiology and overweight children and youth may be especially susceptible to the impact of tobacco smoke on cardiovascular health (Wild and Byrne, 2006). Weitzman et al. (2005) demonstrated that exposure to tobacco smoke, whether by active smoking or exposure to tobacco smoke, is associated with at least a 4-fold increase in the risk of metabolic syndrome among adolescents who are overweight and at risk for overweight. Thus tobacco smoke exposure may be associated with obesity and NAFLD, but the pathway remains unclear. Larger sample sizes with more diverse exposure rates may be necessary to help clarify the relationship of tobacco smoke exposure with obesity and tobacco smoke exposure with NAFLD. The gold standard to diagnose NAFLD is liver biopsy, an invasive procedure. Liver biopsy allows for diagnosis of steatosis, steatohepatitis, and fibrosis. Ultrasound is an adequate screening tool for assessment of steatosis in the liver, but it does not correlate well with fibrosis. The reported sensitivity of abdominal ultrasound in detecting steatosis is 89% and specificity of 93%, but a sensitivity of 77% and specificity of 89% in detecting fibrosis in the liver, respectively (Joseph et al., 1991). Currently no imaging method is able to distinguish between simple steatosis and nonalcoholic steatohepatitis (NASH) and/or indicate the stage of fibrosis. NAFLD is becoming increasingly recognized as a potential cause of progressive and severe liver disease. NASH occurs when fatty liver has progressed to a stage that includes inflammation (steatohepatitis) and scarring (steatonecrosis) of the liver (Marion et al., 2004). NASH has the potential to cause cirrhosis, liver failure, and liver cancer. Patients are asymptomatic in the early stages of the disease, but when NAFLD progresses, it can lead to an irreversible disease (Wild and Byrne, 2006).

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There are several strengths and limitations to this study. First, smoke exposure was based on reported data and may be subject to reporting bias (social desirability). This may have underestimated true exposure and could have decreased our associations. Second, the gold standard for diagnosis of NAFLD is liver biopsy (Rafeey et al., 2009). However, it would be unethical to subject healthy children to the invasive procedure unnecessarily. Ultrasonography is effective in screening for fatty liver, and the cut-off we used should be 86% specific based on a study which used biopsy for validation (Lewis and Mohanty, 2010; Shannon et al., 2011). In addition, ultrasonography cannot distinguish simple fatty liver from NASH, making an association between secondhand tobacco exposure and fatty liver severity undefinable in this study. Third, this analysis was cross-sectional and can only demonstrate associations without implied causality. Moreover, these data cannot be used to determine the timing of development of NAFLD in children with relation to secondhand smoke exposure. Prospective studies are necessary to confirm causal associations. Fourth, our study was limited by a small sample size. In particular, there were a small number of NAFLD cases leading to a few wide confidence intervals for the odds ratios, although the lower bound of the 95% confidence interval still provides evidence of the association. Lastly, the eligible participant response rate was 54%. Low response rates could limit generalizability and introduce sampling biases; however, this rate is similar to the average response rate in academic studies 55.6% (Baruch, 1999).

5. Conclusion We have found an association of secondhand smoke exposure and NAFLD in children. While secondhand smoke exposure is not as strongly associated with NAFLD as obesity is, it represents an addressable risk factor for the development of NAFLD. Thus, along with reduction in obesity, smoke exposure reduction may represent a future NAFLD prevention target.

Funding source This work was supported by internal funds from the Department of Pediatrics, Penn State University, Hershey Medical Center.

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Secondhand tobacco exposure is associated with nonalcoholic fatty liver disease in children.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in children in the United States, and prevalence rates are rising. Smok...
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