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Gastroenterology Research

Original Article

Volume 15, Number 3, June 2022, pages 113-119

Retracted

Association of Smoking and E-Cigarette in Chronic Liver Disease: An NHANES Study

Chronic liver disease contributes significantly to the global burden of disease causing approximately 2 million deaths per year worldwide, 1 million due to cirrhosis and another 1 million due to viral hepatitis and hepatocellular carcinoma [1]. Globally, liver cirrhosis is among the top 20 causes of disability-adjusted life years and years of life lost [1]. According to 2018 CDC estimates, there are 1.8% US adults diagnosed with liver disease.

In developed countries, viral hepatitis specially hepatitis B and C and alcoholic liver disease are considered as the most common causes of liver cirrhosis [2]. There is very limited literature on the effect of smoking on liver conditions. A study conducted in 2009 with 1.3 million UK women found that there is three times higher risk of liver cirrhosis in women who smoke compared to non-smokers [3]. Few more studies have reported that smoking is an independent risk factor for liver cirrhosis irrespective of alcohol intake [4, 5]. There are various chemicals in tobacco smoke which can cause liver fibrosis by different mechanisms including activation of stellate cells probably via nicotinic acetylcholine receptors [6], increasing the production of pro-inflammatory cytokines [7]. Another potential mechanism may be increasing secondary iron overload due to polycythemia causing oxidative stress on hepatocytes as well as necroinflammation in the liver, apoptosis and excess iron deposition in the liver [8].

In the last few years, electronic nicotine delivery systems (ENDS) also known as e-cigarette are trending new products as a safe alternative to traditional smoking with no strong clinical evidence of their harmful effects on health. A study by Hasan et al demonstrates that exposure to nicotine aerosol increases markedly the hepatic lipid accumulation compared to placebo aerosol. The detrimental effect generates a greater oxidative stress, increased hepatic triglycerides levels, and increased apoptosis [9]. A study by Friedman et al in mice showed that twice-daily intraperitoneal injections of nicotine (0.75 mg/kg body weight) combined with a high-fat diet might increase oxidative stress, hepatocyte apoptosis and hepatic steatosis [10]. Another study by Hasan et al on male mice showed that inactivation of AMP-activated protein kinase (AMPK) and activation of its downstream target acetyl-COA carboxylase (ACC) can lead to stimulation of lipogenesis which can be associated with severity of hepatic steatosis due to additional effect of nicotine and high-fat diet (HFD) [11]. There is no literature describing the effects of e-cigarettes on liver fibrosis or cirrhosis in humans. Hence, our primary aim of the study was to find the prevalence of e-cigarette, traditional smoking and dual smoking in respondents with liver disease. Our secondary aim was to evaluate the association of e-cigarette, traditional smoking and dual smoking with liver disease while adjusting for confounding variables. To our knowledge, this is the first study to investigate e-cigarette use in in respondents with various liver diseases using National Health and Nutrition Examination Survey (NHANES), a well-designed survey that includes information about tobacco use in a nationally representative sample of US adults.

The NHANES administered by the CDC is a population-based cross-sectional survey on data released in 2-year cycles and designed to assess the health of children and adults in the USA. The sampling design and protocol of NHANES is reviewed by the US Department of Health and Human Services and approved by the National Center for Health Statistics Research Ethics Review Board on a yearly basis. The NHANES includes demographic, socioeconomic, dietary, laboratory, and health-related questions. The examination component consists of medical, dental, and physiological measurements, as well as laboratory tests administered by highly trained medical personnel. The data of our study were taken from NHANES database which are free publicly available at CDC website: https://wwwn.cdc.gov/nchs/nhanes/Default.aspx, so informed consent or IRB approval was not needed for the study.

We performed a retrospective cross-sectional study using the NHANES database from 2015 to 2018. Participants aged ≥ 18 years, had a diagnosis of any liver disease and had complete data from the NHANES questionnaires on traditional cigarette smoking and e-cigarette use were included. Sociodemographic variables such as age, gender, race, ethnicity and annual household income, comorbid conditions and serum cotinine levels were also obtained. The information for these variables was collected by NHANES representatives via a self-reported participant questionnaire. All missing data were excluded.

We assessed the e-cigarette use by the question: SMQ900: “Have you ever used an e-cigarette?” Similarly, the traditional smoking status of the participants was assessed by the following questions: SMQ020: smoked at least 100 cigarettes in life, SMQ040: “Do you now smoke cigarettes?” and dual smokers were those who answered yes to the following questions: SMQ020: smoked at least 100 cigarettes in life, SMQ040: “Do you now smoke cigarettes?” and SMQ900: “Have you ever used an e-cigarette?” The liver disease of the respondents was assessed with following self-reported questions: MCQ160L: “Has a doctor or other health professional ever told you that you had any kind of liver condition?” MCQ170L: “Do you still have a liver condition?” MCQ510 (a-e) “Which type of liver condition was it, fatty liver/liver fibrosis/liver cirrhosis/viral hepatitis/autoimmune hepatitis/other liver disease?” HEQ010: “Ever told you have hepatitis B?” and HEQ030: “Ever told you have hepatitis C?”

We conducted univariate analysis to find association of smoking, e-cigarette and dual smoking with liver disease and other sociodemographic variables using Chi-square (categorical variable) and t-test/Wilcoxon (continuous variables). Multivariable logistic regression models were used to predict the association of e-cigarette use, traditional smoking, and dual smoking compared to no smoking with liver disease after adjusting for confounding variables. Data were analyzed using SAS software (version 9.4) and P value < 0.05 was considered statistically significant.

Out of total 178,300 respondents in the NHANES survey from 2015 to 2018, 7,756 (4.35%) were e-cigarette users, 48,625 (27.27%) traditional smoking, 23,444 (13.15%) dual smoking and 98,475 (55.23%) non-smokers. E-cigarette users have younger age (median age: 25; interquartile range (IQR): 20 - 31) compared to dual smoking (median age: 41 (30 - 56)) and traditional smoking (median age: 62; IQR: 50 - 71). Females had a higher frequency of e-cigarette use (49.3%) compared to dual (43%) and traditional smoking (40.8%) (P < 0.0001). In our study, Mexican Americans had higher prevalence of e-cigarette use compared to traditional and dual smoking (20% vs. 13.3% vs. 11%; P < 0.0001). On the contrary, whites had a lower prevalence of e-cigarette use compared to traditional and dual smoking (27.6% vs. 42.2% vs. 47%; P < 0.0001). Among all the races, whites (2.2%) have the lowest prevalence of e-cigarettes use (P < 0.0001). Participants with household income > 100,000 had 24% prevalence of e-cigarette use compared to 16% traditional and 13% dual smoking (P < 0.0001) (Table 1).

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Table 1. Epidemiological Characteristics of Respondents

Respondents with a past history of any liver disease had lower frequency of e-cigarette use compared to dual and traditional smoking, respectively (2.4% vs. 6.4% vs. 7.2%; P < 0.0001). Also, participants with current liver disease had lower prevalence of e-cigarette use compared to traditional smoking and dual smoking, respectively (47 vs. 52 vs. 59; P < 0.0001) (Table 2).

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Table 2. Prevalence of Smoking and Liver Disease in US Population From 2015 to 2018

In multivariate logistic regression models, we found that e-cigarette users were associated with 1.06 higher odds of having history of liver disease (OR: 1.06; 95% CI: 1.05 - 1.06; P < 0.0001) and 0.27 lower odds of having active liver disease (OR: 0.27; 95% CI: 0.27 - 0.27; P < 0.0001) compared to non-smokers. Similarly dual smoking was associated with higher risk of having history of liver disease (OR: 1.50; 95% CI: 1.50 - 1.51; P < 0.0001) and having active liver disease (OR: 1.43; 95% CI: 1.43 - 1.44; P < 0.0001) (Table 3).

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Table 3. Multivariate Logistic Regression Models of Association Between Smoking and Liver Diseases

There is an increasing trend of e-cigarette due to being the substitute for tobacco smoking but there is limited literature on long-term effects of e-cigarette use. In our study, we found that e-cigarette users were associated with higher odds of having a history of liver disease (OR: 1.06; P < 0.0001) in comparison to non-smokers. However, we also had lower frequency of e-cigarette use than traditional smoking in respondents with a history of any liver disease and also with current liver disease, respectively. These results show that smoking, whether e-cigarette or traditional smoking, has influence on the progression of liver disease. Although smoking can increase risk of chronic hepatitis B (CHB) infection [12]. There are limited studies that investigated the association between smoking and liver disease. Suzuki et al reported that smoking is associated with high levels of alanine aminotransferase (ALT) in patients with liver disease [13].

According to Liu et al’s study which included 1,290,413 women, there is an increased risk of liver cirrhosis in current smokers (3.76; 95% CI: 3.25 - 4.34) of 20 cigarettes per day in comparison to non-smokers [3]. Another study of 128,934 patients mentioned that development of liver cirrhosis was three times higher with smoking a pack or more per day in comparison with lifelong non-smokers [14]. Yu et al conducted a study on 1,495 male hepatitis B surface antigen carriers and found higher relative risk in those who smoked > 20 cigarettes per day compared to < 20 cigarettes per day [5]. Dam et al’s study on Danish general population found increased risk of alcoholic liver cirrhosis in both men and women who smoked > 10 g of tobacco per day in comparison to those who never smoked and it was alcohol-independent [4]. Hasan et al’s study and other previous studies suggested that in mice nicotine induces adipose tissue lipolysis which leads to hepatic triglyceride accumulation which can be prevented by acipimox which is inhibitor of lipolysis [4], implying the same mechanism in ENDS-induced hepatic steatosis [10]. We do not have human clinical studies reporting the effect of e-cigarette on liver dysfunction progressing to hepatic fibrosis and cirrhosis in various chronic liver diseases.

There are direct and indirect effects of using cigarettes on the liver, which might be harmful on the immune system and can adversely affect the body at cellular level as well as by lipid peroxidation [15-17], resulting in fibrosis formation by overactivation and synthesis of increased amount of some cytokines (interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α) responsible for more liver destruction [18]. Studies have shown the crucial effect of smoking on CHB patients leading to increased fibrosis and facilitating the progression of hepatitis B disease to cirrhosis [5, 19]. Moreover, the abnormally high level of oxidative stress resulting from nicotine in e-cigarette causes the decrement of NAD+ level, SIRT1 activity as well as PARP1 activation, DNA mutation, vacuolization and malfunction of mitochondria [20]. Cigarettes contain more than 4,000 toxic compounds harmful for body organs. We studied the association of e-cigarettes with different liver diseases. The pathogenesis of chronic liver disease due to e-cigarettes is complex. In one study, it was observed that Kupffer cells are involved in robust inflammatory response, oxidative stress production and cytokine release when exposed to tobacco or e-cigarette extracts resulting in decreased cellular life [21]. A study on C57BL/6 and CD-1 mice revealed that chronic inhalation of electronic vapor will lead to increased inflammatory protein like angiopoietin-1 (31-fold) and EGF release into circulation, inducing a systemic inflammatory state and consequently distant organ injury and increased fibrosis in the liver (1.77-fold in CD-1; P < 0.0001) [22]. The AASLD/IDSA mention cigarettes as a probable cofactor in augmentation of liver fibrosis [23], and WHO states that smoking can complicate chronic infection [24]. It has been reported that smoking augments fibrosis score in chronic hepatitis C (CHC) patients and hepatitis B virus (HBV)-related cirrhosis. Smoking is associated with polycythemia in turn causing increased absorption of iron from the intestine due to stimulation of erythropoietin. Increased iron overload in hepatocytes promotes oxidative stress of hepatocytes. Smoking induces elevation of CD8⁺ T-cytotoxic lymphocytes, decreases CD4⁺ cells, impairs natural killer (NK) cell activity and increases the production of pro-inflammatory cytokines (IL-1, IL-6, and TNF-α) [5, 17-19]. Cigarette smoking contains 4-aminobiphenyl, a hepatic carcinogen - a risk factor for hepatocellular carcinoma (HCC). Tobacco smoking is associated with reduction of p53, a tumor suppressor gene that increases the risk for cancer [25-27].

We found that higher income levels are associated with greater e-cigarette use as compared to traditional or dual cigarette use (24% vs. 16% vs. 13% with income bracket $100,000 and over, respectively). Similar results have been consolidated in a study by Friedman et al where education and income levels manifested higher for only e-cigarette users (67.3% in college graduates, 30.7% with income < 200% federal poverty level (FPL)) than dual users (53.7% in college graduates, 42.7% with income < 200% FPL) [28]. They also found that e-cigarette use is more common in white race as compared to other races similar to the results of our study [28]. In another study, it was found that black, Hispanic, and low-income smokers were less prone to switching to e-cigarettes in contrast to white and higher-income smokers [29]. It is well known that tobacco smokers are at increased risk of hazardous drinking and meet criteria for alcohol use disorder (AUD). Although little is known about association of alcohol abuse among e-cigarette users. In our study univariate analysis, we found that alcohol use was higher in e-cigarette user compared to dual, traditional and non-users. In support of our findings, few studies found that e-cigarette users are at higher risk of alcohol abuse [30, 31]. We also discovered that Hb levels are greater in traditional smokers as compared to e-cigarette users consistent with the study by Enc et al which concluded that Hb levels are increased in smoker patients with non-alcoholic fatty liver disease and advanced fibrosis [32].

This study has a random sample collected from a nationally representative sample each year. Therefore, the sample derived from NHANES represents the US population; thus, generalization and external validity of the findings are predictable. Our study is the first study to collect data on e-cigarette amongst respondents with liver disease. NHANES data are cross-sectional survey data, so temporal or causal relationships could not be established. We cannot directly examine the mechanisms of the observed effect. Although, we attempted to reduce the risk of confounding factors by statistically controlling for demographic variables; however, we were not able to control for all potential confounders. Additionally, the survey’s accuracy depends on the memory of the respondents that leads to a recall bias. Though smoking was defined with accuracy, e-cigarette use was not quantified, so correlation between hours of smoking and disease could not be established. In NHANES, there was mention of liver cirrhosis but it was not clear whether it was due to alcohol liver disease or hepatitis infection. Hence, we could not evaluate the effect of alcohol as a potential confounding factor in association of e-cigarette users and liver disease. Also, severity of liver disease was not sub-stratified and some conditions like fatty liver, fibrosis, and autoimmune hepatitis have data in only yes form and no-disease data were missing, so it was difficult for them to compare column percentage and establish the relationship between smoking and liver disease.

Our study concluded that despite the low frequency of e-cigarette use in respondents with a history of liver disease, there were higher odds of e-cigarette use amongst patients with chronic liver disease. Hence, more future prospective studies are needed to further evaluate the effects of e-cigarette on liver disease patients as well as the precise mechanisms of e-cigarette toxicants on the liver. Additionally, our study findings suggest that public health practitioners and policy makers should consider more strong evidence of the toxic effects of e-cigarette when making decisions about regulations of e-cigarette in the United States.

Acknowledgments

None to declare.

Financial Disclosure

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest

The authors declare no conflict of interest.

Informed Consent

The data have been taken from NHANES database (National Health and Nutrition Examination Survey) sponsored by the CDC and is free publicly available database, so informed consent or IRB approval was not needed for the study.

Author Contributions

Conceptualization: Raja Chandra Chakinala and Sameer Dawoodi. Methodology: Preeti Malik. Acquisition of data: Preeti Malik and Raja Chandra Chakinala. Formal analysis and investigation: Raja Chandra Chakinala, Sameer Dawoodi, and Stephanie P. Fabara. Writing - original draft preparation: Raja Chandra Chakinala, Sameer Dawoodi, Stephanie P. Fabara, Muhammad Asad, Azadeh Khayyat, Sangeetha Chandramohan, Aysha Aslam, Nkechi Unachukwu, Bibimariyam Nasyrlaeva, and Richa Jaiswal. Writing - review, critical feedback, and editing: Sriram B. Chowdary, Preeti Malik, and Rizwan Rabbani. Funding acquisition: none. Resources: Supervision: Preeti Malik and Rizwan Rabbani.

Data Availability

NHANES database sponsored by the CDC is free publicly available database. It is available to download at https://wwwn.cdc.gov/nchs/nhanes/Default.aspx.

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