Association between hepatitis virus infection and risk of colorectal polyps: a cross-sectional study of Taiwanese adults

Abstract

Background

Hepatic viral infections, including hepatitis C virus (HCV) and hepatitis B virus (HBV), represent major global health concerns and may lead to cirrhosis and hepatocellular carcinoma. Previous studies have suggested potential associations between viral hepatitis and colorectal malignancies; however, the relationship between hepatic viral infections and benign colorectal polyps remains unclear. This study aimed to investigate the association between hepatic viral infections and benign colorectal polyps in an adult Taiwanese population.

Methods

This cross-sectional study included 69,226 participants who underwent health examinations between 2010 and 2016. Eligible participants were categorized into four groups: uninfected, HBV infection, HCV infection, and HBV + HCV coinfection. Benign colorectal polyps were confirmed by colonoscopy. Logistic regression analysis was performed to evaluate the associations between hepatic viral infections and benign colorectal polyps.

Results

Participants with HCV infection had a significantly lower risk of benign colorectal polyps compared with those without hepatic viral infection across all adjusted models (OR = 0.74 and 0.68). However, this association was not observed in participants with HBV infection. Stratified analysis revealed that the inverse association remained statistically significant only in males, with ORs of 0.66, 0.61, and 0.60.

Conclusion

Hepatic viral infection, particularly HCV infection, was inversely associated with the risk of benign colorectal polyps, especially among males. Routine colorectal cancer screening and appropriate lifestyle modification remain essential regardless of hepatitis virus infection status.

Introduction

Hepatitis virus infection, including hepatitis B virus (HBV) and hepatitis C virus (HCV), is a well-established global risk factor for cirrhosis and hepatocellular carcinoma [1–3]. In a nationwide longitudinal study conducted in Taiwan, hepatic virus infection was significantly associated with an increased risk of extrahepatic malignancies, including colorectal, gastrointestinal tract, kidney cancers, and non-Hodgkin’s lymphoma [4]. Viral hepatitis remains hyperendemic in Taiwan and continues to impose substantial medical and socioeconomic burdens.

Colorectal cancer is one of the most common malignancies and a leading cause of cancer-related mortality in the United States [5]. Numerous studies have identified benign precursor lesions, particularly benign colorectal polyps, as the origin of most colorectal cancers [6, 7]. In Taiwan, the incidence of benign colorectal polyps has increased, likely due to the westernization of diet and lifestyle [8]. Several risk factors, including obesity, smoking, and physical inactivity, have been suggested to promote colorectal carcinogenesis [9, 10].

Previous studies have reported that HCV infection is associated with an increased risk of colorectal cancer [11]. In a Korean study, HBV infection was also implicated in colorectal carcinogenesis [12]. However, most existing evidence has focused on malignant outcomes, and data regarding the relationship between hepatitis virus infection and benign colorectal polyps—the established precursors of colorectal cancer—remain limited and inconsistent. Given the important role of benign colorectal polyps in the adenoma–carcinoma sequence, clarifying whether hepatitis virus infection is associated with the development of these precursor lesions is of particular clinical importance. Therefore, the primary objective of the present study was to specifically examine the association between hepatitis virus infection and the presence of benign colorectal polyps in a cross-sectional study of an adult Taiwanese population.

Materials and methods

Study design

A total of 69,226 Taiwanese adults who underwent health examinations at a medical center between 2010 and 2016 were initially enrolled in this study. The study flowchart is presented in Fig. 1. Participants with missing baseline demographic data, serum hepatitis viral markers, self-reported medical history, or colonoscopy results were excluded. Missing or incomplete colonoscopy data was defined as the absence of a complete colonoscopy report or lack of documentation regarding polyp detection status. In addition, a prior or concurrent diagnosis of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, or a diagnosis of colorectal malignancy before or at the time of the index colonoscopy examination was excluded. These exclusion criteria were applied to ensure that all included participants had complete outcome assessment and were at risk for colorectal polyp development. After applying these exclusion criteria, 10,850 eligible subjects remained and were categorized into four groups according to hepatitis viral status, based on the presence of hepatitis B surface antigen (HBsAg) and/or anti-HCV antibodies: uninfected, HBV infection, HCV infection, and HBV/HCV co-infection. We then examined the association between these hepatitis virus infection subgroups and the risk of colorectal polyps. Written informed consent was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki and was approved by the IRB of XXX with 2-107-05-036; approval date: 08/05/2018.

Fig. 1.

Flow chart which represented the steps of analysis performed in the study

Examination of HBV and HCV infection

All eligible subjects were tested for serological markers of HBV infection by radioimmunoassay (Abbott Laboratories, Chicago, IL, USA) and for serum HBV-DNA by polymerase chain reaction (PCR) assay. In addition, subjects were screened for serological HCV antibody by using an enyzme-linked immunosorbent assay (Abbott Laboratories, Chicago, IL, USA).

Diagnosis of colorectal polyps

All participants underwent colonoscopy as part of their health examination, and the procedure was performed by experienced physicians. A clear liquid diet was prescribed on the day prior to the examination, and bowel preparation with laxatives was administered the evening before the procedure to ensure adequate visualization. Following colonoscopy, biopsy specimens were submitted to the Department of Pathology and evaluated by experienced pathologists. Colorectal polyps were classified according to the WHO Classification of Tumors of the Digestive System [13]. Histopathological diagnoses included hyperplastic polyp, sessile serrated adenoma, tubular adenoma, and tubulovillous adenoma. In this study, tubular adenomas (both low- and high-grade), tubulovillous adenomas (both low- and high-grade), and sessile serrated adenomas were grouped together as neoplastic polyps for analysis, given their established roles as precursors of colorectal cancer through distinct molecular pathways [14].

Variables

Demographic characteristics, including age and sex, as well as lifestyle factors (smoking and alcohol consumption) and medical history (hypertension and fatty liver), were obtained through a self-administered questionnaire. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m²). Laboratory parameters—including uric acid (UA), creatinine (Cr), low-density lipoprotein cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP), aspartate aminotransferase (AST), albumin, and thyroid-stimulating hormone (TSH)—were measured using standardized laboratory methods. All participants fasted for at least 8 h prior to blood sample collection.

Statistical analysis

Continuous and categorical variables were compared among groups using one-way analysis of variance (ANOVA) and the chi-square test, respectively. A two-sided p-value ≤ 0.05 was considered statistically significant. Multivariable logistic regression analyses were performed to evaluate the association between hepatitis virus infection and the presence of colorectal polyps. Model 1 adjusted for age, sex, and BMI. Model 2 further adjusted for proteinuria, LDL-C, UA, Cr, AST, albumin, hsCRP, and TSH. Model 3 additionally included smoking status and alcohol consumption. All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS), version 22.0 (SPSS Inc., Chicago, IL, USA) for Windows.

Results

Baseline data of the study population

Table 1 summarizes the baseline characteristics of the study participants. The mean age in each hepatitis virus infection group was 46.57 ± 13.12 years (uninfected), 48.57 ± 13.22 years (HCV), 47.48 ± 10.65 years (HBV), and 49.01 ± 12.30 years (HBV/HCV co-infection). Compared with uninfected participants, those with hepatitis virus infection were significantly older. In addition, AST levels differed between groups, potentially reflecting variations in liver function status, which may be relevant in the context of hepatitis virus infection. Differences in TSH levels were also observed, which may be related to underlying metabolic or endocrine variations among participants. The prevalence of colorectal polyps was 8.8% in the uninfected group, 7.0% in the HCV group, 11.0% in the HBV group, and 9.8% in the HBV/HCV co-infection group. The proportion of tubular adenomas was 5.1%, 4.1%, 5.4%, and 6.8%, respectively. The proportion of hyperplastic polyps was 2.7%, 1.9%, 3.6%, and 2.3%, respectively. The remaining cases represented polyps detected during colonoscopy that were not biopsied for histopathological confirmation due to personal preference or clinical judgment.

Table 1.

Characteristics of study sample

Variables	Uninfected (N = 8995)	HCV (N = 681)	HBV (N = 1041)	HCV + HBV (N = 133)	P Value
Continuous Variables, mean (SD)
Age (years)	46.57 (13.12)	48.57 (13.22)	47.48 (10.65)	49.01 (12.30)	< 0.001
Body mass index (kg/m2)	23.98 (3.87)	23.84 (3.80)	23.99 (3.81)	23.92 (3.81)	0.839
LDL-C (mg/dL)	118.45 (32.78)	116.42 (32.26)	116.52 (30.94)	119.32 (32.85)	0.164
Uric acid (mg/dL)	5.66 (1.51)	5.67 (1.53)	5.62 (1.46)	5.74 (1.38)	0.792
Creatinine	0.83 (0.33)	0.83 (0.28)	0.83 (0.21)	0.84 (0.36)	0.947
AST (U/L)	20.95 (10.68)	21.73 (12.47)	24.89 (19.83)	23.63 (14.21)	< 0.001
Albumin (g/dL)	4.46 (0.28)	4.43 (0.27)	4.46 (0.27)	4.43 (0.29)	0.025
HsCRP (mg/dL)	0.24 (0.54)	0.25 (0.52)	0.19 (0.33)	0.19 (0.23)	0.129
TSH	2.29 (1.77)	2.40 (2.01)	2.21 (1.52)	2.81 (3.48)	0.004
Category Variables, (%)
Colorectal polyps	794 (8.8)	48 (7.0)	115 (11.0)	13 (9.8)	0.093
Tubular adenoma	460 (5.1)	28 (4.1)	56 (5.4)	9 (6.8)	0.711
Hyperplastic polyp	240 (2.7)	13 (1.9)	37 (3.6)	3 (2.3)	0.360
Gender (male)	4666 (51.9)	342 (50.2)	591 (56.8)	71 (53.4)	0.018
Hypertension	1722 (19.1)	167 (24.6)	188 (18.1)	28 (21.1)	0.632
Fatty liver	4778 (53.1)	346 (50.8)	533 (51.2)	64 (48.1)	0.077
Proteinuria	2258 (28.3)	167 (26.1)	267 (28.3)	37 (29.8)	0.894
Smoking	2448 (27.3)	199 (29.2)	300 (28.9)	42 (31.6)	0.092
Alcohol drinking	3624 (45.8)	311 (46.3)	363 (42.4)	59 (44.7)	0.126

Association between hepatitis virus infections and risk of colorectal polyps

In Table 2, participants with HCV infection had reduced risk for developing colorectal polyps after full adjustment with odd ratios (ORs) of 0.68 (95% CI: 0.50–0.91). However, no significant difference was noted in the association between hepatitis virus groups, tubular adenoma, and hyperplastic polyp.

Table 2.

Association between hepatic infection and the presence of colorectal polyps

Variables	Model a 1 OR (95% CI)	P Value	Model a 2 OR (95% CI)	P Value	Model a 3 OR (95% CI)	P Value
	All
Uninfected	reference	-	reference	-	reference	-
HCV	0.74 (0.55–0.98)	0.037	0.68 (0.51–0.92)	0.011	0.68 (0.50–0.91)	0.010
HBV	1.06 (0.84–1.34)	0.630	1.11 (0.87–1.41)	0.411	1.12 (0.87–1.43)	0.378
HCV + HBV	1.20 (0.70–2.07)	0.504	1.32 (0.75–2.33)	0.334	1.24 (0.70–2.20)	0.456
	Tubular adenoma
Uninfected	reference	-	reference	-	reference	-
HCV	0.81 (0.52–1.25)	0.344	0.74 (0.47–1.16)	0.187	0.74 (0.48–1.16)	0.196
HBV	0.90 (0.62–1.30)	0.569	0.92 (0.63–1.34)	0.661	0.94 (0.64–1.36)	0.735
HCV + HBV	1.55 (0.73–3.28)	0.251	1.70 (0.79–3.68)	0.174	1.65 (0.76–3.56)	0.205
	Hyperplastic polyp
Uninfected	reference	-	reference	-	reference	-
HCV	0.81 (0.46–1.44)	0.476	0.76 (0.42–1.34)	0.354	0.77 (0.43–1.38)	0.377
HBV	0.99 (0.62–1.56)	0.952	0.99 (0.62–1.56)	0.970	1.01 (0.63–1.62)	0.965
HCV + HBV	0.98 (0.30–3.15)	0.972	0.99 (0.30–3.22)	0.986	0.95 (0.29–3.11)	0.936

^a Adjusted covariates:

Model 1 = unadjusted

Model 2 = Model 1 + age, gender, BMI, proteinuria, serum total cholesterol, uric acid, creatinine, AST, albumin, hsCRP, TSH

Model 3 = Model 2 + history of smoking, drinking

Association between hepatitis virus infections and risk of colorectal polyps in gender difference

In subgroup analyses stratified by sex (Table 3), the association between hepatitis virus infection and colorectal polyps was observed in both males and females. In males, HCV infection was inversely associated with colorectal polyps with a fully adjusted OR of 0.60 (95% CI: 0.42–0.87). In females, a similar trend was observed; however, the association did not reach statistical significance. Although statistical significance was only observed in males, the direction of the association was generally consistent across sexes. These findings suggest a potential sex-related difference in effect magnitude, which warrants further investigation.

Table 3.

Association between hepatic infection and colorectal polyp in gender difference

Gender	Variables	Model a 1 OR (95% CI)	P Value	Model a 2 OR (95% CI)	P Value	Model a 3 OR (95% CI)	P Value
Male	All
	Uninfected	reference	-	reference	-	reference	-
	HCV	0.66 (0.46-0.94)	0.021	0.61 (0.42-0.87)	0.007	0.60 (0.42-0.87)	0.006
	HBV	0.98 (0.75-1.30)	0.908	1.08 (0.81-1.43)	0.618	1.09 (0.82-1.46)	0.560
	HCV+HBV	1.28 (0.65-2.52)	0.483	1.28 (0.63-2.58)	0.493	1.20 (0.59-2.43)	0.615
Female	Uninfected	reference	-	reference	-	reference	-
	HCV	0.93 (0.56-1.54)	0.783	0.92 (0.55-1.53)	0.745	0.90 (0.54-1.50)	0.684
	HBV	1.13 (0.72-1.79)	0.588	1.26 (0.79-2.02)	0.326	1.25 (0.78-2.01)	0.346
	HCV+HBV	1.26 (0.49-3.23)	0.627	1.32 (0.50-3.46)	0.573	1.28 (0.49-3.37)	0.620
	Tubular adenoma
Male	Uninfected	reference	-	reference	-	reference	-
	HCV	0.87 (0.52-1.46)	0.591	0.76 (0.45-1.30)	0.321	0.77 (0.45-1.32)	0.345
	HBV	0.70 (0.44-1.12)	0.136	0.75 (0.46-1.20)	0.227	0.76 (0.47-1.22)	0.261
	HCV+HBV	2.21 (0.95-5.13)	0.065	2.28 (0.96-5.41)	0.063	2.22 (0.93-5.33)	0.071
Female	Uninfected	reference	-	reference	-	reference	-
	HCV	0.68 (0.29-1.59)	0.376	0.68 (0.62-1.59)	0.372	0.66 (0.28-1.55)	0.346
	HBV	1.34 (0.73-2.43)	0.343	1.46 (0.79-2.70)	0.221	1.48 (0.80-2.72)	0.213
	HCV+HBV	0.56 (0.08-4.14)	0.569	0.62 (0.08-4.62)	0.637	0.59 (0.08-4.48)	0.614
	Hyperplastic polyp
Male	Uninfected	reference	-	reference	-	reference	-
	HCV	0.87 (0.45-1.69)	0.686	0.81 (0.41-1.58)	0.537	0.83 (0.42-1.63)	0.592
	HBV	1.00 (0.59-1.68)	0.989	1.05 (0.62-1.79)	0.845	1.08 (0.63-1.84)	0.775
	HCV+HBV	0.95 (0.22-4.00)	0.943	0.94 (0.22-4.00)	0.931	0.90 (0.21-3.85)	0.889
Female	Uninfected	reference	-	reference	-	reference	-
	HCV	0.66 (0.21-2.15)	0.493	0.64 (0.19-2.08)	0.454	0.61 (0.19-2.02)	0.421
	HBV	0.77 (0.28-2.16)	0.620	0.81 (0.28-2.31)	0.693	0.80 (0.28-2.29)	0.674
	HCV+HBV	1.11 (0.15-8.26)	0.922	0.95 (0.12-7.64)	0.961	0.91 (0.11-7.11)	0.928

^a Adjusted covariates:

Model 1 = unadjusted

Model 2 = Model 1 + age, BMI, proteinuria, serum total cholesterol, uric acid, creatinine, AST, albumin, hsCRP, TSH

Model 3 = Model 2 + history of smoking, drinking

Discussion

We found that individuals with HCV infection had a lower risk of developing colorectal polyps compared with those without hepatitis virus infection, particularly among men. Notably, to our knowledge, this study is the first to compare the associations between different hepatitis virus infections and the risk of colorectal polyps in a large adult population. An emerging study by Su et al. reported that HCV infection was an important risk factor for colorectal cancer in a case–control study [11]. Another study also demonstrated that HBV infection was associated with an increased risk of colorectal neoplasms [15]. In contrast to these studies, the colorectal polyps evaluated in our study—including hyperplastic polyps, tubular adenomas, sessile serrated adenomas, and tubulovillous adenomas—are benign lesion [16]. Although the precise mechanisms through which hepatitis virus infections influence the development of colorectal polyps remain unclear, differences in the pathogenesis of various polyp subtypes may lead to divergent outcomes. Most hyperplastic polyps harbor activating mutations in BRAF, whereas tubular adenomas undergo neoplastic progression involving mutations in KRAS, APC, and TP53 [17]. Therefore, the potential mechanisms underlying the observed inverse association between HCV infection and colorectal polyp development warrant further investigation.

In a retrospective study of 233 individuals, a higher prevalence of colorectal adenomas and hyperplastic polyps was observed among those with HCV infection compared with the general population [18]. However, the small sample size and single-center design of that study constitute important limitations, particularly because potential confounding variables were not adequately addressed. The mechanisms underlying the observed inverse association between hepatitis virus infection and the risk of developing colorectal polyps remain unclear. Previous studies have suggested that chronic liver injury may reduce the incidence of hepatic metastases from extrahepatic primary malignancies [19]. In addition, chronic liver diseases associated with HBV or HCV infection have been linked to a reduced occurrence of colorectal cancer [20]. Activated cytotoxic T lymphocytes may also eliminate non–antigen-bearing bystander cells, including colorectal cancer cells [21]. Furthermore, active HBV or HCV replication may enhance the production of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-α (IFN-α), by hepatocytes and liver-resident immune cells, which could exert antitumor effects [22]. Another biologically plausible explanation involves the gut–liver axis and gastrointestinal epithelial barrier integrity. Chronic HBV or HCV infection has been associated with gut microbiota alterations and impaired gut–liver homeostasis, which may in turn influence mucosal immune signaling, epithelial repair, and colorectal neoplasia-related processes [23, 24]. In this context, barrier-related molecules such as mucins may be relevant. Recent literature has suggested that MUC6, as a barrier-associated mucin, may participate in gastrointestinal cancer biology [25]. However, because the colonic mucus barrier is regulated by multiple epithelial and mucin-related factors, and because our study did not assess these molecular markers directly, this proposed mechanism should be regarded as hypothesis-generating. Future studies integrating microbiome profiles, barrier biomarkers, and histologic characterization of polyps are needed to clarify these pathways.

Accumulating evidence has shown that abnormal lipid profiles are associated with the risk of colorectal neoplasms [26–28]. Previous studies have demonstrated that individuals with lower levels of HDL-C and higher levels of LDL-C have an increased risk of developing colorectal adenomas [29]. Dyslipidemia may promote colorectal carcinogenesis through several mechanisms, including insulin resistance and chronic inflammation [30]. CRP, a commonly used marker of systemic low-grade inflammation related to adiposity, has been implicated in the early stages of colorectal carcinogenesis [31]. In contrast, lower serum levels of total cholesterol and LDL-C are well-recognized features of HCV infection and reflect altered lipoprotein metabolism [32]. Because the liver plays a pivotal role in cholesterol synthesis, active hepatitis may lead to hepatic synthetic dysfunction, resulting in decreased production of very low-density lipoprotein cholesterol (VLDL-C) and subsequent reductions in total cholesterol and LDL-C levels [33, 34]. Clark et al. reported that hypocholesterolemia in HCV infection was associated with inhibited cholesterol synthesis mediated by specific HCV genotypes [35]. Moreover, microsomal triglyceride transfer protein, a rate-limiting enzyme in VLDL-C production, has been shown to be transcriptionally suppressed by HCV gene expression in both in vitro and in vivo models [36]. In addition to lipid alterations, previous studies have reported viral effects on systemic inflammatory markers [37]. Individuals with HCV infection were found to have lower serum CRP levels compared with control subjects in a cohort of patients undergoing hemodialysis [38]. Given that CRP is primarily synthesized in the liver, impaired hepatic function associated with HCV infection may contribute to decreased CRP expression [39]. Taken together, these findings suggest that reduced serum lipid levels and a lower systemic inflammatory status may be associated with the decreased risk of colorectal polyps observed among individuals with HCV infection in the present study.

In our study, a sex-specific association between HCV infection and colorectal polyps was observed, with statistical significance detected only among male participants. The underlying mechanisms for this difference remain unclear. Although prior studies have suggested that sex hormones, including estrogen, may influence viral pathogenesis and inflammatory responses [40, 41], our study did not include direct hormonal measurements. Therefore, the proposed hormonal explanation should be considered speculative. Further investigations incorporating detailed hormonal and immunological assessments are necessary to elucidate the biological basis of this sex difference.

Treatment history related to hepatitis virus infection may act as a potential confounding factor in the observed associations. Antiviral therapies for HBV and HCV have been shown to modulate systemic inflammation, immune responses, and metabolic profiles, including improvements in insulin resistance and reduction of chronic inflammatory burden [42, 43]. These therapeutic effects may influence colorectal tumorigenesis through mechanisms involving the gut–liver axis, immune surveillance, and epithelial barrier integrity [44, 45]. In addition, intestinal microbiota and dietary structure are important factors in colorectal polyp development and may act as potential confounders. The gut microbiota is closely linked to immune regulation and metabolic homeostasis, while dietary patterns significantly influence both microbial composition and colorectal tumorigenesis [46–48]. However, due to the lack of detailed information of these factors, such as antiviral regimen, treatment duration, microbiota and dietary structure, in the present study database, we were unable to evaluate these effects. Future studies incorporating treatment-related variables are warranted to further clarify the role of therapeutic and lifestyle-related influences in this association.

Despite the strengths of this large population-based survey, several limitations should be acknowledged. First limitation is the lack of detailed information regarding polyp characteristics, including size, number, and anatomical location. Because such data were not available in the health examination database, stratified analyses based on polyp burden or location could not be performed. Second, the cross-sectional design of the study precludes the establishment of causal relationships between hepatitis virus infection and colorectal polyps. A longitudinal study with extended follow-up is warranted to clarify temporal associations and potential causal pathways. Third, a substantial proportion of the initial population was excluded due to missing colonoscopy data or incomplete variables, which may have introduced selection bias. Individuals undergoing colonoscopic screening may differ systematically from those who do not. Although we restricted the analysis to participants with complete data to ensure accurate outcome assessment and multivariable adjustment, residual selection bias cannot be excluded. Next, although a significant association was observed for overall colorectal polyps, the associations were not statistically significant when polyps were stratified into tubular adenomas and hyperplastic polyps. This may be partly attributable to the reduced number of events within each subtype, which limited statistical power in subgroup analyses. A further limitation is the absence of detailed data on antiviral therapy among participants with HBV or HCV infection. Because antiviral treatment—particularly direct-acting antivirals (DAA) for HCV—may influence inflammation and lipid metabolism, residual confounding cannot be excluded. In addition, as the study period (2010–2016) largely preceded widespread DAA use, the findings mainly reflect associations in the pre-DAA era and should be interpreted cautiously in contemporary treated populations.

Conclusion

In this population-based cross-sectional analysis, we observed an inverse association between HCV infection and the presence of benign colorectal polyps. Importantly, this finding indicates a negative association rather than a protective effect, and no causal inference can be drawn from the cross-sectional design of the study. Given the established evidence linking chronic viral hepatitis to adverse health outcomes, appropriate colorectal cancer screening—such as digital rectal examination, fecal occult blood testing, and colonoscopy—remains essential, particularly in high-risk populations. In addition, modification of dietary and lifestyle factors continues to play a crucial role in reducing the risk of colorectal cancer.

Author contributions

Yuan-Yuei Chen contributed to the design of the study, was responsible for the management and retrieval of data, contributed to initial data analysis and interpretation, drafted the initial manuscript. Yuan-Yuei Chen, Tao-Chun Peng, Tung-Wei Kao, and Wei-Liang Chen decided upon the data collection methods. Yuan-Yuei Chen and Wei-Liang Chen were also responsible for the data analysis decisions. Wei-Liang Chen conceptualized and designed the study, supervised all aspects of the study, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors meet the [ICMJE](http:/www.icmje.org/ethical_1author.html) criteria for authorship.

Funding

All authors did not receive any funding support.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the IRB of Tri-Service General Hospital with 2-107-05-036; approval date: 08/05/2018. All procedures performed in this study involving human participants were conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Written informed consent was obtained from all participants prior to enrollment in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.