Background
Cholelithiasis (the presence of one or more gallstones in the bladder) represents a significant burden for healthcare systems worldwide [
1] and is one of the most common disorders among patients presenting to emergency rooms with abdominal discomfort--e.g., epigastric pain, nausea, vomiting, loss of appetite [
2]. Ethnicity and family traits are recognized as contributing factor [
3]. Cholelithiasis is known to affect 60-70% of Native Americans and a proportionately smaller number individuals of mixed Hispanic/Native American background [
4]. The incidence is at least 10% among white adults in Western countries [
5], and even lower in African Americans and East Asians [
4]. Risk factors associated with cholelithiasis in the West include gender (F > M), age, obesity, metabolic syndrome, rapid appetite loss, hepatitis C, cirrhosis, and high caloric intake [
4,
6].
Cholelithiasis is also on the rise and becoming a major health problem in Taiwan [
7,
8], with some estimates indicating an increase in prevalence from 4.3% in 1989 to as high as 10.7% in 1995 [
8]. In the West, 80-90% of gallstones are cholesterol stones [
1], whereas the majority of gallstones found in Asian populations are pigment stones (high-residue pigment, low-residue pigment, and muddy pigment types), derived largely from salts or polymers of bilirubinate [
9‐
11].
In order to establish effective preventative medical strategies for the prevention and detection of cholelithiasis in Taiwan, it will be important to identify and understand risk factors that may be unique in the population. Differences in the prevalent type of gallstone indicate a potential differences in the etiology of cholelithiasis in Taiwan versus the West. A small number of studies have explored risk factors for cholelithiasis in the Taiwanese population [
8,
12‐
15]. Chen et al. [
12] studied individuals from a rural village in Taiwan and found an overall prevalence of gallstone disease of around 5%. They identified age and fatty liver to be significant risk factors in both sexes, with no overall link to gender. Liu et al. [
16] assessed cholelithiasis in healthy, paid volunteers admitted to hospital and identified a prevalence of 5.3%. Cholelithiasis in this study was linked to age, obesity (body mass index [BMI] ≥ 27 kg/m
2), and type 2 diabetes, but not gender. A few additional studies have identified diastolic blood pressure, elevated alanine aminotransferase levels, and waist circumference as risk factors for cholelithiasis within high risk subgroups of obese individuals [
14] and patients with type 2 diabetes [
8,
15].
The above studies suggest similarities as well as differences between the nature of cholelithiasis in Taiwan and in the West. There is a selection bias associated with each of these studies, however, due to the focus on a particular subgroup within the Taiwanese population, and as a result they may not offer an accurate representation of risk factors for cholelithiasis among the general population. The aim of this study was to perform a case-controlled analysis of medical information from the nation-wide 2005 Registry for Beneficiaries of the National Health Insurance Research Database. While the use of such a database provides access to a wealth of information on the health status of a large number of patients, it also has limitations. For example, the database did not reveal the criteria on which the diagnoses of cholelithiasis were based. Nevertheless, our data offer a better understanding of medical factors contributing to the development of cholelithiasis across the general population of Taiwan.
Discussion and Conclusions
Cholelithiasis in some form-silent gallstones [
19], simple biliary colic pain, acute cholecystitis sepsis, and, infrequently, gallstone ileus [
20,
21]--has accounted for an increasing number of hospital admissions and is a growing healthcare concern in Taiwan [
7,
8]. Although the growing prevalence of cholelithiasis has been linked informally to an increase in influence of the Western diet, obesity, and sedentary lifestyle, differences in gallstone composition indicate there may be differences as well in the etiology of cholelithiasis in Taiwan compared to the West. Despite differences in the predominate type of gallstone in Asian versus Western populations, we identified no unique risk factors among the population of Taiwan. Using multivariate conditional logistic regression analysis, we identified the following as independent risk factors for cholelithiasis (in descending order of contribution): Among all patients - hepatitis C (OR = 2.78), cirrhosis (OR = 2.47), hepatitis B (OR = 2.00), obesity (OR = 1.89), and hyperlipidemia (OR = 1.54); Among women - hepatitis C (OR = 3.05), cirrhosis (OR = 1.92), obesity (OR = 1.91), menopause (OR = 1.61), hepatitis B (OR = 1.54), and hyperlipidemia (OR = 1.49).
The prevalence of cholelithiasis has been estimated at approximately 4.3 to 14.4%, with a calculated annual incidence of 2.6~3.56% [
8,
14,
15,
22,
23]. Around one-third of individuals for whom an initial diagnosis of gallstones is asymptomatic or noncritical will undergo a subsequent cholecystectomy for recurrent symptoms or complications [
24,
25]. Prophylactic surgical treatment for complicated cholecystitis has also been discussed for high risk sub-group individuals [
13,
19,
25]. Identifying the major risk factors for cholelithiasis is an important step in preventing the formation of gallstones and reducing cholelithiasis-related illness.
The majority of studies into risk factors for cholelithiasis have been based on data from Western countries [
25,
26]. In the Asia-pacific area, especially in Taiwan, research into the incidence, prevalence, and risk factors associated cholelithiasis are usually conducted in a single hospitals, limited areas, or a limited sub-group of individuals [
8,
14‐
16]. The introduction of the National Health Insurance database offered a means to analyze data from the general population of Taiwan.
In selecting the medical conditions for analysis, we were constrained by the level of specificity within the database (e.g., data for hyperlipidemia were available, but data for HDL and LDL levels were not provided). We were particularly interested in evaluating medical conditions with particular relevance to the population of Taiwan. Hepatitis B and C were of interest, because their prevalence is much higher in Taiwan than in western countries. Conversely, blood cholesterol level was not evaluated, because the majority of cases of cholelithiasis in Taiwan do not involve cholesterol stones (see below).
Gallstones are generally classified as belonging to one of two types: cholesterol stones, and pigment stones [
1]. Pigment stones can be further subdivided into high-residue pigment, low-residue pigment, and muddy pigment stones [
9]. Cholesterol stones are formed by the precipitation of cholesterol as solid crystals from supersaturated bile and reflect high levels of hepatic cholesterol secretion. Pigment stones, which are more predominant in the Asian population [
9‐
11], are composed primarily of bilirubinate salts and oxidized tetrapyrrolic derivatives formed by polymerization of unconjugated bilirubin [
27]. This type of gallstone is linked to hemolysis, bacterial infection, or liver disease, rather than hormonal factors [
1,
12]. Others also report an association between pigment gallstones and advancing age and possibly alcoholism [
28]. We were unable to directly assess the distribution of gallstone types in this study, because no clinical test reports regarding signs of hyperhemolysis (lower hemoglobin content) were available in the database. Chronic liver disease is a well-recognized risk factor for cholelithiasis [
4,
23]. Fatty liver [
12], hepatitis B [
16,
22], hepatitis C [
6,
29], elevated ALT levels [
15], and cirrhosis [
22,
30,
31] have all been found to be related to cholelithiasis in different small studies. In Taiwan there is known to be a higher prevalence of viral hepatitis than in other regions [
32]. Our study confirms that hepatitis B, hepatitis C, and cirrhosis contribute a significant risk for cholelithiasis. Additional studies to understand the mechanistic relationship between cholelithiasis, virus hepatitis, alcohol-related cirrhosis, viral hepatitis cirrhosis, as well as non-alcoholic fatty liver disease are needed [
33].
All of the constituents of metabolic syndrome, with the exception of hypertension, have been reported as independent risk factors for cholelithiasis, including low serum levels of high density lipoprotein [
13,
34,
35], diabetes and glucose intolerance [
12,
13,
16,
22,
29,
34], high BMI [
11,
14,
16,
29,
36,
37], increased waist circumference [
15], and obesity [
15,
34,
35,
38]. In the present study, we identified obesity and hyperlipidemia as strong risk factors in the general population of Taiwan. Overall, these findings point to a likely benefit of life style and dietary modification as effective measures for the prevention of cholelithiasis [
39]. In addition, they support previous observations indicating that medications used to treat dyslipidemia may be of value in the prevention and treatment of cholelithiasis [
31,
40].
We found a strong association between diabetes and cholelithiasis in univariate analysis, but did not identify diabetes as a significant independent risk factor in multivariate analysis. There remains some controversy in the literature regarding type 2 diabetes as an independent risk factor for cholelithiasis. Previous community-based studies in healthy adults in Taiwan have found diabetes mellitus to be highly associated with the prevalence of gallstone disease [
12,
16]. In addition, Chen et al. [
12] found diabetes to be an independent risk factor for gallstone disease in women, but not in men. Type 2 diabetes has also been reported as an independent risk factor for gallstone disease in women but not men in Western studies [
41]. In contrast, other investigators have found no independent link between type 2 diabetes and the development of gallstones. Pacchioni et al. [
42] observed that obesity and type 2 diabetes were both more frequent in patients with gallstones than in those without gallstones, and suggested that age and obesity are the main risk factors for gallstones, with type 2 diabetes playing a lesser role in the development of gallstones. Shaffer et al. [
4] concluded that while diabetes mellitus may be linked to gallstone formation, the relationship is influenced by co-factors such as age, body mass index, and a family history of gallstone disease. Our results support the idea that type 2 diabetes acts in concert with diet, BMI, and other factors to increase the risk of cholelithiasis.
There remains some controversy about gender as a risk factor for cholelithiasis. While the majority of studies conducted in the West have concluded that females are more likely than males to develop cholelithiasis [
4,
38,
43], several studies with among Asian patients have failed to identify a gender-related difference [
12,
14,
29]. In fact Liu et al. [
16] found a higher incidence of cholelithiasis in males than in females below 50 years of age, but a higher incidence in females than in males in age groups above 50 years. In the present study, we did not assess the effect of gender, itself, but did assess the relative risks for pre- and post-menopausal women. Our analysis indicated that menopause is a risk factor for cholelithiasis in females. In the vacillating era of hormone replacement, the effect of estrogen might be an uncertain factor for which we were unable to control [
44].
The relationship between chronic kidney disease and cholelithiasis continues to be investigated [
30,
45]. Chronic kidney disease may alter plasma concentrations of electrolytes, including calcium. Like bilirubin and cholesterol, calcium is a major component of gallstones. In the present study we have defined chronic kidney disease as a condition meeting the criteria for ICD-9-CM 585, 586, 588.8, or 588.9. In this context, we found no significant influence of chronic kidney disease on gallstone formation. However, since pigment gallstones predominate in Asian populations, further studies into the relationship between the renal function, parathyroid hormone, and calcium levels will be of interest.
A significant limitation of this study is that our research database did not reveal the criteria on which the diagnoses of cholelithiasis were based. Thus, it is more appropriate to describe these individuals as having symptomatic cholelithiasis as defined within the ICD-9-CM 574 guidelines, i.e., calculus of the gallbladder without mention of cholecystitis. Similarly, individuals in the control group had no history of cholelithiasis, but we are unable to rule out the possibility of asymptomatic cholelithiasis in some individuals. In addition, because of the inherent limitations of insurance data, some lifestyle risks, such as the use of ground-surface water, cannot be evaluated [
46]. We were also unable to analyze the link between cholelithiasis and family history or parity in our population. Thus, further prospective studies will be required to better understand the relationship of these factors to cholelithiasis in Taiwan.
This study was designed to identify medical risk factors for cholelithiasis in the general population of Taiwan. The goal was to determine if the risk profile in the general population differed from those reported previously from studies with specific segments of the Taiwanese population, as well as from known risk factors in the West. Although no unique risk factors were identified among the population of Taiwan, this study confirms hepatitis B as a risk factor in the Taiwanese population, which is an important finding in view of the higher prevalence of hepatitis in Taiwan. The cholelithiasis-risk profile as represented in this survey of a representative population of Taiwan is similar overall to the profile that has emerged from the study of specific segments of the population, identifying obesity, hyperlipidemia, hepatitis B infection, hepatitis C infection and cirrhosis as risk factors for cholelithiasis in men and women, and menopause as an additional risk factor in females. Our study indicates that diabetes mellitus may not be an independent risk factor for cholelithiasis, and this relationship should be re-examined.
Competing interests
The authors declare that they have no competing interests and no financial support was received.
Authors' contributions
SCH carried out the literature research, manuscript preparation and editing. SWL performed as the guarantor of integrity of the entire study and carried out the study concepts, manuscript review and manuscript editing. CIL performed as the guarantor of integrity of the entire study and carried out statistical analysis. KFL carried out the literature research, data acquisition and study concepts. WCC carried out the manuscript review and study concepts. All authors read and approved the final manuscript.