World J Gastroenterol. 2009 April 21; 15(15): 1886-1891.
Published online 2009 April 21. doi: 10.3748/wjg.15.1886.
©2009 The WJG Press and Baishideng. All rights reserved.
Gender and metabolic differences of gallstone diseases
Hui Sun, Hong Tang, En-Qiang Chen, Tao-You Zhou, Center of Infectious Diseases, West China Hospital of Sichuan University; Division of Molecular Biology of Infectious Diseases, the State Key Laboratory of Biotherapy (Sichuan University), Chengdu 610041, Sichuan Province, China
Shan Jiang, First Department of Internal Medicine, Wusheng People’s Hospital, Guangan 638400, Sichuan Province, China
Li Zeng, You-Juan Wang, Physical Examination Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
Received December 30, 2008; Revised February 22, 2009; Accepted March 1, 2009;
AIM: To investigate the risk factors for gallstone disease in the general population of Chengdu, China.
METHODS: This study was conducted at the West China Hospital. Subjects who received a physical examination at this hospital between January and December 2007 were included. Body mass index, blood pressure, fasting plasma glucose, serum lipid and lipoproteins concentrations were analyzed. Gallstone disease was diagnosed by ultrasound or on the basis of a history of cholecystectomy because of gallstone disease. Unconditional logistic regression analysis was used to investigate the risk factors for gallstone disease, and the Chi-square test was used to analyze differences in the incidence of metabolic disorders between subjects with and without gallstone disease.
RESULTS: A total of 3573 people were included, 10.7% (384/3573) of whom had gallstone diseases. Multiple logistic regression analysis indicated that the incidence of gallstone disease in subjects aged 40-64 or ? 65 years was significantly different from that in those aged 18-39 years (P < 0.05); the incidence was higher in women than in men (P < 0.05). In men, a high level of fasting plasma glucose was obvious in gallstone disease (P < 0.05), and in women, hypertriglyceridemia or obesity were significant in gallstone disease (P < 0.05).
CONCLUSION: We assume that age and sex are profoundly associated with the incidence of gallstone disease; the metabolic risk factors for gallstone disease were different between men and women.
Keywords: Gallstone disease, Metabolic disorder, Risk factor, Sex, Age
Gallstone disease is prevalent worldwide; however, its prevalence varies by region. In Western countries, the prevalence of gallstone disease reportedly ranges from approximately 7.9% in men to 16.6% in women[1
]. In Asians it ranges from approximately 3% to 15%, is nearly non-existent (less than 5%) in Africans[23
], and ranges from 4.21% to 11% in China[4
]. The prevalence of gallstone disease is also high in some ethnic groups, e.g. 73% in Pima Indian women; 29.5% and 64.1% of American Indian men and women, respectively; and 8.9% and 26.7% of Mexican American men and women, respectively[156
]. From a medical economic perspective, gallstone disease is the most common reason for hospitalization and creates a high burden in the United States[7
] and other Western countries[8
]. Many recent studies have shown that gallstone disease is related to age, sex, and metabolic disorders, such as obesity, dyslipidemia (hypertriglyceridemia), and type 2 diabetes[9
]. The pathogenesis of gallstone disease is suggested to be multifactorial and probably develops from complex interactions between many genetic and environmental factors[1213
Because of an increase in the Westernization of dietary habits and a decrease in physical activity, the prevalence of gallstone disease has increased in the Chinese population in recent years. From a public health standpoint, it is not only important to study the background prevalence of gallstone disease regionally, but to also explore the demographic and biological markers related to the development of gallstone disease. Meanwhile, gallstone disease can result in serious outcomes, such as acute gallstone pancreatitis and gallbladder cancer. If we can predict which factors contribute to the development of gallstone disease, we can prevent it by controlling these factors. The present study was designed to explore the potential risk factors for gallstone disease and to improve the understanding of the overall pathogenesis of this disease.
MATERIALS AND METHODS
Data resource and data collection
This study was conducted at the physical examination center of West-China Hospital at Sichuan University. This hospital provides medical care mainly for middle- and high-income individuals from Chengdu City and the surrounding metropolitan areas. Our sample population consisted of consecutive subjects who were referred to the physical examination center by their companies as an annual requirement. Data collection, including age, sex, demographic data, history of systemic diseases and gastrointestinal surgery, and a complete physical examination were done by the doctors at the physical examination center. Ultrasonography of the abdomen was conducted by ultrasonographers using a scanner equipped with a 3.5-MHz transducer (Philips Medical Systems, Bothell, USA). Blood samples were drawn via venipuncture from the study participants, after they had fasted overnight, by clinical nurses for laboratory examination. Fasting plasma glucose (FPG), triglyceride, total cholesterol, high-density-lipoprotein cholesterol (HDL-C), and low-density-lipoprotein cholesterol (LDL-C) concentrations were measured using Hitachi Modular analyze system (Roche Modular DPP, Hitachi Ltd, Tokyo, Japan).
Gallstone disease was defined as the presence of strong intraluminal echoes that were gravity-dependent or that attenuated ultrasound transmission (acoustic shadowing) during abdominal ultrasonography or as a history of cholecystectomy because of gallstone disease.
Obesity was defined as a body mass index (BMI) ? 25 kg/m2
in both men and women according to the redefined World Health Organization criteria for the Asia Pacific Region[14
]. High blood pressure was defined as a systolic blood pressure (SBP) ? 140 mmHg or a diastolic blood pressure (DBP) ? 90 mmHg or a history of hypertension. Subjects with an FPG ? 1260 mg/L and/or a history of diabetes were considered to have diabetes mellitus (DM). Hypertriglyceridemia was defined as a triglyceride concentration ? 1500 mg/L. Low HDL-C was defined as an HDL-C level < 350 mg/L in men or < 390 mg/L in women. Hypercholesterolemia was defined as a total cholesterol level ? 2200 mg/L. High LDL-C was defined as an LDL-C level ? 1550 mg/L.
Categorical data are presented as the number of cases and percentages. Statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL). Odds ratios (ORs) were calculated with the variables coded in a multivariate form. Pearson’s Chi-square or Fisher’s exact tests were used for categorical variables. Multiple logistic regression analysis was performed to investigate the independent factors associated with gallstone disease. In all cases, tests of significance were 2-tailed, P < 0.05 indicated statistical significance.
A total of 3573 subjects undergoing an annual health examination from January to December 2007 were included: 1825 men and 1748 women. The prevalence of gallstone disease among the study subjects was 10.7% (384/3573): 9.9% in men and 11.6% in women. The results of univariate analysis of individual factors and their association with gallstone disease among the 3573 subjects are shown in Table . The factors significantly associated with gallstone disease were an age of 40-64 years and an age ? 65 years, a BMI ? 25.0 kg/m2, high blood pressure, an FPG level between 1100 and 1260 mg/L, an FPG level ? 1260 mg/L, a triglyceride level ? 1500 mg/L, a total cholesterol level ? 2200 mg/L, and an LDL level ? 1550 mg/L (P < 0.05). In contrast, a low HDL-C level was inversely associated with gallstone disease (P < 0.05). As shown in Table , the prevalence of gallstone disease for each metabolic disorder was 14.1% for obesity, 18.0% for hypertension, 30.2% for DM, 15.8% for hypertriglyceridemia, and 10.4% for a low HDL-C level.
OR of individual risk factors and their association with gallstone disease
In order to identify the risk factors, we further performed a multivariate logistic regression analysis (backward stepping); the results are shown in Table . Women aged 40-64 years and ? 65 years, with an FPG level ? 1260 mg/L, and a triglyceride level ? 1500 mg/L were positively correlated with gallstone disease.
Multivariate logistic regression analysis for gallstone disease
The incidence of metabolic disorders in the groups with and without gallstone disease is shown in Table . Obesity, hypertension, DM, hypertriglyceridemia, a low HDL-C level, and hypercholesterolemia were found in 26.8%, 29.9%, 7.6%, 46.4%, 6.8%, and 10.7% of subjects with gallstone disease, respectively. In the group without gallstone disease, the incidences of obesity, hypertension, DM, hypertriglyceridemia, a low HDL-C level, and hypercholesterolemia were 19.7%, 16.5%, 2.1%, 29.8%, 3.4%, and 6.6%, respectively. The incidences of all metabolic disorders were higher in the group with gallstone disease than in the group without gallstone disease (P < 0.01).
Prevalence of metabolic disorders in the subjects with and without gallstone disease n (%)
The results of univariate analysis of metabolic factors and their association with gallstone disease in different sexes are shown in Table . In men, the factors significantly associated with gallstone disease were high blood pressure, an FPG level between 1100 and 1260 mg/L, an FPG level ? 1260 mg/L, and a triglyceride level ? 1500 mg/L (P < 0.05). In women, the factors significantly associated with gallstone disease were a BMI ? 25.0 kg/m2, high blood pressure, an FPG level between 1100 and 1260 mg/L, an FPG level ? 1260 mg/L, a triglyceride level ? 1500 mg/L, a total cholesterol level ? 2200 mg/L, and an LDL-C level ?1550 mg/L (P < 0.05). A low HDL-C level was inversely associated with gallstone disease only in women (P < 0.05).
Univariate analysis of metabolic risk factors for gallstone disease in gender
To control the covariates simultaneously, multivariate logistic regression analysis (backward stepping) was performed (Table ). The analysis revealed that an FPG level ? 1260 mg/L was a significant independent predictor of gallstone disease in men (P = 0.005) and a BMI ? 25.0 kg/m2 and a triglyceride level ? 1500 mg/L were predictors of gallstone disease in women (P < 0.05).
Multivariate logistic regression analysis for gallstone disease in gender
One of the important benefits of early screening for gallstone disease is that ultrasonography can detect asymptomatic cases, which results in early treatment and the prevention of serious outcomes such as acute gallstone pancreatitis and gallbladder cancer[15
]. However, few reports on the prevalence and possible etiology of gallstone disease have been published in China. In the present study, gallstone disease appeared to be common in the test population, i.e. an estimated 10.7% of the test population in Chengdu, China, had gallstone disease. The reported prevalence of gallstone disease is approximately 3.6% in Japan and 4.3%-5.0% in Taiwan[16
]. The apparently higher prevalence rate in our study may have been due to the Westernized lifestyle of our patients, who were of middle-to-high income class. Another possible reason for such differences has been related to the fact that this was a hospital-based study which was unlikely the population study that could represent the general population.
The present study, in accordance with reports from Western countries and other regions of Asia, showed that an older age is a significant risk factor for gallstone disease[161819
]. In contrast, gallstone disease is virtually absent in children and adolescents aged 8-19 years[20
]. Long-term exposure to many risk factors, as is true for the elderly, may increase the risk of gallstone disease. At the same time, sedentary activity, which is greater in the elderly than in younger populations, may also increase the risk of gallstone disease[2122
]. Furthermore, gallstone disease is also an acquired disease influenced by chronic environmental factors plus an aging effect[23
In concordance with the findings of previous studies, female sex was also a major risk factor for gallstone disease in the present study. The commonly perceived opinion that women are at greater risk of developing gallstone disease than men may largely be due to extraneous risk factors, such as pregnancy and sex hormones. The number of pregnancies is the main one related to the high rates of gallstone disease in women. Sex hormones are most likely to be responsible for the increased risk. Estrogen increases biliary cholesterol secretion causing cholesterol super saturation of bile. Thus, hormone replacement therapy in postmenopausal women has been described to be associated with an increased risk for gallstone disease[2425
]. Some studies have also shown a relation between oral contraceptive use and a high prevalence of gallstone disease[2627
Previous population studies have reported inconsistent associations of DM with gallstone disease. A study in Rome showed that DM was associated with an increased risk of gallstone disease in men and women separately[28
]. A study of Hispanic Americans found a positive association between DM and self-reported gallstone disease in women, but not in men[26
]. A study in Italy failed to find any relation between DM and gallstone disease in men and women combined[29
]. The present analyses showed a positive association between DM and gallstone disease in men, but not in women. The mechanism underlying the relation of DM with gallstone disease may be fasting hyperinsulinemia, which can overly activate the rate-limiting enzyme for cholesterol synthesis[30
] and finally leads to cholesterol saturation in the bile. Reduced motility of the gallbladder in persons with diabetes is another possible explanation[3132
In our study, obesity only showed a positive association with gallstone disease in women. Previous studies have found disparate findings for BMI or relative weight in men with gallstone disease[293334
]. However, three population screening surveys using ultrasonography failed to find a positive association between BMI and gallstone disease in men in Italy, Denmark, and the United States[263536
], whereas all three showed a positive association in women. The discrepant findings for BMI in men with gallstone disease have not been fully explained. A possible reason for these findings may be that BMI is not a suitable standard of obesity in men. Waist-to-hip ratio may be a better measure of obesity. The mechanism responsible for the increased risk of gallstone disease in obese persons may be the increase in bile saturation that results from an increase in the biliary secretion of cholesterol, which likely depends on the higher synthesis rate of cholesterol in obese persons[23
The present study showed that hypertriglyceridemia was a risk factor for gallstone disease only in women. However, high total cholesterol, low HDL-C, and high LDL-C levels were negatively associated with the risk of gallstone disease in both men and women. The present finding is different from that of previous studies, which noted a positive relation between hypertriglyceridemia and gallstone disease[36
]. However, a cross-sectional study in Denmark failed to find a significant association between gallstone disease and plasma lipid levels (including triglyceride, total cholesterol, HDL-C, and LDL-C)[37
]. Further studies are needed to clarify whether elevated levels of plasma lipids are independent risk factors for gallstone disease.
A major limitation of the present study was the potential self-selection bias due to the hospital-based study design, which resulted in a sample that was not representative of the general population in western China. However, we believe that our findings are useful as background data for future studies of the epidemiology of gallstone disease in China. Second, our measurements were inadequate. Some factors that might play an important role in gallstone disease development, such as oral contraceptive use and waist-to-hip ratio, were not collected in detail. Third, measurement error and different pathogenicities may have occurred, because the measurements were only made at one time point. Therefore, future studies need to determine whether these factors affect the results of our study.
In conclusion, older age, and female sex are associated with the prevalence of gallstone disease in both men and women. Obesity and hypertriglyceridemia were positively associated with gallstone disease in women, but not in men, whereas DM (FPG ? 1260 mg/L) was positively associated with gallstone disease only in men.
Gallstone disease is one of the most prevalent gastrointestinal diseases with a substantial burden to health care systems. Because the pathogenesis of gallstone disease is still not well defined and strategies for prevention and efficient non-surgical therapies are missing, further studies are required. Many researchers have shown that gallstone disease is related to age, sex, and metabolic disorders, such as obesity, dyslipidemia (hypertriglyceridemia), and type 2 diabetes. However, the findings concerning metabolic disorders and gallstone disease are disparate in different regions and ethnicity.
There are a cluster of metabolic syndromes which includes obesity, glucose intolerance, increased low-density-lipoprotein cholesterol, triacylglycerol, diminished high-density-lipoprotein cholesterol and hypertension. The number of gallstone patients is increasing with a high prevalence of metabolic syndrome.
Innovations and breakthroughs
This study confirmed that age and sex are positive risk factors for gallstone disease; but, the association between metabolic disorders and gallstone disease is different for men and women. Furthermore, the study complemented the background prevalence of gallstone disease in Chengdu, China.
The results of this paper can guide clinicians to target high-risk groups for related inspection and early treatment. Furthermore, preventive strategies can be identified and planned according to these results.
Gallstone disease, formally known as cholelithiasis, occurs when gallstones formed in the bile duct, which are abnormal masses of a solid mixture of cholesterol crystals, mucin, and calcium bilirubinate proteins. It is asymptomatic in most patients. Sometimes it can cause dyspepsia and other gastrointestinal symptoms or biliary colic or Mirizzi syndrome.
This paper provides information about the incidence and risk factors of gallstone disease in China. The results of this study can give information for further research to explore the pathogenesis of gallstone disease and the role of metabolic syndrome in the process of gallstone formation.
Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999;117:632-639.
Miquel JF, Covarrubias C, Villaroel L, Mingrone G, Greco AV, Puglielli L, Carvallo P, Marshall G, Del Pino G, Nervi F. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology. 1998;115:937-946.
Shaffer EA. Epidemiology and risk factors for gallstone disease: has the paradigm changed in the 21st century?. Curr Gastroenterol Rep. 2005;7:132-140.
Xu P, Yin XM, Zhang M, Liang YJ. [Epidemiology of gallstone in Nanjing City in China]. Zhonghua Liuxingbingxue Zazhi. 2004;25:928.
Sampliner RE, Bennett PH, Comess LJ, Rose FA, Burch TA. Gallbladder disease in pima indians. Demonstration of high prevalence and early onset by cholecystography. N Engl J Med. 1970;283:1358-1364.
Everhart JE, Yeh F, Lee ET, Hill MC, Fabsitz R, Howard BV, Welty TK. Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study. Hepatology. 2002;35:1507-1512.
Russo MW, Wei JT, Thiny MT, Gangarosa LM, Brown A, Ringel Y, Shaheen NJ, Sandler RS. Digestive and liver diseases statistics, 2004. Gastroenterology. 2004;126:1448-1453.
Sandler RS, Everhart JE, Donowitz M, Adams E, Cronin K, Goodman C, Gemmen E, Shah S, Avdic A, Rubin R. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500-1511.
Katsika D, Tuvblad C, Einarsson C, Lichtenstein P, Marschall HU. Body mass index, alcohol, tobacco and symptomatic gallstone disease: a Swedish twin study. J Intern Med. 2007;262:581-587.
Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Weight cycling and risk of gallstone disease in men. Arch Intern Med. 2006;166:2369-2374.
Park YH, Park SJ, Jang JY, Ahn YJ, Park YC, Yoon YB, Kim SW. Changing patterns of gallstone disease in Korea. World J Surg. 2004;28:206-210.
Marschall HU, Einarsson C. Gallstone disease. J Intern Med. 2007;261:529-542.
Méndez-Sánchez N, Chavez-Tapia NC, Uribe M. The role of dietary fats in the pathogenesis of gallstones. Front Biosci. 2003;8:e420-e427.
Anuurad E, Shiwaku K, Nogi A, Kitajima K, Enkhmaa B, Shimono K, Yamane Y. The new BMI criteria for asians by the regional office for the western pacific region of WHO are suitable for screening of overweight to prevent metabolic syndrome in elder Japanese workers. J Occup Health. 2003;45:335-343.
Attasaranya S, Fogel EL, Lehman GA. Choledocholithiasis, ascending cholangitis, and gallstone pancreatitis. Med Clin North Am. 2008;92:925-960, x.
Kono S, Shinchi K, Ikeda N, Yanai F, Imanishi K. Prevalence of gallstone disease in relation to smoking, alcohol use, obesity, and glucose tolerance: a study of self-defense officials in Japan. Am J Epidemiol. 1992;136:787-794.
Chen CH, Huang MH, Yang JC, Nien CK, Etheredge GD, Yang CC, Yeh YH, Wu HS, Chou DA, Yueh SK. Prevalence and risk factors of gallstone disease in an adult population of Taiwan: an epidemiological survey. J Gastroenterol Hepatol. 2006;21:1737-1743.
Lu SN, Chang WY, Wang LY, Hsieh MY, Chuang WL, Chen SC, Su WP, Tai TY, Wu MM, Chen CJ. Risk factors for gallstones among Chinese in Taiwan. A community sonographic survey. J Clin Gastroenterol. 1990;12:542-546.
Festi D, Dormi A, Capodicasa S, Staniscia T, Attili AF, Loria P, Pazzi P, Mazzella G, Sama C, Roda E. Incidence of gallstone disease in Italy: Results from a multicenter, population-based Italian study (the MICOL project). World J Gastroenterol. 2008;14:5282-5289.
Kaechele V, Wabitsch M, Thiere D, Kessler AL, Haenle MM, Mayer H, Kratzer W. Prevalence of gallbladder stone disease in obese children and adolescents: influence of the degree of obesity, sex, and pubertal development. J Pediatr Gastroenterol Nutr. 2006;42:66-70.
Kriska AM, Brach JS, Jarvis BJ, Everhart JE, Fabio A, Richardson CR, Howard BV. Physical activity and gallbladder disease determined by ultrasonography. Med Sci Sports Exerc. 2007;39:1927-1932.
Völzke H, Baumeister SE, Alte D, Hoffmann W, Schwahn C, Simon P, John U, Lerch MM. Independent risk factors for gallstone formation in a region with high cholelithiasis prevalence. Digestion. 2005;71:97-105.
Liu CM, Tung TH, Liu JH, Lee WL, Chou P. A community-based epidemiologic study on gallstone disease among type 2 diabetics in Kinmen, Taiwan. Dig Dis. 2004;22:87-91.
Youming D, Bin W, Weixing W, Binghua W, Ruoyu L, Bangchang C. The effect of h(1) calponin expression on gallstone formation in pregnancy. Saudi Med J. 2006;27:1661-1666.
Tierney S, Nakeeb A, Wong O, Lipsett PA, Sostre S, Pitt HA, Lillemoe KD. Progesterone alters biliary flow dynamics. Ann Surg. 1999;229:205-209.
Maurer KR, Everhart JE, Knowler WC, Shawker TH, Roth HP. Risk factors for gallstone disease in the Hispanic populations of the United States. Am J Epidemiol. 1990;131:836-844.
Khan MK, Jalil MA, Khan MS. Oral contraceptives in gall stone diseases. Mymensingh Med J. 2007;16:S40-S45.
De Santis A, Attili AF, Ginanni Corradini S, Scafato E, Cantagalli A, De Luca C, Pinto G, Lisi D, Capocaccia L. Gallstones and diabetes: a case-control study in a free-living population sample. Hepatology. 1997;25:787-790.
Barbara L, Sama C, Morselli Labate AM, Taroni F, Rusticali AG, Festi D, Sapio C, Roda E, Banterle C, Puci A. A population study on the prevalence of gallstone disease: the Sirmione Study. Hepatology. 1987;7:913-917.
Graewin SJ, Kiely JM, Lee KH, Svatek CL, Nakeeb A, Pitt HA. Nonobese diabetic mice have diminished gallbladder motility and shortened crystal observation time. J Gastrointest Surg. 2004;8:824-829; discussion 829-830.
Hahm JS, Park JY, Park KG, Ahn YH, Lee MH, Park KN. Gallbladder motility in diabetes mellitus using real time ultrasonography. Am J Gastroenterol. 1996;91:2391-2394.
Kayacetin E, Kisakol G, Kaya A, Akpinar Z. Real-time sonography for screening of gallbladder motility in diabetic patients: relation to autonomic and peripheral neuropathy. Neuro Endocrinol Lett. 2003;24:73-76.
Thijs C, Knipschild P, Leffers P. Is gallstone disease caused by obesity or by dieting?. Am J Epidemiol. 1992;135:274-280.
Kato I, Nomura A, Stemmermann GN, Chyou PH. Prospective study of clinical gallbladder disease and its association with obesity, physical activity, and other factors. Dig Dis Sci. 1992;37:784-790.
Jørgensen T. Gall stones in a Danish population. Relation to weight, physical activity, smoking, coffee consumption, and diabetes mellitus. Gut. 1989;30:528-534.
The Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO).The epidemiology of gallstone disease in Rome, Italy. Part II. Factors associated with the disease. Hepatology. 1988;8:907-913.
Jørgensen T. Gallstones and plasma lipids in a Danish population. Scand J Gastroenterol. 1989;24:916-922.