Best Practice & Research Clinical Gastroenterology 28 (2014) 623e635
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
8
Obesity and the risk and prognosis of gallstone disease and pancreatitis Leonilde Bonfrate, M.D., Resident a, 1, David Q-H. Wang, M.D., Ph.D., Professor b, 2, Gabriella Garruti, M.D., Ph.D., Assistant Professor c, 3, Piero Portincasa, M.D., Ph.D., Professor d, * a
Residency Programme in Internal Medicine, University of Bari Medical School, 70124 Bari, Italy Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA c Department of Emergency and Organ Transplants, Section of Endocrinology, Andrology and Metabolic Diseases, University of Bari Medical School, 70124 Bari, Italy d Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, Piazza Giulio Cesare 11, 70124 Bari, Italy b
a b s t r a c t Keywords: Bariatric surgery Cholecystectomy Cholesterol Gallbladder motility Metabolic syndrome Rapid weight loss
Obesity is a risk factor for the formation of cholesterol gallstones and exposes patients to increased risk of gallstone-related complications and cholecystectomy. Rapid weight loss achieved by very low calorie diets or bariatric surgery is also a risk factor for cholelithiasis in obese patients, and therapy should take into account the higher prevalence of gallstones, the possibility of more frequent complications and the need for prophylactic treatment with oral ursodeoxycholic acid during weight loss. Obesity is also frequent in children and adolescents, and the burden of cholesterol cholelithiasis is increasing in this population. The chance to develop acute pancreatitis and the severity of the disease are higher in obese subjects because of specific pathogenic factors, including supersaturated bile and crystal formation, rapid weight
Abbreviations: AP, acute pancreatitis; BMI, body mass index; NSAIDs, nonsteroidal anti-inflammatory drugs; SIRS, systemic inflammatory response syndrome; TNF, tumour necrosis factor; UDCA, ursodeoxycholic acid. *Corresponding author. Tel.: þ39 080 5478227; fax: þ39 080 5478232. E-mail addresses: [email protected] (L. Bonfrate), [email protected] (D.Q.-H. Wang), [email protected] (G. Garruti), [email protected] (P. Portincasa). 1 Tel.: þ39 080 5478234; fax: þ39 080 5478232. 2 Tel.: þ1 314 977 9737; fax: þ1 314 977 9909. 3 Tel.: þ39 080 5592314.
http://dx.doi.org/10.1016/j.bpg.2014.07.013 1521-6918/© 2014 Elsevier Ltd. All rights reserved.
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L. Bonfrate et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 623e635
loss, and visceral obesity. All health policies aimed at reducing the incidence of obesity worldwide will decrease the incidence of gallstones and gallstone-related complications. The pathophysiological scenarios and the therapeutic implications for obesity, gallstone disease, and pancreatitis are discussed. © 2014 Elsevier Ltd. All rights reserved.
Introduction From 1980, a progressive shift toward obesity has been showed at any age, with a greater surge of obesity prevalence in lower- and middle-income developing countries rather than in higher-income countries. Whereas the differences in obesity prevalence across countries reflect the differences in national and local environments, the modifications in the global food system and increased sedentary life during the past 3e4 decades have created an obesogenic environment contributing to the increase of obesity epidemic worldwide. Among many other comorbidities, obesity is also frequently associated with hepatobiliary diseases, including gallstone disease [1e3], pancreatitis and liver steatosis [4], three conditions reflecting abnormal cholesterol and triglyceride metabolism. Gallstone disease is one of the most prevalent and costly digestive diseases in Western countries [2]. The prevalence of gallstones in adults is 10e15% [2,5,6], and is rising. Around one million of new cases are diagnosed each year in the USA [7], and the 3rd National Health and Nutrition Examination Survey (NHANES III) reports that in the USA about 6.3 million of men and 14.2 million of women aged 20e74 might suffer from gallbladder disease [5]. During the development of gallstones, solid conglomerates of cholesterol monohydrate crystals, mucin gel, calcium bilirubinate, and proteins accumulate and grow in the gallbladder [8]. Depending on the chemical composition, gallstones are often classified as pure cholesterol, pure pigment, and mixed stones. The latter type contains some amounts of bilirubin salts and calcium. In developed countries, cholesterol gallstones account for about 75% of stones, black pigment stones for 20%, and brown pigment stones for about 5% [8]. Besides some genetic factors, in the majority of cases, gallstones can be induced by non-genetic risk factors [2,8] (Table 1). For cholesterol gallstones, factors comprise female gender (women exposed to a higher level of oestrogen than men), pregnancy, several conditions leading to gallbladder stasis, oral oestrogens and contraceptives, and hypomagnesaemia. The prevalence of both types of cholesterol and pigment stones increases with increasing age, smoking, and liver cirrhosis. Black pigment stones are associated with haemolytic anaemia, cystic fibrosis, high alcohol intake, biliary/intestinal infections, and vitamin B12/folic acid deficient diets. It is the aim of this chapter to describe the pathophysiological scenarios and the therapeutic implications involving the association of obesity with gallstone disease and pancreatitis. Obesity and gallstones Obesity, body mass index (BMI) and gallstones Obesity “per se” is a potent factor associated with the formation of cholesterol gallstones. A genetic predisposition is found in specific ethnic groups such as the Pima Indians of Arizona, in which obesity and non-insulin diabetes mellitus coexist, displaying the highest prevalence rate of cholesterol gallstones (about 80% in women by age 25e30) in the world [9]. Non-genetic risk factors for cholesterol gallstones associated with obesity are depicted in Table 2. Increased BMI is also a causal risk factor for symptomatic gallstone disease [10]. In the Nurses' Health Study, increasing BMI was associated with increased relative risk of cholelithiasis (3-fold), in women initially at 30e55 years of age and followed for up to 18 years [11]. A dramatic increase was observed in the incidence of symptomatic gallstones defined as cholecystectomy, or newly diagnosed symptomatic gallstones, and BMI [12]. The incidence of symptomatic gallstones increased from approximately 0.25% to >2% per year of follow-up in these
L. Bonfrate et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 623e635
625
Table 1 Non-genetic risk factors for gallstones. Stone type/condition Cholesterol Female gender Pregnancy
Estrogen therapy (also to men) Oral contraceptives Total parenteral nutrition, total gastrectomy with lymph node dissection, vagotomy, spinal cord injury, somatostatinoma Fibrates, octreotide, calcineurin inhibitors (tacrolimus, ciclosporin)
Hypomagnesaemia Cholesterol/black pigment Increasing age Smoking Liver cirrhosis
Crohn's disease Extended ileal resection Black pigment Extreme (normal) bilirubinemia
Haemolytic anaemia Sickle cell disease Cystic fibrosis
High alcohol intake Infections (e.g., biliary strictures, duodenal diverticula, cholangitis, pancreatic insufficiency) HCV infection Vitamin B12/folic acid deficient diet Other types Ceftriaxone (i.v.)
Pathophysiology
Steroid hormones Pregnancies Supersaturated gallbladder bile (oestrogen/progesterone) Gallbladder stasis (progesterone) Faster cholesterol crystallization and solid crystal precipitation Supersaturated gallbladder bile Gallbladder stasis Faster precipitation/crystallization of cholesterol Gallbladder stasis Inhibition of cholecystokinin release Supersaturated gallbladder bile Faster cholesterol crystallization and solid crystal precipitation Gallbladder stasis Inhibition of cholecystokinin release Hepatic secretion of supersaturated bile Inhibition of hepatic bile salt export pump Bile concentration Insulin resistance and deranged serum LDL- and HDL-cholesterol
Metabolic factors Haemolytic anaemia Associated metabolic factors Hyperestrogenism Gallbladder stasis Bile salt malabsorption Increased enterohepatic circulation of bilirubin Increased biliary concentration of conjugated and unconjugated bilirubin and calcium Increased enterohepatic circulation of bilirubin
Increased biliary concentration of conjugated and unconjugated bilirubin and calcium Increased enterohepatic circulation of bilirubin Increased calcium bilirubinate concrements Gallbladder stasis Increased biliary concentration of conjugated and unconjugated bilirubin and calcium Increased enterohepatic circulation of bilirubin Liver damage Reduced bile acid synthesis Bacterial b-glucuronization with biotransformation of conjugated to unconjugated bilirubin, precipitation together with calcium and long-chain fatty acids Haemolytic anaemia Precipitation in bile (as calcium ceftriaxonate)
Adapted from Portincasa et al. [2,8,59] and Wang et al. [116].
women with BMI < 24 to >45, respectively. Similar trends with increased relative risk (2.5-fold) for cholelithiasis were confirmed in the Health Professional Study focussing on men initially at 40e55 years of age and followed for up to 10 years [13]. Women [14,15] and morbid obese patients [11,16] carry the highest risk of gallstone disease compared to other risk factors. An early study focussing on morbidly obese subjects concluded that gallbladder disease (i.e., abnormal gallbladder histology even in the absence of gallstones preoperatively) is more frequent in the morbidly obese population (91%) [16]. Likely, as a consequence of obesity-associated gallstone disease, the risk of gallbladder cancer also increases with BMI and obesity [17]. Obesity is also likely to act potently on lithogenic mechanisms by several associated conditions, including the metabolic syndrome and insulin resistance
626
L. Bonfrate et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 623e635
Table 2 Non-genetic risk factors for cholesterol gallstones more closely associated with obesity. Condition
Pathophysiology
Obesity
Hepatic secretion of supersaturated bile Gallbladder stasis Hepatic secretion of supersaturated bile Associated metabolic factors Gallbladder stasis Association with other metabolic abnormalities Hepatic secretion of supersaturated bile Apolipoprotein E4 phenotype Obesity Hepatic secretion of supersaturated bile Dyslipidemia Hypersecretion of biliary mucin Hepatic secretion of supersaturated bile Gallbladder stasis Rapid mobilization of body cholesterol towards the liver Hepatic secretion of supersaturated bile Intestinal and gallbladder hypomotility Decreased secretion of bile acids Increased serum triglycerides and insulin release Overweight, obesity Increased fasting and postprandial gallbladder volume Supersaturated gallbladder bile Faster cholesterol crystallization and solid crystal precipitation
Westernized diet: high-calorie, low-fibre, high-refined carbohydrate, high-fat Dyslipidemia
Metabolic syndrome Insulin resistance Rapid weight loss - very low calorie diet - bariatric surgery of morbid obesity Physical inactivity (especially in men)
Gallbladder stasis
Adapted from Portincasa et al. [2,8,59] and Wang et al. [116].
[18]. Several factors among such criteria have either isolated or combined effects on the lithogenic process of cholesterol gallstones. A recent cross-sectional study from China investigated 7570 subjects including 918 gallstone patients undergoing the physical check-up at the hospital. Gallstone prevalence increased with the number of the criteria of the metabolic syndrome (i.e., from ~5% without, to ~25% with five criteria). The presence of five components of the metabolic syndrome increased the risk of gallstone disease by four times in both sexes [19]. This trend is similar to that already described for development of symptomatic gallstones and BMI [12] (see above). Some other lithogenic conditions might also be associated with obesity, like diabetes mellitus, insulin resistance, autonomic neuropathy and gallbladder stasis, hypertriglyceridemia, low HDL-C, sedentary life, and typical westernized hypercaloric diets [8] (Table 2). Rapid weight loss and gallstones Due to the overall high burden of obesity on health, weight loss and weight maintenance is desirable in obese patients. The likelihood of cholelithiasis is increased if weight loss is too rapid (i.e., more than 1.5 kg/week) [20,21] a possibility with very low calorie diet (containing 60 Kg/m2) the thickness of the abdominal wall inhibits the mobility of the trocars, and this sometimes requires longer trocars (to avoid trocar displacement, insufflation within the abdominal wall and subcutaneous emphysema), longer instruments, additional trocars, and supraumbilical positioning of the initial umbilical trocar (to reach the gallbladder). Oral litholysis with bile acids is restricted to a small subgroup (
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
8
Obesity and the risk and prognosis of gallstone disease and pancreatitis Leonilde Bonfrate, M.D., Resident a, 1, David Q-H. Wang, M.D., Ph.D., Professor b, 2, Gabriella Garruti, M.D., Ph.D., Assistant Professor c, 3, Piero Portincasa, M.D., Ph.D., Professor d, * a
Residency Programme in Internal Medicine, University of Bari Medical School, 70124 Bari, Italy Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA c Department of Emergency and Organ Transplants, Section of Endocrinology, Andrology and Metabolic Diseases, University of Bari Medical School, 70124 Bari, Italy d Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, Piazza Giulio Cesare 11, 70124 Bari, Italy b
a b s t r a c t Keywords: Bariatric surgery Cholecystectomy Cholesterol Gallbladder motility Metabolic syndrome Rapid weight loss
Obesity is a risk factor for the formation of cholesterol gallstones and exposes patients to increased risk of gallstone-related complications and cholecystectomy. Rapid weight loss achieved by very low calorie diets or bariatric surgery is also a risk factor for cholelithiasis in obese patients, and therapy should take into account the higher prevalence of gallstones, the possibility of more frequent complications and the need for prophylactic treatment with oral ursodeoxycholic acid during weight loss. Obesity is also frequent in children and adolescents, and the burden of cholesterol cholelithiasis is increasing in this population. The chance to develop acute pancreatitis and the severity of the disease are higher in obese subjects because of specific pathogenic factors, including supersaturated bile and crystal formation, rapid weight
Abbreviations: AP, acute pancreatitis; BMI, body mass index; NSAIDs, nonsteroidal anti-inflammatory drugs; SIRS, systemic inflammatory response syndrome; TNF, tumour necrosis factor; UDCA, ursodeoxycholic acid. *Corresponding author. Tel.: þ39 080 5478227; fax: þ39 080 5478232. E-mail addresses: [email protected] (L. Bonfrate), [email protected] (D.Q.-H. Wang), [email protected] (G. Garruti), [email protected] (P. Portincasa). 1 Tel.: þ39 080 5478234; fax: þ39 080 5478232. 2 Tel.: þ1 314 977 9737; fax: þ1 314 977 9909. 3 Tel.: þ39 080 5592314.
http://dx.doi.org/10.1016/j.bpg.2014.07.013 1521-6918/© 2014 Elsevier Ltd. All rights reserved.
624
L. Bonfrate et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 623e635
loss, and visceral obesity. All health policies aimed at reducing the incidence of obesity worldwide will decrease the incidence of gallstones and gallstone-related complications. The pathophysiological scenarios and the therapeutic implications for obesity, gallstone disease, and pancreatitis are discussed. © 2014 Elsevier Ltd. All rights reserved.
Introduction From 1980, a progressive shift toward obesity has been showed at any age, with a greater surge of obesity prevalence in lower- and middle-income developing countries rather than in higher-income countries. Whereas the differences in obesity prevalence across countries reflect the differences in national and local environments, the modifications in the global food system and increased sedentary life during the past 3e4 decades have created an obesogenic environment contributing to the increase of obesity epidemic worldwide. Among many other comorbidities, obesity is also frequently associated with hepatobiliary diseases, including gallstone disease [1e3], pancreatitis and liver steatosis [4], three conditions reflecting abnormal cholesterol and triglyceride metabolism. Gallstone disease is one of the most prevalent and costly digestive diseases in Western countries [2]. The prevalence of gallstones in adults is 10e15% [2,5,6], and is rising. Around one million of new cases are diagnosed each year in the USA [7], and the 3rd National Health and Nutrition Examination Survey (NHANES III) reports that in the USA about 6.3 million of men and 14.2 million of women aged 20e74 might suffer from gallbladder disease [5]. During the development of gallstones, solid conglomerates of cholesterol monohydrate crystals, mucin gel, calcium bilirubinate, and proteins accumulate and grow in the gallbladder [8]. Depending on the chemical composition, gallstones are often classified as pure cholesterol, pure pigment, and mixed stones. The latter type contains some amounts of bilirubin salts and calcium. In developed countries, cholesterol gallstones account for about 75% of stones, black pigment stones for 20%, and brown pigment stones for about 5% [8]. Besides some genetic factors, in the majority of cases, gallstones can be induced by non-genetic risk factors [2,8] (Table 1). For cholesterol gallstones, factors comprise female gender (women exposed to a higher level of oestrogen than men), pregnancy, several conditions leading to gallbladder stasis, oral oestrogens and contraceptives, and hypomagnesaemia. The prevalence of both types of cholesterol and pigment stones increases with increasing age, smoking, and liver cirrhosis. Black pigment stones are associated with haemolytic anaemia, cystic fibrosis, high alcohol intake, biliary/intestinal infections, and vitamin B12/folic acid deficient diets. It is the aim of this chapter to describe the pathophysiological scenarios and the therapeutic implications involving the association of obesity with gallstone disease and pancreatitis. Obesity and gallstones Obesity, body mass index (BMI) and gallstones Obesity “per se” is a potent factor associated with the formation of cholesterol gallstones. A genetic predisposition is found in specific ethnic groups such as the Pima Indians of Arizona, in which obesity and non-insulin diabetes mellitus coexist, displaying the highest prevalence rate of cholesterol gallstones (about 80% in women by age 25e30) in the world [9]. Non-genetic risk factors for cholesterol gallstones associated with obesity are depicted in Table 2. Increased BMI is also a causal risk factor for symptomatic gallstone disease [10]. In the Nurses' Health Study, increasing BMI was associated with increased relative risk of cholelithiasis (3-fold), in women initially at 30e55 years of age and followed for up to 18 years [11]. A dramatic increase was observed in the incidence of symptomatic gallstones defined as cholecystectomy, or newly diagnosed symptomatic gallstones, and BMI [12]. The incidence of symptomatic gallstones increased from approximately 0.25% to >2% per year of follow-up in these
L. Bonfrate et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 623e635
625
Table 1 Non-genetic risk factors for gallstones. Stone type/condition Cholesterol Female gender Pregnancy
Estrogen therapy (also to men) Oral contraceptives Total parenteral nutrition, total gastrectomy with lymph node dissection, vagotomy, spinal cord injury, somatostatinoma Fibrates, octreotide, calcineurin inhibitors (tacrolimus, ciclosporin)
Hypomagnesaemia Cholesterol/black pigment Increasing age Smoking Liver cirrhosis
Crohn's disease Extended ileal resection Black pigment Extreme (normal) bilirubinemia
Haemolytic anaemia Sickle cell disease Cystic fibrosis
High alcohol intake Infections (e.g., biliary strictures, duodenal diverticula, cholangitis, pancreatic insufficiency) HCV infection Vitamin B12/folic acid deficient diet Other types Ceftriaxone (i.v.)
Pathophysiology
Steroid hormones Pregnancies Supersaturated gallbladder bile (oestrogen/progesterone) Gallbladder stasis (progesterone) Faster cholesterol crystallization and solid crystal precipitation Supersaturated gallbladder bile Gallbladder stasis Faster precipitation/crystallization of cholesterol Gallbladder stasis Inhibition of cholecystokinin release Supersaturated gallbladder bile Faster cholesterol crystallization and solid crystal precipitation Gallbladder stasis Inhibition of cholecystokinin release Hepatic secretion of supersaturated bile Inhibition of hepatic bile salt export pump Bile concentration Insulin resistance and deranged serum LDL- and HDL-cholesterol
Metabolic factors Haemolytic anaemia Associated metabolic factors Hyperestrogenism Gallbladder stasis Bile salt malabsorption Increased enterohepatic circulation of bilirubin Increased biliary concentration of conjugated and unconjugated bilirubin and calcium Increased enterohepatic circulation of bilirubin
Increased biliary concentration of conjugated and unconjugated bilirubin and calcium Increased enterohepatic circulation of bilirubin Increased calcium bilirubinate concrements Gallbladder stasis Increased biliary concentration of conjugated and unconjugated bilirubin and calcium Increased enterohepatic circulation of bilirubin Liver damage Reduced bile acid synthesis Bacterial b-glucuronization with biotransformation of conjugated to unconjugated bilirubin, precipitation together with calcium and long-chain fatty acids Haemolytic anaemia Precipitation in bile (as calcium ceftriaxonate)
Adapted from Portincasa et al. [2,8,59] and Wang et al. [116].
women with BMI < 24 to >45, respectively. Similar trends with increased relative risk (2.5-fold) for cholelithiasis were confirmed in the Health Professional Study focussing on men initially at 40e55 years of age and followed for up to 10 years [13]. Women [14,15] and morbid obese patients [11,16] carry the highest risk of gallstone disease compared to other risk factors. An early study focussing on morbidly obese subjects concluded that gallbladder disease (i.e., abnormal gallbladder histology even in the absence of gallstones preoperatively) is more frequent in the morbidly obese population (91%) [16]. Likely, as a consequence of obesity-associated gallstone disease, the risk of gallbladder cancer also increases with BMI and obesity [17]. Obesity is also likely to act potently on lithogenic mechanisms by several associated conditions, including the metabolic syndrome and insulin resistance
626
L. Bonfrate et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 623e635
Table 2 Non-genetic risk factors for cholesterol gallstones more closely associated with obesity. Condition
Pathophysiology
Obesity
Hepatic secretion of supersaturated bile Gallbladder stasis Hepatic secretion of supersaturated bile Associated metabolic factors Gallbladder stasis Association with other metabolic abnormalities Hepatic secretion of supersaturated bile Apolipoprotein E4 phenotype Obesity Hepatic secretion of supersaturated bile Dyslipidemia Hypersecretion of biliary mucin Hepatic secretion of supersaturated bile Gallbladder stasis Rapid mobilization of body cholesterol towards the liver Hepatic secretion of supersaturated bile Intestinal and gallbladder hypomotility Decreased secretion of bile acids Increased serum triglycerides and insulin release Overweight, obesity Increased fasting and postprandial gallbladder volume Supersaturated gallbladder bile Faster cholesterol crystallization and solid crystal precipitation
Westernized diet: high-calorie, low-fibre, high-refined carbohydrate, high-fat Dyslipidemia
Metabolic syndrome Insulin resistance Rapid weight loss - very low calorie diet - bariatric surgery of morbid obesity Physical inactivity (especially in men)
Gallbladder stasis
Adapted from Portincasa et al. [2,8,59] and Wang et al. [116].
[18]. Several factors among such criteria have either isolated or combined effects on the lithogenic process of cholesterol gallstones. A recent cross-sectional study from China investigated 7570 subjects including 918 gallstone patients undergoing the physical check-up at the hospital. Gallstone prevalence increased with the number of the criteria of the metabolic syndrome (i.e., from ~5% without, to ~25% with five criteria). The presence of five components of the metabolic syndrome increased the risk of gallstone disease by four times in both sexes [19]. This trend is similar to that already described for development of symptomatic gallstones and BMI [12] (see above). Some other lithogenic conditions might also be associated with obesity, like diabetes mellitus, insulin resistance, autonomic neuropathy and gallbladder stasis, hypertriglyceridemia, low HDL-C, sedentary life, and typical westernized hypercaloric diets [8] (Table 2). Rapid weight loss and gallstones Due to the overall high burden of obesity on health, weight loss and weight maintenance is desirable in obese patients. The likelihood of cholelithiasis is increased if weight loss is too rapid (i.e., more than 1.5 kg/week) [20,21] a possibility with very low calorie diet (containing 60 Kg/m2) the thickness of the abdominal wall inhibits the mobility of the trocars, and this sometimes requires longer trocars (to avoid trocar displacement, insufflation within the abdominal wall and subcutaneous emphysema), longer instruments, additional trocars, and supraumbilical positioning of the initial umbilical trocar (to reach the gallbladder). Oral litholysis with bile acids is restricted to a small subgroup (
