Chapter 4.1 Angela M. Madden1 and Emma Currie2 1University of Hertfordshire, Hatfield, UK 2Addenbrooke’s Hospital, Cambridge, UK Gallstones are dense hard structures formed from the precipitation of solids in bile and are usually located within the gallbladder or, less frequently but with potentially greater clinical significance, lodged in a bile duct outside or within the liver. The type of gallstone is defined by its composition and can be divided into two main groups: those which are cholesterol rich and comprise approximately 70% of cases in Western populations and those composed predominantly of bile pigments [1]. Although there are some common features and the clinical consequences are similar between the two groups, the pathogenesis and risk factors differ. The worldwide prevalence of gallstones varies with stone composition and between countries (Table 4.1.1). Prevalence is generally considered to be increasing as a consequence of nutritional and lifestyle changes, ageing populations, the increasing global prevalence of obesity and improved diagnostic capabilities [9]. Although gallstones are associated with a comparatively low mortality rate of 0.6%, the burden of morbidity and direct and indirect costs are high, estimated in the United States as being approximately $6.2 billion annually [9]. Table 4.1.1 Worldwide prevalencea of gallstones aStudies vary in the age of participants and diagnostic criteria so direct comparisons between populations should be undertaken with caution. A number of nutritional and other aetiological factors, including demographic, genetic and biliary issues (Table 4.1.2), are associated with increased risk of gallstone formation. Cholesterol supersaturation of bile is the primary requirement for the formation of cholesterol-rich gallstones and this is influenced by dietary intake, eating behaviour and body weight but supersaturation alone does not automatically lead to the production of stones. Table 4.1.2 Non-nutritional factors influencing the formation of gallstones Carrying excessive body weight, particularly as abdominal fat, is well recognised as a risk factor for developing cholesterol-rich gallstones [18,19]. The relationship is linear in women with least risk associated with Body Mass Index (BMI) <20 kg/m2, and increasing to a relative risk of 1.7 (95% confidence interval (CI) 1.1–2.7) with BMI between 24.0 and 24.9 kg/m2 and relative risk of 6.0 (95% CI 4.0–9.0) associated with BMI >32 kg/m2 [19]. Increasing waist circumference is also independently associated with greater risk of developing gallstones in both men and women, with the greatest relative risk in men associated with measurements of 102–106 cm (relative risk 3.9, 95% CI 1.5–10.7 compared to <86 cm) and in women with measurements of 81–86 cm (relative risk 2.9, 95% CI 1.6–5.2 compared to <71 cm) [20]. The risk is mediated by increased cholesterol synthesis and cholesterol secretion into bile associated with raised insulin concentrations in excessive body weight. Counterintuitively, weight reduction increases the risk of cholesterol-rich gallstone formation in the short term as a negative energy balance results in cholesterol mobilisation from adipose stores [24]. Risk can be reduced by maintaining a rate of weight loss below 1.5 kg/week [21], minimising weight cycling where body weight is sequentially lost and regained and maintaining weight loss <25% of total body weight after bariatric surgery [24]. Several studies investigating the effects of total dietary fat, monounsaturated and polyunsaturated fatty acids on gallstone formation have provided conflicting results from which no definitive conclusion can be drawn [25]. This equivocal evidence may reflect that although dietary fat is associated with obesity and high cholesterol concentrations, it also stimulates the release of cholecystokinin (CCK) which provokes gallbladder contraction, thus expelling potentially lithogenic bile and reducing stone formation. Studies of dietary cholesterol intake have also yielded no definitive association between intake and gallstone formation. However, examining specific lipid fractions may provide further evidence as epidemiological and experimental investigations into the effects of n-3 fatty acids, i.e. derived from fish oil, have shown that these may have a protective effect [26]. Conversely, long-term consumption of a high intake of trans fatty acids, formed during hydrogenation of lipid in food processing, is associated with a modest but independent increased risk of developing gallstones (comparison of highest and lowest intake quintiles, relative risk 1.23, 95% CI 1.04–1.44) [27]. This is probably mediated via a lowering of serum high-density lipoprotein (HDL) cholesterol which is associated with the reduction of cholesterol saturation in bile [28]. High intakes of refined carbohydrate are associated with increased risk of developing gallstones [29,30]. It has been suggested that this arises because diets containing more carbohydrate usually provide less fat and therefore will provoke less CCK secretion and thus less contraction of the gallbladder. This hypothesis is logical but not supported by any evidence of an association between high intakes of unrefined carbohydrate and increased risk of gallstone formation. It is likely that the lithogenic effects of refined carbohydrate are mediated through increased cholesterol saturation of bile [31] secondary to raised insulin concentrations [32] and through a reduction in sensitivity to CCK in the presence of raised serum triglycerides, which are associated with high refined carbohydrate intake [33]. Studies have identified a protective effect of dietary fibre on cholesterol gallstone formation [18,30,34]. This is probably mediated through the reduction of intestinal transit time by insoluble fibre, thus limiting colonic reabsorption of the bile acid deoxycholic acid (DCA), and so reducing biliary DCA concentrations and increasing the synthesis of bile acids from cholesterol resulting in reduced bile cholesterol saturation [35]. The effects of soluble fibre, which is known to reduce serum cholesterol [36], may be the same but also explained by luminal binding of bile acids or the formation of a physical barrier which reduces bile acid reabsorption [37]. Consumption of alcohol is inversely associated with gallstone development in men and cholecystectomy in women [38]. In a recent study of 2417 adults, the independent relative risk of developing gallstones in those consuming alcohol compared to non-drinkers was 0.67 (95% CI 0.46–0.99) [39]. The EPIC-Norfolk study of 25,639 adults identified a 3% reduction in risk of developing gallstones associated with every unit of alcohol consumed by men but no effect in women [19]. The effect of alcohol in men is probably mediated via an increase in HDL cholesterol which is associated with the reduction of cholesterol saturation in bile [28,31]. A number of other nutrients and foods have been investigated as possible causative agents in gallstone formation, including protein, vitamin C, caffeine and nuts. However, the findings from different studies are conflicting and do not allow firm conclusion to be drawn [25]. Whilst physical activity might not be considered a nutritional variable, it is a potentially modifiable influence on the risk of cholesterol-rich gallstone formation. A number of epidemiological studies have identified the beneficial effects of physical activity in reducing the risk of gallstone disease in men and women [40]. These effects are independent of BMI and probably mediated through an increase in serum HDL cholesterol and reduction in serum insulin [40]. Optimising nutritional intake may play a role in the prevention of cholesterol-rich but not pigment gallstones. However, few dietary intervention studies have been undertaken to investigate nutritional management and therefore advice should be based on evidence from epidemiology which is supported by a plausible mechanism. It is necessary to consider the stage of the individual’s condition as this will influence their dietary intake and the relevance of nutritional advice. Once formed, gallstones may be asymptomatic or lead to chronic or acute cholecystitis when the gallbladder becomes inflamed, causing pain. It is estimated that approximately 10% of the population with asymptomatic gallstones will develop symptoms or require treatment within 5 years [41]. Strategies are based on reducing the cholesterol saturation of bile. This should include consuming an energy intake to achieve or maintain a healthy BMI below 25 kg/m2, reducing excess body weight at a rate of less than 1.5 kg/week, minimising intake of refined carbohydrate and trans fatty acids, consuming alcohol within safe drinking limits and increasing dietary fibre. This is compatible with current healthy eating guidelines in many countries [42,43]. A supplement of n-3 fatty acid may be of benefit to weight reducers [26]. In addition, it is logical to advise regular food intake, including breakfast, in order to stimulate gallbladder contraction and so reduce the time that bile, particularly lithogenic overnight bile, is retained [44]. Pain is usually severe in acute cases of cholecystitis and occurs primarily in the epigastric or right upper abdomen and lasts 2–4 h. It is often accompanied by nausea and sometimes pyrexia. Some patients with acute cholecystitis experience loss of appetite. Short-term dietary management may include encouraging intake through offering food ‘little and often’, food fortification and strategies to address nausea and vomiting. If nutritional requirements cannot be met by consuming food alone, oral nutritional supplements andor enteral nutrition (EN) may be required. When pain subsides, nutritional management compatible with chronic cholecystitis is appropriate.
Gallbladder disease and nutrition
4.1.1 Gallstones
Prevalence (%)
Population (number studied)
Men
Women
Study
USA, North American Indians (3296)
29.5
64.1
Everhart et al. 2002
Italy, Padua (1065)
17
35
Lirussi et al. 1999
Peru, Lima (1534)
16.1
10.7
Moro et al. 2000
Taiwan, Taipei (3647)
10.7
11.5
Chen et al. 1998
USA, Mexican Americans (4174)
8.9
26.7
Everhart et al. 1999
USA, White Americans (5275)
8.6
16.6
Everhart et al. 1999
UK, Bristol (1896)
6.9
8.0
Heaton et al. 1991
India, Uttar Pradesh and Bihar (22861)
2.0
5.6
Unisa et al. 2011
4.1.2 Factors involved in causation
Risk factor
Explanation
Age
Increased risk with increasing age, especially after 40 years
Gender
Increased risk in women, particularly premenopause
Reproductive history
Increased risk with pregnancy, oral contraceptive use and oestrogen replacement therapy in women
Genetics
Increased risk in people with family history of gallstones; some rare monogenetic defects identified but gallstone formation is probably polygenic disorder
Gastrointestinal health
Increased risk associated with disruption to enterohepatic circulation and faecal loss of bile salts and conditions including gastric bypass, pre-existing liver disease, Crohn’s disease and malabsorption due to cystic fibrosis
Biliary health
Increased risk associated with incomplete gallbladder emptying, impaired gallbladder motility, sphincter of Oddi dysfunction, congenitally misshaped or diseased gallbladder and with biliary infections
Obesity
Dietary fat and cholesterol
Dietary carbohydrate and fibre
Alcohol
Other dietary factors
Physical activity
4.1.3 Nutritional management
Minimising risk of gallstone formation and management of asymptomatic gallstones
Acute cholecystitis
Chronic cholecystitis
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