Diet and Gallstone

Abstract

Cholesterol gallstone disease is a major health problem in western countries and depends on genetic and enviromental factors. Diet may influence the formation of gallstone either by altering the biliary lipid composition or by modifying gallbladder motility. Numerous investigations have examined the association of diet and cholesterol gallstone in prospective, cross-sectional, and case-control studies and in experimental animal models. However, these findings are controversial, probably because human studies are mainly epidemiological with differences in study designs, dietary exposure assessment, and methods used. In general, a high intake of saturated fats and refined sugars has been shown to increase the risk of forming cholesterol gallstones, while a high intake of monounsaturated fats and fiber may decrease this process. The pathogenic mechanisms behind these alterations are reviewed, and the need for a nutritional intervention based on a diet low in lipids and rich in fibers is highlighted. A better understanding of the role of diet in gallstone formation may provide tools for those patients who have been diagnosed with symptomatic gallstones and may also contribute to the prophylactic and therapeutic strategies for cholelithiasis.

1. Introduction

Cholesterol gallstone disease is a very common pathology in western populations, with a high global prevalence of approximately 10–20%. The etiology of this pathology is considered multifactorial depending on the interaction of numerous complex factors: obesity, dyslipidemia, insulin resistance, high consumption of refined carbohydrates and cholesterol, age, female sex hormones, ethnicity, and sedentary lifestyles [1, 2, 3]. Pathological conditions result from a rapid and large mobilization of body cholesterol to the liver and then to the bile. This situation may cause biliary cholesterol supersaturation, increased cholesterol crystallization, and gallbaldder stasis [4]. The relationship between the secretion of bile acids and either phospholipids or free cholesterol represents important ratios of the secreted molecules, usually causing disturbances that result in a lithogenic bile [5]. The main risk factors in the pathogenesis of gallstones are biliary cholesterol hypersaturation, cholesterol crystallization, cholesterol crystal agglomeration and growth, and gallbladder dysmotility [6, 7]. The relationships between bile acid secretion and free cholesterol are highly species-dependent and, within certain species, are easily affected by diet. However, not all species present biliary characteristics required for cholesterol crystallization and stone formation, such as bile stasis, sludge formation, and nucleating factors, after cholesterol supersaturation is reached [8]. The use of animal models is limited because relatively few species always develop gallstones, and unlike humans, they do not spontaneously generate supersaturated bile in the gallbladder [9]. Therefore, there are certain contradictions in clinical and research studies, whose conclusions should be carefully analyzed. Another difficulty inherent in these studies is the impossibility of knowing the onset time of the disease caused by a specific dietary factor, in addition to not knowing the exact dimension of energy intake and the estimation of the dietary constituents effectively ingested [10].

Many epidemiological studies have associated the formation of cholesterol gallstones with other pathologies such as obesity, hyperlipidemia, and type 2 diabetes mellitus [11, 12, 13]. The presence of multiple risk factors in common with other disease makes it possible to associate gallstone disease with other cardiovascular diseases such as atherosclerosis carotid disease and metabolic dysfunction [14]. Although cholesterol gallstones genesis is multifactorial, basic physiological correlates associated with dietary modulation of biliary lipid metabolism are discussed in relation to gallstone disease. Several investigations have reported on the role of specific dietary constituents as a potential risk factor for cholelithiasis. Diet may influence the formation of gallstones either by modifying gallbladder motility or by altering the biliary lipid composition. The importance of diet in the pathogenesis of gallstones has been much debated. Most of these epidemiological investigations correspond to prospective, cross-sectional, or case-control studies. Some studies show specific nutrients that promote and others that, on the contrary, protect the process of gallstone formation [15]. Among the many dietary factors suggested in the literature, we will focus mainly on total energy intake, intake of carbohydrates, proteins, total fats, saturated fats, mono- and polyunsaturated fats, cholesterol, total fiber, and alcohol. Evidence on the relation between diet and gallstone formation, however, is somewhat conflicting.

The aim of this chapter is to present experimental and epidemiological evidence of dietetic factors that may favor the process of cholesterol gallstone formation.

2. Specific role of various dietary components

A number of dietary factors have been involved in the pathogenesis of cholesterol gallstone formation (Figure 1). It has been reported that Western-type diets, hypercaloric, high in fat and refined sugars, and limited intake of fiber, are factors that increase the possibility of gallstone formation. It is relevant to review nutritional factors that impact the relationship between the relative flow of cholesterol through bile lipids, which constitutes a crucial event in the process of the formation of cholesterol gallstones. Consequently, diet appears to alter most of the components secreted into the bile.

Figure 1.

Effects of major dietary factors (promoting-, preventing- and controversial factors) on gallstone formation.

2.1 Obesity and caloric intake

An excess in energy intake has been related to an increased risk of developing cholelithiasis. Obesity represents the greatest risk factor for cholelthiasis, since it exhibits an increase in the bile secretion of cholesterol from the liver, which generates cholesterol supersaturated bile; crystallization of cholesterol monohydrates; and agglomeration and growth until macroscopic gallstones formation [16, 17]. This excess cholesterol is secreted by hepatocytes as a direct result of increased body weight. It has been estimated that each extra kilogram of body fat yields the production of approximately 20 mg of additional cholesterol [12, 18]. A relevant factor in the process of the formation of cholesterol gallstones is the relative mass of free cholesterol in the bile, which is associated with the consumption of an overload of calories in the diet. Probably the link between obesity and gallstones reflects an excessive production of cholesterol or an increase in its efflux, which are greatly increased both in nonobese and obese patients with this disease [19]. It has recently been reported that high concentrations of C-reactive protein (CRP) could be an independent risk factor that could trigger the process of gallstone formation [20]. It is unknown how an increase in CRP increases the risk of gallstones, but it is suggested that the secretion of the proinflammatory cytokine interleukin-6 is stimulated by adipose tissue, promoting systemic inflammation in obesity [21, 22]. Many case-control studies have examined the relationship between energy intake and the prevalence of gallstone disease, but the findings are controversial. A French study showed a high risk of gallstone disease in men consuming a high-calorie diet, greater than 2500 Kcal per day, but not in women [23]. Similarly, a Spanish study showed a higher consumption of total calories and fat in patients with gallstones compared to healthy controls [24]. In addition, a prospective study (88,837 controls and 612 symptomatic gallstones patients) reported a positive correlation between energy intake and cholelithiasis [18]. Also, another Mendelian randomization study in 77,679 individuals revealed that an increased BMI caused a link with a risk of symptomatic stones [25]. The distribution of body fat also affects the risk of gallstone, with prospective cohort studies showing an association between gallstone formation and central adiposity compared to lower extremity adiposity [26]. An increase in BMI with high waist circumference and central adiposity can influence the key steps involved in the cholesterol gallstone pathogenesis, particularly an increase in biliary cholesterol concentrations [27, 28]. In addition, obese people frequently show a greater fasting gallbladder volume and a decrease in postprandial gallbladder emptying, which are factors that promote gallstones formation [29, 30].

Generally, a weight loss reduces the risk of gallstones, but an excessive weight loss (greater than 25% of body weight) or undergoing bariatric surgery increases the risk of triggering gallstones [31, 32, 33]. The administration of ursodeoxycholic acid during loss of weight could prevent the development of lithogenic changes in bile and the formation of gallstones [34, 35, 36, 37]. Treatment with ursodeoxycholic acid should be reserved for the occasional symptomatic patients with small stones presumably formed from cholesterol or proven gallbladder sludge [38]. A retrospective cross-sectional Asian study observed participants younger than 50 years to have a higher risk gallstone if they were obese and showed features of metabolic syndrome [39]. However, other studies have not found a relationship between caloric intake and cholelithiasis [40, 41]. In contrast, an Italian large cross-sectional, ultrasound-based study reported a significant negative association between energy intake and risk of gallstone disease in men [42]. These discrepancies in the results can be explained by differences in the study design and the methods used to determine energy intake and to diagnose gallstone disease.

2.2 Dietary fatty acids

The role of total dietary fat as an etiologic factor for cholelithiasis has been extensively studied but remains unresolved. The overall impact of dietary total fat on bile lipids in humans is controversial, where the degree of fat saturation itself has been examined for its influence on lithogenesis with ambiguous results. It has been suggested that the type of dietary fat habitually consumed can influence bile composition in humans. In gallbladder, this influence was noted in the presence of more concentrated bile in the olive oil group. However, this was not translated into a modification of cholesterol saturation, which is likely due to the fact that cholesterol gallstones were present by the time the dietary intervention started [43]. Some epidemiological studies did not find a significant positive correlation between total fat intake and the risk of gallstone disease [18, 41, 44], but other studies showed that patients with gallstones consume more total fat, preferably saturated fatty acids. A cross-sectional Danish study reported a positive, but nonsignificant, correlation between total fat consumption, mainly saturated fatty acids, and gallstone disease detected by ultrasound [40]. Another study also reported a positive correlation between symptomatic cholelithiasis and saturated fat intake [23]. A high intake of saturated fat has been also documented in patients from Southern Italy with incident gallstones detected by ultrasound, as compared to controls [45]. Another article showed that a high-fat diet in Balb/c mice, composed mainly of saturated fatty acids, significantly increased biliary cholesterol concentration, without modifying biliary phospholipids concentration [46]. This biliary cholesterol saturation caused an increase in cholesterol concentration in vesicular transporters. Furthermore, an increase in the cholesterol/phospholipid ratio of vesicular transporters was observed in the bile of animals treated with a high-fat diet. These cholesterol-rich vesicular transporters can aggregate and fuse, favoring the cholesterol crystals formation.

It has also been found that a diet rich in trans fatty acids could promote the formation of cholesterol gallstones [47]. Otherwise, consumption of cis-unsaturated fats was reported to have a protective effect in a prospective cohort study [48]. The effect of monounsaturated fatty acids (MUFA) is more contradictory. A study in hamsters reported that a diet rich in MUFAs may decrease the risk of gallstone formation, relative to saturated fats [49]. Other studies showed that patients with gallstone disease consumed more total lipids, mainly saturated fatty acids [24, 50]. But other case-control study found a protective effect of MUFAs on gallstone formation [45]. No significant differences in biliary lithogenicity were reported in normal persons consuming two lipid-lowering diets: one rich in polyunsaturated fatty acids (PUFAs) and the other rich in oleic acid [51].

It was found that a medical combination of ω-3 PUFAs (EPA and DHA) originating from fish oil had a preventive effect against cholesterol gallstone formation in C57BL/6 J mice [52]. Dietary fish oil supplementation decreases hypertriglyceridemia and reduces cholesterol crystal nucleation along with decreased gallstone formation in prairie dogs [53, 54]. In another study, it was found that the administration of a fish oil diet rich in n-3 PUFA to patients with gallstones decreased biliary cholesterol saturation, although without altering cholesterol crystallization time [55]. Dietary n-3 PUFA supplementation was also shown to have a beneficial effect on bile lithogenicity and bile composition in obese women during weight los [56]. These results suggest that n-3 PUFAs supplementation of obese woman on weight reduction treatment maintains the cholesterol saturation index and cholesterol nucleation time, which might prevent the formation of cholesterol gallstones. Various mechanisms may explain the inhibitory effect of fish oil on gallstone formation: reduction in biliary cholesterol saturation, decrease in cholesterol crystallization due to changes in bile phospholipid composition, and reduction in bile protein concentration [55, 57].

Other studies recommended increased nut consumption to decrease the risk of gallstone occurrence [58, 59]. A large prospective cohort study based on the Nurses’ Health Study reported that frequent nut consumption was associated with a lower risk of cholecystectomy in women [60]. Men who consumed nuts five times or more per week appeared to have an approximately 30% lower risk of gallstone disease [59]. Nuts are mostly unsaturated fats [60, 61], a rich source of dietary fiber [60], and have beneficial effects on blood cholesterol and lipoprotein profiles [58].

2.3 Dietary sterols

It is believed that a high cholesterol intake is a predisposing factor to the formation of gallstones. However, epidemiological studies have shown inconclusive results. The experimental consumption of cholesterol by men tends to increase the relative biliary cholesterol concentration and decrease the moles percent of bile acids in both normal subjects [62, 63] and persons with gallstones [62]. Feeding a cholesterol-cholic acid rich diet induces gallstone formation in mice [64]. Feeding excessive cholesterol (>0.85 mg/kcal or 2 g/day human equivalent) is essencially the only way to regularly induce gallstones in most animal model [65]. Under these conditions, bile is typically enriched with cholesterol and reduced in bile acids. A possible mechanism would be that inhibition of hepatic cholesterol synthesis impairs bile acid production in a manner similar to the coordinated inhibition of both cholesterol and bile acid synthesis by lovastatin in humans, while apoE-rich lipoproteins distribute excess absorbed cholesterol directly into the bile [66]. In contrast, other study found no significant increase in biliary cholesterol saturation after 1 month of cholesterol feeding to chickens, rabbits, and rats [67]. Exposure to low dietary cholesterol intake can lead to increased cholesterol synthesis and cholesterol flux into the bile, causing supersaturated bile and thereby increasing the likelihood of forming cholesterol gallstones [10]. These contradictory results may relate to the inclusion of populations from different ethnic groups, with different genetic predisposition and diets, rather than to the effects of cholesterol itself [68].

Plant sterols in diet have been associated with cholesterol gallstone pathogenesis. It was reported that β-sitosterol (a plant sterol present in corn oil, soy, and bran) prevents gallstone formation in mice fed with a lithogenic diet, by decreasing intestinal cholesterol absorption [69]. More recently, a study has demonstrated that plant sterols could inhibit intestinal cholesterol absorption and thus prevent cholesterol gallstone formation [70]. Plant steroids, like diosgenin and other sapogenins, induce massive secretion of cholesterol into rat bile [71]. Legumes that contain significant amounts of sapogenins increase biliary cholesterol saturation and secretion in men and simultaneously decrease serum LDL cholesterol concentration [72, 73]. It is known that the Pima Indians consume large amounts of beans and have one of the highest prevalences of gallstones in the world, a situation that is common with the Chilean Mapuche Indians [10].

2.4 Dietary carbohydrates

Several studies have evaluated the effect of carbohydrates and have revealed that consumption of refined sugars is directly associated with gallbladder disease [40, 41, 45, 74, 75, 76]. Reducing energy-dense foods, particularly those high in sugar, has shown beneficial effects on both weight and gallstone risk [77]. A prospective study found a significant association between increasing total dietary glycemic load and the subsequent risk of cholecystectomy in women, indicating that both the quality and quantity of carbohydrate intake is important in predicting risk of cholecystectomy [78]. The effect of a high carbohydrate on gallstone risk have been confirmed by a large ultrasonographic study in pregnant women [79]. Women were assessed for dietary habits, and the risk of incident biliary sludge/gallstones during pregnancy was significantly higher among women in the highest quartile of total carbohydrate intake compared with those in the lower quartiles. Another research group concludes that dietary carbohydrates may play a role in cholesterol gallstone formation by altering biliary motility and by enhancing crystal formation. They suggest that a high carbohydrate diet decreases gallbladder volume, shortens cholesterol crystal observation time, and increases crystal mass [80].

Fructose consumption has dramatically increased in past few decades, is mainly consumed through added sugars (sucrose and high fructose corn syrup), and represents up to 10% of total energy in the US and in several European countries [81, 82]. Many studies have assessed the effects of diets providing large amounts of fructose on various species. The general conclusions from these studies are that a high fructose intake almost invariably leads to increased total energy intake, body weight gain, increased plasma triglyceride concentrations, hepatic and extrahepatic insulin resistance, and diabetes mellitus [83, 84, 85]. High intake of fructose (but not sucrose, lactose or galactose) was associated with an increased risk of incident biliary sludge/gallstones, and this association was independent from total carbohydrate intake [79]. The lithogenic effect of fructose appears to depend from several concurrent mechanisms, as induction of insulin resistance, visceral adiposity, metabolic syndrome [86, 87, 88, 89, 90, 91], fatty liver secondary to triglycerides accumulation [92], and gallbladder stasis [80]. The deleterious effects of excess fructose intake can produce gastrointestinal symptoms due to intolerance and intestinal fermentation by resident intestinal microbiota [93] and can affect several liver metabolic pathways (gluconeogenesis, glycerol synthesis, and de novo lipogenesis) [27]. However, other investigations concluded that there is no clear or convincing evidence that any dietary or added sugar has a unique or detrimental impact on the development of obesity or diabetes compared to any other source of calories [94, 95]. It has been recently reported that fructose apparently does not alter the gallstone formation process in Balb/c mice. Changes in plasma, liver, and bile lipids were only observed at very high fructose concentrations diets [96]. The discrepancies in the results with dietary fructose can be explained because an inadequate consideration is often given to the dose at which these effects occur [97] and also because the metabolic effects of fructose differ between individuals based on their genetic background, suggesting heterogeneity in metabolic responses to dietary fructose in humans [98].

2.5 Dietary protein

Dietary protein as a risk modulator for gallbladder disease has been explored with mixed results. Many animal studies have shown a reduction in gallstones, reduced biliary cholesterol and lithogenic index level [99, 100, 101, 102, 103], and lower crystallization rates [104] with higher vegetable protein intake compared to animal protein-rich diets. Human feeding studies examining associations between type (vegetable vs. animal) and quantity of protein and gallbladder disease are limited. Epidemiological studies have observed that people consuming vegetarian diets have a lower incidence of gallbladder disease [105, 106, 107], but specific aspects of the vegetarian diet were not fully elucidated. The studies that probe for associated risks between protein intake and gallbladder disease are conflicting. In the prospective Nurses’ Health Study, women with increased vegetable protein consumption had reduced risk of developing symptomatic gallstones [108] and lower risk for cholecystectomy [109], but two case-control studies [45, 106] and one other prospective cohort study [42] found no association between gallbladder disease and protein intake. A more recent study has measured the associations between gallbladder disease and protein intake patterns, separated by quantity and type (vegetable vs. animal), among postmenopausal women [110]. They concluded that vegetable protein intake is inversely associated with gallbladder disease risk in postmenopausal women. In addition to weight management, healthcare providers could emphasize vegetable protein as an additional dietary modality to promote lower risk for gallbladder disease. In general, the results suggest that the intake of origin and composition of dietary proteins might be more important than total protein intake in gallstone disease risk.

2.6 Dietary fiber

Dietary fiber includes a wide array of complex substances commonly divided into soluble and insoluble components. Some observational studies have illustrated an inverse relationship between dietary fiber intake and the prevalence of gallstones [111, 112]. Another study investigating the effect of diet as a risk factor for cholesterol gallstone disease implicated that lower dietary fiber and higher refined sugar intake were associated with propensity of gallstone formation [10]. Another study shows a protective effect of dietary soluble fiber against cholesterol gallstone formation [113]. In addition, a large number of epidemiological studies have reported an inverse association between insoluble dietary fiber and gallstone disease [40, 41]. In general, by decreasing the intestinal transit time, dietary fibers may reduce the persistence of bacteria located in the colon, which leads to a decrease in the production of secondary bile acids such as deoxycholate, and subsequently, less bile acids are absorbed [114, 115]. Increasing the absorption of deoxycholate can stimulate biliary cholesterol saturation [16, 116]. Significant reverse associations were observed between odds of gallstone disease and each category of dietary fiber intake. The relationship between dietary fiber intake and the risk of gallstones was more prominent in overweight and obese subjects than in subjects with a normal body mass index [117]. It appears that the fiber effect is multifaceted and potentially extremely complex in its influence on lipoproteins, bile acids, bile lipids, and intestinal sterols, including metabolism by the large bowel flora; therefore, an independent effect of fiber on gallbladder disease needs to be carefully analyzed.

Healthy nutrition recommends eating foods rich in fiber such as fruits and vegetables (FVs). Many constituents of fruits and vegetables may reduce the risk for gallstones, but prospective data relating fruit and vegetable intake to gallstone disease are sparse. An identification of the relationship between vegetables and fruits consumption and gallstone disease may provide the opportunity to reduce occurrence of gallstone disease. Higher consumption of fruit and vegetables is recommended as part of a healthy diet, which might be protective against gallstone disease [118, 119]. However, no unequivocal correlation of FVs consumption with the risk of developing gallstones has been identified. The protective role of FVs consumption on decreasing gallstone risk has been reported in several studies, [110, 120, 121, 122, 123], whereas other studies could not confirm an association [124, 125, 126, 127]. In addition, FVs consumption has been revealed to be negatively correlated with gallstone risk in other researches [125, 128]. Moreover, a linear dose-response correlation indicated that gallstone risk was reduced by 3 and 4% for every 200 g per day increment in FVs consumption, respectively [129]. This inverse association can be explained because a higher FVs consumption increases dietary fiber, which shortens the intestinal transit [114], and dietary fiber has been inversely related to gallstone disease risk [130]. Experimental researches indicated that dietary fiber might decrease both total and LDL cholesterol by increasing bile acid excretion and decreasing hepatic synthesis of cholesterol [131]. In addition, higher FVs consumption possibly reduces fat intake [114]. A recent systematic review and meta-analysis has supported the thesis of a high consumption of FVs as a healthy diet and its recommendation for people to decrease the risk of symptomatic gallstone disease requiring cholecystectomy [129].

2.7 Vitamins and minerals intake

Clinical and experimental data in guinea pigs reported in the 1970s suggested a potential protective effect of vitamin C on the formation of gallstones [132, 133]. Furthermore, animal experiments have shown that animals deficient in vitamin C more frequently develop gallstones [134, 135]. An increased development of gallstones in subjects with vitamin C deficiency might also exist in humans [136]. While a report showed that short-term subclinical vitamin C deficiency in five healthy volunteers did not increase the lithogenic potential of gallbladder bile as it did in guinea pigs fed a high cholesterol diet, another study described changes in the bile salt composition and biliary phospholipid levels of vitamin C treated cholesterol gallstone patients and also found support for the notion that vitamin C supplementation might influence the conditions of cholesterol gallstone formation in humans [137, 138]. In humans, observational studies have also suggested an inverse association between vitamin C intake and gallstone disease [24, 121, 139, 140]. Another study evaluated the potential association of regular vitamin C supplement use on gallstone prevalence, as assessed by ultrasonography and patient’s history, in a cross-sectional survey of randomly selected subjects from the general population. They concluded that gallstone prevalence was half in subjects with regular intake of vitamin C (powder, tablets or capsules) as compared to those not taking the vitamin [141]. A group of patients with cholelithiasis and elective surgery were treated with vitamin C (2 g per day for 2 weeks) orally for 2 weeks before surgery. Vitamin C supplementation did not change significantly plasma lipids and bile lipid concentrations, but in supplemented patients, significant reductions in biliary vesicular cholesterol content and biliary vesicular cholesterol/phospholipid ratio were observed [142]. Summing up, a vitamin C deficiency appears to promote gallstone formation, whereas a vitamin C supplement prevents lithogenesis. Vitamin C modulates the hepatic and biliary pathways of cholesterol homeostasis by promoting the conversion of cholesterol into bile acids through liver 7α-hydroxylation, by prolongation of the crystallization time [138] due to qualitative changes in the bile acid composition, and by a decrease in the cholesterol content of the thermodynamically unstable vesicles in the bile [142].

There are few studies on other vitamins and minerals. Calcium intake was inversely associated with gallstone incidence [24, 41, 143], but others found no association [44, 144]. Calcium may alter the composition of bile by preventing the reabsorption of secondary bile acids in the colon, thus reducing the deoxycholate and cholesterol content of the bile [145].

Animals receiving an iron-deficient diet were more likely to have cholesterol crystals in their bile than those on the control diet, suggesting that a low-iron diet may increase the risk of forming gallstones [146]. Some studies have reported associations with vitamin E [144], folate, or magnesium deficiency [147], but they are few and inconclusive [24, 144].

2.8 Coffee consumption

Metabolic studies suggest that coffee intake may influence gallstone formation [148, 149, 150, 151, 152, 153]. Many studies indicate a potential protective effect of caffeine on gallstone formation [154, 155, 156, 157, 158, 159]. On the other hand, other studies are not so clear in showing this effect [105, 160, 161], showing contradictory results. The effect is mainly mediated by the decreased hepatic synthesis and secretion of cholesterol [151, 153] and a positive effect on gallbladder motility [148, 150] and intestinal [162]. An inverse association between coffee consumption and risk of cholecystectomy in women who were premenopausal or used hormone replacement therapy but not in other women or in men was observed [163]. This indicates that the observed association between coffee consumption and cholecystectomy depended on the presence of female sex hormones. In view of the heterogeneous findings from other studies, the true nature of this association is yet to be established.

2.9 Alcohol consumption

Notwithstanding that alcohol consumption is a known risk factor for many chronic diseases and malignancies [164, 165, 166], there have been many clinical epidemiological studies regarding the negative correlation between alcohol consumption and gallstone disease risk. There were two published meta-analyses regarding the correlation between alcohol consumption and gallstone development risk [167, 168]. One meta-analysis found no significant correlation between alcohol consumption and incidental gallstone risks [167]. Another meta-analysis showed a statistically significant, inverse relationship between the highest and lowest consumption categories (RR, 0.62; 95% CI, 0.49 to 0.78), whose pooled risk reduction was larger than that of the overall drinking data relative to nondrinking or to the lowest category in this meta-analysis [168]. Other study discovered a trend of linear decline in gallstone disease risk according to an increase in alcohol consumption and a weakened linear trend between 28 and 40 g/day compared to that of under 28 g/day in the overall and case-control studies but not in the cohort studies [169]. Later studies demonstrated an inverse relation between consumption of different alcoholic beverages (wine, beer, liquors) and the risk of cholecystectomy [170], while a protective effect of small doses of alcohol (particularly in men) was documented in the cohort from the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk) [171]. However, the topic is controversial in many respects: not all studies have confirmed the protective effect of alcohol on gallstone disease [105, 172]. Such general pathophysiological effect of alcohol on biliary function needs clinical confirmation. Alcohol inhibits the cholesteryl ester transfer protein (CETP)-mediated conversion of HDL into low-density lipoprotein (LDL)-cholesterol [173]. This step is followed by increased HDL cholesterol concentrations, which are inversely correlated with biliary cholesterol saturation [174, 175]. Small doses of alcohol also stimulate gallbladder contractility through increased cholecystokinin release [176, 177]. In general, the results of the effect of alcohol on gallstone formation are inconsistent, and it appears that the metabolic status of the host may be an important variable.

2.10 Nicotine and lithogenic diet

Some research has shown an influence of smoking on the development of gallstones [178, 179]. On the other hand, several studies suggest that smoking is not a risk factor for gallstones and even has the opposite effect [180, 181]. Compared with nonsmokers, older smokers who smoke for most of their lives have a lower risk of gallstone disease [182]. Megalin and cubilin proteins are expressed in gallbladder epithelial cells but not in hepatocytes. Dysregulation of megalin and cubilin at the mRNA and protein levels has been found in either humans or mice with gallstones [183, 184]. It was shown that bile acids can regulate the expression of megalin and cubilin, an effect that appeared to be mediated by the bile acid nuclear hormone receptor farnesoid X receptor (FXR) [185]. FXR can regulate the synthesis of bile acids in a tissue-specific manner, regulating bile acid reabsorption, maintaining bile acid cycle homeostasis, and reducing cholesterol and fat production [186]. In animals treated with a lithogenic diet, it was found that nicotine did not prevent cholesterol gallstone formation, but decreased biliary cholesterol secretion, retarding phase transition of cholesterol and that this is likely due to nicotine changing the expression of FXR/megalin pathway [187]. Despite unlikely therapeutic applications, nicotine might have potential beneficial effects for anti-lithogenic activity. However, further assessment of the direct effect of megalin and cubilin regulated by nicotine on gallstone formation is required.

3. Diet after cholecystectomy

Previous studies show that long-term abdominal symptoms are present in up to 40% of patients after laparoscopic cholecystectomy [188, 189, 190], which are summarized as “postcholecystectomy síndrome”. It is thought that the symptoms are not caused by, but are exacerbated by, the cholecystectomy. Symptoms may include upset stomach, nausea, vomiting, gas, bloating, diarrea, or persistent pain in the upper right abdomen. The absence of the gallbladder after a cholecystectomy was reported to cause rapid enterohepatic recycling, an increase in the secretion and a decrease in the reabsorption of bile acid, and a shortened colonic transit time [191, 192]. Some patients who underwent cholecystectomy experienced diarrhea, which could be associated with the malabsorption of bile acid [193]. In addition, patients may experience symptoms of gastritis secondary to duodenogastric reflux of bile acids [191]. These abdominal symptoms suggest a relationship between cholecystectomic symptoms and diet, although the details of this association remain unclear.

There is not a standard guideline for medical nutrition theraphy postcholecystectomy. Many studies have focused on the relationship between a high-fat diet and postcholecystectomic syndromes [194, 195, 196, 197]. A high-fat diet could be associated with postcholecystectomic diarrhea, due to the changes in bile acid metabolism. However, more recent research has not found a significant association between the intake of fat and the risk for postcholecystectomic syndromes [198, 199]. A low-fat diet does not seem to have an influence on the improvement of symptoms after cholecystectomy [199]. Despite this, it is recommended that fat intake should be limited for several months to allow the liver to compensate for the gallbladder’s absence, should be introduced gradually, and excessive amounts at any one meal should be avoided [200]. Eggs could be a source of animal protein and cholesterol, which were also positively associated with the risk of postcholecystectomic syndromes [198]. Intake of protein had been reported to slow gastric emptying in healthy volunteers [201], and dietary cholesterol increased fecal excretion of bile acids in rats [202]. Malabsorption of bile acids has been shown to cause postcholecystectomic diarrhea [193, 203], since the absence of a gallbladder caused more rapid enterohepatic recycling of bile acids, increased bile acid secretion [193], and shortened colonic transit times [192]. The aforementioned studies suggested that excretion and malabsorption of bile acids could be exacerbated by cholesterol intake in patients with cholecystectomies. On the other hand, an increased fiber intake will help normalize bowel movements. It is recommended to increase fiber intake slowly, over several weeks [198, 200]. It has been suggested that adding soluble fiber to the diet will act as a sequestering agent and bind the bile in the stomach between meals to avoid gastritis [204]. In addition, symptomatic patients consumed more bread-based breakfast foods, while asymptomatic patients consumed more rice [198]. Another study found that the risk of nonalcoholic fatty liver disease (NAFLD) was negatively associated with a healthy dietary pattern of consuming whole grains, legumes, vegetables, fish, and fruit and with an erythrocyte level of n-3 polyunsaturated fatty acids rich in fish [205].

Therefore, it is important for patients who have undergone cholecystectomy to maintain a healthy diet that is rich in whole grains, legumes, vegetables, fish, and fruit and low in animal protein, cholesterol, and eggs. Additionally, it is recommended to avoid refined grains, meat, processed meat, and fried foods, which were positively associated with the risk of NAFLD [205]. However, each patient’s dietary needs may vary, and it is recommended to consult with a healthcare professional or a registered dietitian for personalized dietary recommendations.

4. Conclusion

The high prevalence of cholesterol gallstones, the availability of new information about pathogenesis, and the relevant health costs due to the management of cholelithiasis in both children and adults contribute to a growing interest in this disease. Gallstone formation is multifactorial, resulting from an intricate interaction between multiple genetic, environmental, and lifestyle determinants. Cholelithiasis appears as the expression of systemic unbalances that, besides the classic therapeutic approaches to patients with clinical evidence of symptomatic disease or complications (mainly surgery), could be managed with tools oriented to primary prevention such as diet and lifestyle changes, which could imply a reduction in both prevalence and health costs. A major intervention in the general population should include lifestyle change, including dietary models able to possibly reduce the risk of gallstones mainly acting on lipid metabolism and metabolic pathways leading to gallstone formation. The risk of developing gallstones appears to increase with some dietary factors such as an increased of energy intake, low dietary fiber content, high refined sugar intake, and high fructose and fat intake and, on the other hand, to decrease with others like olive oil consumption (ω-3 fatty acids), high intake of monounsaturated fats and fiber, vegetables and fruits, vitamin C supplementation, nut consumption, dietary magnesium-calcium-iron supplementation, and moderate alcohol consumption (Figure 1) [1, 13, 15].

The complex and variable interactions of such pathogenic factors contributing to cholesterol cholelithiasis require a comprehensive discussion to correctly address the management of the disease. Studies that defined specific population with the consideration of multidimensional factors should be employed during the screening of populations with cholelithiasis. A better understanding of the role of diet in the formation of gallstones can provide resources and education to those patients who have been diagnosed with symptomatic gallstones and can also aid in the prevention and therapy of cholelithiasis.

Acknowledgments

• This work was partially supported by DINREG 12/2017 project (Direccion Investigacion, Universidad Catolica de la Santisima Concepcion).

• The graphic work of the Unit of Graphic Support (UAD) of Medicine Faculty, Universidad Catolica de la Santisima Concepcion, is appreciated.