There is little doubt that what we eat (or don’t eat) and drink can play a significant role promoting or inhibiting gallstone formation. There are various types of gallstones, with some composed largely of the calcium salts of bile pigments and some triggered by parasitic infections. In the USA most (80% +) of the gallstones are composed largely of crystalized cholesterol. Over the last several decades, there has been a marked increase in cholesterol-rich gallstones and a steady decline in bile pigment gallstones in East Asian populations as their diets Westernized and they instituted better public health measures to reduce the prevalence of parasitic infections linked to calcium-rich gallstones. Gallstone formation is a multifactorial disease, but there is little doubt that some aspects of a modern Western diet coupled with inactivity and weight gain promote the development cholesterol-rich gallstones. The focus of this article will be on how a modern Western diet and other factors appear to contribute to the formation (or inhibition) of these increasingly common cholesterol-rich gallstones.While gallstones are a common cause of upper abdominal pain, especially after fat-rich meals, these stones often cause few or no symptoms. Even though most people with gallstones are unaware they have them, symptomatic gallstones still result in close to a million Americans being hospitalized each year, with most of them having their gallbladders surgically removed. Up to 80% of people with gallstones have few or no symptoms and so are never diagnosed. Up to 20% of American women and nearly 10% of men have gallstones, although most will never know it. Gallstones can inflame the gallbladder and are believed to be a major cause of about 5000 cases of gallbladder cancer in the USA each year. The other potentially serious complication of gallstones occurs when the stones block one of the ducts through which bile flows. Blockage of the common duct through which bile and pancreatic enzymes flow into the intestines can cause serious damage to the pancreas and liver if not removed surgically. Cholecystectomy (surgical removal of gallbladder) is now the most common elective abdominal surgery performed in the USA with more than 750,000 operations being performed annually. However, even people without a gallbladder can still form cholesterol-rich gallstones in the remaining bile and/or common duct system because cholecystectomy does little to reduce the lithogenic (or stone-forming) potential of the bile.Mechanism of Gallstone FormationCholesterol, being a lipid material, dissolves poorly in water. To keep cholesterol from precipitating and forming, the bile must contain sufficient emulsifying agents. Bile acids (e.g. cholic acid & chenodeoxycholic acid) and phospholipids (e.g., lecithin) emulsify cholesterol in the bile, preventing it from forming gallstones. The liver cells that make bile determine the amount of cholesterol, bile acids (made from cholesterol), and phospholipids in the bile. An increase in bile cholesterol concentration and/or a reduction in bile acids and/or lecithin results in cholesterol-forming crystals that make a sludge. Eventually these crystals can grow large enough to form gallstones. So anything that increases the cholesterol content and/or reduces the concentration of bile acids or phospholipids in the bile will increase the risk of the bile’s cholesterol precipitating and forming gallstones. For example, estrogen causes more liver cholesterol to be dumped into the bile and less into the blood as VLDL particles. These VLDL particles are rich in fat (a.k.a. triglyceride) but also contain cholesterol. As the VLDL particles fat is removed by adipocytes, muscle cells, and other cells and these VLDLs lose some of their proteins (e.g. apoE) and become smaller and cholesterol-rich LDL particles. As a result, women, (especially during child-bearing years) with their much higher estrogen levels, tend to dump less excess cholesterol into their blood (as VLDLs) and more cholesterol into their bile than do men. As a result, women generally have a 2- to 3-fold higher risk of cholesterol-rich gallstones forming, but also significantly lower serum LDL-C levels and a much lower risk of coronary artery disease (CAD) than do men the same age. After menopause, the marked drop in estrogen levels in results in a big rise in serum LDL-C in women while their risk of gallstones developing becomes similar to that of men the same age. Women who take estrogen after menopause are more likely to develop gallstones than those that do not take estrogen.Doctors have used exogenous bile acids such as chenodeoxycholic and ursodeoxycholic acids (which are absorbed and end up in the liver) to increase the ratio of bile acid to cholesterol in the bile. Over time these exogenous bile acids have been shown to help dissolve cholesterol-rich gallstones. However, should the patients stop taking them, the bile will likely revert to its lithogenic (stone-forming) state and gallstones may again start to form. Even so, the use of ursodeoxycholic acid as a treatment for some patients at high surgical risk seems to be appropriate.Anything that increases liver cholesterol content is likely to increase the cholesterol content of bile and so may also increase serum nonHDL-C levels. The absorption of dietary cholesterol leads to increased liver cholesterol and so can contribute to gallstone formation. Diets high in saturated fat are known to stimulate liver cholesterol synthesis and result in higher levels of cholesterol in both the blood and in the bile. Higher intake of animal products rich in saturated fat and cholesterol promote both dyslipidemia and atherosclerosis but also increase cholesterol in the bile and so promote more gallstone formation. By contrast, statin drugs, which block HMG CoA reductase thereby reducing cholesterol synthesis in the liver, can significantly reduce the risk of developing both gallstones and CAD.Weight Gain and Insulin Resistance Promote GallstonesObesity is known to be a major risk factor for developing gallstones. In part this is due to weight gain leading to insulin resistance and much higher insulin levels. Higher insulin levels increase cholesterol synthesis in liver cells. This increased liver cholesterol production can lead to higher levels of VLDL production (increasing serum cholesterol and triglyceride levels), and atherosclerosis, and increase cholesterol dumped into the bile, thus increasing the risk of cholesterol-rich gallstones forming. Weight gain, especially when it leads to insulin resistance, is known to increase fat accumulation in the liver. Fatty liver disease leads to a reduction in bile acid synthesis, thus reducing the bile acid content of the bile. Fewer bile acids in the bile means more gallstone formation. The reduction in bile acids seen with fatty liver disease also leads to a reduction of micelle formation in the intestine and this reduces the absorption of fat and cholesterol. This reduction in cholesterol absorption in the gut may be one reason people with insulin resistance and type 2 DM are less likely to see their serum cholesterol rise in response to increased dietary cholesterol intake than people without insulin resistance. This may explain why the LDL-C levels of Americans today seem less responsive to dietary cholesterol than back in the 1960s when ¾ of American adults were at a normal weight and far fewer had fatty livers and type 2 DM. It may also explain why studies (often funded by the Egg Nutrition Council) seem to focus on the impact of dietary cholesterol on LDL-C levels in subjects who have the metabolic syndrome and/or type 2 DM. In insulin resistant people, dietary cholesterol will be more poorly absorbed due to the reduced bile acids and micelle formation in the gut and greater cholesterol content of the bile. This leads to increased fat and cholesterol being lost in the stool (steatorrhea) rather than ending up in the blood and liver. In people with insulin resistance and type 2 DM, elevated serum cholesterol (and triglyceride) levels are more the result of increased endogenous fat and cholesterol synthesis caused by increased insulin levels and much less impacted by their now more poorly-absorbed dietary cholesterol intake. Of course, should they lose much of their excessive body fat and reverse their fatty liver disease, these formerly insulin-resistant people will now have higher bile acid levels and reduced liver cholesterol synthesis. This would also improve cholesterol absorption from the gut and make their blood lipids more dietary cholesterol responsive and their bile much less likely to form cholesterol-rich stones.Another reason the incidence of cholesterol-rich gallstones has been increasing has been the increased use of bariatric procedures to aid weight loss. Most bariatric procedures lead to rapid weight loss but a significant increased risk of symptomatic gallstone formation. Bariatric surgery so often leads to gallstone formation that some bariatric surgeons have even started recommending “prophylactic” cholecystectomy.A high intake of sugar, especially in beverages, tends to promote weight gain and insulin resistance. Dietary fructose from sugar (and high fructose corn syrup) ends up primarily in the liver and in large amounts this fructose promotes fat and cholesterol synthesis in the liver resulting in higher levels of nonHDL-C in the blood and more cholesterol in the bile. An increase in liver fat may also reduce bile acid production, making gallstone formation even more likely.While weight loss can reverse insulin resistance (which promotes lithogenic bile production), it is also known that rapid weight loss often leads to gallstone formation perhaps due in part to the fact that the increased free fatty acids released from human fat cells will increase saturated fat content in the liver. This may be why fasting for a week or so tends to increase cholesterol in the liver, leading to higher serum LDL-C levels and a markedly increased tendency for cholesterol-rich gallstones to form. Fasting, very low-calorie diets (e.g. Optifast & Medifast) frequently cause gallstones to develop. Part of the reason this happens may be that, with little food intake there is little cholecystokinin (CCK) released by the intestinal mucosa to stimulate gallbladder contractions. This would also explain why long-term total parental nutrition carries such a high risk of gallstone formation.On the other hand, coffee intake stimulates a large release of CCK and this may help explain why regular coffee intake reduces the risk of developing gallstones. Of course, in people who have symptomatic gallstones, it appears that anything that increases CCK release and gallbladder contraction such as a fat-rich meal or even a black cup of coffee can cause painful gallbladder contractions.Unlike saturated fat and cholesterol-rich foods that promote gallstone formation, foods with more fiber and/or unsaturated fats such as nuts, seeds, whole grains, fruits, and vegetables are associated with a reduced risk of gallstone formation. The one possible exception to the “high-fiber foods reduce gallstones” theory may be beans. Studies of some Native Americans (e.g. Pima Indians and Native Chilean Indians) have found that a high intake of beans is associated with an increased risk of gallstones. It is thought that the high saponin content of beans may be a factor as these phytochemicals cause the liver cells to excrete more cholesterol into the bile and less into the blood. It may be that while legumes are good for lowering serum cholesterol levels and reducing atherosclerosis, in large amounts they may promote (because of their saponins) increased cholesterol excretion into the bile, thus heightening the risk of gallstones.Saudi Arabia’s Cholecystectomy EpidemicThe rapid adoption of a much more Western-style diet in Saudi Arabia’s Eastern Province was accompanied by an over 10-fold increase in cholecystectomy operations performed at Riyadh Central Hospital between 1977 and 1988. In that 11-year period, dietary fat, cholesterol, sugar, and calorie intake all increased markedly, while the intake of whole grains and fiber declined by 75%. Back in the 1950s and 1960s, it was not unusual at Saudi Arabia’s top hospital to not have even a single gallbladder removal in an entire year. In all 14 hospitals in Saudi Arabia in 1977 there were only 67 cholecystectomies performed. By 1986, these same 14 hospitals performed 679 cholecystectomies.  During this time frame the consumption of sugar-sweetened drinks increased nearly 7-fold. Saudi women saw a 15.5-fold increase in cholecystectomy procures.Bottom Line: A diet composed largely of whole grains, fruits, and vegetables and very limited in saturated fat, cholesterol, and sugar (especially in drinks) seems optimal for reducing the risk of gallstone formation. Another key to avoiding gallstones is to maintain a healthy body weight throughout life. If overweight, losing weight slowly on a healthful, minimally-processed, plant-rich diet should help reduce the risk of gallstones forming. By contrast, rapid weight loss on a formula of diet shakes, very low-calorie diet, and/or with bariatric surgery puts people at very high risk of forming gallstones.By James J. Kenney, PhD, FACNReferences:

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