Overview and Risk Factors
Cholelithiasis, or gallstones, is a common syndrome in which hard stones composed of cholesterol or bile pigments form in the gallbladder. If stones are present in the common bile duct, the condition is called choledocholithiasis. The syndrome occurs in up to 20% of women and 8% of men worldwide.
Most stones are composed of cholesterol. In bile, cholesterol is in equilibrium with bile salts and with phosphatidylcholine. When the concentration of cholesterol rises to the point of supersaturation, crystallization occurs. A sludge containing cholesterol, mucin, calcium salts, and bilirubin forms, and, ultimately, stones develop.
Most cases are asymptomatic. Some result in biliary colic, in which stones intermittently obstruct the neck of the gallbladder and cause episodic right-upper-quadrant pain. Chronic obstruction may result in cholecystitis (infection and inflammation of the gallbladder) or cholangitis (infection and inflammation of the common bile duct). Both syndromes are serious, and, if untreated, may result in sepsis, shock, and death.
Presenting symptoms include episodic right-upper-quadrant or epigastric pain, which generally occurs after eating a large meal and may radiate to the back, right scapula, or right shoulder. Nausea, vomiting, dyspepsia, burping, and food intolerance (especially to fatty, greasy, or fried foods; meats; and cheeses) are common. More severe symptoms, including fever and jaundice, may signify cholecystitis or cholangitis.
Increasing age. Gallstones are most common in individuals over age 40.
Female gender. Females are more likely to develop gallstones in all age groups, probably due to the effects of estrogens. This increased risk is particularly striking in young women, who are affected 3 to 4 times more often than men of the same age.
Elevated estrogen and progesterone. During pregnancy, oral contraceptive use, or hormone replacement therapy, estrogen and progesterone induce changes in the biliary system that predispose to gallstones.
Obesity. Obesity is a significant risk factor for the development of cholesterol gallstones due to enhanced cholesterol synthesis and secretion.
Rapid weight loss. Bariatric surgery and very-low-calorie diets increase risk of gallstone formation, possibly due to increased concentrations of bile constituents.
Family history. Gallstones are more than twice as common in first-degree relatives of patients with gallstones.
High-fat diet. See Nutritional Considerations.
Cirrhosis. Cirrhosis results in as much as a 10-fold increased risk of gallstones, perhaps due to impaired gallbladder contraction or the high estrogen levels that occur in cirrhotic patients.
Gallbladder stasis. When bile remains in the gallbladder for an extended period, supersaturation can occur, resulting in gallstones. Gallbladder stasis is associated with diabetes mellitus, total parenteral nutrition (probably due to lack of enteral stimulation), postvagotomy, and spinal cord injury.
Ileal disease or resection (as in Crohn's disease). Altered enterohepatic cycling of bile salts increases risk of gallstone formation.
Hemolytic states. The rapid destruction of red blood cells in sickle cell disease and other hemolytic conditions causes the release of bilirubin, which in turn increases the risk of gallstones.
Medications. Drugs implicated in the development of cholelithiasis include clofibrate, octreotide, and ceftriaxone.
Physical inactivity. The Health Professional's Follow-up Study suggests that one third of symptomatic cholelithiasis cases could be prevented by 30 minutes of daily aerobic exercise.
Diagnosis and Treatment
Right-upper-quadrant ultrasound will directly reveal the presence of gallstones and show evidence of cholecystitis, if present.
Hydroxy iminodiacetic acid (HIDA) scan is sometimes indicated to rule out cystic duct obstruction and acute cholecystitis.
Endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) assesses the presence of gallstones within the bile ducts. ERCP also extracts stones when they are found, avoiding the need for surgery.
Laboratory tests include complete blood count (CBC), liver function tests, amylase, and lipase.
Asymptomatic gallstones are generally not treated.
It is important to avoid fatty foods and other dietary triggers.
Cholecystectomy is the treatment of choice for symptomatic disease.
Lithotripsy, which breaks up stones, and oral bile acids (eg, ursodeoxycholic acid), which dissolve small stones and stone fragments, are indicated for patients who are not surgical candidates.
Gallstones are strongly related to a high-fat, low-fiber diet. They are uncommon in Asian and African populations following traditional, largely plant-based, diets, and become more common with a shift toward Westernized diets.1 A surplus of animal protein and animal fat, a lack of dietary fiber, and eating fat from saturated rather than unsaturated sources appear to be the main factors for gallstone development. The following factors are associated with reduced risk of gallstones:
Plant-based diets. Both animal fat and animal protein may contribute to the formation of gallstones. In most Western populations, an estimated 80% of gallstones are cholesterol stones,2 suggesting the value of reducing saturated fat and cholesterol in the diet.
Not surprisingly, vegetarian women have a much lower risk for gallstones, compared with nonvegetarian women.3 Vegetarian diets are high in fiber, and whatever fat they contain is largely unsaturated. Vitamin C, another nutrient found in higher amounts in vegetarian diets, affects the rate-limiting step in the catabolism of cholesterol to bile acids and is inversely related to the risk of gallstones in women.4
Women consuming the most vegetable protein had a 20% to 30% lower risk than those consuming the least.5,6 Similarly, women and men whose fat intake comes primarily from plant sources have a reduced risk of developing gallstones.7 An exception is trans fatty acids-the partially hydrogenated vegetable oils often used in snack foods-which are associated with increased gallstone risk.8
Replacement of sugars and refined starches with high-fiber carbohydrates. The cholesterol saturation index of bile, a known risk factor for gallstone formation,9 is higher with diets that provide carbohydrates in a refined, as opposed to unrefined, form.10 Individuals consuming the most refined carbohydrates had a 60% greater risk for developing gallstones, compared with those who consumed the least.11 Conversely, individuals eating the most fiber (particularly insoluble fiber) have a 15% lower risk for gallstones compared with those eating the least.12,13
Avoidance of overweight and a healthful approach to weight control. Overweight women with a BMI of 30 kg/m2 or more have at least double the risk for gallstone disease, compared with women of normal weight (BMI < than 25 kg/m2). The same degree of risk exists for men with a BMI of at least 25 kg/m2, compared with males with a BMI of <22.5 kg/m2. With more severe obesity (ie, BMI 30 to 45 kg/m2), the risk for women is 3.7 to 7.4 times that of women with a BMI of less than 24 kg/m2.14
Weight cycling (repeatedly losing and regaining weight) increases the likelihood of cholelithiasis. The risk increased from 20% in "light" cyclers (those who lost/regained 5 to 9 lbs) to 70% in "severe" cyclers (those who lost/regained >20 lbs).15
Very-low-calorie diets increase the risk of gallstones. Gallbladder stasis and bile cholesterol saturation index occur during rapid weight loss, accounting for a greater risk of gallstone development. Including a small amount of fat (10 g/day) provides maximal gallbladder emptying and prevents gallstone formation in calorie-restricted dieters.16 Such observations support weight control efforts based on low-fat, plant-based diets, which typically cause healthful and sustained weight control, rather than the use of very-low-calorie formula diets.
Moderate alcohol intake. Compared with infrequent consumption or abstinence, moderate alcohol intake was found to be either inversely associated with the risk for gallstones,17 or to confer a 10% to 50% lower risk for the disease.18 However, given the current epidemic of nonalcoholic fatty liver disease in 50% to 75% of obese persons19 and other health risks (eg, breast cancer) due to alcohol consumption, alcohol use cannot be recommended as a gallstone prevention strategy.
Physical activity. Some evidence suggests that physical activity reduces gallstone risk. Young or middle-aged men (65 years or younger) who were the most physically active had half the risk for developing gallstones, compared with those who were least active. In older men, physical activity cut risk by 25%.20 Physical activity also protects against gallstones in women.21
What to Tell the Family
Gallstones can largely be avoided by following a high-fiber diet, particularly a vegetarian diet. Patients should avoid foods high in saturated fat (eg, animal products) and trans-unsaturated fat (eg, processed foods). Foods high in polyunsaturated fat (eg, nuts and other vegetable sources) may reduce risk.
1. Burkitt DP. The protective properties of dietary fiber. N C Med J. 1981;42:467-471.
2. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease: observations in the Framingham Study. J Chronic Dis. 1966;19:273-292.
3. Pixley F, Wilson D, McPherson K, Mann J. Effect of vegetarianism on development of gallstones in women. BMJ. 1985;291:11-12.
4. Simon JA, Hudes ES. Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III). Arch Intern Med. 2000;160:931-936.
7. Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. The effect of long-term intake of cis unsaturated fats on the risk for gallstone disease in men: a prospective cohort study. Ann Intern Med. 2004;141:514-522.
9. Erlinger S. Gallstones in obesity and weight loss. Eur J Gastroenterol Hepatol. 2000;12:1347-1352.
14. Everhart JE. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med. 1993;119:1029-1035.
18. de Lorimier AA. Alcohol, wine, and health. Am J Surg. 2000;180:357-361.
19. Patrick L. Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Altern Med Rev. 2002;7:276-291.
21. Leitzmann MF, Rimm EB, Willett WC, et al. Recreational Physical Activity and the Risk of Cholecystectomy in Women. N Engl J Med. 1999;341:777-784.