Cholelithiasis, or gallstones, is a common condition 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. In the US about 9% of women and 6% of men have gallstone s; most are asymptomatic.
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.
Although gallstones are typically asymptomatic, some cause biliary colic, in which stones intermittently obstruct the neck of the gallbladder and/or the common bile duct 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 often occurs in the middle of the night after eating a large meal and may radiate to the back, right scapula, or right shoulder. Diaphoresis, 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.
Family history. Gallstones are more than twice as common in first-degree relatives of patients with gallstones.
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 most notable in young women, who are affected 3-4 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 elevated production and secretion of cholesterol.
Rapid weight loss. Bariatric surgery and very-low-calorie diets increase risk of gallstone formation, possibly due to gallbladder stasis and increased concentrations of bile constituents.
Diabetes mellitus. High triglycerides, gallbladder stasis, and hepatic insulin resistance may contribute to an increased risk for development of gallstones.
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, rapid weight loss, celiac sprue, and spinal cord injury.
Cirrhosis. Cirrhosis results in as much as a 10-fold increased risk of gallstones.
Ileal disease or resection (as in Crohn’s disease). Changes in 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 pigment gallstones.
Medications. Drugs implicated in the development of cholelithiasis include clofibrate, octreotide, and ceftriaxone.
Physical inactivity. The Health Professionals Follow-up Study suggested that many cases of symptomatic cholelithiasis could be prevented by 30 minutes of daily aerobic exercise. 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%. Physical activity also protects against gallstones in women.
Right-upper-quadrant (trans-abdominal) 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 can also be used to extract 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. Cholecystectomy is the treatment of choice for symptomatic disease.
Oral bile acids (e.g., ursodeoxycholic acid) can be used to dissolve small stones and stone fragments. However, they work in only a small percentage of cases and stones typically recur after the treatment is discontinued.
It is helpful to avoid large, fatty meals, as a large caloric load is the most likely trigger for biliary colic symptoms.
Gallstones are strongly related to a high-fat, low-fiber diet. They are uncommon in Asian and African populations that follow traditional, largely plant-based diets, and they become more common with a shift toward Westernized diets. A surplus of animal protein and animal fat, a lack of dietary fiber, and the consumption of fat from saturated rather than unsaturated sources appear to be the main nutritional risk 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. Up to 90% of gallstones are cholesterol stones (≥ 20% cholesterol composition), suggesting the possibility that dietary changes (e.g., reducing dietary saturated fat and cholesterol and increasing soluble fiber) may reduce the risk of gallstone formation.
Vegetarian women have a lower risk for gallstones, compared with nonvegetarian women. This may relate to the fact that vegetarian diets are often high in fiber and provide fat mainly in unsaturated form. However, vegetarian women may also be more health-conscious in general, compared with omnivores, and may be more physically active (see Treatment section). Fruit and vegetable intake may account for part of this protection; consuming roughly 7 servings of fruits and vegetables per day was associated with a 20% lower risk for cholecystectomy, compared with women who ate less than 3.5 servings per day. Vitamin C, another nutrient found in higher amounts in vegetarian diets than in nonvegetarian 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.
Women consuming the most vegetable protein had a 20%-30% lower risk than those consuming the least. , Similarly, women and men whose fat intake comes primarily from plant sources have a reduced risk of developing gallstones. An exception is trans fatty acids—the partially hydrogenated vegetable oils often used in snack foods—which are associated with increased gallstone risk.
Within the general population, high LDL cholesterol levels are associated with gallstone formation, emphasizing the importance of a diet (i.e., high-fiber, low-fat) that keeps blood lipids in a healthy range.
Replacement of sugars and refined starches with high-fiber carbohydrates. The cholesterol saturation index of bile, a known risk factor for gallstone formation, is higher with diets that provide carbohydrates in a refined, as opposed to unrefined, form. Individuals consuming the most refined carbohydrates had a 60% greater risk for developing gallstones, compared with those who consumed the least. Conversely, individuals eating the most fiber (particularly insoluble fiber) have a 15% lower risk for gallstones compared with those eating the least. , However, no intervention trial has tested whether a diet that is low in sugar and high in unrefined starches reduces gallstone risk.
Avoidance of overweight and a healthful approach to weight control. Obese women with a BMI of 30 kg/m 2 or more have at least double the risk for gallstone disease, compared with women of normal weight (BMI < 25 kg/m 2). The same degree of risk exists for men with a BMI of at least 25 kg/m 2, compared with males with a BMI of < 22.5 kg/m 2. With more severe obesity (i.e., BMI 30 to 45 kg/m 2), the risk for women is 3.7-7.4 times that of women with a BMI of less than 24 kg/m 2.
Weight cycling (repeatedly losing and regaining weight) increases the likelihood of cholelithiasis. In women, the risk increased from 20% in “light” cyclers (those who lost and regained 5lbs-9 lbs) to 70% in “severe” cyclers (those who lost and regained ≥ 20 lbs). A similar pattern has been shown in men.
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. Such observations support weight control efforts based on low-fat, plant-based diets, which typically cause healthful and sustained weight control, rather than those based on very-low-calorie formula diets.
Moderate alcohol intake. Compared with infrequent consumption or abstinence, moderate alcohol intake was found to be inversely associated with the risk for gallstones. , However, given the current epidemic of nonalcoholic fatty liver disease in 50%-75% of obese persons and other health risks (e.g., breast cancer) due to alcohol consumption, caution regarding alcohol use is warranted.
What to Tell the Family
Several studies suggest that the risk of gallstones is lower among individuals following high-fiber diets, particularly vegetarian diets, and that patients are well advised to avoid foods high in saturated fat (e.g., animal products) and trans fat (e.g., processed foods). Family members can help the patient by serving high-fiber, vegetarian meals at home and encouraging similar eating habits at restaurants. Diet changes are easiest when the whole family changes together.
- Biddinger SB, Haas JT, Yu BB, et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med. 2008;14(7):778-82. [PMID:18587407]
- Leitzmann MF, Giovannucci EL, Rimm EB, et al. The relation of physical activity to risk for symptomatic gallstone disease in men. Ann Intern Med. 1998;128(6):417-25. [PMID:9499324]
- Leitzmann MF, Rimm EB, Willett WC, et al. Recreational physical activity and the risk of cholecystectomy in women. N Engl J Med. 1999;341(11):777-84. [PMID:10477775]
- Erichsen R, Frøslev T, Lash TL, et al. Long-term statin use and the risk of gallstone disease: A population-based case-control study. Am J Epidemiol. 2011;173(2):162-70. [PMID:21084557]
- Bodmer M, Brauchli YB, Krähenbühl S, et al. Statin use and risk of gallstone disease followed by cholecystectomy. JAMA. 2009;302(18):2001-7. [PMID:19903921]
- Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver. 2012;6(2):172-87. [PMID:22570746]
- Ahmed A, Cheung RC, Keeffe EB. Management of gallstones and their complications. Am Fam Physician. 2000;61(6):1673-80, 1687-8. [PMID:10750875]
- Pixley F, Wilson D, McPherson K, Mann J. Effect of vegetarianism on development of gall stones in women. Br Med J (Clin Res Ed) . 1985;291:11-12.
- Tsai CJ, Leitzmann MF, Willett WC, et al. Fruit and vegetable consumption and risk of cholecystectomy in women. Am J Med. 2006;119(9):760-7. [PMID:16945611]
- 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(7):931-6. [PMID:10761957]
- Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Dietary protein and the risk of cholecystectomy in a cohort of US women: the Nurses' Health Study. Am J Epidemiol . 2004;60:11-18.
- Maclure KM, Hayes KC, Colditz GA, et al. Dietary predictors of symptom-associated gallstones in middle-aged women. Am J Clin Nutr. 1990;52(5):916-22. [PMID:2239768]
- Tsai CJ, Leitzmann MF, Willett WC, et al. 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(7):514-22. [PMID:15466768]
- Tsai CJ, Leitzmann MF, Willett WC, et al. Long-term intake of trans-fatty acids and risk of gallstone disease in men. Arch Intern Med. 2005;165(9):1011-5. [PMID:15883239]
- Halldestam I, Kullman E, Borch K. Incidence of and potential risk factors for gallstone disease in a general population sample. Br J Surg. 2009;96(11):1315-22. [PMID:19847878]
- Erlinger S. Gallstones in obesity and weight loss. Eur J Gastroenterol Hepatol. 2000;12(12):1347-52. [PMID:11192327]
- Thornton JR, Emmett PM, Heaton KW. Diet and gall stones: effects of refined and unrefined carbohydrate diets on bile cholesterol saturation and bile acid metabolism. Gut. 1983;24(1):2-6. [PMID:6293939]
- Tsai CJ, Leitzmann MF, Willett WC, et al. Dietary carbohydrates and glycaemic load and the incidence of symptomatic gall stone disease in men. Gut. 2005;54(6):823-8. [PMID:15888792]
- Tsai CJ, Leitzmann MF, Willett WC, et al. Long-term intake of dietary fiber and decreased risk of cholecystectomy in women. Am J Gastroenterol. 2004;99(7):1364-70. [PMID:15233680]
- Attili AF, Scafato E, Marchioli R, et al. Diet and gallstones in Italy: the cross-sectional MICOL results. Hepatology. 1998;27(6):1492-8. [PMID:9620318]
- Everhart JE. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med. 1993;119(10):1029-35. [PMID:8214980]
- Syngal S, Coakley EH, Willett WC, et al. Long-term weight patterns and risk for cholecystectomy in women. Ann Intern Med. 1999;130(6):471-7. [PMID:10075614]
- Tsai CJ, Leitzmann MF, Willett WC, et al. Weight cycling and risk of gallstone disease in men. Arch Intern Med. 2006;166(21):2369-74. [PMID:17130391]
- Gebhard RL, Prigge WF, Ansel HJ, et al. The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss. Hepatology. 1996;24(3):544-8. [PMID:8781321]
- Leitzmann MF, Giovannucci EL, Stampfer MJ, et al. Prospective study of alcohol consumption patterns in relation to symptomatic gallstone disease in men. Alcohol Clin Exp Res. 1999;23(5):835-41. [PMID:10371403]
- de Lorimier AA. Alcohol, wine, and health. Am J Surg. 2000;180(5):357-61. [PMID:11137687]
- 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(4):276-91. [PMID:12197781]