More than 25 million Americans have gallstones, and a million are diagnosed each year. However, only 1 to 3% of the population complains of symptoms during the course of a year, and fewer than half of these people have symptoms that return.
Risk Factors in Women
Women are much more likely than men to develop gallstones. Gallstones occur in nearly 25% of women in the U.S. by age 60, and as many as 50% by age 75. In most cases, they have no symptoms. In general, women are probably at increased risk because estrogen stimulates the liver to remove more cholesterol from blood and divert it into the bile.
Pregnancy. Pregnancy increases the risk for gallstones, and pregnant women with stones are more likely to develop symptoms than women who are not pregnant. Surgery should be delayed until after delivery if possible. In fact, gallstones may disappear after delivery. If surgery is necessary, laparoscopy is the safest approach.
Hormone Replacement Therapy. Several large studies have shown that the use of hormone replacement therapy (HRT) doubles or triples the risk for gallstones, hospitalization for gallbladder disease, or gallbladder surgery. Estrogen raises triglycerides, a fatty substance that increases the risk for cholesterol stones. How the hormones are delivered may make a difference, however. Women who use a patch or gel form of HRT face less risk than those who take a pill. HRT may also be a less-than-attractive option for women because studies have shown it has negative effects on the heart and increases the risk for breast cancer.
Risk Factors in Men
About 20% of men have gallstones by the time they reach age 75. Because most cases do not have symptoms, however, the rates may be underestimated in elderly men. One study of nursing home residents reported that 66% of the women and 51% of the men had gallstones. Men who have their gallbladder removed are more likely to have severe disease and surgical complications than women.
Risks in Children
Gallstone disease is relatively rare in children. When gallstones do occur in this age group, they are more likely to be pigment stones. Girls do not seem to be more at risk than boys. The following conditions may put children at higher risk:
- Spinal injury
- History of abdominal surgery
- Sickle-cell anemia
- Impaired immune system
- Receiving nutrition through a vein (intravenous)
Because gallstones are related to diet, particularly fat intake, the incidence of gallstones varies widely among nations and regions. For example, Hispanics and Northern Europeans have a higher risk for gallstones than do people of Asian and African descent. People of Asian descent who develop gallstones are most likely to have the brown pigment type.
Native North and South Americans, such as Pima Indians in the U.S. and native populations in Chile and Peru, are especially prone to developing gallstones. Pima women have an 80% chance of developing gallstones during their lives, and virtually all native Indian females in Chile and Peru develop gallstones. Such cases are most likely due to a combination of genetic and dietary factors.
Having a family member or close relative with gallstones may increase the risk. Up to 33% of cases of painful gallstones may be related to genetic factors.
A mutation in the gene ABCG8 significantly increases a person's risk of gallstones. This gene controls a cholesterol pump that transports cholesterol from the liver to the bile duct. It appears this mutation may cause the pump to continuously work at a high rate. A single gene, however, does not explain the majority of cases, so multiple genes and environmental factors play a complex role.
Defects in transport proteins involved in biliary lipid secretion appear to predispose certain people to gallstone disease, but this alone many not be sufficient to create gallstones. Studies indicate that the disease is complex and may result from the interaction between genetics and environment. Some studies suggest immune and inflammatory mediators may play key roles.
People with diabetes are at higher risk for gallstones and have a higher-than-average risk for acalculous gallbladder disease (without stones). Gallbladder disease may progress more rapidly in patients with diabetes, who tend to have worse infections.
Obesity and Weight Changes
Obesity. Being overweight is a significant risk factor for gallstones. In such cases, the liver over-produces cholesterol, which is delivered into the bile and causes it to become supersaturated.
Weight Cycling. Rapid weight loss or cycling (dieting and then putting weight back on) further increases cholesterol production in the liver, which results in supersaturation and an increased risk for gallstones.
- The risk for gallstones is as high as 12% after 8 to 16 weeks of restricted-calorie diets.
- The risk is more than 33% within 12 to 18 months after gastric bypass surgery.
About 30% of gallstone cases in these situations have symptoms. The risk for gallstones is highest in the following dieters:
- Those who lose more than 24% of their body weight
- Those who lose more than 1.5 kg (3.3 lb.) a week
- Those on very low-fat, low-calorie diets
Men are also at increased risk for developing gallstones when their weight fluctuates. The risk increases proportionately with dramatic weight changes as well as with frequent weight cycling.
Bariatric Surgery. Patients who have either Roux-en-Y or laparoscopic banding bariatric surgery are at increased risk for gallstones. For this reason, many centers request that patients undergo cholecystectomy before their bariatric procedure. However, doctors are now questioning this practice.
Metabolic syndrome is a cluster of conditions that includes obesity (especially belly fat), low HDL (good) cholesterol, high triglycerides, high blood pressure, and high blood sugar. Research suggests that metabolic syndrome is a risk factor for gallstones.
Low HDL Cholesterol, High Triglycerides and Their Treatment
Although gallstones are formed from the supersaturation of cholesterol in the bile, high total cholesterol levels themselves are not necessarily associated with gallstones. Gallstone formation is associated with low levels of "good" HDL cholesterol and high triglyceride levels. Some evidence suggests that high levels of triglycerides may impair the emptying actions of the gallbladder.
Unfortunately, fibrates (drugs that may be used to correct these abnormalities) increase the risk for gallstones by boosting the amount of cholesterol secreted into the bile. These medications include gemfibrozil (Lopid) and fenofibrate (Tricor). Other cholesterol-lowering drugs do not have this problem.
Other Risk Factors
Prolonged Intravenous Feeding. Prolonged intravenous feeding reduces the flow of bile and increases the risk for gallstones. Up to 40% of patients on home intravenous nutrition develop gallstones, and the risk may be higher in patients on total intravenous nutrition. It is suspected that the cause is lack of stimulation in the gut, because patients who also take some food by mouth have less risk of developing gallstones. However, treatment for gallstones in this population is associated with a low risk of complications.
Crohn's Disease. Crohn's disease, an inflammatory bowel disorder, leads to poor reabsorption of bile salts from the digestive tract and substantially increases the risk of gallbladder disease. Patients over age 60 and those who have had numerous bowel operations (particularly in the region where the small and large bowel meet) are at especially high risk.
Cirrhosis. Cirrhosis poses a major risk for gallstones, particularly pigment gallstones.
Organ Transplantation. Bone marrow or solid organ transplantation increases the risk of gallstones. The complications can be so severe that some organ transplant centers require the patient's gallbladder be removed before the transplant is performed.
Medications. Octreotide (Sandostatin) poses a risk for gallstones. In addition, cholesterol-lowering drugs known as fibrates and thiazide diuretics may slightly increase the risk for gallstones.
Blood Disorders. Chronic hemolytic anemia, including sickle cell anemia, increases the risk for pigment gallstones.
Heme. High consumption of heme iron, the type of iron found in meat and seafood, has been shown to lead to gallstone formation in men. Gallstones are not associated with diets high in non-heme iron foods such as beans, lentils, and enriched grains.