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Gallstones are present in about 80% of people with gallbladder cancer. This cancer is very rare, however, even among people with gallstones. Certain conditions in the gallbladder pose a higher than average risk for cancer:

Porcelain Gallbladders. People with gallstones and so-called porcelain gallbladders have a very high risk for cancer. (In this condition, the gallbladder walls have become so calcified that they look like porcelain on an x-ray.) Whether gallstones themselves cause the cancer or whether some factor in bile is responsible for both conditions is unknown. One study demonstrated that gallbladder removal reduced the likelihood of bile duct cancer, suggesting that gallstones themselves were responsible.

Gallbladder Polyps and Primary Scerlosing Cholangitis. Polyps (growths) are sometimes detected during diagnostic tests for gallbladder disease. Small gallbladder polyps (up to 10 mm) pose little or no risk, but large ones (greater than 15 mm) pose some risk for cancer, so the gallbladder should be removed. Patients with polyps 10 mm to 15 mm have a lower risk but they should still discuss removal of their gallbladder with their physician. Of special note is a condition called primary sclerosing cholangitis, which causes inflammation and scarring in the bile duct. It is associated with a lifetime risk of 7% to 12% for gallbladder cancer. The cause is unknown, although primary sclerosing cholangitis tends to strike younger men who have ulcerative colitis. Polyps are often detected in this condition and have a very high likelihood of malignancy.

Symptoms of gallbladder cancer are usually not present until the disease has reached an advanced stage and may include weight loss, anemia, recurrent vomiting, and a lump in the abdomen. When the cancer is caught at an early stage and has not spread deeper than the mucosa (the inner lining), removal of the gallbladder results in five-year survival rates of 68%. If cancer has spread to deeper layers, more extensive surgery or other treatments may be required.

WHO GETS GALLSTONES AND GALLBLADDER DISEASE?
About 20 million Americans harbor gallstones. Only 1% to 3% of the population, however, complains of symptoms during the course of a year, and less than have of these people will experience recurrent symptoms.

Risk Factors in Women

Women are much more likely than men to develop gallstones. They occur in nearly 25% of women in the US by age 60 and up to 50% by age 75. (Again, in most cases they are asymptomatic.) 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, although they may disappear after delivery. Pregnant women with stones are more likely to have symptoms than nonpregnant women.

Hormone Replacement Therapy. Several large studies have shown that use of hormone replacement therapy results in a twofold to threefold increased risk for gallstones or gallbladder surgery. Estrogen has an effect on the liver itself and raises triglycerides, a fatty acid that increases the risk for cholesterol stones. Recent studies on HRT reporting negative effects on the heart and increased risks for breast cancer are also making this treatment a less attractive option for most postmenopausal women. [ See , Menopause, Estrogen Loss, and Their Treatments.] )

Risk Factors in Men

About 20% of men have gallstones by the time they reach 75 years of age. Because most cases are asymptomatic, however, the rates may be underestimated in older men. One study of nursing home residents reported that 66% of the women and 51% of the men had gallstones. Men who have their gallbladders removed, moreover, are more likely to have severe disease and operative complications than women.

Risks in Children

Gallstone disease is relatively rare in children. When gallstones occur in this age group they are more likely to be pigment stones. Girls do not seem to be at a higher risk than boys. The following conditions may put children at higher risk:

• Spinal injury.

• History of abdominal surgery.

• Sickle-cell anemia.

• Impaired immune system.

• Intravenous nutrition.

Ethnicity

Because gallstones is 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 people of Asian and African descent do. (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 US 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 American women in Chile and Peru develop gallstones during their lifetimes. Such cases are most likely due to a combination of genetic and dietary factors.

Genetics

Having a family member or close relative with gallstones may increase the risk of gallstones. Up to a third of cases of painful gallstones may be related to genetic factors, although the genetics of gallbladder disease remains poorly understood. Many genes may be involved, including those that lead to obesity or other risk factors that predispose to gallstones.

Diabetes

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 develop worse infections in general.

Obesity and Weight Changes

Obesity. Being overweight is a significant risk factor for gallstones. In such cases, the liver overproduces cholesterol and delivers it into the bile, which then becomes supersaturated. Some evidence suggests that specific dietary factors (saturated fats and refined sugars) are the primary culprit in these cases, although studies are conflicting. Animal studies, however, suggest that obesity itself, not any particular foods, triggers the process leading to cholesterol supersaturation and the formation of stones.

Weight Cycling. Rapid weight loss or weight cycling (dieting and then putting back weight) further increases cholesterol production in the liver, with resulting supersaturation and risk for gallstones. A 2000 study suggested the following rates for gallstones related to extreme and rapid weight loss:

• The risk for gallstones is as high as 12% after eight to 16 weeks of restricted-calorie diets.

• The risk is more than 30% within a year to 18 months after gastric bypass surgery.

About one-third of gallstone cases in these situations are symptomatic. The risk for gallstones is highest in the following dieters:

• Those who lose more than 24% of their initial body weight.

• Those who lose more than 1.5 kg (3.3. lb) per week.

• Those on very low-fat, low-calorie diets.

Weight cycling also puts people at risk for gallstones. For example, a 16-year study found that the risk for gallstone surgery was 68% higher for women who lost and then regained more than 20 lb at least once than in women whose weight remained stable.

Cholesterol and Cholesterol-Lowering Drugs

Gallstone formation does not correlate with overall cholesterol levels, but persons with low HDL cholesterol (the so-called good cholesterol) levels or high triglyceride levels are at increased risk for stones. In fact, the cholesterol-lowering drugs gemfibrozil (Lopid) and clofibrate (Atromid-S) reduce cholesterol levels in the blood by increasing the amount secreted into the bile, thus creating a higher risk for gallstones. (Other cholesterol-lowering agents do not have this effect.) [See Well-Connected report #23, Cholesterol.]

Other Risk Factors

Prolonged Intravenous Feeding. Prolonged intravenous feeding reduces the flow of bile and increases the risk for gallstones.

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 older than 60 and those who have had numerous bowel surgeries (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.
Diuretics. In addition to the cholesterol-lowering drugs mentioned above, thiazide diuretics may slightly increase the risk for gallstones.
Blood Disorders. Chronic hemolytic anemia, including sickle cell anemia, increases the risk for pigment gallstones.

HOW CAN GALLSTONES AND GALLBLADDER DISEASE BE PREVENTED?

Dietary Considerations

Dietary Factors. Some studies have suggested that certain dietary factors may be protective:

• Although fats have been associated with gallstone attacks -- particularly saturated fats (found in meats, butter, and other animal products) -- evidence suggests that fat intake may have benefits under specific conditions. Some studies, for example, have found a lower risk for gallstones in people who consumed foods containing monounsaturated fats (found in olive and canola oils) or omega-3 fatty acids (found in canola, flaxseed, and, particularly, fish oil). A 2002 study reported that a fatty meal improved liver clearance in patients who had undergone endoscopic sphincterotomy, a procedure for removing common bile duct stones.

• High intake of fiber has been associated with a lower risk for gallstones.

• Low levels of lecithin, a type of fat known as a phospholipid and a key component of bile, may precipitate the formation of cholesterol gallstones. Animal studies have suggested that lecithin-rich soy and buckwheat protein may protect against gallstones. (Buckwheat may be more protective than soy.) Dietary lecithin is available in health food stores and is found in eggs, soybeans, liver, wheat germ, and peanuts. There is no evidence, however, that lecithin supplements or foods containing it can prevent gallstones in humans.

• High intake of sugar has been associated with an increased risk for gallstones.

• Alcohol in small amounts (one ounce per day) has been found to reduce the risk of gallstones in women by 20%. It should be stressed that alcohol is easily abused, and higher amounts may increase the risk of many diseases, including breast cancer, in women.

• Ascorbic acid (vitamin C) appears to help break cholesterol down in bile. Vitamin C deficiencies have been associated with a higher risk for gallstones. One 2000 study, which confirmed some previous research, reported that supplements were associated with a reduced risk for gallbladder disease in women. (Vitamin C had no effect one way or the other in men.)

• In one study, men who drank two or more cups of regular coffee daily (instant, filtered, or espresso) had a 40% lower risk of developing gallbladder disease over 10 years than men who did not drink coffee regularly. Those who drank more than four cups had the lowest risk. A more recent study in 2000 did not find any general protective effect, although women with gallstones who drank coffee reported fewer symptoms than those who didn't.

Preventing Gallstones during Weight Loss. Maintaining a normal weight and avoiding rapid weight loss are the keys to reducing the risk of gallstones. Taking the medication ursodiol (also called ursodeoxycholic acid, or Actigall) during weight loss may reduce the risk for people who are very overweight and need to lose weight quickly. This medication is ordinarily used to dissolve existing gallstones. It should be noted, however, that it is very expensive. A promising 2001 study suggested that orlistat (Xenical), a drug for treating obesity, may protect against gallstone formation during weight loss. The drug appears to reduce bile acids and other components involved in gallstone production.

Exercise

Exercising regularly and vigorously may reduce the risk of gallstones and gallbladder disease, even in people who are overweight. Studies are reporting a lower risk for gallstones in both men and women who exercise. Active sports exercise appears to be most protective for both men and women. A 1999 study of women reported that exercise reduced gallstone risk regardless of whether the women lost weight or not. Some evidence suggests that in addition to controlling weight, exercise helps reduce cholesterol levels in the biliary tract, which could help prevent gallstones.

Nonsteroidal Anti-Inflammatory Drugs

Some data had indicated that taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil) protects against the development of gallstones. Recent studies have been mixed, although a 2001 study reported significant protection against gallstone recurrence in people who took NSAIDs after being treated with lithotripsy.

HOW ARE GALLSTONES AND GALLBLADDER DISEASE DIAGNOSED?

The diagnostic challenge posed by gallstones is to be sure that abdominal pain is caused by stones and not by some other condition. Ultrasound or other imaging techniques usually detect gallstones readily. Nevertheless, because gallstones are common and most cause no symptoms, simply finding stones does not necessarily explain a patient's pain, which may be caused by numerous other ailments.

Ruling Out Other Disorders

In patients with abdominal pain, causes other than gallstones are usually responsible if the pain lasts less than 15 minutes, frequently comes and goes, or is not severe enough to limit activities.
Irritable Bowel Syndrome. Irritable bowel syndrome (IBS) has some of the same symptoms as gallbladder disease, including difficulty digesting fatty foods. In IBS, however, pain usually occurs in the lower abdomen.
Other Conditions with Similar Symptoms. Acute appendicitis, inflammatory bowel disease (Crohn's disease or ulcerative colitis), pneumonia, stomach ulcers, gastroesophageal reflux and hiatal hernia, viral hepatitis, kidney stones, urinary tract infections, diverticulosis or diverticulitis, pregnancy complications, and even a heart attack may mimic a gallbladder attack.
 
Physical Examination

A physical exam often reveals tenderness in the upper right area of the abdomen in acute cholecystitis and sometimes in biliary colic. There is usually no tenderness in chronic cholecystitis.

Laboratory Tests

Blood tests are usually normal in people with simple biliary colic or chronic cholecystitis. The following abnormalities may indicate gallstones or complications:

• The enzyme alkaline phosphatase and bilirubin are usually elevated in acute cholecystitis, and especially choledocholithiasis (common bile duct stones). Bilirubin is the orange-yellow pigment found in bile. High levels cause jaundice, which gives the skin a yellowish tone.

• Liver enzymes known as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are elevated when common bile duct stones are present. A threefold or more increase in ALT strongly suggests pancreatitis.

• A high white blood cell count is a common finding in many (but not all) patients with cholecystitis.

Imaging Techniques for Diagnosing Gallstones and Infection (Cholecystitis)

Ultrasound. Ultrasound, the diagnostic method most frequently used to detect gallstones, is a simple, rapid, and noninvasive imaging technique. Ultrasound detects gallstones as small as 2 mm in diameter with an accuracy of 90% to 95%. Some experts recommend that if an ultrasound does not detect stones, but gallstones are still strongly suspected, the test should be repeated.

The patient must not eat for six or more hours before the test, which takes only about 15 minutes. During the procedure, the physician can check the liver, bile ducts, and pancreas and quickly scan the gallbladder wall for thickening (characteristic of cholecystitis). Air in the gallbladder wall may indicate gangrene.

Ultrasound is not as useful for common bile duct stones and cannot image the cystic duct. According to one 2000 study, ultrasound is not useful for identifying cholecystitis in patients who do not have gallstones but have fever and abdominal pain. In this study, ultrasound detected some gallbladder abnormalities, no matter what the cause of the abdominal pain. In only a few cases were the symptoms actually caused by cholecystitis.

Cholescintigraphy. Cholescintigraphy, a nuclear imaging technique, is not as useful as ultrasound for detecting gallstones, but it is more sensitive for diagnosing acute cholecystitis. It is noninvasive but can take one to two hours or longer. The procedure involves the following steps:

• A tiny amount of a radioactive dye is injected intravenously. This material is excreted into bile.

• A camera detects the dye as it passes from the liver into the gallbladder.

• If the dye does not enter the gallbladder, the cystic duct is obstructed, thereby indicating acute cholecystitis.

The scan cannot identify individual gallstones. Nor can it detect chronic cholecystitis. Occasionally the scan gives false positive results. (In other words, it appears to detect acute cholecystitis in people who do not have the condition.) Such results are most likely in alcoholic patients with liver disease or patients who are fasting or receiving all nutrients intravenously.

Oral Cholecystography. Oral cholecystography uses a tablet containing a dye that is employed during an x-ray. It has been available since 1924 but is not performed very often anymore. It may be useful in some cases for determining the structural and functional status of the gallbladder, often before non-surgical procedures.