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Epidemiology of Gallbladder Disease: Cholelithiasis and Cancer

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Diseases of the gallbladder are common and costly. The best epidemiological screening method to accurately determine point prevalence of gallstone disease is ultrasonography. Many risk factors for cholesterol gallstone formation are not modifiable such as ethnic background, increasing age, female gender and family history or genetics. Conversely, the modifiable risks for cholesterol gallstones are obesity, rapid weight loss and a sedentary lifestyle. The rising epidemic of obesity and the metabolic syndrome predicts an escalation of cholesterol gallstone frequency. Risk factors for biliary sludge include pregnancy, drugs like ceftiaxone, octreotide and thiazide diuretics, and total parenteral nutrition or fasting. Diseases like cirrhosis, chronic hemolysis and ileal Crohn's disease are risk factors for black pigment stones. Gallstone disease in childhood, once considered rare, has become increasingly recognized with similar risk factors as those in adults, particularly obesity. Gallbladder cancer is uncommon in developed countries. In the U.S. it accounts for only

5,000 cases per year. Elsewhere, high incidence rates occur in North and South American Indians. Other than ethnicity and female gender, additional risk factors for gallbladder cancer include cholelithiasis, advancing age, chronic inflammatory conditions affecting the gallbladder, congenital biliary abnormalities, and diagnostic confusion over gallbladder polyps.


Diseases of the gallbladder commonly manifest as gallstones and gallbladder cancer. To identify risk factors in a given population, epidemiological studies must first define the frequency of disease. Studies employing necropsy surveys or healthcare databases carry biases by their implicit nature: being postmortem or requiring biliary symptoms/complications, respectively. 1 - 3 Another potential measure of disease burden, the frequency of cholecystectomy, is a limited marker for the prevalence of gallstones, as the perceived threshold for surgery and patient access to care differ greatly. 4 Some epidemiological studies have been confounded by inadequate sample size or selection bias. Small sample size is open to a beta-II type error: a failure to accurately identify a true difference (i.e. a false negative result). Selection bias may lead to spurious differences (i.e. a false positive result). More reliable epidemiological studies now use transabdominal ultrasound to screen robust numbers in defined asymptomatic populations. Ultrasonography is an ideal means to quantitate the frequency of gallstone disease, being a noninvasive and safe imaging technique that accurately can detect the point prevalence of gallstones in a defined asymptomatic population.


1. Burden of gallstone disease

Gallstones constitute a significant health problem in developed societies, affecting 10% to 15% of the adult population, meaning 20 to 25 million Americans have (or will have) gallstones. 2. 5 - 7 The resultant direct and indirect cost of gallbladder disease represents a consumption of

$6.2 billion annually in the U.S. constituting a major health burden that has increased more than 20% over the last 3 decades. 2. 8. 9 With an estimated 1.8 million ambulatory care visits each year, gallstone disease is a leading cause for hospital admissions related to gastrointestinal problems. 10 These numbers are likely an underestimate because laparoscopic cholecystectomy is often performed as a day procedure and thus not captured by hospital statistics that require overnight admission. Although the mortality rate for gallstones disease is relatively low at 0.6%, the high burden of disease imposes troubling mortality figures, such as an estimated 1,092 gallstone-related deaths for 2004 in the U.S. Fortunately, case fatality rates have steadily diminished from over 5,000 deaths in 1950, falling >50% between the years 1979 and 2004. This decline represents the greatest decrease for any digestive disease. 9

Gallstone disease per se also carries inherent risks. Prospective population-based surveys have revealed an increased overall mortality, particularly from cardiovascular disease and cancer, as seen in Americans and Pima Indians with cholelithiasis. 11. 12 Further, as the incidence of gallstone disease escalates, there is a concomitant increase in complications like gallstone-related pancreatitis. 13

The number of surgical procedures for cholelithiasis has risen markedly in developed countries since 1950. 14 The introduction of laparoscopic cholecystectomy in 1989 further increased the cholecystectomy rate. 14 - 16 From 1990 to 1993, for example, there was a 28% escalation in the number of cholecystectomies performed. 17 The change in practice emanated from the laparoscopic surgical approach, which represented a less invasive, more cosmetically acceptable operation while providing a lower surgical risk compared to the then conventional or "open" procedure. This likely resulted in more surgeries being done in patients previously thought to be too high a risk, or in those with minimal symptoms. Although there is undoubtedly an element of overuse, cholecystectomy is now the most common elective abdominal surgery performed in the U.S. with over 750,000 operations being performed annually. 6. 16. 18 The cholecystectomy rate,

though increased, fortunately appears to have stabilized in the late 1990s and may even be on the decline in the U.S. 19

2. Clinical aspects of gallstone disease

1) Asymptomatic/Silent gallstones

Gallstones are common. 10% to 20% of Americans will develop stones at some time. 20 The majority will not develop symptoms: up to 80% will never experience biliary pain or complications such as acute cholecystitis, cholangitis, or pancreatitis. 21 Hence, most gallstones are clinically "silent," an incidental finding often uncovered during abdominal ultrasound being performed for another reason. 22 People with such asymptomatic cholelithiasis, however, eventually may develop symptoms (biliary pain) that require treatment, 23 but this risk is quite low averaging 2% to 3% per year, 24 10% by 5 years. 1. 23 An even lower proportion, 1% to 2% per year, develop major gallstone complications. 20. 25 Therefore, expectant management is an appropriate choice for silent gallstones in the general population. The exception is patients at high risk for experiencing biliary complications:

(1) Large gallstones (>3 cm) or gallbladders crammed with stones that carry a higher risk of developing gallbladder cancer, perhaps an indication for prophylactic cholecystectomy. 26. 27

(2) Sickle cell disease is associated with the development of pigment gallstones, frequently necessitating cholecystectomy. Prophylactic cholecystectomy should be considered because stone complications is frequently difficult to distinguish from the clinical features of a sickle cell crisis or its complications such as infarction of the liver or abdominal viscera. 28 When performed early, outside the emergency setting, cholecystectomy lessens the surgical risks, but still carries a high mortality rate at 1% and postoperative complications of >30%. 29

(3) Solid organ transplantation (heart, lung, kidney, pancreas). Although stem cell (bone marrow) transplantation carries its own problems from cholelithiasis and biliary sludge developing, more problematic is the aftermath of solid organ transplantation in which gallstones that develop frequently progress to symptoms and complications like cholecystitis, principally during the first 2 years. 30 Liver transplantation is exempt; the gallbladder is removed at the time of hepatectomy. Controversy exists in patients with asymptomatic gallstone disease who are undergoing solid organ transplantation: expectant management with routine screening ultrasonography vs prophylactic (pre-/posttransplantation) cholecystectomy.

(4) Abdominal surgery, performed for other reasons, may benefit from a simultaneous cholecystectomy in situations where the risk of gallstone formation and complications are high. Prophylactic cholecystectomy therefore should be considered in morbidly obese patients undergoing bariatric surgery. 31

2) Symptomatic gallstone disease

Since most gallstones are asymptomatic, it is essential to define exactly which symptoms are caused by gallstones: true biliary pain and/or complications, versus nonspecific abdominal complaints including dyspepsia. 32 - 34 Gallstone-associated pain seems to follow a certain pattern in most patients. 35. 36 Consensus groups have attempted to establish criteria for biliary pain relative to defined characteristics (e.g. episodic, steady, severe pain located in the upper abdomen and lasting more than 30 minutes) and some accompanying features (e.g. nocturnal onset; nausea and vomiting; radiating through to the back). 11 The importance for clarifying what constitutes true biliary pain is to better predict relief following cholecystectomy. Currently, cholecystectomy does not relieve biliary pain in 10% to 33% of people with documented gallstones. 37. 38 Confusion with other functional gut disorders like irritable bowel syndrome (IBS) and dyspepsia will not provide a favorable outcome from cholecystectomy. 39. 40 The avoidance of an unnecessary cholecystectomy becomes critically germane in an era of escalating rates of surgery.

3) Functional (acalculous) gallbladder disease

Biliary pain seemingly results from increased intraluminal pressure as the gallbladder contracts against an obstructed outlet. In gallstone disease, the obstruction is obvious: a stone in the cystic duct. In functional gallbladder disease (also termed; acalculous gallbladder disease, gallbladder dyskinesia or biliary dyskinesia), the pain mechanism may be obstruction located at the gallbladder outlet, incoordination between gallbladder contraction and sphincter of Oddi relaxation, or visceral hypersensitivity. A clue to its existence is impaired gallbladder emptying, reliably quantitated by cholecystokinin-cholescintigraphy. 41. 42 Yet the frequency and management of acalculous gallbladder disease remains unclear. Eliminating the apparent problem, the gallbladder, via laparoscopic cholecystectomy is fraught with challenges, particularly in selecting those who would most benefit. Although the exact frequency of biliary dyskinesia is unknown, any increase in the employment of cholecystectomy for such cases most certainly would impact surgical rates. Thus, there is insufficient evidence to support a role for cholecystectomy in functional gallbladder disease at this time. 43 Hence, patients with suspected functional biliary pain but whose intact gallbladder lacks ultrasonographic evidence of gallstones should be carefully evaluated to exclude other causes for their symptoms.

3. Risk factors for gallstone formation

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