Age

The incidence of gallstones increases with age across all ethnic groups, and it is very low among infants and children (Chen et al, 1998). Some specific populations such as Pima Indians, mentioned previously, have an increased incidence of gallstones (up to 70%) by 30 years of age, implicating hereditary metabolic factors (Sampliner et al, 1970). Pediatric populations with chronic hemolytic conditions, such as sickle cell anemia, also represent another distinct group in whom gallstones develop early.

Gender

Female gender is a risk factor for developing gallstones, surpassing males in the incidence of gallstones and the chance of having surgery by 2 : 1 or 3 : 1 in most studies (see Table 30.1). Pregnancy is associated with up to a 30% risk of developing biliary sludge, and low-dose estrogen therapy in postmenopausal women increases the risk of gallstone formation (Maringhini, et al, 1993; Hulley et al, 1998).

Obesity, Diet, Physical Activity, and Weight Loss

Obesity is a well-established major risk factor for the development of gallstones. The association with simple obesity is important in females; in males it is mostly associated with intraabdominal (central) obesity and metabolic syndrome (Maclure et al, 1989; Heaton et al, 1991; De Santis et al, 1997; Tsai et al, 2004).

The frequency of gallstones has almost doubled in the last 60 years, in parallel with the changed composition of stones from pigment to cholesterol. In humans, most cholesterol found in gallstones is from the diet, since de novo hepatic synthesis is only about 20% (Paigen & Carey, 2002). This emphasizes the importance of high caloric and carbohydrate intake as risk factors for the development of gallstones in modern society.

Bariatric patients are at a high risk for the development of cholelithiasis after weight-reduction surgery. Sludge and gallstones form in up to 35% of patients following bariatric procedures, with weight loss more than 1.5 kg/week being a risk factor (Shiffman, et al, 1991; Weinsier et al, 1995).

Patients receiving total parenteral nutrition (TPN) are another group with a high incidence of gallstone and sludge development. After 3 months of TPN therapy, approximately 45% of patients will develop gallstones; 100% of patients will develop sludge within 6 weeks (Shaffer, 2001; Murray et al, 1992). Low levels of physical activity are associated with development of gallstones in large observational and population studies also related to obesity and diet (Leitzmann et al, 1999). Finally, patients receiving long-term somatostatin analogue therapy for various disorders (acromegaly, functional neuroendocrine tumors) are at increased risk for gallstone formation as a result of reduced gallbladder motility and reduced bile flow (Bornschein et al, 2009).

Genetics

Population studies indicate a 30% genetic component in the development of gallstone disease. Hepatic cholesterol hypersecretion, resulting in bile supersaturation and cholesterol stone formation, may be caused by increased hepatic uptake and synthesis of cholesterol, decreased hepatic synthesis of bile salts, decreased hepatic synthesis of cholesterol esters for inclusion in very-low-density lipoprotein (VLDL), and derangements in the intestinal absorption of cholesterol and bile salts. Genes controlling hepatic cholesterol metabolism have been implicated in the pathogenesis of gallstone formation in transgenic/knockout mouse models and in humans (Table 30.2). Excess cholesterol load in smooth muscles of the gallbladder can affect signaling via the cholecystokinin A (CCK-A) receptor and contribute to the development of gallstones by inducing bile stasis. Intestinal cholesterol/bile salt absorption is tightly controlled and genes responsible for cholesterol absorption (NPC1L1, Niemann-Pick C1-like protein) or cholesterol efflux (ABCG5/G8) have been implicated in the development of gallstones in certain populations because of intestinal bile salt loss. Single-gene mutations result in hemolysis and increase the incidence of black stones because of an excess of unconjugated bile acids forming polymerized calcium bilirubinate stones. A summary of genes found to be involved in gallstone pathogenesis can be found in Table 30.2 (Grünhage & Lammert, 2006).

Table 30.2 Genes Involved in Gallstone Pathogenesis