Gallstone formation is influenced by interactions between genetic, metabolic, and environmental factors (Pak 2016). Some of those factors include:
- Diet. A Western-style diet is one of the strongest risk factors for cholesterol gallstones. Specifically, high intakes of calories, carbohydrates, saturated fats, and sugar coupled with low intake of fiber have been linked to increased risk, while consumption of polyunsaturated fats, fiber, fish, fruits and vegetables, and nuts have been associated with lower risk (Pak 2016).
Food Intolerances and Gallstone Risk
Evidence from several studies suggest food allergies and intolerances promote gallstone formation by triggering gallbladder inflammation and slowing gallbladder emptying (Gaby 2009). In one study in 69 participants with gallstones or post-cholecystectomy syndrome, gallbladder symptoms resolved in all participants after one week on an elimination diet. Reintroducing certain foods triggered a return of symptoms, presumably due to food allergy or intolerance. Between one and seven trigger foods were identified for each participant, the most common being eggs (causing symptoms in 93% of participants), pork (causing symptoms in 64% of participants), and onions (causing symptoms in 52% of participants) (Breneman 1968; Gaby 2009).
Celiac disease, an autoimmune disease caused by permanent gluten intolerance, may be an underappreciated risk factor for gallstones (Wang, Liu 2017). A higher risk of gallstone-related pancreatitis has been noted in people with celiac disease (Sadr-Azodi 2012). Decreased gallbladder motility, possibly due to poor communication between the digestive tract and gallbladder, appears to be a contributing factor (Fraquelli 2003). Adhering to a gluten-free diet may help restore normal gallbladder function and prevent gallstones in celiac disease patients (Wang, Liu 2017).
- Age. Risk of developing cholesterol and pigmented stones increases with age (Shaffer 2018; Lee 2015). One reason may be that bile acid production declines with age, leading to greater concentration of cholesterol in bile (Pak 2016). Aging may also be associated with reduced gallbladder motility (Macias 2012).
- Gender. Women have a higher risk of cholesterol gallstones than men. This may be due to the effects of female hormones: estrogens increase cholesterol secretion into bile, and progesterone decreases gallbladder motility. Exposure to elevated levels of female hormones, such as during pregnancy or due to estrogen therapy and possibly oral contraceptives, further increase the risk (Pak 2016; Shaffer 2018; Fogel 2016; Wang, Wang 2017).
- Ethnicity. Native North and South Americans, as well as Mexican Americans, have higher rates of gallstones and gallbladder disease than other ethnic groups. For example, among Native Americans, over 64% of women and nearly 30% of men have gallstones (Stinton 2012). South Asians have a higher risk of brown pigmented gallstones, which are related to bacterial and parasitic infections (Tanaja 2018; Vitek 2012).
- Genetics. Having a family member who has had gallstones is associated with an increased risk, and research suggests some individuals are genetically predisposed to forming cholesterol or pigment gallstones (Shaffer 2018; Lammert 2016).
- Obesity. A higher incidence of cholesterol gallstones is seen in people who are overweight or obese, especially women. The risk is particularly high in those with abdominal obesity (Pak 2016; Sekine 2015).
- Fasting and rapid weight loss. While gradual weight loss may reduce gallstone risk, rapid weight loss increases the risk of gallstone formation. Prolonged fasting and weight cycling (eg, as a result of "yo-yo dieting") are also correlated with higher cholesterol gallstone risk (Pak 2016; Shaffer 2018; Njeze 2013).
- Total parenteral nutrition (TPN). TPN, in which all nutrition is delivered intravenously, is frequently associated with rapid weight loss and lack of gallbladder stimulation, both of which can contribute to gallstone formation (Shaffer 2018).
- Other diseases and conditions. Metabolic syndrome, characterized by a group of cardiovascular risk factors, including insulin resistance, high blood pressure, high blood glucose levels, low HDL cholesterol levels, high triglyceride levels, and abdominal obesity, is associated with increased cholesterol secretion and gallstone formation (Shabanzadeh, Skaaby, Sorensen, Eugen-Olsen 2017; Sang 2016). Celiac disease, which may impair gallbladder function, has also been proposed as a risk factor for cholesterol gallstones (Wang, Liu 2017). Cirrhosis, nonalcoholic fatty liver disease, other liver diseases; cystic fibrosis; and Crohn's disease are also risk factors for gallstones; as are certain blood disorders like sickle cell anemia, beta-thalassemia, and other causes of hemolytic anemia (Shaffer 2018; Stinton 2012; Njeze 2013).
- Medications. Several pharmaceuticals are known to increase the risk of gallstones. In addition to estrogens, these include octreotide (Sandostatin, used mainly to treat acromegaly), ceftriaxone (Rocephin, an antibiotic), and thiazide diuretics (such as hydrochlorothiazide [Apo-hydro], used mainly to treat high blood pressure). On the other hand, statins (such as atorvastatin [Lipitor], used to treat high cholesterol levels) and metformin (Glucophage, used to treat type 2 diabetes) may decrease gallstone risk (Stinton 2012; Liao 2017).
- Sedentary lifestyle. Physical activity protects against cholesterol gallstone formation, possibly by improving gallbladder and gut motility and through positive effects on cholesterol metabolism. It has been suggested that an average of two to three hours of recreational physical activity each week could reduce the chance of needing surgery for gallstone disease by 20% (Pak 2016).
Hormone Therapy and Gallstones
The effects of female hormones on gallbladder function and bile composition appear to underlie the higher gallstone risk seen in women compared with men (Lee 2015; Shaffer 2018). Some studies have shown that additional hormone exposure through oral contraceptives and post-menopausal hormone therapy may further elevate risk, but findings have been mixed. A recent meta-analysis of the research found that hormone therapy use increased risk of gallstones by 79%, but oral contraceptives had no effect (Wang, Wang 2017). Estrogen seems to be responsible for this negative effect, as the addition of progesterone to estrogen therapy does not appear to alter its effect on gallstone risk (Simonsen 2013; Dhiman 2006). Although most of the participants in these studies were using oral conjugated estrogens from horse urine, a preliminary comparison trial found that topical bioidentical estradiol had the same effect as oral conjugated estrogens on bile cholesterol saturation and crystallization time after eight weeks of use (Uhler 1998).