In addition to the variability of gallstones in different ethnic populations, a number of other risk factors for this condition have been identified.
Age — Age is a major risk factor for the gallstones. Gallstones are exceedingly rare in children except in the presence of hemolytic states; in addition, less than 5 percent of all cholecystectomies are performed in children. Age 40 appears to represent the cut-off between relatively low and high rates of cholecystectomies.
Gender — As noted above, a higher prevalence of gallstones has been observed in women in all age groups. The difference between women and men is particularly striking in young adults. The GREPCO study found
a female-to-male ratio of
2.9 between the ages of 30 to 39 years; the ratio narrowed to
1.6 between the ages of 40 to 49 years and
1.2 between the ages of 50 to 59 years.
The higher rates in young women is almost certainly a result of pregnancy and sex steroids.
Pregnancy — Pregnancy is a major risk factor for the development of cholesterol gallstones. The risk is related to both the frequency and number of pregnancies. In one report, for example, the prevalence of gallstones increased from
1.3 percent in nulliparous females to
12.2 percent in multiparous females.
Another study recruited 272 women in the first trimester of pregnancy. The incidence of new biliary sludge and gallstones was 31 and 2 percent, respectively.
Sex hormones induce a variety of physiologic changes in the biliary system, which ultimately cause bile to become supersaturated with cholesterol, thereby promoting gallstone formation: • Supersaturation occurs as a result of an
· estrogen induced increase in cholesterol secretion and a
· progesterone induced reduction in bile acid secretion.
Pregnancy induces a qualitative change in bile acid synthesis characterized by
relative overproduction of hydrophobic bile acids such as chenodeoxycholate,
thereby reducing the ability of bile to solubilize cholesterol
Progesterone induced slowing of gallbladder emptying further promotes the formation of stones by causing bile stasis.
These changes normalize one to two months following delivery.
In the postpartum period, gallbladder sludge resolves in 61 percent of cases and approximately 30 percent of stones smaller than 10 mm disappear due at least in part to unsaturation of bile.
Oral contraceptives and estrogen replacement therapy — Studies evaluating the risk associated with estrogen use have been conflicting, although the majority of studies have shown that estrogen therapy is associated with higher rates of gallstones.
The following associations have been noted in different reports:
• Postmenopausal women given estrogen replacement had 3.7 times the relative risk of developing symptomatic gallstones compared to nonusers. Similar findings were noted in the HERS trial which randomized 2763 postmenopausal women with coronary heart disease to ERT or placebo. After an average follow-up of four years, gallbladder disease was more frequent in those receiving estrogen therapy (6.1 versus 4.5 percent, relative hazard 1.38).
• In the Nurses' Health Study of almost 55,000 postmenopausal women, those currently using postmenopausal hormones were at an increased risk of cholecystectomy (relative risk 2.1) compared to never-users.
- For current users, the risk of cholecystectomy increased with increasing duration of hormone use and higher doses of estrogen.
- The risk for past hormone users decreased substantially in women who had discontinued use within the preceding one to three years (relative risk 1.6), a small but significant risk persisted for women who had stopped taking ERT five or more years previously (relative risk 1.3).
• Men receiving estrogen therapy had an increased rate of gallstones compared to controls.
- In one study of men who had had a myocardial infarction, treatment with estrogen or clofibrate was associated with more than a twofold increase in risk of gallbladder disease compared to those receiving placebo. In another report of men with prostate cancer, new gallstones detected by ultrasonography developed at one year in 5 of 28 men treated with estrogen compared to none of 26 who underwent orchiectomy.
- Estrogen treated men had a 40 percent increase in biliary cholesterol excretion compared to age matched controls.Oral contraceptive use also appears to cause a slight increase in the risk of gallstone formation.
- Women under the age of 40 and those taking high-dose estrogen (>50 µg) preparations have the greatest added risk. It has been suggested that oral contraceptive has only a transient effect on gallstone formation
Family history and genetics — Family history studies suggest that genetics has a significant role in the development of gallstones. Investigators performed oral cholecystography in 171 first-degree relatives of patients with gallstones and 200 age matched controls.
Gallstones occurred more than twice as often in the family group: 20.5 versus 9 percent.
The risk was greater in female relatives in both of these studies.
The great variation in gallstone rates amongst different ethnic groups described above could be due to genetic as well as dietary and cultural habits.
A dramatic example occurs in Pima Indians who have exceptionally high rates of cholesterol gallstones: 73 percent in women over the age of 25 years.
Obesity — Obesity (defined as weight greater than 120 percent of ideal body weight) is a well established risk factor for the development of cholesterol gallstones, presumably due to enhanced cholesterol synthesis and secretion. The risk is particularly high in women, in those with morbid obesity, and in younger age groups in which a threefold increase in risk has been reported.It has also been suggested that the incidence of gallbladder disease in morbidly obese subjects may be higher than expected from ultrasonography or oral cholecystography. In one report, 62 morbidly obese patients underwent prophylactic cholecystectomy at the time of a gastric exclusion procedure. Among the 47 who had normal imaging studies, 40 had abnormal histologic findings in the gallbladder.Rapid weight loss — Rapid weight loss is also a risk factor for gallstone formation, occurring in approximately 35 percent of patients after proximal gastric bypass, a form of bariatric surgery. High rates of gallstone formation have also been associated with very low calorie diets. Gallstones which form in association with rapid weight loss appear to be more common in Caucasians and women.The mechanism by which this occurs is incompletely understood. One report evaluated changes in gallbladder bile during periods of weight loss. Bile mucin content increased 18-fold and bile calcium concentration rose 40 percent. These factors may promote cholesterol nucleation and stone formation.In contrast to the general population in which the great majority of gallstones are asymptomatic, persons with weight loss related cholelithiasis are more likely to be symptomatic. In one series, for example, 28 percent of patients required urgent cholecystectomy within three months after a gastric exclusion procedure.Prophylaxis with ursodeoxycholic acid (UDCA) has been shown to be effective at reducing the risk of stone formation during rapid weight loss. In one trial of 1004 patients treated with a very low calorie diet, ultrasonography was performed at baseline and 8 and 16 weeks. The incidence of gallstones was 28 percent in the placebo group compared to 8, 3, and 2 percent of those treated with 300, 600, and 1200 mg/day of UDCA, respectively.In another controlled trial, 68 obese subjects were randomized to UDCA (1200 mg/day), aspirin, or placebo at the time of entry into a 520 kcal/day diet program. The patients were treated for up to 16 weeks and were reevaluated at four and three weeks after treatment. None of the patients treated with UDCA developed gallstones or cholesterol crystals in the bile compared to five and six patients, respectively, in the placebo group (p<0.001). name="11">Diabetes mellitus — Diabetes mellitus appears to be associated with an increased risk of gallstones. As an example, a case control study compared 336 patients who had gallstones or had undergone cholecystectomy to 336 controls. Diabetes was more prevalent in the patients with gallbladder disease (11.6 versus 4.8 percent). In another case control study, an increased prevalence of gallstones in diabetes could only be demonstrated in women (42 versus 26 percent in nondiabetic women).How diabetes predisposes to gallstones is not well understood. Two possible contributing factors are hypertriglyceridemia and autonomic neuropathy leading to biliary stasis due to gallbladder hypomotility. One study suggested that in women, hyperinsulinemia itself may be a predisposing condition even in those without diabetes.Serum lipids — The precise role of serum lipids on gallstone formation is not known. Gallstones appear to be positively associated with apolipoprotein E4 phenotype and elevated serum triglycerides. In contrast, a negative association exists between gallstones and high density lipoprotein. There is no conclusive evidence linking elevated serum cholesterol and gallstones. Cirrhosis — Cirrhosis is a major risk factor for gallstones. The increased risk was illustrated in a combined cross-sectional and longitudinal study that included 1010 patients with cirrhosis. The overall prevalence of gallstones was 29.5 percent. During an average follow-up of 50 months, 141 of 618 patients (23 percent) developed gallstones (which is approximately 10 times higher than would be expected in a general population). Multivariate analysis demonstrated that the risk was increased in patients with Child classes B and C cirrhosis (regardless of the cause), and in patients with a high body mass index. The increased risk of gallstone formation in these patients may be due to several factors, including reduced hepatic synthesis and transport of bile salts and nonconjugated bilirubin, high estrogen levels, and impaired gallbladder contraction in response to a meal.
Gallbladder stasis — Conditions that result in bile stasis are associated with a higher prevalence of gallstones. In the normal state, the gallbladder avidly absorbs water from bile.
Thus, if bile remains within the gallbladder for a prolonged period, it can become overly concentrated with cholesterol, thereby promoting stone formation.
Common examples of this mechanism include
- spinal cord injuries,
- prolonged fasting
- and the use of total parenteral nutrition (both of which prevent the normal enteral stimulation of gallbladder activity),
- and excess somatostatin.
• Gallstones are a frequent complication of prolonged total parenteral nutrition. As an example, one study of 84 patients with severe short bowel syndrome treated with total parenteral nutrition found asymptomatic gallstones in 44 percent.
Two factors are thought to contribute:
- biliary stasis due to lack of enteral stimulation;
- in patients with ileal resection, interruption of the enterohepatic circulation of bile acids results in a reduction in hepatic bile acid secretion and an altered composition of hepatic bile which becomes supersaturated with respect to cholesterol.
• Somatostatin, probably via reduced cholecystokinin release, is a potent inhibitor of gallbladder emptying. Thus, stasis-induced gallstones may be seen in patients with a somatostatinoma or the long-term administration of the somatostatin analogue octreotide in the treatment of acromegaly and other disorders.
.Other drugs — In addition to estrogen, oral contraceptives, and octreotide, two other drugs can promote the formation of gallstones: clofibrate and ceftriaxone.
• Clofibrate, a now rarely used cholesterol lowering agent, is strongly associated with gallstones. Clofibrate and other fibrates (eg, bezafibrate) reduce bile acid secretion by inhibiting the rate limiting enzyme in bile acid synthesis, cholesterol 7-alpha-hydroxylase; this results in cholesterol supersaturated bile and stone precipitation.
• Ceftriaxone is a major cause of biliary sludge formation in hospitalized patients. Biliary excretion accounts for up to 40 percent of ceftriaxone elimination and drug concentrations in bile can reach 200 times that of the serum. When supersaturated, ceftriaxone complexes with calcium and precipitates out of bile. This process is probably potentiated in intensive care unit patients who are not fed enterally and have bile stasis.
Decreased physical activity — Physical activity is associated with a decreased risk of symptomatic cholelithiasis. This was illustrated in the Physicians' Health Study, a prospective cohort study of over 45,000 men, in which 828 subjects developed symptomatic gallstones during eight years of follow-up. The study included 60,290 women between the ages of 40 to 65 who were followed for 10 years during which 3257 underwent cholecystectomy. On multivariate analysis, the relative risk for women in the highest compared to the lowest quintile of physical activity was 0.69. In contrast, women who had a sedentary lifestyle were at increased risk of cholecystectomy (relative risk 1.42).
Crohn's disease — The prevalence of gallstones is increased in patients with Crohn's disease. In a population based study in Sweden, for example, gallstones were detected in 26 percent of patients with Crohn's disease, which was approximately twice as frequent as the general population. Gallstones in patients with ileal Crohn's disease (or those who have undergone ileal resection) are frequently pigment based, reflecting an increased concentration of bilirubin conjugates, unconjugated bilirubin, and total calcium in the gallbladder bile due perhaps to altered enterohepatic cycling of bilirubin.
PROTECTIVE FACTORS — A number of drugs have been used to treat patients with symptomatic gallstones disease and to prevent the development of symptoms in high risk patients. In addition, a number of dietary factors have also been suggested as possibly being protective.
Ascorbic acid — The observation that deficiency of ascorbic acid (vitamin C) is associated with the development of gallstones in guinea pigs prompted investigation of the relationship between ascorbic acid levels and gallstones in humans. The benefit of ascorbic acid may be related to its effects on cholesterol catabolism.
Coffee — Moderate coffee consumption was associated with a reduced risk of symptomatic gallstone disease in a cohort study involving 46,008 male health professionals who were followed for up to 10 years. Subjects who consistently drank two to three cups of regular coffee per day were approximately 40 percent less likely to develop symptomatic gallstones during follow-up. The benefit was even greater in those who drank four or more cups per day (relative risk 0.55). In contrast, decaffeinated coffee was not protective.