Cholecystitis, Biliary Tract Surgery, and Pancreatitis

A history of clinical gallbladder disease, either symptomatic gallstones or prior cholecystectomy, is present in approximately 11% of U.S. women. In the Third National Health and Nutrition Examination Survey, 1988– 1994, abdominal ultrasound examination diagnosed asymptomatic gallstones in an additional 8% of women, for a total prevalence of gallbladder disease of 19%. At baseline in the Heart and Estrogen/Progestin Replacement Study (HERS), before initiating hormone therapy (HT), 629 HERS participants (23% of 2,744 women aged 44–79 years) reported a history of gallbladder disease, and 508 of these women with gallbladder disease also reported a history of cholecystectomy. A number of factors modify the risk for gallbladder disease. In the HERS, alcohol drinkers who used ascorbic acid supplements had a decreased baseline prevalence of gallbladder disease (adjusted odds ratio OR 0.5, 95% confidence interval CI 0.31–0.81). In the Nurse’s Health Study, physical activity reduced the risk of gallbladder disease. The relative risk of cholecystectomy in women in the highest quintile of physical activity was 30% less than women who exercised less. Other factors associated with gallbladder disease include older age, female sex, white ethnicity, obesity, rapid weight loss, greater parity, and use of estrogen either as contraceptives or postmenopausal HT. The majority of gallstones are composed primarily of cholesterol. Three factors are required for their formation: supersaturation of bile with cholesterol, bile stasis, and destabilization of bile. Oral estrogens, by decreasing bile acid synthesis and secretion, increase biliary cholesterol saturation, a prerequisite for cholesterol gallstone formation. Estrogens may also contribute to bile stasis. Whether transdermal estrogen has similar effects on bile and the potential for gallstone formation as oral estrogens has not been conclusively established, but in a randomized trial of biliary markers of gallstone formation, both oral and nonoral estrogen altered bile in ways that would be expected to form gallstones. Progestins may inhibit gallbladder motility and alter the rate of cholesterol breakdown to bile acids. Acute pancreatitis, an inflammation of the pancreas characterized by abdominal pain, nausea, emesis, fever, and tachycardia, is usually caused by alcohol or biliary calculi. There are about 5,000 new cases of pancreatitis in the United States per year with a mortality rate of about 10%. Other factors contributing to acute pancreatitis include metabolic disorders such as hypertriglyceridemia and medications. Estrogen-containing preparations, either oral contraceptives or postmenopausal HT, have been associated with acute episodes of pancreatitis. In a number of case reports, affected patients usually have familial dyslipidemia characterized by hypertriglyceridemia, which might be exacerbated or manifested for the first time after oral estrogen administration. Diabetic women seem to have an exaggerated hypertriglyceridemic response to HT. Any factor that causes an abrupt increase in serum triglycerides to levels greater than 11 mmol/L (1,000 mg/dL) can precipitate an episode of pancreatitis. The precise mechanism whereby hypertriglyceridemia contributes to pancreatitis has not been fully elucidated. The augmentation of serum triglycerides in response to HT is due to an estrogen effect. In the Postmenopausal Estrogen/Progestin Interventions Trial, women who did not have a history of hypertriglyceridemia had a similar increase in serum triglyceride levels with oral regimens of conjugated equine estrogens with or without medroxyprogesterone acetate or micronized progesterone. In one case report, pancreatitis occurred in a woman who had discontinued medroxyprogesterone acetate and continued on unopposed estrogen therapy. Transdermal estrogens alter serum triglyceride concentrations less than oral preparations, but whether the risk of pancreatitis is lower than with oral estrogen has not been studied. Another published case report describes recurrent acute pancreatitis in conjunction with intermittent estrogen administration without evidence of lipid abnormalities. This suggests that additional mechanisms beyond hypertriglyceridemia might contribute to some cases of estrogen-induced pancreatitis.