Gallbladder disease

During pregnancy when female sex hormones are naturally raised, biliary sludge (particulate material derived from bile that is composed of cholesterol, calcium bilirubinate, and mucin) appears in 5% to 30% of women. Resolution frequently transpires during the post-partum period: sludge disappears in two-thirds; small (<1 cm) gallstones (microlithiasis) vanish in one-third, but definitive gallstones become established in ~5%. Additional risk factors for stone formation during pregnancy include obesity (prior to the pregnancy), reduced high density lipoprotein (HDL) cholesterol and the metabolic syndrome.[3]

Women are almost twice as likely as men to form gallstones especially during the fertile years; the gap narrows after the menopause. The underlying mechanism is female sex hormones; parity, oral contraceptive use and estrogen replacement therapy are established risk factors for cholesterol gallstone formation. Female sex hormones adversely influence hepatic bile secretion and gallbladder function. Estrogens increase cholesterol secretion and diminish bile salt secretion, while progestins act by reducing bile salt secretion and impairing gallbladder emptying leading to stasis. A new 4th generation progestin, drospirenone, used in some oral contraceptives may further heighten the risk of gallstone disease and cholecystectomy; however, the increased risk is quite modest and not likely to be clinically meaningful.[3]

A retrospective (historical) cohort study was performed on a very large data base including 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared with 341,478 nonusers. Oral contraceptives were shown as risk factors for gallbladder disease, although the risk is of sufficient magnitude to be of potential clinical importance only in young women.[4]

The 1984 Royal College of General Practitioners' Oral Contraception Study suggests that, in the long-term, oral contraceptives are not associated with any increased risk of gallbladder disease, although there is an acceleration of the disease in those women susceptible to it.[5]

Newer research suggests otherwise. A 1993 meta-analysis concludes that oral contraceptive use is associated with a slightly and transiently increased rate of gallbladder disease, but laters confirms that modern low-dose oral contraceptives are safer than older formulas, though an effect cannot be excluded.[6]

A 2001 comparative study of the IMS LifeLink Health Plan Claims Database interpreted that in a large cohort of women using oral contraceptives, there was found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethisterone compared with levonorgestrel. No statistically significant increase in risk was associated with the other formulations of oral contraceptive (etynodiol diacetate, norgestrel and norgestimate).[7]

While some observational studies had suggested that estrogens increase the risk for gallbladder disease by as much as twofold to fourfold, such an association had not been reported consistently.[8][9]  More recent randomized clinical trial data among postmenopausal women now support a causal role for oral menopausal hormone therapy estrogens. Confirming the positive finding of another large study,[10] the landmark Women's Health Initiative (WHI) reported very significant increases (p < 0.001) for risk of gallbladder disease or surgery attributed to treatments with both estrogen alone (conjugated equine estrogen; CEE) and estrogen-plus-progestin (conjugated equine estrogen with medroxyprogesterone; CEE+MPA ). Specifically, a 67% increase (CEE versus placebo) and 59% increase (CEE+MPA versus placebo) among healthy postmenopausal women that reported either having had a hysterectomy (n = 8376)  or not (n = 14203) prior to randomization, respectively.[11] 

A prospective study in 1994 noted that body mass index remains the strongest predictor of symptomatic gallstones among young women. Other risk factors are having over four pregnancies, weight gain, and cigarette smoking. Alcohol was shown to have an inverse relationship between use and gallbladder disease.[12]