Gallbladder disease

Gallbladder diseases are diseases involving the gallbladder.

Gallbladder disease
Micrograph of cholesterolosis of the gallbladder, a very common gallbladder disease. Cholecystectomy specimen. H&E stain.

Gallstones may develop in the gallbladder as well as elsewhere in the biliary tract. If gallstones in the gallbladder are symptomatic, surgical removal of the gallbladder, known as cholecystectomy may be indicated.

Gallstones form when the tenuous balance of solubility of biliary lipids tips in favor of precipitation of cholesterol, unconjugated bilirubin, or bacterial degradation products of biliary lipids. For cholesterol gallstones, metabolic alterations in hepatic cholesterol secretion combine with changes in gallbladder motility and intestinal bacterial degradation of bile salts to destabilize cholesterol carriers in bile and produce cholesterol crystals. For black pigment gallstones, changes in heme metabolism or bilirubin absorption lead to increased bilirubin concentrations and precipitation of calcium bilirubinate. In contrast, mechanical obstruction of the biliary tract is the major factor leading to bacterial degradation and precipitation of biliary lipids in brown pigment stones.[1]

About 104 million new cases of gallbladder and biliary disease occurred in 2013.[2]

Risk factors


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]

Hormonal contraceptives

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]

Menopausal hormone therapy

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] 

Other factors

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]

Xanthogranulomatous cholecystitis

Xanthogranulomatous cholecystitis is a rare form of gallbladder disease which mimics gallbladder cancer although it is not cancerous.[13][14] It was first discovered and reported in the medical literature in 1976 by J.J. McCoy, Jr., and colleagues.[13][15]

See also


  1. Donovan, J. M. (1999). "Physical and metabolic factors in gallstone pathogenesis". Gastroenterology Clinics of North America. 28 (1): 75–97. doi:10.1016/s0889-8553(05)70044-3. PMID 10198779.
  2. Global Burden of Disease Study 2013, Collaborators (22 August 2015). "Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 386 (9995): 743–800. doi:10.1016/S0140-6736(15)60692-4. PMC 4561509. PMID 26063472.
  3. Stinton LM, Shaffer EA (2012). "Epidemiology of gallbladder disease: cholelithiasis and cancer". Gut Liver. 6 (2): 172–87. doi:10.5009/gnl.2012.6.2.172. PMC 3343155. PMID 22570746.
  4. Strom, B. L.; Tamragouri, R. N.; Morse, M. L.; Lazar, E. L.; West, S. L.; Stolley, P. D.; Jones, J. K. (1986). "Oral contraceptives and other risk factors for gallbladder disease". Clinical Pharmacology and Therapeutics. 39 (3): 335–41. doi:10.1038/clpt.1986.49. PMID 3948473.
  5. Kay, C. R. (1984). "The Royal College of General Practitioners' Oral Contraception Study: Some recent observations". Clinics in Obstetrics and Gynaecology. 11 (3): 759–86. PMID 6509858.
  6. Thijs C, Knipschild P (1993). "Oral contraceptives and the risk of gallbladder disease: a meta-analysis". Am J Public Health. 83 (8): 1113–20. doi:10.2105/ajph.83.8.1113. PMC 1695167. PMID 8342719.
  7. Etminan M, Delaney JA, Bressler B, Brophy JM (2011). "Oral contraceptives and the risk of gallbladder disease: a comparative safety study". CMAJ. 183 (8): 899–904. doi:10.1503/cmaj.110161. PMC 3091897. PMID 21502354.
  8. Diehl, A. K. (March 1991). "Epidemiology and natural history of gallstone disease". Gastroenterology Clinics of North America. 20 (1): 1–19. ISSN 0889-8553. PMID 2022415.
  9. Uhler, M. L.; Marks, J. W.; Judd, H. L. (May 2000). "Estrogen replacement therapy and gallbladder disease in postmenopausal women". Menopause. 7 (3): 162–167. doi:10.1097/00042192-200007030-00006. ISSN 1072-3714. PMID 10810961.
  10. Simon, J. A.; Hunninghake, D. B.; Agarwal, S. K.; Lin, F.; Cauley, J. A.; Ireland, C. C.; Pickar, J. H. (2001-10-02). "Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study". Annals of Internal Medicine. 135 (7): 493–501. doi:10.7326/0003-4819-135-7-200110020-00008. ISSN 0003-4819. PMID 11578152.
  11. Cirillo, Dominic J.; Wallace, Robert B.; Rodabough, Rebecca J.; Greenland, Philip; LaCroix, Andrea Z.; Limacher, Marian C.; Larson, Joseph C. (2005-01-19). "Effect of estrogen therapy on gallbladder disease" (PDF). JAMA. 293 (3): 330–339. doi:10.1001/jama.293.3.330. ISSN 1538-3598. PMID 15657326.
  12. Grodstein, F; Colditz, G. A.; Hunter, D. J.; Manson, J. E.; Willett, W. C.; Stampfer, M. J. (1994). "A prospective study of symptomatic gallstones in women: Relation with oral contraceptives and other risk factors". Obstetrics and Gynecology. 84 (2): 207–14. PMID 8041531.
  13. Makino, Isamu; Yamaguchi, T; Sato, N; Yasui, T; Kita, I (2009). "Xanthogranulomatous cholecystitis mimicking gallbladder carcinoma with a false-positive result on fluorodeoxyglucose PET". World Journal of Gastroenterology. 15 (29): 3691–3. doi:10.3748/wjg.15.3691. PMC 2721248. PMID 19653352.
  14. Rao, RV; Kumar, A; Sikora, SS; Saxena, R; Kapoor, VK (2005). "Xanthogranulomatous cholecystitis: Differentiation from associated gall bladder carcinoma". Tropical Gastroenterology. 26 (1): 31–3. PMID 15974235.
  15. McCoy Jr, JJ; Vila, R; Petrossian, G; McCall, RA; Reddy, KS (1976). "Xanthogranulomatous cholecystitis. Report of two cases". Journal of the South Carolina Medical Association. 72 (3): 78–9. PMID 1063276.
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