Gallstones are concretions that form in the biliary system, usually the gallbladder. Although rarely recognized in animals, they affect a large number of people. In the US alone, it is estimated that about 20 million people have gallstones at any given time, resulting in expeditures of about $5 billion for diagnosis and treatment. A majority of cases are asymptomatic, but signs in clinicially affected patients range from mild abdominal pain or minor "indigestion" to excrutiating pain, often manifest at night. There are two major types of gallstones, which seem to form due to distinctly different pathogenetic mechanisms.
Cholesterol Stones
About 90% of gallstones are of this type. These stones can be almost pure cholesterol or mixtures of cholesterol and substances such as mucin. Stones recovered at surgery range from about 5 mm to greater than 25 mm in diameter.
The key event leading to formation and progression of cholesterol stones is precipitation of cholesterol in bile. Unesterified cholesterol is virtually insoluble in aqueous solutions and is kept in solution in bile largely by virtue of the detergent-like effect of bile salts. This is however a rather precarious situation and several factors can tip the balance in favor of precipitation, including:
Hypersecretion of cholesterol into bile due to such things as obesity, acute high calorie intake, chronic polyunsaturated fat diet, contraceptive steroids or pregnancy, diabetes mellitus and certain forms of familial hypercholesterolemia.
Hyposecretion of bile salts due to such things as impaired bile salt synthesis and abnormal intestinal loss of bile salts (e.g. recirculation failure due to ileal disease).
Impaired gallbladder function with incomplete emptying or stasis is seen in late pregnancy and with oral contraceptive use, in patients on total parenteral nutrition and due to unknown causes, perhaps associated with neuroendocrine dysfunction.
There are clearly important genetic determinants for cholesterol stone formation. For example, the prevelance of the disease in descendents of Chilean Indians and in American Indians is extraordinarily high and not accounted for by environment.
There is also an important sex bias in development of stones - the prevelance in adult females is two to three times that seen in males and use of contraceptive steroids is a risk factor for development of gallstones.. This sex difference is likely the manifestation of differences in sex steroids: progesterone and also probably estrogen impair gall bladder emptying and are associated with hypersecretion of cholesterol into bile. Additionally, estrogen treatment reduces synthesis of bile acids. These pro-precipitation factors peak during late pregnancy when the levels of these steroid hormones are hightest, then dissipate rapidly after birth.
The gold standard for treatment is open cholecystectomy, but laparoscopic cholecystecomy is rapidly becoming the treatment of choice. Medical treatment with bile salts is not extremely useful in the long term and is expensive.
Pigment Stones
Roughly 10% of human gallstones are pigment stones composed of large quantities of bile pigments, along with lesser amounts of cholesterol and calcium salts. The most important risk factor for development of these stones is chronic hemolysis from almost any cause - this makes sense considering that bilirubin is a major constituent of these stones. Additionally, some forms of pigment stones are associated with bacterial infections. Apparently, some bacteria release glucuronidases that deconjugate bilirubin, leading to precipitation as calcium salts.
References and Reviews
Johnston DE, Kaplan MM: Pathogenesis and treatment of gallstones. New Eng J Med 328:412, 1993.
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