Pathophysiology of Stone Formation

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Morphology and Composition

There are three kinds of gall stone: cholesterol, black pigment, or brown pigment stones. Cholesterol stones constitute 75-90% of all gall stones. They are composed purely of cholesterol or have cholesterol as the major chemical constituent. Most cholesterol gall stones are of mixed composition. Pigmented stones get their color and their name from precipitated bilirubin. Increased production of unconjugated bilirubin causes black pigmentation. Formation of black pigment stones is typically associated with chronic hemolysis, cirrhosis, and pancreatitis. Brown pigment stones are usually associated with infection. Cytoskeletons of bacteria can be seen microscopically in brown pigment stones, and bacterial infection seems to be a prerequisite for brown stone formation.


Three factors have been recognized in gall stone formation: cholesterol supersaturation, accelerated nucleation, and gall bladder hypomotility. Among these, the degree of cholesterol saturation in gall bladder bile is the most important factor in crystal formation.

Cholesterol supersaturation Cholesterol is hydro-phobic and not easily soluble in water. Its solubility is dependent on the presence of bile salts and lecithin. It is easy to imagine that as the ratio of cholesterol to bile salts and lecithin increases, cholesterol precipitation, crystal formation, and therefore stone formation ensue.

Nucleating and antinucleating factors Pronucleators include mucin glycoproteins, immunoglobulin G (IgG) and IgM, aminopeptidase N, haptoglobin, and a1 acid glycoprotein; the most prominent of these is mucin glycoproteins. The hydrophobic centers of these proteins can bind to cholesterol, phos-pholipids, and bilirubin.

Gall bladder hypomotility The gall bladder concentrates and acidifies the bile. The most powerful stimulant of gall bladder contraction is CCK. CCK release is stimulated by (in order of decreasing potency) long-chain fatty acids, amino acids, and carbohydrates.

Risk Factors Associated with Cholesterol Gall Stone Formation

Major risk factors predisposing to gall stones are age, sex, genetic profile, nutritional status (including the route of nutrition), hormones, drugs, and some other diseases such as diseases of the terminal ileum. A summary of these elements is provided in Table 1.

Age, sex, and genetic profile As mentioned previously, women are affected more than men, and the incidence of gall stone increases with age. A positive family history of gall bladder disease increases risk to more than twice that of the general population. Native Americans and Scandinavians are more predisposed to this disease than other ethnic groups.

Obesity, weight loss, and total parenteral nutrition Obesity is a well-known risk factor for cholelithiasis. A large prospective study of obese women found a strong linear association between

Table 1 Risk factors associated with cholesterol gall stone formation

Female gender Genetics Prima Indians Chileans

Family history of gall stone Pregnancy

Small bowel diseases Crohn's disease Terminal ileum resection Drugs Estrogens Ceftriaxone

Lipid-lowering agents (Clofibrate) Octreotide Nutritional status Obesity

Rapid weight loss Total parenteral nutrition Diabetes Other conditions Immobility Cirrhosis Spinal cord injury body mass index and the reported incidence of cholelithiasis. In this study, those with the highest body mass index (>45kg/m2) had a 7-fold increased risk of development of gall stones compared to non-obese controls. This relationship is somewhat weaker in men than in women. The association between obesity and gall stone formation may result from increased secretion of cholesterol into the bile as a result of higher 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA).

In studies of gall bladder motility in obese patients, no impairment in gall bladder contraction has been documented. Abnormal processing of the cholecystokinin receptor gene has been reported in one obese patient who had gall stones. Such an abnormality could lead to gall bladder stasis and ultimately to cholelithiasis.

Rapid weight loss is a recognized risk factor for cholesterol gall stone formation. As many as 30% of obese patients on restricted calorie intake may develop (usually asymptomatic) gall stones. This rate is higher, up to 50%, for obese patients who undergo gastric bypass surgery. It has been shown that hepatic cholesterol secretion increases in patients with low calorie intake. Other predisposing factors for the same patients are increased mucin secretion and decreased gall bladder motility. Gall stone formation may be prevented in this high-risk population possibly through prophylactic administration of a bile salt, ursodeoxycholic acid.

Low-fat diet by itself seems to be a predisposing factor. Cholecchia et al. studied 32 gall-stone-free obese patients and concluded that during a significant weight loss period, 54% of subjects following the low-fat diet, but none in the high-fat intake group, formed asymptomatic gall stones.

Total parenteral nutrition (TPN) is associated with the development of acalculous cholecystitis as well as cholelithiasis, cholecystitis, and gall bladder sludge. The latter can occur as early as 3 weeks after initiation of TPN. After 3 or 4 months of TPN, approximately 45% of patients will develop gall stones. Prolonged fasting resulting in gall bladder hypomotility seems to be the major cause of the bile stasis. Cholecystokinin-octapeptide 50ng/kg intravenous infusion for 10 minutes once daily has been shown to prevent gall bladder sludge and gall stone formation in patients on TPN.

Hormones and drugs Hormones such as estrogen and progesterone have a significant effect on the risk of gall stone formation. One interesting illustration of these effects is seen in pregnant woman. Increased estrogen levels during pregnancy cause increased cholesterol secretion and supersaturation of bile, which results in more lithogenic bile. Progesterone, on the other hand, reduces gall bladder motility, resulting in stasis and sludge formation in 30% of cases.

Among lipid-lowering drugs, Clofibrate seems to have the greatest association with increased gall stone formation. The role of statins in gall bladder disease remains to be elucidated. Approximately one-third of patients treated with octreotide, a somatostatin analog, develop new gall stones. Cef-triaxone (Rocephin) has been shown to cause sludge formation in children. A large fraction of ceftriax-one is secreted in bile (40%) and forms complexes with calcium, resulting in an insoluble salt. The sludge disappears when ceftriaxone is discontinued.

Diet and lipid profile The ingestion of refined sugars has been shown to be associated with gall stone disease. However, no such association has been shown for alcohol or tobacco. It is not clear if high serum cholesterol predisposes to gall stone formation. In fact, the contrary has been shown in some studies. This is also the case for dietary cholesterol ingestion, which was shown to be a protective factor for gall stone formation in one study. Hypertriglyceridemia, on the other hand, is positively associated with an increased incidence of gall stones.

Dietary antioxidant deficiency, particularly of a-tocopherol, as well as low intakes of linoleic acid and essential amino acids may increase the incidence of gall stone disease. One study showed that there is an inverse correlation between the incidence of gall stone disease and the amount of certain foods, particularly fish and fruits, consumed per day. The gall stone subjects ate fewer meals per day but ate more cereals, oils, sugars, and meats. They also had more fluctuation in their weight. They consumed less fiber, folate, magnesium, vitamins, and minerals.

Other conditions predisposing to gall bladder disease Insulin-resistant diabetes predisposes to cholelithiasis. A Swedish study showed that the prevalence of gall stones in Crohn's disease was twice that seen in the general population. Cirrhosis is another major risk factor for gall stones. The incidence of gall stone formation in cirrhosis is 10 times that seen in the general population. The incidence increases with the severity of cirrhosis, being worse in Child's class B and C disease and in patients with higher body mass index. High estrogen level and reduced hepatic synthesis and transport of bile salts are reasons for the increased risk in cirrhosis. The Physicians' Health Study showed that 30 minutes of endurance-type exercise five times per week prevents approximately one-third of cases of symptomatic gall stones in men. The Nurses' Health Study confirmed the same trend in women.

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