A cholesterol stone is usually solitary (the cholesterol 'solitaire').

It is oval or rounded in shape, and vary from 1 to 4 cm in diameter, or larger. It is light in weight as well as in color.

In its absolutely pure state it is very pale yellow in colour and feebly translucent.

More often bile pigments are deposited within it.

On section it has a radiating crystalline interior.

Cholesterol stones, which make up some 6% of all gallstones, are believed to be formed primarily in aseptic static bile (in a "stasis" gallbladder). They tend to reside in Hartmann’s pouch.

The stone is composed of  50 to 100% cholesterol, the rest consists of calcium salts and mucin.

Cholesterol stones are often detected at autopsy. During their reproductive period, women are three times more likely to develop cholesterol gallstones than men.The incidence is higher in users of oral contraceptives and in women  with several pregnancies.

Interestingly, cholesterol gallstones are exceedingly common in Pima Indian women in the American Southwest, among whom three-quarters are affected by age 25, and 90% above the age of 60 years. This may be due to the genetic factors.

Blacks in the US have a lower incidence of gallstones than whites, but a higher incidence than blacks in Africa. This difference probably reflects environmental influence, although a role of genetic admixtures is also possible.

A brood of mixed (secondary or inflammatory) gallstones may be formed later, or a mixed covering of pigment and cholesterol may form around the primary cholesterol stone. This is known as combination stone.

Pathogenesis:  

Diagram showing Pathogenesis of Cholesterol stone: click here

Pathogenesis of cholesterol stones relates mainly to the composition of the bile.

Normally, cholesterol, a compound highly insoluble in water, is secreted by the hepatocytes into the bile, where it is held in solution by the combined action of the bile acids and lecithin and carried in the form   of mixed lipid micelles. If the bile contains excess cholesterol or is deficient in bile acids, the bile becomes supersaturated, and under some circumstances the cholesterol precipitates as solid crystals.

The bile of persons afflicted with cholesterol gallstones has more cholesterol as it leaves the liver than that of normal individuals, pointing to the liver, rather than gallbladder as the culprit in the genesis of cholesterol stones.

The hepatocytes of patients with cholesterol gallstones are deficient in  7alpha-hydroxylase, the enzyme involved in the rate-limiting step by which bile salts are formed from cholesterol.

As a result, the total size of the bile salt pool is reduced.

The resulting decrease in bile salt secretion contributes to the stone-forming (lithogenic) properties of the bile.

Furthermore, in obese people, cholesterol secretion by the liver is augmented, further adding to the supersaturation of the bile with cholesterol.

Although cholesterol supersaturation of the bile is apparently required for gallstone formation , additional factors are also required.

Cholesterol does not precipitate from saturated bile obtained from patients without gallstones.

On the other hand , bile from persons without gallstones, but with properties similar to those in the bile of patients with gallstones, crystallizes without difficulty.

It is thought that the mucinous glycoproteins secreted by the gallbladder epithelium provide the necessary nidus for crystallization.

Risk factors:

The higher prevalence of gallstones in premenopausal women has been attributed to the fact that estrogens stimulate the formation of  lithogenic bile by the liver.

Estrogens increase the hepatic secretion of cholesterol and may  decrease the secretion of bile acids.

These effects are augmented during pregnancy, because the gallbladder empties more slowly in the last trimester, thereby causing stasis and increasing the opportunity for precipitation of cholesterol crystals.

Progesterone has been shows to inhibit discharge of bile from the gallbladder. These mechanisms are also invoked to explain the increased incidence of gallstones in users of oral contraceptives.

Other risk factors for the development of cholesterol gallstones can be divided into those that relate to increased biliary cholesterol secretion, those that relate to decreased secretion of bile salts and lecithin, and those that relate to combination of the two.

Risk factors associated with increased biliary cholesterol secretion include the following:

Increasing age ; Obesity ; Membership of certain ethnic groups (e.g. Chilean women, some northern European groups) ; Familial  predisposition ; Diets high in calories and cholesterol ; Certain metabolic abnormalities associated with high blood cholesterol levels, for instance diabetes ; Some genetic hyperlipoproteinemias, and  Primary biliary cirrhosis.

Decreased secretion of bile salts and lecithin occurs in nonobese Caucasians who develop gallstones.

Gastrointestinal absorptive  disorders that interfere with the  enterohepatic circulation of bile acids - for instance pancreatic insufficiency secondary to cystic fibrosis and Crohn's disease also  decrease secretion of bile acids and favour gallstone formation.

Cholesterol synthesis is increased while that of bile salt and lecithin is reduced in American Pima Indians and in those who take certain drugs (e.g. clofibrate).

BACKGROUND: There is a high prevalence of gallstone disease in Western countries as a consequence of genetic, biochemical, and environmental factors. Animal and clinical studies have explored the importance of dietary elements. Overwhelming but conflicting information has been reported about the relationship between specific dietary components and gallstone disease. Although the detailed biochemical pathways have been described in experimental models, human studies are mainly epidemiological. METHODS: We performed a Medline search with the terms "diet", "gallstones", "cholesterol", "risk factors", including results from 1965 to 2006 and the author's personal library to review the relationship between dietary factors and cholesterol gallstone disease. RESULTS: We identified over 150 references and present their results with respect to the author's criteria. CONCLUSIONS: The best delineated relationship between cholesterol gallstones and diet was found in the studies that analyzed total calorie intake, refined sugars and fiber. The possible mechanisms are discussed in base of experimental studies.

Effect of hypolipidemic treatment on the composition of bile and the risk or cholesterol gallstone disease.Cas Lek Cesk. 2007;146(1):24-34.

Obesity, diabetes mellitus type 2 and dyslipidemia, characterized by hypertriglyceridemia and low HDL-cholesterol levels, are risk factors for cholesterol gallstone disease. The common denominator of above-mentioned states is insulin resistance. Hypolipidemic treatment significantly influences not only the biliary lipid composition, but also other etiopathogenetic mechanisms of the disease. Three principal defects are involved in gallstone formation - cholesterol supersaturation, accelerated nucleation, and gallbladder dysmotility. The degree of cholesterol saturation in gallbladder bile is the most important predictor of cholesterol crystal formation. Cholesterol, lecithin and bile acids are the major components in bile. According to the molar ratios of the three main components, simple or mixed micelles, unstable unilamellar or multilamellar vesicles are formed in the bile. The cholesterol supersaturation of the gallbladder bile and cholesterol crystal formation from the unstable multilamellar vesicles initiates the onset of cholesterol cholelithiasis. The pool of unesterified cholesterol is the source for VLDL synthesis; together with HDL-cholesterol, it is also the source for cholesterol secretion into the bile. The main metabolic products of cholesterol degradation are bile acids, which are synthesized predominantly from LDL-cholesterol. The rate of the production of primary bile acids is principally regulated by cholesterol 7alpha-hydroxylase (CYP7A 1). The treatment of dyslipidemia with niacin and resins does not influence the saturation of bile with cholesterol or the incidence of cholelithiasis. The effects of ezetimibe in human patients with the respect of cholesterol cholelithiasis have not been published. The fibrate treatment is associated with increased cholesterol saturation of bile due to inhibition of CYP7A1 activity, enhanced flux of cholesterol via HDL and increased secretion of cholesterol into bile. The clinical studies describe cholesterol supersaturation in bile and increased frequency of cholelithiasis as well. The administration of pravastatin and simvastatin led to reduced cholesterol saturation indexes. The patients with endogenous hypertriglyceridemia and low HDL-cholesterol being administered with polyunsaturated fatty acids of n-3 family had decreased cholesterol concentration in bile. Other authors described beneficial effect of fish oil on the biliary cholesterol nucleation time, improvement of gallbladder sensitivity to cholecystokinin and the prevention of cholesterol gallstone formations caused by rapid weight loss.

Genetic predisposition of cholesterol gallstone disease.Ann Hepatol. 2006 Jul-Sep;5(3):140-9.

Gallstone disease (GSD) is the result of the interaction between genetic and environmental factors and it is a major disease cause of surgery with high costs to health systems. Worldwide prevalence varies according to the ethnic population suggesting that high prevalence of GSD in certain ethnic groups is due to the presence of genetic factors implicated in different metabolic pathways. However, environmental factors play a determinant role in gene expression. This review summarizes the genes involved in biliary salt and cholesterol synthesis, lipids transport and the Lith genes. Future studies should be focused on the study of interactions between genetic and environmental factors which could be specific for each population.

Effect of the type of dietary fat on biliary lipid composition and bile lithogenicity in humans with cholesterol gallstone disease.Nutrition. 2005 Mar;21(3):339-47.

OBJECTIVE: The effect of the type of dietary fat on bile lipids and lithogenicity is unclear. This study compared the effects of two dietary oils that differed in fatty acid profile on biliary lipid composition in humans. METHODS: Female patients who had cholesterol gallstones and were scheduled for elective cholecystectomy were studied. For 30 d before surgery, subjects were kept on diets that contained olive oil (olive oil group, n = 9) or sunflower oil (sunflower oil group, n = 9) as the main source of fat. Gallbladder bile and stones were sampled at surgery. After cholecystectomy, duodenal samples were collected by nasoduodenal intubation during fasting and after administration of mixed liquid meals that included the corresponding dietary oil. Duodenal and gallbladder bile samples were analyzed for cholesterol, phospholipids, and total bile acids by established methods. Individual bile acid conjugates in gallbladder bile were measured by high-performance liquid chromatography. Gallstones were analyzed by semiquantitative polarizing light microscopy. RESULTS: Despite marked differences in the absolute concentration of biliary lipids and total lipid content, manipulation of dietary fat ingestion did not influence the cholesterol saturation or the profile of individual bile acids in gallbladder bile obtained from patients who had gallstones. All but one subject had mixed cholesterol stones. A cholesterol saturation index of hepatic bile in fasted cholecystectomized patients was similar in both dietary groups and indicative of supersaturation. In response to the test meal, the cholesterol saturation index decreased significantly in patients given the olive oil diet, reaching values lower than one at 120 min postprandially. In contrast, hepatic bile secreted by patients who consumed sunflower oil appeared supersaturated (cholesterol saturation index >1.5) throughout the experiment. CONCLUSIONS: Our results suggest that the type of dietary fat habitually consumed can influence bile composition in humans. In gallbladder, this influence was noted in the presence of more concentrated bile in the olive oil group. However, this was not translated into a modification of cholesterol saturation, which is likely due to the fact that cholesterol gallstones were present by the time the dietary intervention started. The finding that a typical postprandial variation in hepatic bile lithogenicity occurred only in olive oil patients was revealing. While keeping in mind the methodologic limitations of this part of the study, some gastrointestinal and metabolic mechanisms for this effect are discussed.

Helicobacter pylori in the etiology of cholesterol gallstones.J Clin Gastroenterol. 2005 Feb;39(2):134-7.

GOALS: We aimed to investigate the presence of bacterial structures in cholesterol gallstones and particularly presence of Helicobacter spp/H. pylori in gallstones by microbiologic cultivation, histopathologic staining, and polymerase chain reaction (PCR). BACKGROUND: Many studies suggest that different mechanisms are responsible for the formation of pigmented gallstones and cholesterol gallstones. Recently, studies showed that infection could have an important role in the formation of cholesterol gallbladder stones. STUDY: We examined 77 mixed cholesterol gallstones. After cholecystectomy, gallbladder cultures were done for H. pylori and other bacterium. Gallbladder has also been examined by three histopathologic staining methods (Warthin-Starry, hematoxylin eosin, and gram staining) for Helicobacter spp. In addition, 16S rRNA-PCR amplification was performed for Helicobacter spp in gallstones. Twenty postmortem gallbladders without gallstones were investigated by the same histopathologic and PCR methods for Helicobacter spp. as a control group. RESULTS: Different bacterium were isolated from 22 gallbladder samples (12 Escherichia coli, 8 Pseudomonas, and 2 clostridium) and H. pylori was isolated in 6 gallbladder samples. Helicobacter spp was found in 7 gallstones by PCR amplification. Helicobacter-like organisms were demonstrated in 18 samples by three different histopathologic methods. Helicobacter-like organisms were also found in five samples by the same histopathologic methods (Warthin-Starry, hematoxylin-eosin, and gram staining). Only four samples were found positive for Helicobacter spp/H. pylori by all methods. CONCLUSIONS: Bacterial population including H. pylori could have a possible role in the formation of cholesterol gallstones.

Cholesterol gallstone pathogenesis: a study of potential nucleating agents for cholesterol crystal formation in bile.Clin Sci (Lond). 1985 May;68(5):589-96.

Cholesterol monohydrate crystal formation was measured quantitatively in model bile solutions, which were supersaturated with cholesterol, by a radiochemical method and qualitatively in human gallbladder bile by polarizing microscopy. Various agents, which have been postulated to act as nucleating factors for cholesterol crystal and gallstone formation, were added to bile and their effect on the appearance of cholesterol crystals was determined. These agents included calcium salts found in gallstones (calcite, aragonite, apatite, bilirubinate), Escherichia coli bacteria, pigment residues from cholesterol gallstones, bilirubin and several mucin preparations. Human gallbladder bile, which was collected from patients with and without cholesterol gallstones, was also mixed with model bile to examine whether nucleating or anti-nucleating factors were present. None of the agents tested markedly and consistently promoted cholesterol monohydrate crystal formation in model or human bile, except seed crystals of cholesterol monohydrate which were used as a control. Human gallbladder bile from obese patients without gallstones delayed the appearance of cholesterol crystals in model bile solutions, whereas gallbladder bile from gallstone patients did not. These results do not provide experimental support for the hypothesis that calcium salts and pigment material found in gallstones, or gallbladder mucin at concentrations less than 10 mg/ml, act as nucleating agents for cholesterol crystal and stone formation. The difference between gallbladder biles from patients with and without gallstones in their propensity to form cholesterol crystals may be due to the presence of an anti-nucleating factor in normal bile.

Evidence for a potent nucleating factor in the gallbladder bile of patients with cholesterol gallstones.Gastroenterology. 1983 Oct;85(4):801-7.

A study was performed to determine whether the rapid nucleation time of gallbladder bile obtained from patients with cholesterol gallstones was due to the addition of a nucleating agent or the removal of an antinucleating agent by the gallbladder. Isotropic phases of gallbladder bile from normal controls (control bile) and from patients with gallstones (abnormal bile) were mixed 50:50 (vol/vol) and the nucleation times of the mixtures and parent biles were determined. The mixtures had rapid nucleation times, similar to those of the gallbladder bile from gallstone patients, indicating that a nucleating factor was present in the abnormal bile. Experiments were then performed using mixtures in which the proportion of abnormal bile was reduced. These studies showed that the nucleating agent was potent. The results were not due to changes in cholesterol saturation or total lipid concentration. The conclusions reached in the first study were supported in a second set of similar experiments in which hepatic bile from gallstone patients was mixed with their own gallbladder bile. It was also found that filtration of abnormal bile through an XM-300 Amicon filter did not eliminate its nucleating potency, indicating that the results could not be explained by the presence of residual microcrystals in the abnormal bile.

Histopathology-India.net

Pathology-India.com

Pancreatic Pathology Online

Gall Bladder Pathology Online

Paediatric Pathology Online

Paraganglioma-Online

Endocrine Pathology Online

Eye Pathology Online

Ear Pathology Online

Cardiac Path Online

Mesothelioma-Online

Pulmonary Pathology Online

Nutritional Pathology Online

Environmental Pathology Online

Pathology Quiz Online

Dermpath-India

Soft Tissue Pathology

Case Index

OBJECTIVE: Cholesterol phospholipid vesicles play an important role in the nucleation of cholesterol in bile. Recent studies have identified an additional vesicle population in human bile. In this study, the role of these small vesicles as cholesterol carriers was examined. METHODS: Gallbladder bile was obtained from 60 patients at cholecystectomy. Large vesicles, small vesicles, lamellae, and mixed micelles were separated using gel filtration chromatography. RESULTS: Small vesicles were present in bile from the majority of patients both with and without cholesterol gallstones, whereas the void volume vesicle fraction was found almost exclusively in bile from patients with cholesterol gallstones. Both large vesicular and small vesicular cholesterol increased as total bile cholesterol concentration increased; however, the cholesterol-phospholipid ratio in the large vesicle fraction from patients with cholesterol stones was significantly greater than the ratio in small vesicles (1.6 +/- 0.3 vs. 1.0 < or = 0.1, p < 0.05). Whole bile cholesterol crystal appearance time was correlated significantly with the percentage of cholesterol transported by large vesicles (r = 0.63, p < 0.001) but not with the percentage of cholesterol present in small vesicles. Finally, large vesicles isolated by gel filtration chromatography formed cholesterol crystals faster than small vesicles (5.3 +/- 2 vs. 17.4 +/- 4 days, p < 0.01). CONCLUSIONS: These data suggest that a heterogenous population of vesicles is present in human gallbladder bile. As bile becomes saturated with cholesterol, it increasingly is solubilized by both small and large vesicles. The small vesicles have relatively less cholesterol and are more stable than the larger variety, from which cholesterol is most likely to precipitate.

Cholesterol gallstones and cancer of gallbladder (CAGB): molecular links.Med Hypotheses. 2007 Sep 11

There is a known association between cholesterol gallstones and cancer of gall bladder (CAGB). However, the exact relation is not clear. It is proposed they are linked at molecular level by the activity of the orphan nuclear receptors (ONRs) and ABC transporter pumps involved in cholesterol and xenobiotic efflux from the liver into bile. There is evidence that these two pathways are closely interlinked and influence each other. Genetic and environmental factors that upregulate these systems can lead to the simultaneous pumping of cholesterol (which precipitate as gallstones) and a food carcinogen into the bile in gall bladder; the latter causes malignant transformation. Aflatoxin B, a potent hepatocarcinogen, could be the culprit in endemic regions such as South America and North India.

Gram-positive cocci are associated with the formation of completely pure cholesterol stones.Am J Gastroenterol. 2002 Jan;97(1):83-8.

OBJECTIVES: Recently it has been reported that bacterial DNA has been detected in mixed cholesterol stones (cholesterol content < 95%), which were not previously believed to be related to bacteria, using the polymerase chain reaction (PCR). We examined bacterial DNA in pure cholesterol stones to clarify the mechanism of initiation or promotion of the formation of cholesterol gallstones. METHODS: We examined 69 gallstones (30 brown pigment stones, 21 pure cholesterol stones, and 18 mixed cholesterol stones). Bacterial DNA was extracted from the core of the gallstones and amplified by PCR. Bacteria species in gallstones were identified by DNA sequencing of the PCR products. RESULTS: Bacterial DNA was detected in 26/30 brown pigment stones (87%), in 12/21 pure cholesterol stones (57%) (cholesterol content = 100%), and in 12/18 mixed cholesterol stones (67%) (cholesterol content = 82-95%). Bacterial species in gallstones were identified by DNA sequencing of PCR products. Eighty percent of bacteria in brown pigment stones were gram-negative rods or anaerobes. In contrast, 100% of bacteria in pure cholesterol stones were gram-positive cocci. The bacteria in mixed cholesterol stones consisted of 40% gram-positive cocci, 50% gram-negative rods, and 10% anaerobes. CONCLUSIONS: It was strongly suggested that gram-positive cocci are associated with the formation of pure cholesterol stones.