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US National Library of Medicine ÊÆ¹ñ¹ñΩ°å³Ø¿Þ½ñ´Û
National Institutes of Health¡¡¹ñΩ±ÒÀ¸¸¦µæ½ê
Niger J Surg. 2013 Jul-Dec¡¡Gabriel E Njeze
イメージ 1

Abstract
Gallstone disease is a worldwide medical problem, but the incidence rates show substantial geographical variation, with the lowest rates reported in African populations.

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 Publications in English language on gallstones which were obtained from reprint requests and PubMed database formed the basis for this paper. Data extracted from these sources included authors, country, year of publication, age and sex of patients, pathogenesis, risk factors for development of gallstones, racial distribution, presenting symptoms, complications and treatment. 

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Gallstones occur worldwide, however it is commonest among North American Indians and Hispanics but low in Asian and African populations. High biliary protein and lipid concentrations are risk factors for the formation of gallstones, while gallbladder sludge is thought to be the usual precursor of gallstones. Biliary calcium concentration plays a part in bilirubin precipitation and gallstone calcification. ¡ÊÃæÎ¬¡Ë

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Introduction
Gallstones are hardened deposits of the digestive fluid bile, that can form within the gallbladder. They vary in size and shape from as small as a grain of sand to as large as a golf ball. Gallstones occur when there is an imbalance in the chemical constituents of bile that result in precipitation of one or more of the components.

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Gallstone disease is often thought to be a major affliction in modern society.However, gallstones must have been known to humans for many years, since they have been found in the gallbladders of Egyptian mummies dating back to 1000 BC. This disease is however, a worldwide medical problem, even though there are geographical variations in gallstone prevalence Gallstones are becoming increasingly common; they are seen in all age groups, but the incidence increases with age; and about a quarter of women over 60 years will develop them. In most cases they do not cause symptoms, and only 10% and 20% will eventually become symptomatic within 5 years and 20 years of diagnosis. Thus the average risk of developing symptomatic disease is low, and approaches 2.0-2.6%/year.¡ÊÃæÎ¬¡Ë

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Method
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Pathogenesis
Gallstones are composed mainly of cholesterol, bilirubin, and calcium salts, with smaller amounts of protein and other materials. There are three types of gallstones[20] (i) Pure cholesterol stones, which contain at least 90% cholesterol, (ii) pigment stones either brown or black, which contain at least 90% bilirubin and (iii) mixed composition stones, which contain varying proportions of cholesterol, bilirubin and other substances such as calcium carbonate, calcium phosphate and calcium palmitate. Brown pigment stones are mainly composed of calcium bilirubinate whereas black pigment stones contain bilirubin, calcium and/or tribasic phosphate. In Western societies and in Pakistan more than 70% of gallstones are composed primarily of cholesterol, either pure or mixed with pigment, mucoglycoprotein, and calcium carbonate. Pure cholesterol crystals are quite soft, and protein contributes importantly to the strength of cholesterol stones.

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In the simplest sense, cholesterol gallstones form when the cholesterol concentration in bile exceeds the ability of bile to hold it in solution, so that crystals form and grow as stones. Cholesterol is virtually insoluble in aqueous solution, but in bile it is made soluble by association with bile salts and phospholipids in the form of mixed micelles and vesicles.

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Three types of abnormalities have been considered to be responsible for cholesterol gallstone formation. Cholesterol supersaturation, the essential requirement for cholesterol gallstone formation, might occur via excessive cholesterol biosynthesis, which is the main lithogenic mechanism in obese persons. In the non-obese, defective conversion of cholesterol to bile acids, due to a low or relatively low activity of cholesterol 7¦Á hydroxylase, the rate limiting enzyme for bile acid biosynthesis and cholesterol elimination could result in excessive cholesterol secretion. Finally, interruption of the enterohepatic circulation of bile acids could increase bile saturation. Temporary interruption of the enterohepatic bile acid circulation during overnight fasting leads to a higher cholesterol/phospholipid ratio in the vesicles secreted by the liver. Estrogen treatment also reduces the synthesis of bile acid in women.

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Pigment stones occur when red blood cells are being destroyed, leading to excessive bilirubin in the bile. Black pigment stones are more common in patients with cirrhosis or chronic hemolytic conditions such as the thalassemias, hereditary spherocytosis, and sickle cell disease, in which bilirubin excretion is increased. Primary bile-duct stones, defined as stones that originate in the bile ducts, are usually brown pigment stones associated with infection. Bacteria in the biliary system release ¦Â-glucuronidases, which hydrolyze glucuronic acid from conjugated bilirubin. The resulting unconjugated bilirubin precipitates as its calcium salts. Primary brown pigment stones of the bile ducts often occur in Asians, associated with decreased biliary secretory Immunogloblin A (IgA.) About 15% of gallstones are calcified enough to be seen on a plain abdominal radiograph, and of these, two thirds are pigment stones.

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High biliary protein and lipid concentrations are risk factors for the formation of gallstones. Gallbladder sludge, i.e., thickened gallbladder mucoprotein with tiny entrapped cholesterol crystals is thought to be the usual precursor of gallstones. Sludge can sometimes cause biliary pain, cholecystitis, or acute pancreatitis, but sludge may also resolve without treatment. The sources of sludge are pregnancy, prolonged total parenteral nutrition,starvation, or rapid weight loss. The antibiotic ceftriaxone can also precipitate in the gallbladder as sludgeand rarely, as gallstones.

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The biliary calcium concentration plays a part in bilirubin precipitation and gallstone calcification. Many patients with gallstones have increased biliary calcium, with supersaturation of calcium carbonate.

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Intestinal hypomotility has been recently recognised as a primary factor in cholesterol lithogenesis. Fiber may protect against gallstone formation by speeding intestinal transit and reducing the generation of secondary bile acids such as deoxycholate which has been associated with increased cholesterol saturation of the bile.

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Epidemiology of Gallstones
Epidemiological studies have suggested a marked variation in overall prevalence between different populations. Gallstone is one of the diseases prevalent in developed nations, but it is less prevalent in the developing populations that still consume traditional diets. Its prevalence is especially high in the Scandinavian countries and Chile and among Native Americans. Gallstones are more common in North America, Europe, and Australia, and are less prevalent in Africa, India, China, Japan, Kashmir, and Egypt.

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Factors influencing gallstone disease
Age
All epidemiological studies showed that increasing age was associated with an increased prevalence of gallstones. Gallstones are 4-10 times more frequent in older than younger subjects. Biliary cholesterol saturation increases with age, due to a decline in the activity of cholesterol 7¦Á hydroxylase, the rate limiting enzyme for bile acid synthesis. Deoxycholic acid proportion in bile increases with age through enhanced 7¦Á dehydroxylation of the primary bile acids by the intestinal bacteria.

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Gender, parity, and oral contraceptives
In all populations of the world, regardless of overall gallstone prevalence, women during their fertile years are almost twice as likely as men to experience cholelithiasis. This preponderance persists to a lesser extent into the postmenopausal period, but the sex difference narrows with increasing age.Increased levels of the hormone estrogen, as a result of pregnancy or hormone therapy, or the use of combined (estrogen-containing) forms of hormonal contraception, may increase cholesterol levels in bile and also decrease gallbladder movement, resulting in gallstone formation.

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Genetics
Both necropsy and population studies have clearly shown the existence of racial differences that cannot completely be explained by environmental factors. Cholesterol gallstone prevalence varies widely, from extremely low (<5%) in Asian and African populations, to intermediate (10-30%) in European and Northern American populations, and to extremely high (30-70%) in populations of Native American ancestry (Pima Indians in Arizona, Mapuche Indians in Chile).¡ÊÃæÎ¬¡Ë

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Obesity and body fat distribution
Obesity is an important risk factor for gallstone disease, more so for women than for men. It raises the risk of cholesterol gallstones by increasing biliary secretion of cholesterol, as a result of an increase in 3-hydroxy-3-mthylglutaryl coenzyme A (HMGCoA) reductase activity. Epidemiological studies have found that the lithogenic risk of obesity is strongest in young women, and that slimness protects against cholelithiasis.

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Rapid weight loss
Rapid weight loss is associated with occurrence of sludge and gallstones in 10-25% of patients in a few weeks of initiating the slimming procedures. If a person loses weight too quickly, the liver secretes extra cholesterol; in addition there is rapid mobilization of cholesterol from adipose tissue stores. In fasting associated with severely fat restricted diets, gallbladder contraction is reduced, and the accompanying gallbladder stasis favors gallstone formation. Enhancing gallbladder emptying by inclusion of a small amount of dietary fat inhibits gallstone formation in patients undergoing rapid weight loss.Fasting in the short term increases the cholesterol saturation of gallbladder bile and in the longer term, causes gallbladder stasis which can lead to sludge, and eventually gallstone formation. Younger women with gallstones were shown to be more prone to skip breakfast than controls. A shorter overnight fasting is protective against gallstones in both sexes.

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Diet
Nutritional exposure to western diet, i.e., increase intake of fat, refined carbohydrates and decrease in fibre content is a potent risk factor for development of gallstones.Calcium intake seems to be inversely associated with gallstone prevalence. Dietary calcium decreases cholesterol saturation of gallbladder bile by preventing the reabsorption of secondary bile acids in the colon. Vitamin C influences 7¦Á hydroxylase activity in the bile and it was shown that ascorbic acid might reduce lithogenic risk in adults. Coffee consumption seems to be inversely correlated with gallstone prevalence, due to an increased enterohepatic circulation of bile acids. Coffee components stimulate cholecystokinin release, enhance gallbladder motility, inhibit gallbladder fluid absorption, decrease cholesterol crystallization in bile and perhaps increase intestinal motility.

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Physical activity
Regular exercise, in addition to facilitating weight control, alone or in combination with dieting, improves several metabolic abnormalities related to both obesity and cholesterol gallstones. In contrast, sedentary behaviour, is positively associated with the risk of cholecystectomy.

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Clinical Presentations of Gallstone Disease
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US National Library of Medicine 
National Institutes of Health
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