Gallstones

Pathogenesis Gallstones are quite prevalent in most western countries. In the United States, autopsy series have shown gallstones in at least 20% of women and in 8% of men over the age of 40. It is estimated that 16 to 20 million persons in the United States have gallstones and that approximately 1 million new cases of cholelithiasis develop each year.

Gallstones are formed by concretion or accretion of normal or abnormal bile constituents. They are divided into three major types; cholesterol and mixed stones account for 80% of the total, with pigment stones comprising the remaining 20%. Mixed and cholesterol gallstones usually contain more than 50% cholesterol monohydrate plus an admixture of calcium salts, bile pigments, proteins, and fatty acids. Pigment stones are composed primarily of calcium bilirubinate; they contain less than 20% cholesterol.

Cholesterol and Mixed Stones and Biliary Sludge Cholesterol is essentially water insoluble and requires aqueous dispersion into either micelles or vesicles, both of which require the presence of a second lipid to "liquefy" the cholesterol. Cholesterol and phospholipids are secreted into bile as unilamellar bilayered vesicles, which are converted into mixed micelles consisting of bile acids, phospholipids, and cholesterol by the action of bile acids. If there is an excess of cholesterol in relation to phospholipids and bile acids, unstable cholesterol-rich vesicles remain, which aggregate into large multilamellar vesicles from which cholesterol crystals precipitate (Fig. 302-1).

There are several important mechanisms in the formation of lithogenic (stone-forming) bile. The most important is increased biliary secretion of cholesterol. This may occur in association with obesity, high-caloric and cholesterol-rich diets, or drugs (e.g., clofibrate) and may result from increased activity of HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis, and increased hepatic uptake of cholesterol from blood. In patients with gallstones, dietary cholesterol increases biliary cholesterol secretion. This does not occur in non-gallstone patients on high-cholesterol diets. In addition to environmental factors such as high-caloric and cholesterol-rich diets, genetic factors play an important role in cholesterol hypersecretion and gallstone formation. A high prevalence of gallstones is found among first-degree relatives of gallstone carriers and in certain ethnic populations such as American Indians as well as Chilean Indians and Chilean Hispanics. A common genetic trait has been identified for some of these populations by mitochondrial DNA analysis. A genetic defect in the control of cholesterol secretion also exists in certain strains of inbred mice who develop gallstones under a lithogenic diet. In some patients, impaired hepatic conversion of cholesterol to bile acids may also occur, resulting in an increase of the lithogenic cholesterol/bile acid ratio. Lithogenic bile may also result from conditions affecting the enterohepatic circulation of bile acids (e.g., prolonged parenteral alimentation or ileal disease or resection). In addition, most patients with gallstones may have reduced activity of hepatic cholesterol 7-hydroxylase, the rate-limiting enzyme for primary bile acid synthesis.

Thus an excess of biliary cholesterol in relation to bile acids and phospholipids is primarily due to hypersecretion of cholesterol, but hyposecretion of bile acids may contribute. Two additional disturbances of bile acid metabolism that are likely to contribute to supersaturation of bile with cholesterol are (1) reduction of the bile acid pool and (2) enhanced conversion of cholic acid to deoxycholic acid, with replacement of the cholic acid pool by an expanded deoxycholic acid pool. The first disorder may be caused by more rapid loss of primary bile acid from the small intestine into the colon. The second disturbance may result from enhanced dehydroxylation of cholic acid and increased absorption of newly formed deoxycholic acid. An increased deoxycholate secretion is associated with hypersecretion of cholesterol into bile. While supersaturation of bile with cholesterol is an important prerequisite for gallstone formation, it is not sufficient by itself to produce cholesterol precipitation in vivo. Most people with supersaturated bile do not develop stones because the time required for cholesterol crystals to nucleate and grow is longer than the time bile spends in the gallbladder.

A second important mechanism is nucleation of cholesterol monohydrate crystals, which is greatly accelerated in human lithogenic bile; it is this feature rather than the degree of cholesterol supersaturation that distinguishes lithogenic from normal gallbladder bile. Accelerated nucleation of cholesterol monohydrate in bile may be due to either an excess of pronucleating factors or a deficiency of antinucleating factors. Mucin and certain non-mucin glycoproteins appear to be pronucleating factors, while apolipoproteins AI and AII and other glycoproteins appear to be antinucleating factors. Cholesterol monohydrate crystal nucleation and crystal growth probably occur within the mucin gel layer. Vesicle fusion leads to liquid crystals, which, in turn, nucleate into solid cholesterol monohydrate crystals. Continued growth of the crystals occurs by direct nucleation of cholesterol molecules from supersaturated unilamellar or multilamellar biliary vesicles.

A third important mechanism in cholesterol gallstone formation is gallbladder hypomotility. If the gallbladder emptied all supersaturated or crystal-containing bile completely, stones would not be able to grow. A high percentage of patients with gallstones exhibits abnormalities of gallbladder emptying. Ultrasonographic studies show that gallstone patients have an increased gallbladder volume during fasting and also after a test meal (residual volume) and that fractional emptying after gallbladder stimulation is decreased. Gallbladder emptying is a major determinant of gallstone recurrence in patients who underwent biliary lithotripsy. Within 3 years, only 13% of patients with good but 53% of patients with poor gallbladder emptying form recurrent stones.

Biliary sludge is a thick mucous material that upon microscopic examination reveals lecithin-cholesterol crystals, cholesterol monohydrate crystals, calcium bilirubinate, and mucin thread or mucous gels. Biliary sludge typically forms a crescent-like layer in the most dependent portion of the gallbladder and is recognized by characteristic echoes on ultrasonography (see below). The presence of biliary sludge implies two abnormalities: (1) the normal balance between gallbladder mucin secretion and elimination has become deranged and (2) nucleation of biliary solutes has occurred. That biliary sludge may be a precursor form of gallstone disease is evident from several observations. In one study, 96 patients with gallbladder sludge were followed prospectively by serial ultrasound studies. In 18%, biliary sludge disappeared and did not recur for at least 2 years. In 60%, biliary sludge disappeared and reappeared; in 14%, gallstones (8% asymptomatic, 6% symptomatic) developed, and in 6%, severe biliary pain with or without acute pancreatitis occurred. In 12 patients, cholecystectomies were performed, 6 for gallstone-associated biliary pain and 3 in symptomatic patients with sludge but without gallstones who had prior attacks of pancreatitis; the latter did not recur after cholecystectomy. It should be emphasized that biliary sludge can develop with disorders that cause gallbladder hypomotility, i.e., surgery, burns, total parenteral nutrition, pregnancy, and oral contraceptivesall of which are associated with gallstone formation.

Two other conditions are associated with cholesterol stone or biliary sludge formation: pregnancy and very low calorie diet. There appear to be two key changes during pregnancy that contribute to a "cholelithogenic state." First, the composition of the bile acid pool and the cholesterol-carrying capacity of bile change, with a resultant marked increase in cholesterol saturation during the third trimester. Second, ultrasonographic studies have demonstrated that gallbladder contraction in response to a standard meal is sluggish, resulting in impaired gallbladder emptying. That these changes are related to pregnancy per se is supported by several studies that show reversal of these abnormalities after delivery. During pregnancy, gallbladder sludge develops in 20 to 30% of women and gallstones in 5 to 12%. While biliary sludge is a common finding during pregnancy, it is usually asymptomatic and often resolves spontaneously after delivery. Gallstones, which are less common than sludge and frequently associated with biliary colic, may also disappear after delivery because of spontaneous dissolution related to bile becoming unsaturated with cholesterol post partum.

From 10 to 20% of people having rapid weight reduction through very low calorie dieting develop gallstones. In a study involving 600 patients who completed a 16-week, 520-kcal/d diet, UDCA in a dosage of 600 mg/d proved highly effective in preventing gallstone formation; gallstones developed in only 3% of UDCA recipients compared to 28% of placebo-treated patients.

To summarize, cholesterol gallstone disease occurs because of several defects, which include (1) bile supersaturation with cholesterol, (2) nucleation of cholesterol monohydrate with subsequent crystal retention and stone growth, and (3) abnormal gallbladder motor function with delayed emptying and stasis. Other important factors known to predispose to cholesterol stone formation are summarized in Table 302-1.

Pigment Stones Gallstones composed largely of calcium bilirubinate are much more common in the Far East than in western countries. The presence of increased amounts of unconjugated, insoluble bilirubin in bile results in the precipitation of bilirubin, which may aggregate to form pigment stones or may form the nidus for growth of mixed cholesterol gallstones. In western countries, chronic hemolytic states (with increased conjugated bilirubin in bile) or alcoholic liver disease are associated with an increased incidence of pigment stones. Deconjugation of an excess of soluble bilirubin mono- and diglucuronide may be mediated by endogenous -glucuronidase but may also occur by spontaneous alkaline hydrolysis. Sometimes, the enzyme is also produced when bile is chronically infected by bacteria. Pigment stone formation is especially prominent in Asians and is often associated with infections in the biliary tree (Table 302-1).

Diagnosis Procedures of potential use in the diagnosis of cholelithiasis and other diseases of the gallbladder are detailed in Table 302-2. The plain abdominal film may detect gallstones containing sufficient calcium to be radiopaque (10 to 15% of cholesterol and mixed stones and approximately 50% of pigment stones). Plain radiography may also be of use in the diagnosis of emphysematous cholecystitis, porcelain gallbladder, limey bile, and gallstone ileus.

Ultrasonography of the gallbladder is very accurate in the identification of cholelithiasis and has several advantages over oral cholecystography (Fig. 302-2A). The gallbladder is easily visualized with the technique, and in fact, failure to image the gallbladder successfully in a fasting patient correlates well with the presence of underlying gallbladder disease. Stones as small as 2 mm in diameter may be confidently identified provided that firm criteria are used [e.g., acoustic "shadowing" of opacities that are within the gallbladder lumen and that change with the patient's position (by gravity)]. In major medical centers, the false-negative and false-positive rates for ultrasound in gallstone patients are about 2 to 4%. Biliary sludge is material of low echogenic activity that typically forms a layer in the most dependent position of the gallbladder. This layer shifts with postural changes but fails to produce acoustic shadowing; these two characteristics distinguish sludges from gallstones. Ultrasound can also be used to assess the emptying function of the gallbladder.

Oral cholecystography (OCG) is a useful procedure for the diagnosis of gallstones but has been largely replaced by ultrasound. However, OCG is still useful for the selection of patients for nonsurgical therapy of gallstone disease such as lithotripsy or bile acid dissolution therapy. In both these settings, OCG is used to assess the patency of the cystic duct and gallbladder emptying function. Further, OCG can also delineate the size and number of gallstones and determine whether they are calcified. Factors that may produce nonvisualization of the OCG are summarized in Table 302-2.

Radiopharmaceuticals such as ^99mTc-labeled N-substituted iminodiacetic acids (HIDA, DIDA, DISIDA, etc.) are rapidly extracted from the blood and are excreted into the biliary tree in high concentration even in the presence of mild to moderate serum bilirubin elevations. Failure to image the gallbladder in the presence of biliary ductal visualization may indicate cystic duct obstruction, acute or chronic cholecystitis, or surgical absence of the organ. Such scans have their greatest application in the diagnosis of acute cholecystitis.

Symptoms of Gallstone Disease Gallstones usually produce symptoms by causing inflammation or obstruction following their migration into the cystic duct or CBD. The most specific and characteristic symptom of gallstone disease is biliary colic. Obstruction of the cystic duct or CBD by a stone produces increased intraluminal pressure and distention of the viscus that cannot be relieved by repetitive biliary contractions. The resultant visceral pain is characteristically a severe, steady ache or pressure in the epigastrium or right upper quadrant (RUQ) of the abdomen with frequent radiation to the interscapular area, right scapula, or shoulder.

Biliary colic begins quite suddenly and may persist with severe intensity for 30 min to 5 h, subsiding gradually or rapidly. An episode of biliary pain is sometimes followed by a residual mild ache or soreness in the RUQ, which may persist for 24 h or so. Nausea and vomiting frequently accompany episodes of biliary colic. An elevated level of serum bilirubin and/or alkaline phosphatase suggests a common duct stone. Fever or chills (rigors) with biliary colic usually imply a complication, i.e., cholecystitis, pancreatitis, or cholangitis. Complaints of vague epigastric fullness, dyspepsia, eructation, or flatulence, especially following a fatty meal, should not be confused with biliary colic. Such symptoms are frequently elicited from patients with gallstone disease but are not specific for biliary calculi. Biliary colic may be precipitated by eating a fatty meal, by consumption of a large meal following a period of prolonged fasting, or by eating a normal meal.

Natural History Gallstone disease discovered in an asymptomatic patient or in a patient whose symptoms are not referable to cholelithiasis is a common clinical problem. The natural history of "silent" or asymptomatic gallstones has occasioned much debate. A study of predominantly male silent gallstone patients suggests that the cumulative risk for the development of symptoms or complications requiring surgery is relatively low10% at 5 years, 15% at 10 years, and 18% at 15 years. Patients remaining asymptomatic for 15 years were found to be unlikely to develop symptoms during further follow-up, and most patients who did develop complications from their gallstones experienced prior warning symptoms. Similar conclusions apply to diabetic patients with silent gallstones. Decision analysis has suggested that (1) the cumulative risk of death due to gallstone disease while on expectant management is small, and (2) prophylactic cholecystectomy is not warranted.

Complications requiring cholecystectomy are much more common in gallstone patients who have developed symptoms of biliary colic. Patients found to have gallstones at a young age are more likely to develop symptoms from cholelithiasis than are patients older than 60 years at the time of initial diagnosis. Patients with diabetes mellitus and gallstones may be somewhat more susceptible to septic complications, but the magnitude of risk of septic biliary complications in diabetic patients is incompletely defined. In addition, asymptomatic gallstone patients with nonvisualization of the gallbladder on OCG appear to have an increased tendency to develop symptoms and complications.