Uncomplicated gallstone disease

Author

Salam F Zakko, MD, FACP Section Editor

Sanjiv Chopra, MD Deputy Editor

Peter A L Bonis, MD

Last literature review version 17.1: January 2009 | This topic last updated: January 28, 2008 (More)

INTRODUCTION — The most significant challenge in the evaluation of patients with upper digestive symptoms who are found to have gallstones, is whether the stones are the cause of the symptoms (ie, gallstone disease) or are an incidental finding. Making this distinction is important because both gallstones and upper digestive symptoms are common in the general population but are not always related. While cholecystectomy can be curative in those whose symptoms are related to gallstones, it exposes the rest to unnecessary risk, delays definitive treatment for the actual cause of symptoms, and incurs unnecessary expense.

This topic review will provide an overview of the evaluation of patients with possible, uncomplicated gallstone-related disease. An approach to asymptomatic patients found to have gallstones is presented separately. (See "Approach to the patient with incidental gallstones"). Complications related to gallstones are discussed on their corresponding topic reviews.

CLINICAL FEATURES — When considering gallstone disease it is helpful to categorize patients into the following clinical groups: Gallstones on imaging studies but without symptoms (category 1) Typical biliary symptoms and gallstones on imaging studies (category 2) Atypical symptoms and gallstones on imaging studies (category 3) Typical biliary symptoms but without gallstones on imaging studies (category 4)

As will be discussed below, the approach to patients in category 1 and 2 is generally straightforward. Patients in category 1 should generally be left alone, while those in category 2 should undergo treatment aimed at eliminating the gallstones. By contrast, optimal approaches to patients who fall into the last two categories (3 and 4) are less clear. Management of such patients should be individualized but depends largely upon the likelihood (based upon clinical features and diagnostic testing) that the patient's symptoms are related to the gallstones. The following discussion provides guidance to aid in this process.

Biliary type symptoms — In most patients, the first symptoms experienced from gallstones are recurrent pain attacks generated by the gallstones (biliary colic). Less frequently, the initial symptoms are those of one of the complications of gallstones (most commonly acute cholecystitis, acute biliary pancreatitis, acute cholangitis, or choledocholithiasis with extrahepatic cholestasis).

Biliary colic — Biliary colic is usually caused by the gallbladder contracting in response to hormonal or neural stimulation usually due to a fatty meal, forcing a stone (or possibly sludge or microlithiasis) against the gallbladder outlet or cystic duct opening, and leading to increased intragallbladder pressure and pain. The stones often fall back from the cystic duct as the gallbladder relaxes. As a result, the discomfort progresses in less than an hour to a steady plateau that ranges from moderate to excruciating and remains constant for more than an hour, then slowly subsides over several hours. In most patients the pain is not very severe which is why it takes several attacks before a patient seeks medical attention. The frequency of recurrent attacks is variable ranging from years to hours [1] .

Despite the term "colic", the pain is usually constant and not colicky. The classic attack is described as an intense dull pressure-like discomfort in the right upper or mid abdomen or in the chest that may radiate to the back and the right shoulder blade [2,3] . The pain classically follows ingestion of a fatty meal (about one to two hours after) and usually does not occur during fasting. However, the pain may be unrelated to meals in a substantial proportion of patients [4] . One group suggested that the pain had a circadian pattern, peaking at 9:30 PM [4,5] . In most cases the pain has a characteristic pattern and timing for individual patients.

The pain is often associated with diaphoresis, nausea and vomiting. It is not exacerbated by movement and not relieved by squatting, bowel movements, or flatus [1] . After the attack, the physical examination is usually normal with the possible exception of residual upper abdominal tenderness.

Although many patients are not symptomatic when they are undergoing medical evaluation, some patients present during an attack of symptoms. In such cases, biliary colic must be distinguished

from the more serious complication of acute cholecystitis, which is associated with gallbladder wall inflammation, fever and an elevated white cell blood count. Prolonged or recurrent cystic duct blockage can progress to total obstruction causing acute cholecystitis. An episode of prolonged right upper quadrant pain (greater than four to six hours), especially if associated with fever, should arouse suspicion for acute cholecystitis as opposed to an attack of simple biliary colic. (See "Clinical features and diagnosis of acute cholecystitis"). Other acute abdominal pain diagnoses must also be considered in such patients. (See "Differential diagnosis of abdominal pain in adults").

PREDICTIVE VALUE OF SYMPTOMS — Multiple studies have evaluated the association of gallstones with symptoms [2,6-14] . A consistent observation has been that the most specific feature pointing toward gallstones as the cause of symptoms was biliary colic. However, up to 80 percent of patients with gallstones referred for cholecystectomy had other abdominal symptoms [8] . At least two systematic reviews have provided estimates of the strength of the association between symptoms and gallstones: One systematic review focused on a total of 24 relevant studies that evaluated the association between seven abdominal symptoms and the presence of gallstones on ultrasonography or oral cholecystography as the reference standard [8] . The presence of biliary colic (diagnostic odds ratio {OR} 2.6, 95 percent CI 2.4 to 2.9), radiating pain (OR 2.8, 95 percent CI 2.2 to 3.7) and use of analgesics (OR 2, 95 percent CI 1.6 to 2.5) were consistently related to the presence of gallstones. However, the magnitude of these associations was notably weak. Similar conclusions were reached in an earlier systematic review that included 21 controlled studies evaluating an association between gallstones and dyspeptic symptoms [7] . Upper abdominal pain was most consistently associated with the presence of gallstones (OR 2.0). A weaker association was found with nausea and vomiting (OR 1.4). In contrast, there was no significant association with other symptoms such as flatulence, heartburn, acid regurgitation, bloating and belching.

A limitation of these studies is that the reference standard chosen was the presence of gallstones on imaging tests. A more clinically relevant reference standard may be whether symptoms were relieved following cholecystectomy, a question that has also been addressed in several reports [10,11,14] .

An illustrative study focused on 92 patients who had undergone cholecystectomy for symptomatic gallstones and were followed for a mean of 31 months [10] . Abdominal pain continued to be present (or arose de novo) in 30 percent of patients. A pain-free outcome was significantly associated with a preoperative diagnosis of biliary colic, fatty food intolerance, and a thick-walled gallbladder on ultrasound.

Interestingly, several other symptoms appeared to be improved after cholecystectomy including abdominal bloating, dyspepsia, heartburn, fat intolerance, nausea and vomiting. However, these observations should not be interpreted as suggesting that gallstones are a possible cause of all these complaints. Relief of symptoms may have been due to the natural history of some of these

disorders, a placebo response, or other nonspecific effect of the procedure. Furthermore, it is notable that abdominal symptoms continued or developed in one-third of patients, despite this being a highly selected group of patients whose symptoms had implicated gallstones to an extent that warranted cholecystectomy.

Similar findings were noted in a second study that included 225 patients who had undergone laparoscopic cholecystectomy, 91 percent of whom had biliary pain [11] . Pain was relieved in 82 percent of such patients when stones were documented preoperatively. However, pain was also relieved in 52 percent of patients without gallstones preoperatively (patients thought to have acalculous cholecystitis), in 80 percent of patients with atypical pain, and in 44 percent of patients with non-pain syndromes.

A third report included 2481 patients who had undergone elective cholecystectomy at one of several centers [14] . The mean number of abdominal symptoms per patient decreased significantly. However, 27 percent of patients who had identified a symptom that was most bothersome before surgery, still had that symptom six months after surgery. Symptom persistence rates ranged for 6 percent (for vomiting) to 40 percent (for gas and flatulence). The authors concluded that symptoms categorized as dyspeptic were more likely to persist compared with the more typical biliary symptoms, although the prevalence of all symptoms decreased after cholecystectomy.

Conclusion — In aggregate, these data suggest that in patients with gallstones, no single clinical feature or combination of features confidently predicts that symptoms will be relieved following cholecystectomy. Symptom relief is most likely in patients whose principal symptom is biliary colic. Non-specific atypical symptoms like indigestion, abdominal bloating, and belching, although commonly reported by patients with gallstones, are less likely to be caused by cholelithiasis since they are least likely to disappear after cholecystectomy. As will be discussed below, additional testing has been proposed to better discriminate those with symptoms attributable to gallstones. However, none has been proven to be superior to clinical judgment.

DIAGNOSIS — The diagnosis of uncomplicated gallstone disease should be suspected based upon the clinical features described above (ie, principally biliary colic). Such patients should then undergo evaluation to diagnose the presence of gallbladder stones or sludge.

Gallstone disease is usually considered as part of the differential diagnosis of patients presenting with upper abdominal symptoms. Thus, the decision to implicate the gallbladder has to be made based upon clinical suspicion for a varied group of disorders that include peptic ulcer disease, cardiac chest pain, esophageal chest pain, gastroesophageal reflux disease, nonulcer dyspepsia, irritable bowel syndrome, sphincter of Oddi dyskinesia, hepatitis, and chronic pancreatitis.

It is important to consider that many of these diagnoses are common in the general population and thus may coexist but be unrelated to the gallstones. Thus, a hunting expedition with imaging studies to look for gallstones in patients with nonspecific or atypical symptoms is discouraged. Such patients should be considered to have dyspepsia, and undergo appropriate evaluation and/or treatment based upon the predominant symptoms and suspicion for particular diagnoses. (See "Approach to the patient with dyspepsia").

As discussed earlier, biliary colic is the most accurate predictor of gallstone disease, but while imaging studies can detect gallstones, there is no clinical or laboratory test that can make the diagnosis of biliary colic. The diagnosis is based upon a meticulous history; questioning should focus on eliciting a history consistent with biliary colic as described above.

Physical examination — Patients with simple biliary colic are not usually ill appearing and do not have fever or tachycardia. The pain is characteristically dull and not severe enough to bring the patient to the emergency department, but, if a patient does present during a pain episode, the abdominal examination is generally benign and non-revealing. There are no peritoneal signs since the pain is purely visceral without gallbladder inflammation. However, voluntary guarding may be encountered depending upon the severity of the pain.

Physical examination can also help distinguish patients with acute cholecystitis. While biliary-type pain is present in both uncomplicated biliary colic and in acute cholecystitis, the pain in uncomplicated biliary colic is entirely visceral in origin since the gallbladder wall is not inflamed. Thus, it is generally less well localized and patients do not exhibit a positive "Murphy" sign on physical examination. A Murphy's sign is elicited by palpating the area of the gallbladder fossa just beneath the liver edge while the patient is asked to inspire deeply, causing the gallbladder to descend toward the examining fingers. Patients with acute cholecystitis commonly experience increased discomfort and may have an associated inspiratory arrest (a positive Murphy's sign). (See "Clinical features and diagnosis of acute cholecystitis").

Laboratory studies — Laboratory studies should be normal in patients with uncomplicated biliary colic both during asymptomatic periods and during attacks of symptoms. However, laboratory studies can be helpful for excluding other diagnoses. Although the choice and order of testing varies depending upon the clinical presentation and suspicion for a particular diagnosis, the following are reasonable screening tests: Liver biochemical tests (serum AST, ALT, total bilirubin, alkaline phosphatase). (See "Approach to the patient with abnormal liver function tests"). Serum amylase and lipase (to evaluate for pancreatitis) Complete blood count (to evaluate for leukocytosis and anemia) Urine analysis

IMAGING STUDIES — Imaging studies are useful for confirming the presence of gallstones or sludge in a patient with a history suggestive of biliary colic. They may also be useful for excluding other diagnoses.

Ultrasonography — Ultrasonography is generally considered to be the most useful test to detect the presence of gallstones since it is non-invasive, readily available, relatively inexpensive, and does not subject the patient to ionizing radiation. As noted above, it should generally be requested in patients suspected of having gallstones based upon a history of biliary colic.

Multiple studies have evaluated test characteristics of ultrasonography in determining the presence of gallstones. A systematic review estimated that the sensitivity was 84 percent (95 percent CI 76 to 99 percent) and specificity was 99 percent (95 percent CI 97 to 100 percent) [15] .

However, it is important to recognize that precise estimates of sensitivity and specificity are difficult to determine since surgical confirmation of a negative sonogram is unlikely. In a study that compared ultrasonography with direct percutaneous mini-endoscopy in patients who had undergone topical gallstone dissolution, ultrasonography was negative in 12 of 13 patients in whom endoscopy demonstrated 1 to 3 mm stones or fragments [16] (show endoscopy 1).

Furthermore, the accuracy of ultrasonography is operator dependent. The ultrasound examination must be conducted with the patient having fasted for at least eight hours, because stones are best seen in a distended gallbladder when they are surrounded with bile. The entire gallbladder must be examined axially and sagittally. Every effort should be made to examine the outlet of the gallbladder (Hartmann's pouch), where gallstones may be hidden. The gallbladder neck must be traced all the way into the porta hepatis to exclude stones in this region. If an out-pouching from the gallbladder (phrygian cap) is present, the redundant portion of the fundus must not be overlooked.

Even with an experienced operator, it is generally accepted that ultrasound is not highly sensitive for determining the number or size of stones in the gallbladder. This is especially true for very small stones approaching 1 or 2 mm in diameter that frequently, when present in large numbers, can appear on ultrasonography as one large stone.

Characteristics of stones on ultrasound — On ultrasonography, gallstones appear as an echogenic focus that casts an acoustic shadow (show radiograph 1) and seeks gravitational dependency [17,18] :

Two additional ultrasonographic entities that are frequently described are sludge and gravel. Gravel is the appearance of multiple small stones that are echogenic and cast a shadow. Sludge is echogenic in appearance but does not cast an acoustic shadow. It also is more viscous and does not move to the dependent portion of the gallbladder as rapidly as gravel [19,20] . If the gallbladder is totally filled with stones, or if it is contracted around many stones, it may be confused with gas in a partially collapsed duodenal bulb, emphysematous cholecystitis, porcelain gallbladder, or a calcified hepatic artery aneurysm. The ultrasonographer performing the procedure regularly uses specific maneuvers and techniques to identify and distinguish gallstones from some of these other appearances, further underscoring the degree to which ultrasonography is operator dependent.

Gallstones must be distinguished from gallbladder polyps, which can produce similar sonographic images. This is usually done by examining the patient in different positions to demonstrate the movement of stones to the dependent region of the gallbladder. Occasionally, vigorous rolling of the patient or pressure on the gallbladder in sharp jerky movements may be necessary to make the distinction. In addition, stones cast an acoustic shadow while polyps do not. (See "Gallbladder polyps and cholesterolosis").

Plain abdominal X-ray — Plain abdominal x-rays are generally not useful in looking for gallstones in symptomatic patients. Only about 10 percent of gallstones have enough calcium in their composition to make them sufficiently radio-opaque to be visible on a plain radiograph (show radiograph 2).

Oral cholecystography — Oral cholecystography (OCG), once used commonly to diagnose gallstones and measure gallbladder function, is now used only rarely since it is less sensitive and specific compared with ultrasonography [15,21] . It is still occasionally used in patients in whom a high quality ultrasound examination cannot be obtained (such as in obese patients), to confirm the presence of adenomyomatosis of the gallbladder, and to evaluate patients who are being considered for medical dissolution therapy with ursodeoxycholic acid, in whom it is important to demonstrate stone number and size, relative density of the stones to bile, cystic duct patency and the gallbladder's concentrating ability. (See "Patient selection for the nonsurgical treatment of gallstone disease").

OCG is based upon an orally administered contrast agent that is absorbed through the intestine, taken up by the liver, and secreted into bile. Gallstones appear as filling defects within the contrast (show radiograph 3). Several contrast agents have been used; in the United States the most frequently used is iopanoic acid (Telepaque, Winthrop Pharmaceuticals, New York, New York). The standard dose of contrast is 3 grams (six tablets) of Telepaque. If the gallbladder shows no visualization, then a repeat dose of another six tablets is given the next evening and the x-ray

examination is repeated the following morning. Other available similar agents are sodium tyropanoate (Bilopaque, Winthrop Pharmaceuticals), and calcium ipodate (Oragraffin, Squibb, Princeton, New Jersey).

False negative results can occur due to poor absorption from the intestine (due to malabsorption syndromes, inflammatory bowel disease, and ileal bypass), diminished liver function (such as in patients with hepatitis or cirrhosis, where the dye may not be adequately conjugated and excreted), or extrahepatic biliary obstruction. It is unlikely that the gallbladder will visualize when the serum bilirubin is greater than 2 to 3 mg/dL.

An approximation of gallbladder motor function can also be obtained if the patient is given a fatty meal following which the decrease in gallbladder size is estimated on serial x-rays. However, this is not recommended in patients who have known gallbladder stones since it may induce biliary colic.

Computed tomography — The sensitivity of computed tomography (CT) for gallstones is poor since most stones are isodense with bile and thus not visible on CT scanning [22,23] . CT can be useful for screening patients in whom medical dissolution therapy is being considered since the presence of calcifications within gallstones (readily apparent on CT) makes it unlikely that such therapy will be successful. (See "Patient selection for the nonsurgical treatment of gallstone disease")

Cholescintigraphy — Cholescintigraphy has no role in the diagnosis of gallstones but is very useful in excluding acute cholecystitis in patients who present with acute biliary colic. (See "Clinical features and diagnosis of acute cholecystitis").

APPROACH TO THE PATIENT — As noted above, the approach to the patient can be understood based upon the categorization described above.

Patients with gallstones but no symptoms (category 1) — Patients who are asymptomatic but found to have incidental gallstones on an imaging test should be left alone since the risk of developing life threatening severe complications is arguably less than the likelihood of developing such complications from prophylactic treatment. This recommendation is based upon studies showing that the rate of progression from asymptomatic to symptomatic gallstones is very low (about 1 percent per year). Furthermore, when patients do become symptomatic, the initial presenting symptoms are usually not severe. (See "Approach to the patient with incidental gallstones").

As a result, patients with incidental gallstones can be educated about potentially concerning symptoms, allowing the uncommon patient destined to develop symptoms to seek treatment before severe complications arise. Thus, prophylactic cholecystectomy is not advised. (See "Approach to the patient with incidental gallstones")

Patients with biliary symptoms and gallstones (category 2) — In contrast to patients with incidental gallstones, prophylactic treatment should be advised to patients of category 2 who have or had biliary type symptoms (see "Biliary colic" abovesee "Biliary colic" above) or complications (such as cholangitis, pancreatitis, cholecystitis, choledocholithiasis, gallstone ileus and Mirizzi syndrome) clearly related to gallstones, since such patients are likely to have recurrent and more severe symptoms. The National Cooperative Gallstone Study (one of the most definitive studies on the subject) showed that the risk of further symptoms and complications in such patients was approximately 70 percent within two years after initial presentation [24] .

Patients with gallstones but atypical symptoms (category 3) — Atypical symptoms in patients with gallstones (category 3) are unlikely to be caused by the gallstones. Thus, a careful search for other causes of symptoms is prudent. However, symptoms as described by patients are highly subjective and often change. As a result, it is always useful to review the symptoms on more than one occasion to see if any particular patient can be assigned to one of the other categories with the understanding that the less consistent the symptoms are, the higher the likelihood that they will not respond to treating the gallstones.

An empiric trial of oral dissolution therapy with ursodeoxycholic acid is reasonable if other serious illnesses such as cardiac disease or peptic ulcer disease have been excluded and the patient is a candidate for medical gallstone dissolution therapy. (See "Nonsurgical treatment of gallstone disease"). If the symptoms were indeed from the gallstones, ursodeoxycholic acid therapy relieves the symptoms in most patients within three months, long before the stones have dissolved [25] . Thus, a response to therapy may be helpful in guiding further management.

Patients with typical biliary symptoms but without gallstones on ultrasonography (category 4) — Patients in this category have either small stones (microlithiasis) or sludge that were missed on conventional imaging studies or other causes of biliary symptoms unrelated to gallstones such as sphincter of Oddi dysfunction. There is now increasing evidence that sludge can produce symptoms [26-28] and that it represents lithogenic bile containing cholesterol monohydrate crystals, bilirubin granules, and a mucus glycoprotein gel [29] . The conversion of ultrasonographic sludge into macroscopic gallstones has been documented in several studies [30,31] .

It is important to confirm the presence of microlithiasis or sludge in patients of this category because while symptomatic sludge and microlithiasis will respond to cholecystectomy or medical therapy, cholecystectomy may worsen the symptoms of patients with sphincter of Oddi dysfunction [32] .

As noted earlier, ultrasonography may not detect small gallstones or biliary sludge. Sensitivity for small gallstones can be improved upon by repeating the examination at a later time [33] . Further evaluation for microlithiasis can be considered in patients whose repeat ultrasonography is unrevealing.

Microlithiasis, or microcrystalline disease, can cause symptoms and complications similar to those seen with larger gallstones including biliary colic, cholecystitis, cholangitis, obstructive jaundice, and acute pancreatitis [26-28,34,35] . The diagnosis can be established by bile microscopy and endoscopic ultrasonography, which, in patients with typical biliary symptoms, considered as the next step [36] . Both these tests are done through an upper endoscopy, which also serves to exclude other conditions such as peptic ulcer disease.

Bile microscopy — Bile microscopy is regarded as the reference standard for the diagnosis of microlithiasis with an overall sensitivity of 65 to 90 percent [37-41] . The test relies upon the theory that patients with cholesterol microlithiasis have bile that is supersaturated with cholesterol and thus have cholesterol monohydrate crystals (show figure 1) in their gallbladder bile while those with bilirubinate microlithiasis have amorphous reddish-brown bilirubinate granules in their gallbladder (show figure 2) [42,43] . However, the methods of performing the test have not been well standardized leading to a great deal of confusion regarding how to collect and process the bile samples for analysis and what constitutes a positive test.

Most available studies describe the test as it pertains to the detection of microlithiasis in patients with idiopathic recurrent pancreatitis, but even then, no two reports seem to have used the same technique for bile collection, bile processing, or microscopic crystal analysis. Nevertheless, most investigators agree that microcrystals are formed in the gallbladder where bile is concentrated and they produce biliary colic or pancreatitis as they pass through the cystic duct and/or ampulla. Thus, microcrystals should ideally be sought in gallbladder bile; hepatic bile is significantly less concentrated and thus has a lower yield for the detection of microlithiasis [28,38,44] .

Gallbladder bile can be collected using one of the following techniques: Through direct percutaneous puncture of the gallbladder under ultrasound or fluoroscopic guidance During ERCP either through selective gallbladder cannulation or by aspirating bile from the common bile duct after stimulating gallbladder contraction by an infusion of the CCK analogue sincalide During endoscopy during which

bile is suctioned from the duodenum around the region of the ampulla after gallbladder stimulation with intravenous cholecystokinin (sincalide), which causes the gallbladder to contract

Collection during endoscopy is the simplest and most practical method. The procedure can be combined with endoscopic ultrasonography (see below) to further increase sensitivity [36,48] . At our center, if the endoscopic ultrasound examination is negative, then while the endoscope is still in the patient sincalide (Kinevac 0.03 microg/kg body weight) is given by intravenous drip over 45 minutes; the longer infusion is safer and more effective than a short bolus technique [45] . The tip of the endoscope is positioned next to the ampulla and the bile is aspirated. Bile flow usually starts to accelerate within five minutes of the start of the CCK infusion. The first 5 to 10 minutes of bile flow is normally light in color representing common bile duct and hepatic bile. Gallbladder bile is the darker bile that starts flowing several minutes later.

The darker bile is collected in a separate collecting tube and kept for analysis. The bile is incubated at 37 degrees C for 24 hours, then centrifuged at 3,000 G for 30 minutes [46] . The supernatant is discarded and the sediment is made to mix into the liquid remaining at the bottom of the tube. A drop of that liquid is placed on a slide and examined using a polarizing microscope; a polarizing filter facilitates identification of cholesterol crystals, which exhibit birefringence (they shine against the dark background of the polarizing microscope). The test is considered positive if any cholesterol crystals or amorphous red brick bilirubinate granules are seen.

The proportion of patients found to have microcrystals has varied substantially in various reports. More recent studies seem to show a lower prevalence of microlithiasis (around 3.5 percent) [47] in patients of clinical category 4 compared to earlier reports in which the prevalence ranged from 33 to 90 percent [38,46] . This is thought to be in part due to the methods used to detect microcrystals and the definition of a positive test.

In earlier prospective studies, investigators inspected a drop of uncentrifuged bile on a slide and the test was considered positive if any cholesterol crystals or amorphous calcium bilirubinate granules were observed. These results correlated well with the presence or absence of gallstones in human subjects [38] . Subsequent studies demonstrated that the sensitivity of the test could be improved significantly if the bile was centrifuged and made to stand overnight at 37 degrees C [46] . While the presence of any cholesterol crystals is theoretically abnormal, to increase specificity, some of the newer reports considered the test to be positive only if more than three crystals were seen per high power field [47] . However, whether findings based upon this approach correlate with clinical outcomes has not been established. As a result, this methodology has not been widely accepted. Furthermore, improved sensitivity of extracorporeal ultrasonography for detection of small stones and sludge has reduced the need for microcrystal analysis, since relatively fewer patients are designated as having typical symptoms without gallstones (ie, clinical category 4).

In initial studies, for example, investigators inspected a drop of uncentrifuged bile on a slide. When any cholesterol crystals or amorphous calcium bilirubinate granules were observed, the test was considered positive; the results correlated well with the presence or absence of gallstones in human subjects [38] . Subsequent studies demonstrated that the sensitivity of the test could be improved significantly if the bile was centrifuged and made to stand overnight at 37 degrees C [46] .

While presence of any cholesterol crystals is theoretically abnormal, specificity can be increased by considering the test positive only if more than three crystals are seen per high power field [47] . This definition has been used in the relatively recent reports, which may explain why they have described a lower prevalence of microlithiasis (around 3.5 percent) in patients in clinical category 4 compared to earlier reports in which the prevalence ranged from 33 to 90 percent.

Endoscopic ultrasonography — Imaging of the gallbladder can be obtained by endoscopic ultrasound (EUS) during which an ultrasound transducer, on the tip of an endoscope, is placed into contact with the gastric antrum, which is in close proximity to the gallbladder, thereby allowing for its visualization without interference from bowel gas, subcutaneous tissue or the liver. As a result, EUS is more sensitive than extracorporeal ultrasonography for the detection of gallstones, particularly in patients who are obese or have other anatomic considerations limiting views with transabdominal ultrasonography [48,49] .

Several studies have demonstrated EUS can be useful for the detection of small stones and microcrystals as illustrated by the following examples: In a study of 45 patients in whom there was a clinical suspicion of cholelithiasis but with at least two normal US examinations, EUS detected evidence of cholelithiasis in 26 patients and was more sensitive than microscopic examination of duodenal bile [48] . In a study of 89 patients with acute pancreatitis, EUS revealed small gallbladder stones (1 to 9 mm) in 14 patients who had otherwise negative standard imaging studies including ultrasonography [49] . Subsequent ERCP and cholecystectomy confirmed the presence of stones in all 14 patients. EUS detected microcrystals in 5 of 15 patients with pancreatitis but a negative ultrasound examination [37] . The sensitivity of EUS combined with bile microscopy in detecting microcrystals was 92 percent in 66 patients with biliary type pain and a negative abdominal ultrasound [36] . Resolution of symptoms after cholecystectomy was noted in 90 of these patients.

Because it is invasive, EUS is generally reserved for patients with biliary colic or suspected complications of gallstones (such as pancreatitis) who have a negative transabdominal ultrasound [36,50] . EUS also has a role in diagnosis of patients with suspected choledocholithiasis. (See "Endoscopic ultrasonography in patients with suspected choledocholithiasis").

MANAGEMENT — There are two general considerations in the management of uncomplicated gallstone disease. Management of biliary colic Prophylactic treatment to prevent further attacks and/or the development of complications

Biliary colic — The management of acute biliary colic mainly involves pain control. Pain control can usually be achieved with intravenous administration of meperidine, which is preferred to morphine since it has less of an effect on sphincter of Oddi motility [51-53] . Patients should be instructed to remain NPO to prevent the release of cholecystokinin. Those with prolonged attacks (especially if accompanied by vomiting) should also receive intravenous hydration.

If the diagnosis is fairly certain there is increasing evidence that the use of nonsteroidal antiinflammatory drugs (NSAIDs) can produce effective analgesia for biliary colic, and may favorably alter its natural history. The latter benefit may reflect the role of prostaglandins in the development of acute cholecystitis. (See "Clinical features and diagnosis of acute cholecystitis", section on Pathogenesis).

We use ketorolac (30 to 60 mg adjusted for age and renal function given in a single intramuscular dose) for patients who present to the emergency department with biliary colic. Treatment usually relieves symptoms within 20 to 30 minutes. Patients are then prescribed ibuprofen 400 mg orally to be taken during subsequent attacks, until definitive treatment can be accomplished. In a study comparing ketorolac with meperidine in 324 patients, the two agents were found to be equivalent for pain control but meperidine caused more adverse events mainly in the form of nausea and dizziness [54] .

Prophylactic treatment — When the acute attack of biliary colic subsides, definitive prophylactic therapy should be considered to remove the offending stones to prevent recurrent attacks of biliary colic and the occurrence of more severe complications. Several modalities are available ranging from the surgical removal of the gallbladder to the medical dissolution of the stones while sparing the gallbladder. The choice of the management pathway is generally based upon the patient's surgical risk and preference.

Cholecystectomy is the most commonly recommended modality. The gallbladder along with its contained stones is removed under general anesthesia. This surgical procedure may be performed through an open right upper quadrant muscle cutting incision or laparoscopically. The latter has become popular since the early 1990s since it eliminates the need to cut the rectus abdominis muscle leading to significantly shortened hospital stay and convalescence.

However, the laparoscopic procedure has been associated with an increased risk of common bile duct injury [54,55] . In addition, the laparoscopic procedure has to be converted to an open procedure in about 10 percent of cases due to a variety of technical or patient issues. Ultimately, the choice of technique is based upon the experience and preference of the surgeon performing the procedure and the medical condition of the patient. (See "Complications of laparoscopic cholecystectomy").

While removal of the gallbladder is commonly considered to have no lasting physiologic consequences, about 50 percent of patients note more frequent and less formed stools while 10 to 15 percent of patients develop frank diarrhea for which they seek medical attention [6] . An increased risk of right sided colon cancer in patients who have undergone cholecystectomy has also been suggested [56] .

In some cases, surgical removal of the gallbladder may not be feasible, usually because of patient comorbidities. Several nonsurgical techniques for treatment of gallstones have been developed. These include principally medical dissolution therapy with oral bile acids, topical chemical dissolution using solvents to lavage the gallbladder, and extracorporeal shock wave lithotripsy. While the development of laparoscopic cholecystectomy has generally reduced enthusiasm for these approaches, they remain reasonable options in selected patients. (See "Patient selection for the nonsurgical treatment of gallstone disease").

SUMMARY AND RECOMMENDATIONS — When considering gallstone disease it is helpful to categorize patients into the following clinical categories.

Gallstones but without symptoms — These patients are unlikely to develop symptoms and when they do occur they are generally mild. Thus, patients should be educated about symptoms potentially related to gallstones (principally biliary colic) without recommending specific therapy to address the gallstones. (See "Approach to the patient with incidental gallstones").

Typical biliary symptoms and gallstones — Such patients should generally undergo treatment (generally cholecystectomy) since they are likely to develop recurrent symptoms, which can be severe. The National Cooperative Gallstone Study (one of the most definitive studies on the subject) showed that the risk of further symptoms and complications in such patients was approximately 70 percent within two years after initial presentation [24] .

Atypical symptoms and gallstones — Such patients should undergo a search for non-gallstone-related causes of symptoms. If investigation is unrevealing, treatment of gallstones can be

considered with the understanding that the rate of persistent symptoms is high. (See "Approach to the patient with dyspepsia").

Typical biliary symptoms but without gallstones — Clinical suspicion for gallstone disease should be maintained in such patients. A repeat extracorporeal ultrasound should be obtained. If results are unrevealing, EUS and collection of duodenal bile for microscopy should be considered. If results continue to be unrevealing, a search for other causes of biliary pain is reasonable.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Gallstones"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.