Most gallstones are cholesterol laden and develop as a consequence of bile becoming supersaturated with cholesterol. Age, hereditary factors, female gender, obesity, pregnancy, rapid weight loss, gallbladder stasis (as occurs during treatment with certain medications or parenteral nutrition), and terminal ileal disease are important risk factors for the formation of cholesterol stones. All of these factors contribute to either higher biliary cholesterol levels or to decreased solubility of biliary cholesterol. In men, regular exercise protects against developing symptomatic disease (the effect is unknown in women). Biliary sludge is a microprecipitate mixture of bile, cholesterol crystals, and calcium bilirubinate that forms when bile becomes supersaturated. Its pathogenesis is believed to be similar to that of gallstones and may represent a transitional state en route to gallstone formation. This is not an inevitable progression however, and both asymptomatic gallstones and biliary sludge can resolve spontaneously. Pigment stones are the other major type of gallstone, accounting for approximately 20% of gallstones. These occur most commonly in patients with hemolytic disorders. Once gallstones have formed, they may take one of several clinical courses. Most remain asymptomatic, but several symptomatic courses may ensue. Acute calculous cholecystitis occurs when a stone acutely obstructs the cystic duct causing biliary colic due to gallbladder distension and inflammation. Chronic cholecystitis is manifested by recurrent pain caused by gallbladder constriction against stones or transient obstruction of the cystic duct by stones. Choledocholithiasis occurs when a stone exits the gallbladder into the common bile duct; this results in cholangitis when it leads to biliary obstruction with biliary infection. Gallstone pancreatitis is caused by transient obstruction of the pancreatic duct by a gallstone in the common bile duct.

As noted, cholelithiasis is usually asymptomatic, but when it presents clinically, it is most commonly manifested by recurrent pain termed biliary colic. Characteristically, biliary colic is rapid in onset, builds to a maximum within 1 hour, is steady, localizes to the epigastrium or right upper quadrant, lasts 2 to 4 hours, and occasionally radiates to the back or the right
scapula. There is often nausea and vomiting. This classic presentation should be distinguished from dyspeptic symptoms such as fatty food intolerance, belching, and bloating. Dyspeptic symptoms are common in the general population, including in patients with cholelithiasis, but are seldom attributable to gallstones. Gallstone-directed therapy (either medical or surgical) is usually ineffective if undertaken to relieve dyspeptic symptoms.

While biliary colic is the most common clinical presentation of gallstone disease, approximately 10% of patients will present with complicated gallbladder disease, which encompasses the entities of acute cholecystitis, gallstone pancreatitis, choledocholi-thiasis, and cholangitis. Each presentation is slightly different, and the diagnosis of each is discussed below.

The rare patient with true biliary colic but no evidence of cholelithiasis on ultrasound may have a form of acalculous gallbladder disease termed gallbladder dyskinesia. This is a poorly characterized gallbladder motility disorder that is usually diagnosed by the presence of classic biliary colic symptoms with no evidence for gallstones and a gallbladder ejection fraction of less than 35% during cholecystokinin cholescintigraphy. Although it does not involve gallstones, gallbladder dyskinesia is mentioned here because its clinical presentation is very similar to that of biliary colic. It is often effectively treated with cholecystectomy.

The clinical course of untreated cholelithiasis depends on whether the patient is symptomatic. In asymptomatic people (with silent gallstones) followed expectantly for up to 20 years, there is a cumulative probability of developing biliary colic of about 20%. Among symptomatic patients with at least one bout of biliary colic, about 70% have recurrent pain within 2 years. Complicated gallstone disease occurs at a rate of about 1% to 2%/year in most studies. After a single episode of complicated disease, the recurrence rate is higher. Biliary sludge follows a variable clinical course, ranging from complete resolution, to waxing and waning, to the formation of gallstones. In cases of acute abdominal pain associated with the presence of sludge, there is a disappearance of sludge and symptoms in 50% of cases, and another 20% remain asymptomatic with sludge persisting. In the remainder, stones may develop, and/or symptoms may persist.

Asymptomatic gallstones are usually detected as an incidental finding during a radiologic or ultrasound investigation that encompasses the upper abdomen for a reason other than suspected gallbladder disease. With the advent and widespread application of ultrasound and computed tomography, the frequency of detection of asymptomatic disease has been increasing. When cholelithiasis is suspected based on symptoms, transabdominal ultrasound is the test of choice. Ultrasound is 85% to 95% sensitive and about 99% specific for the diagnosis of cholelithiasis. For best results, the patient should have fasted for up to 6 hours. If suspicion is high after a negative ultrasound, the study may be repeated as a first step in further workup.

One of the key points allowing the primary physician to discern between biliary colic and complicated gallbladder disease is duration of symptoms. While all the entities listed above can present with some combination of upper abdominal pain, nausea, and vomiting, biliary colic nearly always resolves within 4 to 6 hours. If symptoms persist beyond that time frame, further and more urgent diagnostic evaluation as below is warranted.

Ultrasound is the diagnostic test of choice in patients with recurrent episodes of biliary colic, which is often termed chronic cholecystitis. There are no ultrasonographic features that can distinguish chronic cholecystitis from asymptomatic gallstones— the distinction must be made on the basis of clinical symptoms. The oral cholecystogram may be used in patients being considered for gallstone dissolution because the test can provide information on gallbladder function and stone composition (see later discussion).

Abdominal ultrasound is also the primary diagnostic modality for suspected acute cholecystitis. In addition to gallstones, ultrasonographic findings suggesting the diagnosis are gallbladder wall thickening, pericholecystic fluid, and a “sonographic Murphy sign” in which tenderness is elicited over the gallbladder by the ultrasound probe. Sensitivity and specificity of the ultrasound are greater than 95%.

Patients with a nondiagnostic ultrasound but still strongly suspected of having acute cholecystitis can undergo scintigraphy with the radionuclide ^99mTc hepatobiliary iminodiacetic acid scan (a HIDA scan). The isotope is taken up by the liver and excreted into the bile. Images are obtained after 1 hour. The patient needs to be fasting (but for no longer than 2 to 4 hours) and free of underlying hepatocellular disease and alcoholism (which cause false-positive tests). The gallbladder, cystic duct, common bile duct, and duodenum are visualized by 60 minutes in the normal person. Nonvisualization of the gallbladder after 1 hour is characteristic of acute cholecystitis (the common bile duct and duodenum remain visualized). Sensitivity and specificity approach those of ultrasound, but the cost is greater, radiation exposure results, and the test takes more time. Computed tomography is not sensitive for the detection of gallstones and is not a top choice imaging modality in suspected acute cholecystitis. Nonetheless, it often shows gallbladder distension and inflammation in acute cholecystitis. If a CT scan obtained for the evaluation of abdominal pain convincingly shows acute cholecystitis, there is no need for further evaluation.

Symptomatic patients with recurrent pain plus persistent mild elevations in liver function tests, a dilated common bile duct, jaundice, or signs of acute pancreatitis require further evaluation for a stone in the common bile duct. Transabdominal ultrasound may be nondiagnostic because the sensitivity of a single study for detecting stones in the duct is only 50% when there is no ductal dilation and 75% when ductal dilation is present. Overlying bowel gas can obscure visualization of a common duct stone. If clinical suspicion remains high, a repeat ultrasound study is indicated. Computed tomography has about the same sensitivity (75%) as ultrasound for the detection of a common duct stone. Magnetic resonance cholangiopancreatography has a sensitivity of greater than 90% and represents a major advance in the noninvasive imaging of the biliary tree for the detection of stones; it requires no iodinated contrast or invasive procedure, and its high sensitivity can obviate the need for invasive study. If noninvasive testing is nondiagnostic in the setting of suspected common duct stone, then endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) deserves consideration. Sensitivity for both modalities exceeds 90%. EUS is
less invasive and carries less risk, but ERCP has the advantage of enabling therapeutic sphincterotomy and stone extraction to be performed at the same time.