AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Background

Cholelithiasis is the pathologic state of stones or calculi within the gallbladder lumen. A common digestive disorder worldwide, the annual overall cost of cholelithiasis is approximately $5 billion in the United States, where 75-80% of gallstones are of the cholesterol type, and approximately 10-25% of gallstones are bilirubinate of either black or brown pigment. In Asia, pigmented stones predominate, although recent studies have shown an increase in cholesterol stones in the Far East.

Each type of stone has a particular pathophysiology and specific set of risk factors that alter the equilibrium and solubility of the components of bile. Biliary microlithiasis refers to the presence of gallbladder calculi smaller than 2 mm, which is too small to be detected by current imaging techniques. Although it originally referred to sonographic findings of echogenic, nonshadowing, microscopic material within the gallbladder, the term biliary sludge currently indicates a precipitate of microcrystals occurring in bile with high mucous content. Sludge may contain microliths. Milk of calcium bile, a calcium carbonate precipitate opaque on plain radiographs, may coexist with cholelithiasis.

For excellent patient education resources, see eMedicine's Liver, Gallbladder, and Pancreas Center and Cholesterol Center. Also, visit eMedicine's patient education article Gallstones.

Pathophysiology

Cholesterol stones

Supersaturation of bile, crystallization, and stone growth are the 3 steps in cholesterol stone formation. Many conditions promote biliary cholesterol secretion and saturation, including aging, obesity, rapid weight loss, pregnancy, female gender, slow intestinal transit, genetic predisposition, ileal disease (eg, Crohn disease), diet high in fat and simple sugars, and the drug clofibrate. Cholesterol crystallization occurs in the presence of altered biliary kinetics and appears to result from procrystallizing protein action on the bile. These proteins enhance cholesterol crystallization and are secreted in the presence of gallbladder mucosal inflammation, which occurs in the presence of supersaturated bile. At the molecular level, regulatory genes that control hepatic lipid secretion have been identified. Several gene polymorphisms and mutations have also been found to be associated with gallstone formation.

Cholesterol crystallization and stone growth also are encouraged by decreased gallbladder contractility. Factors associated with diminished gallbladder motility include pregnancy, birth control pills, total parenteral nutrition, administration of octreotide, and rapid weight loss. High biliary cholesterol concentration also is associated with diminished gallbladder contractility resulting from the direct effect of cholesterol on gallbladder smooth muscle. As a point of interest, the moderate use of alcohol appears to protect against gallstone formation by decreasing cholesterol secretion in the bile. Ascorbic acid affects catabolism of cholesterol into bile salts and may reduce stone formation. In addition, aspirin prevents the formation of gallstones during rapid weight loss.

Pigment stones

The pathophysiology of pigment stones is less understood. Black pigment stones occur when bilirubin conjugates hypersecrete into the bile, with subsequent precipitation of calcium bilirubinate. An alteration of biliary pH, possibly the result of mucosal inflammation, may facilitate stone formation. Biliary cholesterol is normal in patients with black pigment stones, but gallbladder motility is reduced, although not as severely as in patients with cholesterol stones.

Chronic hemolytic states (eg, sickle cell disease, thalassemia, hereditary spherocytosis, artificial heart valves) are risk factors for black pigment stone formation. Increased risk also is associated with a diet high in protein and carbohydrates, long-term total parenteral nutrition, and cirrhosis. Of patients with cirrhosis who have cholelithiasis, 50-75% have black pigment stones; the remainder have cholesterol stones. The frequency of stone formation increases with worsening liver function.

Brown pigment stones are seen in patients with cholestasis and biliary infection. Escherichia coli, Bacteroides, Clostridium, and Ascaris usually are the infectious organisms. Brown pigment stones also can occur in patients with duodenal diverticula, probably as a result of ascending biliary infection. Brown pigment stones can form in the gallbladder and bile ducts as a result of bacterial glucuronidase production of insoluble unconjugated bilirubin, which then precipitates as calcium salt. The role of parasitic infection is not clear, and the pathogen may serve as a nidus for stone formation.

Frequency

United States

In the United States, 10-15% of adults have gallstones. The annual diagnosis is 800,000 to 1 million new patients.

International

Worldwide occurrence varies from 6-20%. The highest incidence is seen in Sweden, where 50% of the people have gallstones by age 70 years.

Mortality/Morbidity

Asymptomatic gallstone patients develop complications at an annual rate of 1-2%. In symptomatic patients, the complication rate increases to 1-3%. Lifetime probability of death from complications of gallstone disease has been reported at 6%, with most deaths occurring in persons older than 65 years. In a review of 40,571 patients who underwent cholecystectomy, Glasgow reported the following rates of complications:

• Biliary colic - 56%
• Acute cholecystitis - 36%
• Acute pancreatitis - 4%
• Choledocholithiasis - 3%
• Gallbladder cancer - 0.3%
• Cholangitis - 0.2%

An increased risk of acute pancreatitis is associated with biliary microlithiasis. Risk of gallbladder cancer is low in those with cholelithiasis but significant in patients with porcelain gallbladder.

Other unusual complications include hemobilia, gallstone ileus (bowel obstruction resulting from a gallstone eroding into the small bowel), Bouveret syndrome (gallstone duodenal pyloric obstruction), and Mirizzi syndrome (gallstone impacted in Hartman pouch or cystic duct, causing obstruction of the common hepatic duct). The incidence of symptomatic gallbladder disease appears to be decreased in men who consume coffee regularly.

Race

Significant ethnic differences are seen, and a lithogenic gene is hypothesized to exist in racial groups with the highest incidence of gallstones, which include Amerindians, particularly the Pima Indians, and Mexican Americans. By age 30 years, 70% of female Pima Indians have gallstones; and 70% of male Pima Indians are affected by age 60 years. Gallstones are rare in inhabitants of sub-Saharan Africa and in Eskimos.

Sex

Adult male-to-female ratio is 1:2-3, presumably in part because of the effect of estrogen on cholesterol metabolism. Conversely, a recent report by Kumar (2000) reviewing 102 children with gallstones showed a male-to-female ratio of 3:2.

Age

The incidence of cholelithiasis increases with age. Although rare in patients younger than 20 years, cholelithiasis may occur in children who have a variety of conditions including hemolytic anemia, sickle cell disease, and obesity. In addition, cholelithiasis may be idiopathic or may occur in children following ileal resection, other abdominal surgery, prolonged total parenteral nutrition, or prolonged fasting. Gallstones have been diagnosed in utero, and in some infants, spontaneous resolution occurs postpartum. In children, cholelithiasis usually presents around puberty. When idiopathic, calculi usually are of the cholesterol type and occur in obese females with a positive family history of cholelithiasis.

Anatomy

The gallbladder originates embryologically from primitive endoderm as an outpouching of the hepatic diverticulum. The gallbladder is situated on the undersurface of the right lobe of the liver adjacent to the quadrate lobe and in close apposition to the duodenum and hepatic flexure. It is a pear-shaped, hollow organ composed of a body, fundus, and neck, and it terminates in the cystic duct. A diverticulum or Hartmann pouch located at the junction of the neck and cystic duct may be present, not as a normal anatomic feature but as a result of chronic inflammation. The fundus occasionally folds upon itself, producing a variant termed a Phrygian cap.

A mucosal septation may occur as a developmental variant, predisposing the patient to gallstone formation. The gallbladder is adherent to the liver and covered by peritoneum. Occasionally, the gallbladder is suspended by a mesentery and, in these patients, may be prone to torsion. Gallbladder blood is supplied via the cystic artery, which is a branch of the right hepatic artery.

Several variations in cystic duct and cystic artery anatomy may occur. The cystic duct may join the common hepatic duct in several configurations such as angular, parallel, or spiral. A recent study reports that patients with cholelithiasis had significantly narrower and longer cystic ducts and a narrower angle between the gallbladder and cystic duct. Vascular variations include accessory cystic artery, short cystic artery, and anterior transposition of the right hepatic artery and cystic artery. Lymphatics drain to local cystic ducts and foramen of Winslow nodes.

Clinical Details

Most patients with cholelithiasis are asymptomatic, with only 1-4% developing symptoms annually. Once the initial diagnosis is made, 10% of patients develop symptoms in the first 5 years and approximately 25% develop symptoms by 20 years. Once symptoms occur, they tend to recur with an increased likelihood of complications. A classic symptom is episodic right upper quadrant (RUQ) pain associated particularly with intake of fatty foods. Pain may radiate to the right shoulder and be associated with nausea. On physical examination, patients experience tenderness to palpation of the RUQ. Complications are more common in patients with small, multiple stones.

Preferred Examination

Sonography is the procedure of choice for identifying gallstones. Current high-resolution, real-time ultrasound (US) can identify gallstones as small as 2 mm, with a sensitivity greater than 95%. The technique is rapid, noninvasive, can be performed at the bedside, and does not involve ionizing radiation.

Limitations of Techniques

• Radiographs: Only 15-20% of stones are visible on plain radiographs.
• Oral cholecystography (OCG): Nonvisualization of the gallbladder may occur in malabsorption, gastric outlet obstruction, inflammatory bowel disease, ileal disease, liver disease, and in some patients with chronic cholecystitis. Calcified stones may be missed in an opacified gallbladder. Side effects to contrast may occur.
• US: False negatives may occur with small stones in the presence of biliary sludge. The technique is operator-dependent. Inadequate visualization of the gallbladder may occur in obese or contracted patients, or in patients with abdominal wounds.
• CT: Only 74-79% of gallstones are identified in patients with CT. CT is not a screening tool for uncomplicated cholelithiasis.
• MRI: MRI is not a screening tool. Stones may be incidental findings on abdominal MRI.

DIFFERENTIALS

Section 3 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Other Problems to be Considered

Cholecystitis, emphysematous
Choledocholithiasis

RADIOGRAPH

Section 4 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

Plain radiography: Typically, gallstones appear as single or multiple, pyramidal, faceted, or cuboidal calcifications located in the RUQ. Calcification may be central, homogeneous, or rimlike. When multiple gallstones are seen, the stones are clustered and usually faceted. Air may be present within central fissures, creating a stellate lucency termed the Mercedes Benz sign. On erect films, stones may layer in the dependent portion of the gallbladder.

OCG: Single or multiple lucent-filling defects within an opacified gallbladder are seen and usually are gravity-dependent; however, stones with high cholesterol or that contain air content may float. Mobility is demonstrated by a change in position on supine and upright films. Compression films may be necessary to displace bowel gas.

Degree of Confidence

Plain film radiography: Investigate with US those RUQ calcifications that are not typical in appearance or location.

OCG: The described findings are characteristic, and no further imaging is required. OCG assessment of the number and size of gallstones is more accurate than US.

False Positives/Negatives

Plain film radiography: Only 50% of pigment stones and 20% of cholesterol stones contain sufficient calcium to be visible on plain radiographs. Differentiation from right renal calculi usually is not problematic, since calyceal stones normally conform in shape to the collecting system. Occasionally, an oblique radiograph may be required to confirm the anterior location of gallbladder calcification.

Porcelain gallbladder is characteristic in appearance, presenting as eggshell calcification in the RUQ. Other RUQ calcifications, such as hepatic granulomas, tumoral calcification, costal cartilage calcification, calcified mesenteric lymph nodes, and rarely, hepatic artery or renal artery aneurysms, usually are not confused with gallbladder calculi.

OCG: A nonmobile filling defect may be an adherent stone but must be differentiated from polyps, adenomyomas, or rarely, primary or metastatic tumors, heterotopic gastric mucosa, or pancreatic mucosa. Calcified stones may be obscured by contrast within the gallbladder.

CT SCAN

Section 5 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

Gallstones appear as single or multiple filling defects within the gallbladder and are densely calcified (Image 7), rim calcified, laminated, or have a central nidus of calcification. Stones also may present as a soft-tissue density or a lucent filling defect within the bile. Some stones may contain air (Image 8).

Degree of Confidence

Although approximately 20% of gallstones are not identified on CT, when calcified stones are present, the appearance is characteristic and no further imaging is warranted. Perform US for filling defects in which calcification is not clearly present.

False Positives/Negatives

A mucosal fold in the gallbladder lumen may be confused with rim-calcified stone on contrast CT. Partial volume averaging of adjacent colon contrast may obscure or mimic stones. Noncalcified stones that are isodense with bile are not visualized. Single, noncalcified stones may be indistinguishable from polyps or tumors.

MRI

Section 6 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

Most gallstones have no signal on MRI and present as signal void-filling defects within the gallbladder. These are most apparent on T2-weighted sequences where signal-void stones are contrasted against high-signal bile (Image 11). On T1-weighted sequences, bile usually shows a homogeneous low signal; however, since the composition and concentration of bile varies, it may appear inhomogeneous with areas or levels of higher signal.

Therefore, signal-void stones also may be apparent on T1-weighted images (Image 12). High signal may be seen occasionally on T2-weighted images within stones that contain bile within clefts. Stones with high fatty acid content may demonstrate high signal on T1-weighted images.

Degree of Confidence

Multiple, faceted, or pyramidal signal void-filling defects on T2-weighted scans are most suggestive of stones. Since the accuracy of MRI in the identification of stones within the gallbladder has not been established, confirm findings with US to rule out polyps or tumor.

False Positives/Negatives

Stones may be indistinguishable from polyps or tumors. Stones may be missed because they are small or because of respiratory or motion artifacts.

ULTRASOUND

Section 7 of 11  

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• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

In a fasting gallbladder patient, stones appear as intraluminal, echogenic, mobile foci that are gravity-dependent and create a clean acoustic shadow (Image 1). In contracted and noncontracted gallbladders filled with stones, the wall-echo shadow triad is present (Image 4): visualization of the anterior gallbladder wall followed by the echogenic structure of intraluminal stones, with distal acoustic shadow.

Differentiation from bowel is easier if there is a small amount of bile between the gallbladder wall and the stone. Air present within gallbladder calculi creates reverberation artifacts and a dirty shadow. Small stones produce an acoustic shadow only if scanned by a high-frequency transducer (5 MHz or higher), since these transducers have a smaller beam width. A shadow is produced only if the stone intercepts the entire beam.

Degree of Confidence

An optimal gallbladder examination visualizes the entire organ from the distal fundus to the cystic duct/common hepatic duct junction with the patient in supine, right anterior oblique, and if necessary, prone or upright positions. This yields an examination sensitivity and specificity of more than 95%. In patients in whom small stones are present and a 5 MHz or higher frequency transducer cannot be used, acoustic shadowing is not seen. In these patients, demonstrate mobility by changing patient position to confirm the diagnosis. In some nonfasting patients, repeat scans after fasting may be necessary to better distend the gallbladder to confirm the absence or presence of small stones.

False Positives/Negatives

The false-negative rate is 1-4%. Sludge may obscure stones; adherent, nonshadowing stones may mimic polyps. Focal shadowing at the gallbladder neck resulting from refraction of the US beam may simulate a stone (Image 5). Rarely, a stone in the cystic duct may be missed. A stone-filled Phrygian cap or gallstones distal to a mucosal septum may be missed if mistaken for an adjacent bowel.

A mucosal fold located at the junction of the gallbladder body and infundibulum may simulate a polyp or stone. This finding, termed a junctional fold, usually can be diagnosed accurately with careful real-time US examination.

Stones smaller than 2 mm in diameter may be mistaken for sludge, particularly if patient body habitus prevents the use of an appropriately high-frequency transducer. A porcelain gallbladder may be indistinguishable from a large intraluminal stone.

Emphysematous cholecystitis or air within the gallbladder from an enteric fistula creates reverberation artifacts that may prevent adequate examination of the gallbladder lumen. Rarely, a contracted gallbladder may not be visualized. Most importantly, if the gallbladder cannot be adequately visualized, stones may be missed.

NUCLEAR MEDICINE

Section 8 of 11  

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• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Findings

Hepatobiliary imaging is a functional imaging tool used to diagnose acute cholecystitis and evaluate gallbladder contractility with determination of the gallbladder ejection fraction. In uncomplicated cholelithiasis, the study is normal (ie, the gallbladder visualizes within 60 min of radiopharmaceutical injection). However, the gallbladder ejection fraction, typically greater than 35%, may be reduced in the presence of cholelithiasis and/or chronic cholecystitis.

Degree of Confidence

Normal gallbladder visualization excludes acute cholecystitis with an accuracy of 99%. Delayed visualization of the gallbladder may be seen in patients with cholelithiasis and chronic cholecystitis. In these patients, the gallbladder may not visualize until 4 hours after radiopharmaceutical injection.

False Positives/Negatives

A false-positive (for acute cholecystitis) result occurs in nonfasting patients, patients with other diseases (ie, acute pancreatitis), and in some patients with cholelithiasis and a gallbladder contracted due to chronic cholecystitis. Occasionally, stasis of radioactivity within the duodenal bulb may be difficult to differentiate from gallbladder activity. In these patients, oblique/lateral views (gallbladder will be anterior and duodenum posterior), delayed images, or imaging that follows administration of fluids by mouth may demonstrate clearance of radioactivity from the duodenum (Image 13).

INTERVENTION

Section 9 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to take precautions to ensure optimal US examination of the gallbladder in all patients (since US is the screening procedure for cholelithiasis, and medical liability is incurred through misdiagnosis)
• Failure to meet standard of care, which requires imaging a fasting gallbladder patient (with the highest frequency transducer possible) from the cystic duct to the distal fundus with changes in patient position
• Failure to note in the descriptive report any technical limitations that are encountered during an examination
• Failure to be alert to unusual conditions, such as agenesis of the gallbladder, anomalous gallbladder position, and duplication of the gallbladder
• Failure to carefully assess the gallbladder wall (gallbladder cancer is increasingly associated with cholelithiasis)
• Failure to recommend correlation with other imaging studies when US findings are questionable or suboptimal

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Media file 1:  Cholelithiasis. Ultrasound image obtained with a 4-MHz transducer demonstrates a stone in the gallbladder neck with typical acoustic shadow.
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Media file 2:  Cholelithiasis. Ultrasound image obtained with a 3-MHz transducer demonstrates pyramidal nonshadowing stones.
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Media file 3:  Cholelithiasis. Ultrasound image obtained with a 3.5-MHz transducer demonstrates gallbladder sludge and tiny calculi.
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Media file 4:  Cholelithiasis. Wall-echo shadow sign indicates a stone-filled gallbladder.
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Media file 5:  Cholelithiasis. Do not confuse the reflective echo caused by the curve of the gallbladder neck with acoustic shadow related to a stone.
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Media file 6:  Cholelithiasis. Ultrasound image obtained with a 4-MHz transducer of a gallbladder filled with sludge and stones.
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Media file 7:  Cholelithiasis. Noncontrast CT demonstrates a typical, laminated, calcified gallstone.
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Media file 8:  Cholelithiasis. Contrast CT demonstrates multiple stones that are faintly rim calcified and contain air.
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Media file 9:  Cholelithiasis. Contrast-enhanced CT demonstrates a layer of calcific-dense material in the gallbladder that may be gravel or milk of calcium bile.
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Media file 10:  Cholelithiasis. A noncalcified filling defect is present in the gallbladder on this contrast-enhanced CT. Ultrasound examination confirmed a mobile stone and excluded the other possible diagnoses of polyp or tumor.
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Media file 11:  Cholelithiasis. Typical appearance of a gallstone as a signal void-filling defect within the gallbladder on this T2 fat-saturated MRI of the abdomen
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Media file 12:  Cholelithiasis. Multiple tiny gallstones appear as signal void-filling defects in the gallbladder on this T1-weighted spoiled gradient-echo sequence.
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Media type:  MRI

Media file 13:  Cholelithiasis. Stasis of radioactivity in the duodenal bulb (seen on this technetium Tc 99m diisopropyl iminodiacetic acid scan) can be misinterpreted as gallbladder activity. Delayed scans reveal clearance of activity from the duodenum and nonvisualization of the gallbladder in this patient with acute cholecystitis.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

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Article Last Updated: Apr 26, 2005