Introduction
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 studies have shown an increase in cholesterol stones in the Far East.
Cholelithiasis. Ultrasound image obtained with a 3-MHz transducer demonstrates pyramidal nonshadowing stones.
Cholelithiasis. Typical appearance of a gallstone as a signal void-filling defect within the gallbladder on this T2 fat-saturated MRI of the abdomen
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, Glasgow1 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).2 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 report by Kumar3 reviewing 102 children with gallstones showed a male-to-female ratio of 3:2.
Age
The incidence of cholelithiasis increases with age.4 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.3,5 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,6 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.7
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. One study reported 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.
Presentation
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.8
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.
Differential Diagnoses
Cholecystitis, Acute
Mirizzi Syndrome
Porcelain Gallbladder
Other Problems to Be Considered
Cholecystitis, emphysematous
Choledocholithiasis
More on Cholelithiasis |
 Overview: Cholelithiasis |
| Imaging: Cholelithiasis |
| Follow-up: Cholelithiasis |
| Multimedia: Cholelithiasis |
| References |
| Further Reading |
| Next Page » |
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Further Reading
Clinical guidelines
ACR Appropriateness Criteria® right upper quadrant pain.
American College of Radiology - Medical Specialty Society. 1996 (revised 2005). 5 pages. [NGC Update Pending] NGC:004781
ASGE guideline: the role of ERCP in diseases of the biliary tract and the pancreas.
American Society for Gastrointestinal Endoscopy - Medical Specialty Society. 2005 Jul. 8 pages. NGC:004486
Ultrasonographic examinations: indications and preparation of the patient.
Finnish Medical Society Duodecim - Professional Association. 2000 Apr 18 (revised 2007 Jan 11). Various pagings. NGC:005501
Clinical trials
Laparoendoscopic Rendez Vous Versus Standard Two Stage Approach for the Management of Cholelithiasis/Choledocholithiasis
Minimally Invasive Surgery: Using Natural Orfices
Gallbladder Cholesterolosis, Body Mass Index and Serum Cholesterol and Triglycerides
Related eMedicine topics
Cholelithiasis (Radiology)
Cholelithiasis (Emergency Medicine)
Cholelithiasis (Pediatrics)
Biliary Colic
Biliary Obstruction
Keywords
cholelithiasis, cholecystolithiasis, gallstones, calculi, gallbladder disease, digestive disorder, biliary microlithiasis, biliary sludge, microliths, milk of calcium bile, calcium carbonate precipitate
