Gallstones (Cholelithiasis)

Practice Essentials

Cholelithiasis involves the presence of gallstones (see the image below), which are concretions that form in the biliary tract, usually in the gallbladder. Choledocholithiasis refers to the presence of one or more gallstones in the common bile duct (CBD). Treatment of gallstones depends on the stage of disease.

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Magnetic resonance cholangiopancreatography (MRCP) showing 5 gallstones in the common bile duct (arrows). In this image, bile in the duct appears whit....

Signs and symptoms

Gallstone disease may be thought of as having the following four stages:

1. Lithogenic state, in which conditions favor gallstone formation
2. Asymptomatic gallstones
3. Symptomatic gallstones, characterized by episodes of biliary colic
4. Complicated cholelithiasis

Symptoms and complications result from effects occurring within the gallbladder or from stones that escape the gallbladder to lodge in the CBD.

Characteristics of biliary colic include the following:

• Sporadic and unpredictable episodes
• Pain that is localized to the epigastrium or right upper quadrant, sometimes radiating to the right scapular tip
• Pain that begins postprandially, is often described as intense and dull, typically lasts 1-5 hours, increases steadily over 10-20 minutes, and then gradually wanes
• Pain that is constant; not relieved by emesis, antacids, defecation, flatus, or positional changes; and sometimes accompanied by diaphoresis, nausea, and vomiting
• Nonspecific symptoms (eg, indigestion, dyspepsia, belching, or bloating)

Patients with the lithogenic state or asymptomatic gallstones have no abnormal findings on physical examination.

Distinguishing uncomplicated biliary colic from acute cholecystitis or other complications is important. Key findings that may be noted include the following:

• Uncomplicated biliary colic – Pain that is poorly localized and visceral; an essentially benign abdominal examination without rebound or guarding; absence of fever
• Acute cholecystitis – Well-localized pain in the right upper quadrant, usually with rebound and guarding; positive Murphy sign (nonspecific); frequent presence of fever; absence of peritoneal signs; frequent presence of tachycardia and diaphoresis; in severe cases, absent or hypoactive bowel sounds

The presence of fever, persistent tachycardia, hypotension, or jaundice necessitates a search for complications, which may include the following:

• Cholecystitis
• Cholangitis
• Pancreatitis
• Other systemic causes

See Presentation for more detail.

Diagnosis

Patients with uncomplicated cholelithiasis or simple biliary colic typically have normal laboratory test results; laboratory studies are generally not necessary unless complications are suspected. Blood tests, when indicated, may include the following:

• Complete blood count (CBC) with differential
• Liver function panel
• Amylase
• Lipase

Imaging modalities that may be useful include the following:

• Abdominal radiography (upright and supine) – Used primarily to exclude other causes of abdominal pain (eg, intestinal obstruction)
• Ultrasonography – The procedure of choice in suspected gallbladder or biliary disease
• Endoscopic ultrasonography (EUS) – An accurate and relatively noninvasive means of identifying stones in the distal CBD
• Laparoscopic ultrasonography – Promising as a potential method for bile duct imaging during laparoscopic cholecystectomy
• Computed tomography (CT) – More expensive and less sensitive than ultrasonography for detecting gallbladder stones, but superior for demonstrating stones in the distal CBD
• Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) – Usually reserved for cases in which choledocholithiasis is suspected
• Scintigraphy – Highly accurate for the diagnosis of cystic duct obstruction
• Endoscopic retrograde cholangiopancreatography (ERCP)
• Percutaneous transhepatic cholangiography (PTC)

See Workup for more detail.

Management

The treatment of gallstones depends upon the stage of the disease, as follows:

• Lithogenic state – Interventions are currently limited to a few special circumstances
• Asymptomatic gallstones – Expectant management
• Symptomatic gallstones – Usually, definitive surgical intervention (eg, cholecystectomy), although medical dissolution may be considered in some cases

Medical treatments, used individually or in combination, include the following:

• Oral bile salt therapy (ursodeoxycholic acid)
• Extracorporeal shockwave lithotripsy

Cholecystectomy for asymptomatic gallstones may be indicated in the following patients:

• Those with large (>2 cm) gallstones
• Those who have a nonfunctional or calcified (porcelain) gallbladder on imaging studies and are at high risk of gallbladder carcinoma
• Those with spinal cord injuries or sensory neuropathies affecting the abdomen
• Those with sickle cell anemia in whom the distinction between painful crisis and cholecystitis may be difficult

Patients with the following risk factors for complications of gallstones may be offered elective cholecystectomy, even if they have asymptomatic gallstones:

• Cirrhosis
• Portal hypertension
• Children
• Transplant candidates
• Diabetes with minor symptoms

Surgical interventions to be considered include the following:

• Cholecystectomy (open or laparoscopic)
• Cholecystostomy
• Endoscopic sphincterotomy

See Treatment and Medication for more detail.

• References

Background

Cholelithiasis is the medical term for gallstone disease. Gallstones are concretions that form in the biliary tract, usually in the gallbladder (see the image below).

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Excised gall bladder opened to show 3 gallstones. Image from Science Source (http://www.sciencesource.com/).

Gallstones develop insidiously, and they may remain asymptomatic for decades. Migration of a gallstone into the opening of the cystic duct may block the outflow of bile during gallbladder contraction. The resulting increase in gallbladder wall tension produces a characteristic type of pain (biliary colic). Cystic duct obstruction, if it persists for more than a few hours, may lead to acute gallbladder inflammation (acute cholecystitis).

Choledocholithiasis refers to the presence of one or more gallstones in the common bile duct. Usually, this occurs when a gallstone passes from the gallbladder into the common bile duct (see the image below).

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Common bile duct stone (choledocholithiasis). The sensitivity of transabdominal ultrasonography for choledocholithiasis is approximately 75% in the pr....

A gallstone in the common bile duct may impact distally in the ampulla of Vater, the point where the common bile duct and pancreatic duct join before opening into the duodenum. Obstruction of bile flow by a stone at this critical point may lead to abdominal pain and jaundice. Stagnant bile above an obstructing bile duct stone often becomes infected, and bacteria can spread rapidly back up the ductal system into the liver to produce a life-threatening infection called ascending cholangitis. Obstruction of the pancreatic duct by a gallstone in the ampulla of Vater can trigger activation of pancreatic digestive enzymes within the pancreas itself, leading to acute pancreatitis.^{[1, 2]}

Chronically, gallstones in the gallbladder may cause progressive fibrosis and loss of function of the gallbladder, a condition known as chronic cholecystitis. Chronic cholecystitis predisposes to gallbladder cancer.

Ultrasonography is the initial diagnostic procedure of choice in most cases of suspected gallbladder or biliary tract disease (see Workup).

The treatment of gallstones depends upon the stage of disease. Asymptomatic gallstones may be managed expectantly. Once gallstones become symptomatic, definitive surgical intervention with excision of the gallbladder (cholecystectomy) is usually indicated. Cholecystectomy is among the most frequently performed abdominal surgical procedures (see Treatment). Complications of gallstone disease may require specialized management to relieve obstruction and infection.

See Pediatric Cholelithiasis for complete information on this topic.

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Pathophysiology

Gallstone formation occurs because certain substances in the bile are present in concentrations that approach the limits of their solubility. When bile is concentrated in the gallbladder, it can become supersaturated with these substances, which then precipitate from the solution as microscopic crystals. The crystals are trapped in the gallbladder mucus, producing gallbladder sludge. Over time, the crystals grow, aggregate, and fuse to form macroscopic stones. Occlusion of the ducts by sludge and/or stones produces the complications of gallstone disease.

The two main substances involved in gallstone formation are cholesterol and calcium bilirubinate.

Cholesterol gallstones

More than 80% of gallstones in the United States contain cholesterol as their major component. Liver cells secrete cholesterol into bile along with phospholipid (lecithin) in the form of small spherical membranous bubbles, termed unilamellar vesicles. Liver cells also secrete bile salts, which are powerful detergents required for the digestion and absorption of dietary fats.

Bile salts in bile dissolve the unilamellar vesicles to form soluble aggregates called mixed micelles. This happens mainly in the gallbladder, where bile is concentrated by the reabsorption of electrolytes and water.

Compared with vesicles (which can hold up to 1 molecule of cholesterol for every molecule of lecithin), mixed micelles have a lower carrying capacity for cholesterol (about 1 molecule of cholesterol for every 3 molecules of lecithin). If bile contains a relatively high proportion of cholesterol to begin with, then as bile is concentrated, progressive dissolution of vesicles may lead to a state in which the cholesterol-carrying capacity of the micelles and residual vesicles is exceeded. At this point, bile is supersaturated with cholesterol, and cholesterol monohydrate crystals may form.

Thus, the main factors that determine whether cholesterol gallstones will form are (1) the amount of cholesterol secreted by the liver cells, relative to lecithin and bile salts, and (2) the degree of concentration and the extent of stasis of bile in the gallbladder.

Calcium, bilirubin, and pigment gallstones

Bilirubin, a yellow pigment derived from the breakdown of heme, is actively secreted into bile by liver cells. Most of the bilirubin in bile is in the form of glucuronide conjugates, which are water soluble and stable, but a small proportion consists of unconjugated bilirubin. Unconjugated bilirubin, like fatty acids, phosphate, carbonate, and other anions, tends to form insoluble precipitates with calcium. Calcium enters bile passively along with other electrolytes.

In situations of high heme turnover, such as chronic hemolysis or cirrhosis, unconjugated bilirubin may be present in bile at higher than normal concentrations. Calcium bilirubinate may then crystallize from the solution and eventually form stones. Over time, various oxidations cause the bilirubin precipitates to take on a jet-black color, and stones formed in this manner are termed black pigment gallstones. Black pigment stones represent 10%-20% of gallstones in the United States.

Bile is normally sterile, but in some unusual circumstances (eg, above a biliary stricture), it may become colonized with bacteria. The bacteria hydrolyze conjugated bilirubin, and the resulting increase in unconjugated bilirubin may lead to precipitation of calcium bilirubinate crystals.

Bacteria also hydrolyze lecithin to release fatty acids, which also may bind calcium and precipitate from the solution. The resulting concretions have a claylike consistency and are termed brown pigment stones. Unlike cholesterol or black pigment gallstones, which form almost exclusively in the gallbladder, brown pigment gallstones often form de novo in the bile ducts. Brown pigment gallstones are unusual in the United States but are fairly common in some parts of Southeast Asia, possibly related to liver fluke infestation.

Mixed gallstones

Cholesterol gallstones may become colonized with bacteria and can elicit gallbladder mucosal inflammation. Lytic enzymes from the bacteria and leukocytes hydrolyze bilirubin conjugates and fatty acids. As a result, over time, cholesterol stones may accumulate a substantial proportion of calcium bilirubinate and other calcium salts, producing mixed gallstones. Large stones may develop a surface rim of calcium resembling an eggshell that may be visible on plain x-ray films.

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Etiology

Cholesterol gallstones, black pigment gallstones, and brown pigment gallstones have different pathogeneses and different risk factors.

Cholesterol gallstones

Cholesterol gallstones are associated with female sex, European or Native American ancestry, and increasing age. Other risk factors include the following:

• Obesity
• Pregnancy
• Gallbladder stasis
• Drugs
• Heredity

The metabolic syndrome of truncal obesity, insulin resistance, type II diabetes mellitus, hypertension, and hyperlipidemia is associated with increased hepatic cholesterol secretion and is a major risk factor for the development of cholesterol gallstones.

Cholesterol gallstones are more common in women who have experienced multiple pregnancies. A major contributing factor is thought to be the high progesterone levels of pregnancy. Progesterone reduces gallbladder contractility, leading to prolonged retention and greater concentration of bile in the gallbladder.

Other causes of gallbladder stasis associated with increased risk of gallstones include high spinal cord injuries, prolonged fasting with total parenteral nutrition, and rapid weight loss associated with severe caloric and fat restriction (eg, diet, gastric bypass surgery^[3] ).

A number of medications are associated with the formation of cholesterol gallstones. Estrogens administered for contraception or for the treatment of prostate cancer increase the risk of cholesterol gallstones by increasing biliary cholesterol secretion. Clofibrate and other fibrate hypolipidemic drugs increase hepatic elimination of cholesterol via biliary secretion and appear to increase the risk of cholesterol gallstones. Somatostatin analogues appear to predispose to gallstones by decreasing gallbladder emptying.

About 25% of the predisposition to cholesterol gallstones appears to be hereditary, as judged from studies of identical and fraternal twins. At least a dozen genes may contribute to the risk.^[4] A rare syndrome of low phospholipid–associated cholelithiasis occurs in individuals with a hereditary deficiency of the biliary transport protein required for lecithin secretion.^{[5, 6]}

Black and brown pigment gallstones

Black pigment gallstones occur disproportionately in individuals with high heme turnover. Disorders of hemolysis associated with pigment gallstones include sickle cell anemia, hereditary spherocytosis, and beta-thalassemia. In cirrhosis, portal hypertension leads to splenomegaly. This, in turn, causes red cell sequestration, leading to a modest increase in hemoglobin turnover. About half of all cirrhotic patients have pigment gallstones.

Prerequisites for the formation of brown pigment gallstones include intraductal stasis and chronic colonization of bile with bacteria. In the United States, this combination is most often encountered in patients with postsurgical biliary strictures or choledochal cysts.

In rice-growing regions of East Asia, infestation with biliary flukes may produce biliary strictures and predispose to formation of brown pigment stones throughout intrahepatic and extrahepatic bile ducts. This condition, termed hepatolithiasis, causes recurrent cholangitis and predisposes to biliary cirrhosis and cholangiocarcinoma.

Other comorbidities

Crohn disease, ileal resection, or other diseases of the ileum decrease bile salt reabsorption and increase the risk of gallstone formation.

Other illnesses or states that predispose to gallstone formation include burns, use of total parenteral nutrition, paralysis, ICU care, and major trauma. This is due, in general, to decreased enteral stimulation of the gallbladder with resultant biliary stasis and stone formation.

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Epidemiology

The prevalence of cholelithiasis is affected by many factors, including ethnicity, gender, comorbidities, and genetics.

United States statistics

In the United States, about 20 million people (10%-20% of adults) have gallstones. Every year 1%-3% of people develop gallstones and about 1%-3% of people become symptomatic. Each year, in the United States, approximately 500,000 people develop symptoms or complications of gallstones requiring cholecystectomy.

Gallstone disease is responsible for about 10,000 deaths per year in the United States. About 7000 deaths are attributable to acute gallstone complications, such as acute pancreatitis. About 2000-3000 deaths are caused by gallbladder cancers (80% of which occur in the setting of gallstone disease with chronic cholecystitis). Although gallbladder surgery is relatively safe, cholecystectomy is a very common procedure, and its rare complications result in several hundred deaths each year.

International statistics

The prevalence of cholesterol cholelithiasis in other Western cultures is similar to that in the United States, but it appears to be somewhat lower in Asia and Africa.

A Swedish epidemiologic study found that the incidence of gallstones was 1.39 per 100 person-years.^[7] In an Italian study, 20% of women had stones, and 14% of men had stones. In a Danish study, gallstone prevalence in persons aged 30 years was 1.8% for men and 4.8% for women; gallstone prevalence in persons aged 60 years was 12.9% for men and 22.4% for women.

The prevalence of choledocholithiasis is higher internationally than in the United States, mainly because of the additional risk of primary common bile duct stones caused by parasitic infestation with liver flukes such as Clonorchis sinensis.

Race-, sex-, and age-related demographics

Prevalence of gallstones is highest in people of northern European descent, and in Hispanic populations and Native American populations.^[8] Prevalence of gallstones is lower in Asians and African Americans.

Women are more likely to develop cholesterol gallstones than men, especially during their reproductive years, when the incidence of gallstones in women is 2-3 times that in men. The difference appears to be attributable mainly to estrogen, which increases biliary cholesterol secretion.^[9]

Risk of developing gallstones increases with age. Gallstones are uncommon in children in the absence of congenital anomalies or hemolytic disorders. Beginning at puberty, the concentration of cholesterol in bile increases. After age 15 years, the prevalence of gallstones in US women increases by about 1% per year; in men, the rate is less, about 0.5% per year. Gallstones continue to form throughout adult life, and the prevalence is greatest at advanced age. The incidence in women falls with menopause, but new stone formation in men and women continues at a rate of about 0.4% per year until late in life.

Among individuals undergoing cholecystectomy for symptomatic cholelithiasis, 8%-15% of patients younger than 60 years have common bile duct stones, compared with 15%-60% of patients older than 60 years.

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Prognosis

Less than half of patients with gallstones become symptomatic. The mortality rate for an elective cholecystectomy is 0.5% with less than 10% morbidity. The mortality rate for an emergent cholecystectomy is 3%-5% with 30%-50% morbidity.

Following cholecystectomy, stones may recur in the bile duct. Separately, single-incisional laparoscopic cholecystectomy appears to be associated with an incisional hernia rate of 8%, with age (≥50 years) and body mass index (BMI) (≥30 kg/m²) as independent predictive factors.^[10]

Approximately 10%-15% of patients have an associated choledocholithiasis. The prognosis in patients with choledocholithiasis depends on the presence and severity of complications. Of all patients who refuse surgery or are unfit to undergo surgery, 45% remain asymptomatic from choledocholithiasis, while 55% experience varying degrees of complications.

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Patient Education

Patients with asymptomatic gallstones should be educated to recognize and report the symptoms of biliary colic and acute pancreatitis. Alarm symptoms include persistent epigastric pain lasting for greater than 20 minutes, especially if accompanied by nausea, vomiting, or fever. If pain is severe or persists for more than an hour, the patient should seek immediate medical attention.

For patient education information, see the Digestive Disorders Center and Cholesterol Center, as well as Gallstones.

View Video

What are gallstones? Gallstones are solid stones that are produced in the gallbladder when there’s an imbalance in the composition of bile. The main types of gallstones are cholesterol stones, bilirubin stones, and brown stones.

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History

Gallstone disease may be thought of as having the following four stages:

1. The lithogenic state, in which conditions favor gallstone formation
2. Asymptomatic gallstones
3. Symptomatic gallstones, characterized by episodes of biliary colic
4. Complicated cholelithiasis

Symptoms and complications of gallstone disease result from effects occurring within the gallbladder or from stones that escape the gallbladder to lodge in the common bile duct.

Asymptomatic gallstones

Gallstones may be present in the gallbladder for decades without causing symptoms or complications. In patients with asymptomatic gallstones discovered incidentally, the likelihood of developing symptoms or complications is 1%-2% per year. In most cases, asymptomatic gallstones do not require any treatment.

Because they are common, gallstones often coexist with other gastrointestinal conditions. There is little evidence to support a causal association between gallstones and chronic abdominal pain, heartburn, postprandial distress, bloating, flatulence, constipation, or diarrhea.

Dyspepsia that occurs reproducibly following ingestion of fatty foods is often wrongly attributed to gallstones, when irritable bowel syndrome or gastroesophageal reflux is the true culprit. Gallstones discovered during an evaluation for nonspecific symptoms are usually innocent bystanders, and treatment directed at the gallstones is unlikely to relieve these symptoms.

Biliary colic

Pain termed biliary colic occurs when gallstones or sludge fortuitously impact in the cystic duct during gallbladder contraction, increasing the gallbladder wall tension. In most cases, the pain resolves over 30 to 90 minutes as the gallbladder relaxes and the obstruction is relieved.

Episodes of biliary colic are sporadic and unpredictable. The patient localizes the pain to the epigastrium or right upper quadrant and may describe radiation to the right scapular tip (Collins sign^[11] ). The pain begins postprandially (usually within an hour after a fatty meal), is often described as intense and dull, and may last from 1-5 hours. From the onset, the pain increases steadily over about 10 to 20 minutes and then gradually wanes when the gallbladder stops contracting and the stone falls back into the gallbladder. The pain is constant in nature and is not relieved by emesis, antacids, defecation, flatus, or positional changes. It may be accompanied by diaphoresis, nausea, and vomiting.

Other symptoms, often associated with cholelithiasis, include indigestion, dyspepsia, belching, bloating, and fat intolerance. However, these are very nonspecific and occur in similar frequencies in individuals with and without gallstones; cholecystectomy has not been shown to improve these symptoms.

Most patients develop symptoms prior to complications. Once symptoms of biliary colic occur, severe symptoms develop in 3%-9% of patients, with complications in 1%-3% per year and a cholecystectomy rate of 3%-8% per year. Therefore, in people with mild symptoms, 50% have complications after 20 years.

Zollinger performed studies in the 1930s in which the gallbladder wall or the common bile duct was distended with a balloon; pain was elicited in the epigastric region. Only if the distended gallbladder touched the peritoneum did the patient experience right upper quadrant pain. Associated symptoms of nausea, vomiting, or referred pain were present with distention of the common bile duct (CBD) but not of the gallbladder.

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Physical Examination

Patients with the lithogenic state or asymptomatic gallstones have no abnormal findings on physical examination.

Distinguishing uncomplicated biliary colic from acute cholecystitis or other complications is important. Both often present with the same constellation of symptoms, and physical examination may help to differentiate the two.

Since the gallbladder is not inflamed in uncomplicated biliary colic, the pain is poorly localized and visceral in origin; the patient has an essentially benign abdominal examination without rebound or guarding. Fever is absent.

In acute cholecystitis, inflammation of the gallbladder with resultant peritoneal irritation leads to a well-localized pain in the right upper quadrant, usually with rebound and guarding. Although nonspecific, a positive Murphy sign (inspiratory arrest on deep palpation of the right upper quadrant during deep inspiration) is highly suggestive of cholecystitis. Fever is often present, but it may lag behind other signs or symptoms.

Although voluntary guarding may be present, no peritoneal signs are present. Tachycardia and diaphoresis may be present as a consequence of pain. These should resolve with appropriate pain management.

The presence of fever, persistent tachycardia, hypotension, or jaundice necessitate a search for complications of cholelithiasis, including cholecystitis, cholangitis, pancreatitis, or other systemic causes.

In severe cases of acute cholecystitis, ascending cholangitis, or acute pancreatitis, bowel sounds are often absent or hypoactive.

Choledocholithiasis with obstruction of the common bile duct produces cutaneous and scleral icterus that evolves over hours to days as bilirubin accumulates.

The Charcot triad of severe right upper quadrant tenderness with jaundice and fever is characteristic of ascending cholangitis.

Acute gallstone pancreatitis is often characterized by epigastric tenderness. In severe cases, retroperitoneal hemorrhage may produce ecchymoses of the flanks and periumbilical region (Cullen sign and Grey-Turner sign).

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Complications

Complications of gallbladder stones

Acute cholecystitis occurs when persistent stone impaction in the cystic duct causes the gallbladder to become distended and progressively inflamed. Patients experience the pain of biliary colic, but, instead of resolving spontaneously, the pain persists and worsens.

Overgrowth of colonizing bacteria in the gallbladder often occurs, and, in severe cases, accumulation of pus in the gallbladder, termed gallbladder empyema, occurs. The gallbladder wall may become necrotic, resulting in perforation and pericholecystic abscess formation. Acute cholecystitis is considered a surgical emergency, although pain and inflammation may subside with conservative measures, such as hydration and antibiotics.

Chronically, gallstones may cause progressive fibrosis of the gallbladder wall and loss of gallbladder function, termed chronic cholecystitis. The pathogenesis of this complication is not completely understood. Repeated attacks of acute cholecystitis may play a role, as may localized ischemia produced by pressure of stones against the gallbladder wall. The chronically fibrotic gallbladder may become shrunken and adherent to the adjacent viscera.

Gallbladder adenocarcinoma is an uncommon cancer that usually develops in the setting of gallstones and chronic cholecystitis. Gallbladder cancers commonly invade the adjacent liver and common bile duct, producing jaundice. The prognosis is poor unless the cancer is localized to the gallbladder, in which case cholecystectomy may be curative.

Occasionally, a large stone may erode through the wall of the gallbladder into an adjacent viscus (typically the duodenum), producing a cholecystoenteric fistula. The stone, if sufficiently large, may obstruct the small intestine, usually at the level of the ileum, a phenomenon termed gallstone ileus.

Complications of stones in the common bile duct

Gallstones are initially retained in the gallbladder by the spiral valves of the cystic duct. Following episodes of gallstone impaction in the cystic duct, these valves may become obliterated and stones may pass into the common bile duct. Patients who have passed one stone tend to pass more stones over the subsequent months.

Stones in the common bile duct may be asymptomatic, but, more commonly, they impact distally in the ampulla of Vater. This may produce biliary colic indistinguishable from that caused by cystic duct stones. Because impaction of common bile duct stones occludes the flow of bile from the liver to the intestine, pressure rises in the intrahepatic bile ducts, leading to elevation of liver enzymes and jaundice.

Bacterial overgrowth in stagnant bile above an obstructing common duct stone produces purulent inflammation of the liver and biliary tree, termed ascending cholangitis. The characteristic features include the Charcot triad of fever, jaundice, and right upper quadrant pain. Patients may rapidly develop septic shock unless the ductal obstruction is relieved.

A stone impacted at the ampulla of Vater may transiently obstruct the pancreatic duct, leading to in situ activation of pancreatic proteases and triggering an attack of acute pancreatitis. Pancreatic pain is different from biliary pain. The pain is located in the epigastric and midabdominal areas and is sharp, severe, continuous, and radiates to the back. Nausea and vomiting are frequently present, and a similar previous episode is reported by approximately 15% patients.

Stone impaction in the distal common bile duct is often relieved spontaneously within hours to days by passage of the stone into the intestine.

Other complications

Inflammation from chronic cholelithiasis may result in fusion of the gallbladder to the extrahepatic biliary tree, causing Mirizzi syndrome. Alternatively, a fistula into the intestinal tract may form, causing gallstone ileus.^[12]

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Approach Considerations

Patients with uncomplicated cholelithiasis or simple biliary colic typically have normal laboratory test results. Laboratory testing is generally not necessary unless cholecystitis is a concern.^[13]

Asymptomatic gallstones are often found incidentally on plain radiographs, abdominal sonograms, or computed tomography (CT) scans for workup of other processes. Plain radiographs have little role in the diagnosis of gallstones or gallbladder disease. Cholesterol and pigment stones are radiopaque and visible on radiographs in only 10%-30% of instances, depending on their extent of calcification.

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Hematologic Studies

In patients with suspected gallstone complications, blood tests should include a complete blood cell (CBC) count with differential, liver function panel, and amylase and lipase.

Acute cholecystitis is associated with polymorphonuclear leukocytosis. However, up to one third of the patients with cholecystitis may not manifest leukocytosis.

In severe cases, mild elevations of liver enzymes may be caused by inflammatory injury of the adjacent liver.

Patients with cholangitis and pancreatitis have abnormal laboratory test values. Importantly, a single abnormal laboratory value does not confirm the diagnosis of choledocholithiasis, cholangitis, or pancreatitis; rather, a coherent set of laboratory studies leads to the correct diagnosis.

Choledocholithiasis with acute common bile duct (CBD) obstruction initially produces an acute increase in the level of liver transaminases (alanine and aspartate aminotransferases), followed within hours by a rising serum bilirubin level. The higher the bilirubin level, the greater the predictive value for CBD obstruction. CBD stones are present in approximately 60% of patients with serum bilirubin levels greater than 3 mg/dL.

If obstruction persists, a progressive decline in the level of transaminases with rising alkaline phosphatase and bilirubin levels may be noted over several days. Prothrombin time may be elevated in patients with prolonged CBD obstruction, secondary to depletion of vitamin K (the absorption of which is bile-dependent). Concurrent obstruction of the pancreatic duct by a stone in the ampulla of Vater may be accompanied by increases in serum lipase and amylase levels.

Repeated testing over hours to days may be useful in evaluating patients with gallstone complications. Improvement of the levels of bilirubin and liver enzymes may indicate spontaneous passage of an obstructing stone. Conversely, rising levels of bilirubin and transaminases with progression of leukocytosis in the face of antibiotic therapy may indicate ascending cholangitis with the need for urgent intervention. Blood culture results are positive in 30%-60% of patients with cholangitis.

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Abdominal Radiography

Upright and supine abdominal radiographs are occasionally helpful in establishing a diagnosis of gallstone disease.

Black pigment or mixed gallstones may contain sufficient calcium to appear radiopaque on plain films. The finding of air in the bile ducts on plain films may indicate the development of a choledochoenteric fistula or ascending cholangitis with gas-forming organisms. Calcification in the gallbladder wall (the so-called porcelain gallbladder) is indicative of severe chronic cholecystitis.

The main role of plain films in evaluating patients with suspected gallstone disease is to exclude other causes of acute abdominal pain, such as intestinal obstruction, visceral perforation, renal stones, or chronic calcific pancreatitis.

See Imaging of Cholelithiasis for complete information on this topic.

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Ultrasonography

Ultrasonography is the procedure of choice in suspected gallbladder or biliary disease; it is the most sensitive, specific, noninvasive, and inexpensive test for the detection of gallstones.^[14] Moreover, it is simple, rapid, and safe in pregnancy, and it does not expose the patient to harmful radiation or intravenous contrast. An added advantage is that it can be performed by skilled practitioners at the bedside. The American College of Radiology (ACR) in its Appropriateness Criteria right upper quadrant pain, published in 2010, supports this conclusion.^[15]

Sensitivity is variable and dependent upon operator proficiency, but in general, it is highly sensitive and specific for gallstones greater than 2 mm. It is less so for microlithiasis or biliary sludge.

Ultrasonography is very useful for diagnosing uncomplicated acute cholecystitis. The sonographic features of acute cholecystitis include gallbladder wall thickening (>5 mm), pericholecystic fluid, gallbladder distention (>5 cm), and a sonographic Murphy sign. The presence of multiple criteria increases its diagnostic accuracy.

Gallstones appear as echogenic foci in the gallbladder. They move freely with positional changes and cast an acoustic shadow. (See the image below.)

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Cholecystitis with small stones in the gallbladder neck. Classic acoustic shadowing is seen beneath the gallstones. The gallbladder wall is greater th....

Ultrasonography is also helpful in cases of suspected acute cholecystitis to exclude hepatic abscesses and other liver parenchymal processes.

When the gallbladder is completely filled with gallstones, the stones may not be visible on ultrasound. However, closely spaced double echogenic lines (one from the gallbladder wall and one from the stones) with acoustic shadowing may be evident. (See the images below.)

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The WES (wall echogenic shadow) sign, long axis of the gallbladder. The arrow head points to the gallbladder wall. The second hyperechoic line represe....

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Wall echogenic shadow (WES sign), short axis view of the gallbladder. Image courtesy of Stephen Menlove.

Common bile duct (CBD) stones are missed frequently on transabdominal ultrasonography (sensitivity, 15%-40%). The detection of CBD stones is impeded by the presence of gas in the duodenum, possible reflection and refraction of the sound beam by the curvature of the duct, and the location of the duct beyond the optimal focal point of the transducer.

On the other hand, dilatation of the CBD on ultrasonographic images is an indirect indicator of CBD obstruction. CBD dilatation is identified accurately, with up to 90% accuracy. However, this finding may be absent if the obstruction is of recent onset. The usefulness of ultrasonography findings as a predictor of CBD stones is at best 15%-20%.

See Imaging of Cholelithiasis for complete information on this topic.

Endoscopic ultrasound

Endoscopic ultrasound (EUS) is also an accurate and relatively noninvasive technique to identify stones in the distal common bile duct. Sensitivity and specificity of CBD stone detection are reported in range of 85%-100%.^[16]

Laparoscopic ultrasound

Laparoscopic ultrasound has shown some promise as a primary method for bile duct imaging during laparoscopic cholecystectomy.^[17] Yao et al were able to evaluate the common bile duct with laparoscopic ultrasound during laparoscopic cholecystectomy in 112 of 115 patients (97.4%) with cholelithiasis.

In patients who were categorized preoperatively as having a low probability of bile duct stones, the occurrence rate of stones was found to be 7%; in those who were preoperatively assessed as having an intermediate probability of such stones, the occurrence rate was 36.4%; and in those who were rated with the highest probability of bile duct stones, the occurrence rate was 78.9%.^[17]

The investigators suggested that as experience increases with laparoscopic ultrasound, this method may become routine for evaluating the bile duct during laparoscopic cholecystectomy. In addition, Yao et al advised mandatory aggressive preoperative evaluation of the common bile duct in those who are suspected to have an intermediate or high risk of having choledocholithiasis.^[17]

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Computed Tomography Scanning

Computed tomography (CT) scanning is more expensive and less sensitive than ultrasonography for the detection of gallbladder stones. CT scanning is often used in the workup of abdominal pain, as it provides excellent images of all the abdominal viscera. CT scanning is superior to ultrasonography for the demonstration of gallstones in the distal common bile duct.

Gallstones are often found incidentally on CT. Findings on CT for acute cholecystitis are similar to those found on sonograms. Although not the initial study of choice in biliary colic, CT can be used in diagnostic challenges or to further characterize the complications of gallbladder disease. CT is particularly useful for the detection of intrahepatic stones or recurrent pyogenic cholangitis.

See Imaging of Cholelithiasis for complete information on this topic.

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Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) has emerged as an excellent imaging study for the noninvasive identification of gallstones anywhere in the biliary tract, including the common bile duct (see the image below). Because of its cost and the need for sophisticated equipment and software, it is usually reserved for cases in which choledocholithiasis is suspected. The 2010 ACR guidelines recommend MRI as a secondary imaging study if ultrasound images do not result in a clear diagnosis of acute cholecystitis or gallstones.^[15]

View Image

Magnetic resonance cholangiopancreatography (MRCP) showing 5 gallstones in the common bile duct (arrows). In this image, bile in the duct appears whit....

See Imaging of Cholelithiasis for complete information on this topic.

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Scintigraphy

Technetium-99m (^99m Tc) hepatoiminodiacetic acid (HIDA) scintigraphy is occasionally useful in the differential diagnosis of acute abdominal pain. Scintigraphy gives little information about nonobstructing cholelithiasis and cannot detect other pathologic states, but it is highly accurate for the diagnosis of cystic duct obstruction.

HIDA is normally taken up by the liver and excreted into bile, where it fills the gallbladder and can be detected with a gamma camera. Failure of HIDA to fill the gallbladder, while flowing freely into the duodenum, is indicative of cystic duct obstruction. A nonvisualizing gallbladder on a HIDA scan in a patient with abdominal pain supports the diagnosis of acute cholecystitis.

A meta-analysis by Mahid et al found that patients without gallstones who have right upper quadrant pain and a positive HIDA scan result are more likely to experience symptom relief if they undergo cholecystectomy than if they are treated medically.^[18]

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Endoscopic Retrograde Cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) permits radiographic imaging of the bile ducts. In this procedure, an endoscope is passed into the duodenum and the papilla of Vater is cannulated. Radiopaque liquid contrast is injected into the biliary ducts, providing excellent contrast on radiographic images. Stones in bile appear as filling defects in the opacified ducts. Currently, ERCP is usually performed in conjunction with endoscopic retrograde sphincterotomy and gallstone extraction.^[19]

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Percutaneous Transhepatic Cholangiography

Percutaneous transhepatic cholangiography (PTC) may be the modality of choice in patients in whom ERCP is difficult (eg, those with previous gastric surgery or distal obstructing CBD stone), in the absence of an experienced endoscopist, and in patients with extensive intrahepatic stone disease and cholangiohepatitis. A long large-bore needle is advanced percutaneously and transhepatically into an intrahepatic duct, and cholangiography is performed. A catheter can be placed in the biliary tree over a guidewire.

Uncorrected coagulopathy is a contraindication for PTC, and the normal size of the intrahepatic ducts makes the procedure difficult. Prophylactic antibiotics are recommended to reduce the risk of cholangitis.

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Approach Considerations

The treatment of gallstones depends upon the stage of disease.^[20] Ideally, interventions in the lithogenic state could prevent gallstone formation, although, currently, this option is limited to a few special circumstances. Asymptomatic gallstones may be managed expectantly.

Once gallstones become symptomatic, definitive surgical intervention with cholecystectomy is usually indicated (typically, laparoscopic cholecystectomy is the first-line therapy at centers with experience in this procedure).^[21] Careful selection of patients is warranted and should fulfill the following criteria:

• Small stone size (< 0.5 to 1 cm)
• Good gallbladder function (eg, normal filling and emptying)
• Minimal or no calcification

Open surgery may be indicated when concomitant gallbladder cancer is present.^[21]

In patients with complicated cholecystitis, stabilization of the patient and gallbladder drainage, followed by cholecystectomy, may be considered.^[21]

The role of medical management of gallstones has declined in recent years. However, medical therapy may be a useful alternative to cholecystectomy in select patients, particularly in those who are not suitable surgical candidates or who are unwilling to undergo surgery. Medical treatment, beyond pain control, is not initiated in the emergency department.

Medical treatments for gallstones, used alone or in combination, include the following^[21] :

• Oral bile salt therapy (ursodeoxycholic acid) (particularly for x-ray-negative cholesterol gallstones in patients with normal gallbladder function)
• Extracorporeal shockwave lithotripsy (particularly for noncalcified cholesterol gallstones in patients with normal gallbladder function)

Medical management is more effective in patients with good gallbladder function who have small stones (< 1 cm) with a high cholesterol content. Bile salt therapy may be required for more than 6 months and has a success rate of less than 50%.

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Treatment of Asymptomatic Gallstones

Surgical treatment of asymptomatic gallstones without medically complicating diseases is discouraged.^[21] The risk of complications arising from interventions is higher than the risk of symptomatic disease. Approximately 25% of patients with asymptomatic gallstones develop symptoms within 10 years.

Persons with diabetes and women who are pregnant should have close follow-up to determine if they become symptomatic or develop complications.

However, cholecystectomy for asymptomatic gallstones may be indicated in the following patients:

• Patients with large gallstones, greater than 2 cm in diameter (In a case-control study of 81 gallbladder cancer cases, the risk of malignancy was more than doubled [odd ratio: 2.4] for patients with gallstone diameters of 2.0-2.9 cm; the neoplastic risk was more than 10-fold [10.1] in those with gallstone diameters of ≥3 cm.^[22] These findings suggested implications for the management of asymptomatic gallstones, including annual follow-up with physical examination, abdominal ultrasonography, and other studies as appropriate.^[21] )
• Patients with nonfunctional or calcified (porcelain) gallbladder observed on imaging studies and who are at high risk of gallbladder carcinoma
• Patients with spinal cord injuries or sensory neuropathies affecting the abdomen
• Patients with sickle cell anemia in whom the distinction between painful crisis and cholecystitis may be difficult

Patients with risk factors for complications of gallstones may be offered elective cholecystectomy, even if they have asymptomatic gallstones. These groups include persons with the following conditions and demographics:

• Cirrhosis
• Portal hypertension
• Children
• Transplant candidates
• Diabetes with minor symptoms

Patients with a calcified or porcelain gallbladder should consider elective cholecystectomy due to the possibly increased risk of carcinoma (25%). Refer to a surgeon for removal as an outpatient procedure.

Medical dissolution of gallstones

Ursodeoxycholic acid (ursodiol) is a gallstone dissolution agent. In humans, long-term administration of ursodeoxycholic acid reduces cholesterol saturation of bile, both by reducing liver cholesterol secretion and by reducing the detergent effect of bile salts in the gallbladder (thereby preserving vesicles that have a high cholesterol carrying capacity). Desaturation of bile prevents crystals from forming and, in fact, may allow gradual extraction of cholesterol from existing stones.

In patients with established cholesterol gallstones, treatment with ursodeoxycholic acid at a dose of 8-10 mg/kg/d PO divided bid/tid may result in gradual gallstone dissolution. This intervention typically requires 6-18 months and is successful only with small, purely cholesterol stones. Patients remain at risk for gallstone complications until dissolution is completed. The recurrence rate is 50% within 5 years. Moreover, after discontinuation of treatment, most patients form new gallstones over the subsequent 5-10 years.

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Treatment of Patients with Symptomatic Gallstones

In patients with symptomatic gallstones, discuss the options for surgical and nonsurgical intervention; emergency physicians should refer patients to their primary care provider and obtain a surgical consult for outpatient follow-up.

Cholecystectomy

Removal of the gallbladder (cholecystectomy) is generally indicated in patients who have experienced symptoms or complications of gallstones, unless the patient's age and general health make the risk of surgery prohibitive. In some cases of gallbladder empyema, temporary drainage of pus from the gallbladder (cholecystostomy) may be preferred to allow stabilization and to permit later cholecystectomy under elective circumstances.

In patients with gallbladder stones who are suspected to have concurrent common bile duct stones, the surgeon can perform intraoperative cholangiography at the time of cholecystectomy. The common bile duct can be explored using a choledochoscope. If common duct stones are found, they can usually be extracted intraoperatively. Alternatively, the surgeon can create a fistula between the distal bile duct and the adjacent duodenum (choledochoduodenostomy), allowing stones to pass harmlessly into the intestine.

Open versus laparoscopic cholecystectomy

The first cholecystectomy was performed in the late 1800s. The open approach pioneered by Langenbuch remained the standard of care until the late 1980s, when laparoscopic cholecystectomy was introduced.^{[23, 24]} Laparoscopic cholecystectomy was the vanguard of the minimally invasive revolution, which has affected nearly all areas of modern surgical practice. Currently, open cholecystectomy is mainly reserved for special situations.

The traditional open approach to cholecystectomy employed a large, right subcostal incision. In contrast, laparoscopic cholecystectomy employs four very small incisions. Recovery time and postoperative pain are diminished markedly by the laparoscopic approach.

Currently, laparoscopic cholecystectomy is commonly performed in an outpatient setting. By reducing inpatient stay and the time lost from work, the laparoscopic approach has also reduced the cost of cholecystectomy.^[25]

In its 2010 guidelines for the clinical application of laparoscopic biliary tract surgery, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) states that patients with symptomatic cholelithiasis are eligible for laparoscopic surgery. Cholelithiasis patients whose laparoscopic cholecystectomy was uncomplicated may be sent home the same day if postoperative pain and nausea are well controlled. Patients older than 50 years may be at greater risk of readmission.^[26]

During laparoscopic cholecystectomy, a surgeon must retrieve stones that might escape through a perforated gallbladder. Conversion to an open procedure might be required in certain cases.

In patients in whom gallstones have been lost in the peritoneal cavity, the current recommendation is follow-up with ultrasonographic examinations for 12 months. Most of the complications (usually, abscess formation around the stone) occur within this time frame.

The most dreaded and morbid complication of cholecystectomy is damage to the common bile duct. Bile duct injuries increased in incidence with the advent of laparoscopic cholecystectomy, but the incidence of this complication has since declined as experience and training in minimally invasive surgery have improved.^[27]

Routine cholangiography is only of minimal help in preventing common bile duct injury. However, good evidence indicates that it leads to intraoperative detection of such injuries.

Cholecystostomy

In patients who are critically ill with gallbladder empyema and sepsis, cholecystectomy can be treacherous. In this circumstance, the surgeon may elect to perform cholecystostomy, a minimal procedure involving placement of a drainage tube in the gallbladder. This usually results in clinical improvement. Once the patient stabilizes, definitive cholecystectomy can be performed under elective circumstances.

Cholecystostomy also can be performed in some cases by invasive radiologists under CT-scan guidance. This approach eliminates the need for anesthesia and is especially appealing in a patient who is clinically unstable.

Endoscopic sphincterotomy

If surgical removal of common bile duct stones is not immediately feasible, endoscopic retrograde sphincterotomy can be used. In this procedure, the endoscopist cannulates the bile duct via the papilla of Vater. Using an electrocautery sphincterotome, the endoscopist makes an incision measuring approximately 1 cm through the sphincter of Oddi and the intraduodenal portion of the common bile duct, creating an opening through which stones can be extracted.

Endoscopic retrograde sphincterotomy is especially useful in patients who are critically ill with ascending cholangitis caused by impaction of a gallstone in the ampulla of Vater. Other indications for the procedure are as follows:

• Removal of common bile duct stones inadvertently left behind during previous cholecystectomy
• Preoperative clearing of stones from the common bile duct to eliminate the need for intraoperative common bile duct exploration, especially in situations where the surgeon's expertise in laparoscopic bile duct exploration is limited or the patient's anesthesia risk is high
• Preventing recurrence of acute gallstone pancreatitis or other complications of choledocholithiasis in patients who are too sick to undergo elective cholecystectomy or whose long-term prognosis is poor

Intraoperative endoscopic sphincterotomy (IOES) during laparoscopic cholecystectomy has been suggested as an alternative treatment to preoperative endoscopic sphincterotomy (POES) followed by laparoscopic cholecystectomy; this is because IOES is as effective and safe as POES and results in a significantly shorter hospital stay.^[28]

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Prevention of Gallstones

Ursodeoxycholic acid treatment can prevent gallstone formation. This has been demonstrated in the setting of rapid weight loss caused by very low-calorie diets or by bariatric surgery, which are associated with a high risk of new cholesterol gallstones (20%-30% within 4 mo). Administration of ursodeoxycholic acid at a dose of 600 mg daily for 16 weeks reduces the incidence of gallstones by 80% in this setting.

Recommending dietary changes of decreased fat intake is prudent; this may decrease the incidence of biliary colic attacks. However, it has not been shown to cause dissolution of stones.

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Diet and Activity

Little evidence suggests that dietary composition affects the natural history of gallstone disease in humans. Obese patients who undertake aggressive weight-loss programs or undergo bariatric surgery^[29] are at risk to develop gallstones; short-term prophylaxis with ursodeoxycholic acid should be considered.

Coffee consumption appears to be associated with a reduced risk of gallstone disease.^[30]

Regular exercise may reduce the frequency of cholecystectomy.

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Consultations

Patients who have experienced an episode of typical biliary colic or a complication of gallstones should be referred to a general surgeon with experience in laparoscopic cholecystectomy.

If symptoms are atypical, consultation with a gastroenterologist may be appropriate. A gastroenterologist specializing in biliary endoscopy should be consulted if endoscopic retrograde sphincterotomy may be required.

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Long-Term Monitoring

Following cholecystectomy, about 5%-10% of patients develop chronic diarrhea. This is usually attributed to bile salts. The frequency of enterohepatic circulation of bile salts increases after the gallbladder is removed, resulting in more bile salt reaching the colon. In the colon, bile salts stimulate mucosal secretion of salt and water.

Postcholecystectomy diarrhea is usually mild and can be managed with occasional use of over-the-counter antidiarrheal agents, such as loperamide. More frequent diarrhea can be treated with daily administration of a bile acid-binding resin (eg, colestipol, cholestyramine, colesevelam).

Following cholecystectomy, a few individuals experience recurrent pain resembling biliary colic. The term postcholecystectomy syndrome is sometimes used for this condition.

Many patients with postcholecystectomy syndrome have long-term functional pain that was originally misdiagnosed as being of biliary origin.^[31] Persistence of symptoms following cholecystectomy is unsurprising. Diagnostic and therapeutic efforts should be directed at the true cause.

Some individuals with postcholecystectomy syndrome have an underlying motility disorder of the sphincter of Oddi, termed biliary dyskinesia, in which the sphincter fails to relax normally following ingestion of a meal. The diagnosis can be established in specialized centers by endoscopic biliary manometry. In established cases of biliary dyskinesia, endoscopic retrograde sphincterotomy is usually effective in relieving the symptoms.

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Ursodiol (Actigall, Urso 250, Urso Forte)

• Dosing, Interactions, etc.

Clinical Context:  Ursodiol (ursodeoxycholic acid) is indicated for radiolucent noncalcified gallbladder stones smaller than 20 mm in diameter when conditions preclude cholecystectomy. Ursodiol suppresses hepatic secretion and inhibits intestinal absorption of cholesterol. It appears to have little inhibitory effect on the synthesis and secretion into bile of endogenous bile acids and does not appear to affect the secretion of phospholipids into bile. After repeated doses, the drug reaches steady-state bile concentrations in about 3 weeks. Cholesterol is insoluble in aqueous media, but it can be solubilized in at least 2 different ways in the presence of dihydroxy bile acids. In addition to solubilizing cholesterol in micelles, ursodiol acts by dispersing cholesterol as liquid crystals in aqueous media. The overall effect of ursodiol is to increase the concentration level at which saturation of cholesterol occurs.

The various actions of ursodiol combine to change the bile of patients with gallstones from cholesterol-precipitating to cholesterol-solubilizing bile, thus resulting in bile conducive to cholesterol stones dissolution.

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Class Summary

These agents suppress hepatic cholesterol secretion and inhibit intestinal absorption of cholesterol. Ursodiol is the most common drug used. It solubilizes cholesterol in micelles and acts by dispersing cholesterol in aqueous media.

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