CHOLELITHIASIS

Gallstones are concretions that form in the biliary tract, usually in the gallbladder. Cholelithiasis is the
presence of gallstones in the gallbladder (see the image below).

Gallstones develop insidiously, and they may remain asymptomatic for decades. Migration of gallstones
may lead to obstruction of the cystic duct (biliary colic), with subsequent inflammation (acute
cholecystitis). Cholangitis occurs when a gallstone obstructs the biliary or hepatic ducts, causing
inflammation and infection. Obstruction of pancreatic duct can cause acute pancreatitis.
[1, 2]

Choledocholithiasis is the presence of a gallstone in the common bile duct (see the image below).
Choledocholithiasis complicates the workup and management of cholelithiasis, necessitates additional
diagnostic and therapeutic procedures, and adds to the morbidity and mortality of gallstone disease.
Chronic gallstone disease may lead to fibrosis and loss of function of the gallbladder, and it predisposes
to gallbladder cancer.
Ultrasonography is the procedure of choice in suspected gallbladder or biliary 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. In some cases, however, medical dissolution may
be considered (see Treatment and Management)
Go to Pediatric Cholelithiasis for complete information on this topic.

PATHOPHYSIOLOGY
Gallstone formation occurs because certain substances in 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 solution as microscopic crystals. The
crystals are trapped in gallbladder mucus, producing gallbladder sludge (see the image below). 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.
Although sludge may be a step in the formation of stones, it may also cause disease in itself. Five to
fifteen percent of patients with acute cholecystitis present without stones (acalculous cholecystitis). This
typically occurs in patients with prolonged illness, such as those with major trauma or with prolonged
ICU stays.
The 2 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 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 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 liver cells, relative to lecithin and bile salts, and (2) the degree of concentration
and 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 quite 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
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 stones. 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.
Bacterial hydrolysis of lecithin leads to the release of fatty acids, which complex with calcium and
precipitate from solution. The resulting concretions have a claylike consistency and are termed brown
pigment stones. Unlike cholesterol or black pigment stones, which form almost exclusively in the
gallbladder, brown pigment stones often form de novo in the bile ducts. Brown pigment stones 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 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.
Common bile duct stones
Choledocholithiasis occurs as a result of either the primary formation of stones in the common bile duct
(CBD) or the passage of gallstones from the gallbladder through the cystic duct into the CBD. (Images of
CBD stones are shown below.) Obstruction of the CBD by gallstones leads to symptoms and
complications that include pain, jaundice, cholangitis, pancreatitis, and sepsis.
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). More than one third of patients develop
gallstones after bariatric surgery. Weight loss greater than 25% is the best predictor for the gallstone
formation. Rapid weight loss mobilizes tissue cholesterol stores and increases the saturation of bile.
[3]

Obesity, a high-fat diet, and hypertriglyceridemia are strongly associated with the formation of
gallstones. Diosgenin-rich beans, particularly associated with a South American diet, increase cholesterol
secretion and gallstone formation.
Estrogens administered for contraception or for treatment of prostate cancer increase the risk of
cholesterol gallstones. 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 phospholipidassociated cholelithiasis occurs in individuals with a hereditary deficiency
of the biliary transport protein required for lecithin secretion.
Black pigment gallstones
Black pigment gallstones occur disproportionately in individuals with high heme turnover. In most cases,
however, no risk factor can be identified.
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 formation of brown pigment gallstones include colonization of bile with bacteria and
intraductal stasis. In the United States, this combination is most often encountered in patients with
postsurgical biliary strictures or choledochal cysts.
In hepatolithiasis, a condition encountered mainly in rice-growing regions of East Asia, intraductal
formation of brown pigment stones accompanies multiple strictures throughout intrahepatic and
extrahepatic bile ducts. This condition causes recurrent cholangitis and predisposes to biliary cirrhosis
and cholangiocarcinoma. The etiology is unknown, but liver flukes have been implicated.
Other comorbidities
Diabetes mellitus is associated with an increased risk of gallstone, though the mechanism is unclear;
once symptomatic, patients with diabetes are prone to more severe complications.
Crohn disease, ileal resection, or other diseases of the ileum decrease bile salt reabsorption and increase
the risk of gallstone formation.
Bacterial or parasitic infections from organisms that contain B -glucuronidase, an enzyme that
deconjugates bilirubin glucuronide, increase the risk for pigmented stones.
Cirrhosis carries major multifactorial risks for gallstone formation and gallbladder disease. Reduced
hepatic synthesis and transport of bile salts, hyperestrogenemia, impaired gallbladder contraction, and
increased biliary stasis, among other factors, contribute to the formation of gallstones (typically pigment
stones) in cirrhosis.
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.
Bile duct stones
Primary common bile duct stones are caused by conditions leading to bile stasis and chronic bactibilia.
Up to 90% of patients with brown pigment CBD stones have bile culture results positive for bacteria.
In Western populations, biliary stasis is secondary to factors such as sphincter of Oddi dysfunction,
benign biliary strictures, sclerosing cholangitis, and cystic dilatation of the bile ducts. Bile stasis
promotes growth of bacteria, which produce phospholipase A1, thus releasing fatty acids from biliary
phospholipids.
The duct epithelium and/or bacteria (eg, Escherichia coli) produce beta-glucuronidase in amounts
sufficient to deconjugate bilirubin diglucuronide. The presence of free fatty acids, deconjugated
bilirubin, and bile acids leads to the formation of insoluble calcium bilirubinate particles. With the loss of
bile acids, cholesterol becomes insoluble, resulting in the formation of biliary sludge. The sludge also
contains mucin and bacterial cytoskeletons, which further aid in stone formation.
In Asian populations, infestation with Ascaris lumbricoides and Clonorchis sinensis may promote stasis by
either blocking the biliary ducts or by damaging the duct walls, resulting in stricture formation. Bactibilia
is also common in these instances, probably secondary to episodic portal bacteremia. Some authors
have suggested that the stones are formed because of the bactibilia alone and that the parasites'
presence is just a coincidence.
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 gallstone surgery is relatively safe, cholecystectomy is a very common
procedure, and its rare complications result in several hundred deaths each year.
Choledocholithiasis complicates 10-15% of cholelithiasis cases.
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.
[5]
In a study of randomly selected individuals aged 35-85 years in a general population who had been
screened previously with ultrasonography and found to have no gallbladder stones, Halldestam et al
reexamined 503 study subjects after a minimum interval of 5 years. On reexamination, 8.3% (42/503)
had developed gallstones. Gallstone development was related to length of follow-up and low-density
lipoprotein (LDL) cholesterol levels, and inversely related to alcohol consumption.
[5]

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 incidence rate of choledocholithiasis is higher internationally than in the United States, mainly
because of the additional problem of primary common bile duct stones caused by parasitic infestation
with Ascaris lumbricoides and Clonorchis sinensis.
Race-, sex-, and age-related demographics
Prevalence of gallstones is highest in fair-skinned people of northern European descent and in Hispanic
populations and Native American populations.
[6]

Prevalence of gallstones is low in Asians and African Americans; however, African Americans with sickle
cell disease have gallstones early in life secondary to associated hemolysis.
The lifetime risk of developing gallstones in whites is 50% for women and 30% for men.
Women are more likely to develop cholesterol gallstones than men, especially during their reproductive
years, when the incidence of gallstones in women is 2 to 3 times that in men. The difference appears to
be attributable mainly to estrogen, which increases biliary cholesterol secretion.
[7]
Pigment gallstones
affect men and women equally.
Risk of developing gallstones increases with age. Gallstones are uncommon in children. Children with
gallstones are more likely to have congenital anomalies, biliary malformation and disease, or hemolytic
pigment stones.
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
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.
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.
HISTORY
Gallstone disease may be thought of as having the following 4 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 a
gallbladder contraction, increasing 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
[7]
). 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 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 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 in distention of the common bile duct (CBD) but not of
the gallbladder.
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 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 ecchymoses
(Cullen sign and Grey-Turner sign).
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. 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 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 increased 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. Characteristic features include
the Charcot triad of fever, jaundice, and right upper quadrant pain. Patients may rapidly develop septic
shock unless ductal obstruction is relieved.
A stone impacted in 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.
Consider that both intra-abdominal and extra-abdominal pathology can present as upper abdominal
pain, and that these conditions often coexist with cholelithiasis. Among the different entities to consider
are peptic ulcer disease, pancreatitis, (acute or chronic), hepatitis, dyspepsia, gastroesophageal reflux
disease (GERD), irritable bowel syndrome, esophageal spasm, pneumonia, cardiac chest pain, and
diabetic ketoacidosis. A careful history and physical examination should guide further workup.
Differentials
Appendicitis
Bile Duct Strictures
Bile Duct Tumors
Cholangiocarcinoma
Cholecystitis
Gallbladder Cancer
Gastric Ulcers
Gastritis and Peptic Ulcer Disease
Gastroenteritis
Pancreatic Cancer
Pancreatitis, Acute
BLOOD 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 need for urgent
intervention. Blood culture results are positive in 30-60% of patients with cholangitis.
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 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.
ltrasonography 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. 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.
[10]

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.)
Cholecystitis with small stones in the gallbladder neck. Classic acoustic
shadowing is seen beneath the gallstones. The gallbladder wall is greater than 4 mm. Image courtesy of
DT Schwartz.
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.)
The WES (wall echogenic shadow) sign, long axis of the gallbladder.
The arrow head points to the gallbladder wall. The second hyperechoic line represents the edge of the
congregated gallstones. Acoustic shadowing (AS) is readily seen. The common bile duct can be seen just
above the portal vein (PV). Image courtesy of Stephen Menlove. 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 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%.
Go to 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%.
Laparoscopic ultrasound
Laparoscopic ultrasound has shown some promise as a primary method for bile duct imaging during
laparoscopic cholecystectomy.
[11]
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%.
[11]

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.
CT SCAN
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 complications of gallbladder disease. CT is particularly useful for
the detection of intrahepatic stones or recurrent pyogenic cholangitis.
MRI
Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) has
emerged as an excellent imaging study for 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.
[10]

Magnetic resonance cholangiopancreatography (MRCP) showing 5
gallstones in the common bile duct (arrows). In this image, bile in the duct appears white; stones appear
as dark-filling defects. Similar images can be obtained by taking plain radiographs after injection of
radiocontrast material in the common bile duct, either endoscopically (endoscopic retrograde
cholangiography) or percutaneously under fluoroscopic guidance (percutaneous transhepatic
cholangiography), but these approaches are more invasive.
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 a 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.
ERCP
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.
PTC
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.
TREATMENT FOR ASYMPTOMATIC
Surgical treatment of asymptomatic gallstones without medically complicating diseases is discouraged.
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
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.
TREATMENT FOR SYMPTOMATIC
In patients with symptomatic gallstones, discuss the options for surgical and nonsurgical intervention;
emergency physicians should refer patients to their primary care provider and surgical consultant 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 until the late 1980s, when laparoscopic cholecystectomy was
introduced.
[15, 16]
Laparoscopic cholecystectomy was the vanguard of the minimally invasive revolution,
which has affected 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 4 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 time lost from work, the laparoscopic approach has also reduced the cost of
cholecystectomy. 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.
[17]

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.
[18]

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 at present 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.
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
are at risk to develop gallstones; short-term prophylaxis with ursodeoxycholic acid should be
considered.
Regular exercise may reduce the frequency of cholecystectomy.
MEDICATION
Ursodiol (ursodeoxycholic acid) is indicated for radiolucent noncalcified gallbladder stones smaller than
20 mm in diameter when conditions preclude cholecystectomy. Ursodiol suppresses hepatic cholesterol
synthesis and secretion and inhibits intestinal absorption. It appears to have little inhibitory effect on
the synthesis and secretion into bile of endogenous bile acids and does not appear to affect 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.