Mark J.
Koruda
Cholelithiasis
Introduction
The prevalence of gallstones in the United States increases from about 4% in 20-year-olds to more than 15%
in those older than 60 years. Cholecystectomy is the most common abdominal operation performed in this
country, with about 750,000 completed each year. The annual cost for the management of gallstones, their
complications, and the associated economic losses to society is close to $5 billion.
Etiology and Pathogenesis
Gallstones are classied according to their composition.
They vary in shape, number, size, and consistency;
however, these characteristics play little role in whether
symptoms develop (Fig. 54-1).
Cholesterol gallstones are the most common type.
Three factors are necessary for their formation: supersatu-
ration of gallbladder bile with cholesterol, crystal nucle-
ation, and gallbladder hypomotility (Fig. 54-2). The
solubility of cholesterol in bile depends on the incorpora-
tion of cholesterol in solubilizing bile acidlecithin micelles.
Alterations in the relative concentrations of cholesterol,
bile acids, or lecithin can lead to cholesterol supersatura-
tion. Mucin glycoprotein molecules act as nucleating
agents to form gallstones. Cholesterol crystals in the mucin
gel, coupled with defective emptying of the gallbladder,
lead to the growth and development of stones.
Pigmented stones include black or brown varieties.
Black pigmented stones are composed of pure calcium
bilirubinate or polymer-like complexes of calcium, copper,
and large amounts of glycoproteins. These stones are most
common in cirrhosis and chronic hemolytic states. Brown
pigmented stones are usually associated with infection.
Bacteria present in the biliary system hydrolyze glucuronic
acid from conjugated bilirubin. Calcium salts of the now
unconjugated bilirubin crystallize and form brown
stones.
Most epidemiologic series indicate that the prevalence
of gallstones in women varies from 5% to 20% between
the ages of 20 and 55 years, and from 25% to 30% after
age 50 years. The prevalence for men is about half that
386
54
of women at any age. Other risk factors are listed in
Box 54-1.
Clinical Presentation
Gallstones cause symptoms by obstruction of the cystic
duct, common bile duct, or erosion into neighboring
organs (Fig. 54-3). Seventy-ve percent of gallstones do
not cause symptoms; 20% cause intermittent pain or biliary
colic; 10% result in acute cholecystitis; 5% pass into the
common duct, causing bile duct obstruction or pancreati-
tis; and less than 0.1% are associated with stulas or gall-
bladder cancer.
Biliary Colic and Chronic Cholecystitis
About 75% of patients with symptomatic cholelithiasis
present with biliary colic. Pain results from the intermit-
tent obstruction of the cystic duct by one or more stones.
Inammation is not present, so there are usually few, if
any, systemic signs or symptoms. Biliary colic is a visceral
pain that is poorly localized but typically felt in the epigas-
trium, right upper quadrant, or even left upper quadrant.
The pain is steady rather than intermittent and lasts 1 to
6 hours. Describing the pain as colic is a misnomer. Pain
lasting longer than 6 hours is more commonly associated
with the onset of inammation and hence cholecystitis.
Physical examination is typically normal, but mild tender-
ness in the right upper quadrant may be elicited. Labora-
tory tests are frequently unrevealing. Seventy percent of
patients experience recurrent symptoms within 2 years of
 54  Cholelithiasis 387

Figure 54-1 Cholelithiasis: Pathologic Features, Choledocholithiasis.

Large stone and numerous small

ones: chronic cholecystitis
Markedly thickened
Multiple, faceted stones gallbladder contracted
about solitary large stone

Transduodenal view:
bulging of ampulla

Multiple, faceted stones

in common bile duct

Solitary stone in
common duct

Ampullary stone

Intrahepatic stones

Box 54-1 Risk Factors for Gallstone Development the initial attack. Recurrent episodes of biliary colic are
referred to as chronic cholecystitis.
 Older age
 Female
 Obesity
 Weight loss Acute Cholecystitis
 Total parenteral nutrition
 Pregnancy Similar to biliary colic, acute cholecystitis is brought on by
 Genetic predisposition impaction of a gallstone or stones in the cystic duct or
 Diseases of the terminal ileum
 Hypertriglyceridemia
infundibulum (Fig. 54-4). Prolonged obstruction of the
cystic duct leads to stasis of bile within the gallbladder,
damage to the gallbladder mucosa, and the consequent
release of intracellular enzymes and activation of inam-
matory mediators. As concentrations of inammatory
mediators rise within the gallbladder, ongoing inamma-
tion produces increased protein and prostaglandin secre-
388 SECTION VI  Disorders of the Gastrointestinal Tract

Figure 54-2 Pathogenesis of Gallstones.

Cholesterol
Liquid crystal
Mixed micelle
Bile acids (soluble)
Cholesterol
monohydrate
crystal (insoluble)
Lecithin
Cholesterol solubility in bile Lecithin vesicle (soluble)
Solubility of cholesterol in bile depends on incorporation of cholesterol in bile acidlecithin micelles and lecithin vesicles. When bile
becomes saturated with cholesterol, vesicles fuse to form liposomes, or liquid crystals, from which crystals of cholesterol monohydrate nucleate
Stage 1 Stage 2 Stage 3 Stage 4
HMGCoAR
Cholesterol
Nucleation promoters
Normal Mucous glycoproteins
bile acids
Heat-labile proteins
Normal
lecithin
Normal
cholesterol
Bile acids
7OHase
Normal Saturation Nucleation
lecithin Microstone
HMGCoAR
Nucleation inhibitors
Cholesterol Apolipoprotein Growth
Lecithin vesicles
Bile acids Gallstone formation
7OHase
Normal Conditions that increase biliary cholesterol relative to bile acids and lecithin favor saturation
lecithin of bile and formation of gallstones

Cholesterol stones Predisposing factors

Pigment stones
Female
Genetics
Multiparity

Cirrhosis of liver Secondary hemolytic

Antilipemic drugs anemia
Congenital biliary tract
anomalies
Type IV hyperlipemia
Oral contraceptives

Weight loss

Obesity
Crohn's disease of ileum Native American Primary hemolytic anemia

tion, decreased water absorption, and white blood cell
inltration. Acute cholecystitis is initially a chemically
mediated inammatory process. Enteric bacteria may be
cultured from the bile, but they are not responsible for the
onset or activation of acute cholecystitis.
Symptoms persist and usually worsen. Over time,
inammation of the gallbladder ensues, and the pain
becomes parietal in nature with localization to the right
upper quadrant. Radiation of pain to the back or scapular
area is common. Fever is fairly common, but the tempera-
ture is usually less than 102o F. Nausea and vomiting may
occur. Jaundice may develop in up to 20% of patients,
whereas bilirubin levels typically are less than 4 mg/dL.
Frequently, white blood cell counts are elevated. Abdomi-
nal examination often reveals right subcostal tenderness. A
palpable gallbladder occurs in about one third of patients.
Murphys sign, an insensitive but moderately specic
nding described as inspiratory arrest during palpation of
 54  Cholelithiasis 389

Figure 54-3 Cholelithiasis II: Clinical Aspects.

Types of gallstones

Single large stone or

barrel stones

Decubital ulcer
and inflammation

Fistula Contracted,
thickened
gallbladder
Large stone Multiple, faceted
obstructing cystic small stones
duct; distended Common
gallbladder (hydrops) duct stone

Biliary colic

Relief of
Spasm
spasm

Intrahepatic

Gallbladder
Common hepatic duct

Cystic duct

Common bile duct

Sites of gallstones Ampulla

the right subcostal area during deep inspiration, may be
detected.
Choledocholithiasis, Cholangitis, and
Gallstone Pancreatitis
Gallstones may pass from the gallbladder into the common
bile duct and cause pain, obstructive jaundice, cholangitis,
or pancreatitis (Fig. 54-5). Five to 15% of patients with
gallstones also have common duct stones. Stones within
the common duct cause pain that is colicky, occurring in
the epigastrium with radiation to the back. Jaundice is very
common because bilirubin levels rise with the degree of
obstruction. Elevations in alkaline phosphatase occur
frequently.
Of all the complications of gallstones, cholangitis kills
most quickly. The usual clinical presentation consists of
390 SECTION VI  Disorders of the Gastrointestinal Tract

Figure 54-4 Mechanisms of Biliary Pain.

Sudden obstruction
(biliary colic)

Stone in
Hartmann's pouch

Sites of pain in biliary colic

Stone in
common duct

Steady pain
Visceral pain, mediated by splanchnic nerve,
results from increased intraluminal pressure and Patient restless and moves
distention caused by sudden calculous obstruction about seeking position
of cystic or common duct of relief

Persistent obstruction
(acute cholecystitis)
Edema, ischemia, and
transmural inflammation

Sites of pain and hyperesthesia

in acute cholecystitis
Patient lies motionless
because minor movement
(even breathing) increases
pain. Nausea common Prosta-
glandins,
lysolecithins

Parietal epigastric or right upper quadrant pain results from

ischemia and inflammation of gallbladder wall caused by
persistent calculous obstruction of cystic duct. Prostaglandins
and lysolecithins released

pain, jaundice, and chills (i.e., Charcots triad). Refractory
sepsis characterized by altered mentation, hypotension,
with Charcots triad constitutes Reynolds pentad.
Gallstone pancreatitis occurs when a biliary stone causes
a transient or sustained blockage of the ampulla of Vater.
Most patients experience a mild, self-limited attack that
resolves within several days, characterized by abdominal or
back pain and elevated serum amylase and lipase levels.
Clinical symptoms and abnormal serum biochemistries
resolve slowly during this time. Severe pancreatitis devel-
ops in a nite number of patients, manifested by persistent
retroperitoneal inammation, pseudocyst formation, or
pancreatic necrosis with or without peripancreatic sepsis.
Uncommon Complications of
Gallstone Disease
Emphysematous cholecystitis occurs when gas-forming
organisms infect the gallbladder secondary to acute chole-
cystitis. Gas pockets present within the gallbladder wall
 54  Cholelithiasis 391

Figure 54-5 Calculus Obstruction of Common Duct (Choledocholithiasis).

Gallbladder distention mild or absent; chronic

cholecystitis prevents further distention

Common duct obstruction and distention

cause biliary colic and jaundice

Stone obstructs common

duct at ampulla

Secondary biliary cirrhosis

results from recurrent
obstruction and cholangitis

Common duct obstruction

causes acute ascending
cholangitis

Hepatic abscesses, septicemia, and shock may follow either ascending

or suppurative cholangitis. Acute suppurative cholangitis caused by
persistent, complete common duct obstruction. Purulent material
Hepatic collects in ducts under increasing pressure
abscesses

can be detected radiographically. Urgent cholecystectomy
is recommended. Cholecystoenteric stulas occur when a
stone erodes through the gallbladder wall into an adjacent
viscus. The most common sites include the duodenum, the
hepatic exure of the colon, and the stomach.
Dierential Diagnosis
Biliary Colic and Chronic Cholecystitis
Colic and chronic cholecystitis mimic episodic upper
abdominal symptoms, including gastroesophageal reux,
peptic ulcer disease, pancreatitis, renal colic, diverticulitis,
colon cancer, and angina pectoris. Although complaints of
gas, bloating, atulence, and dyspepsia are frequent in
patients with gallstones, these symptoms are nonspecic
and should not be considered characteristic clinical mani-
festations of gallstone disease.
Acute Cholecystitis
The signs and symptoms of acute cholecystitis mimic those
of acute appendicitis, acute pancreatitis, right kidney dis-
eases, pneumonia with pleurisy, acute hepatitis, hepatic
abscesses, and gonococcal perihepatitis (Fitzhugh-Curtis
syndrome).
Choledocholithiasis and Cholangitis
Because the symptoms associated with cystic and common
duct obstruction are so similar, biliary colic and acute
392 SECTION VI  Disorders of the Gastrointestinal Tract
cholecystitis are always in the differential diagnosis. Malig-
nant obstruction of the common bile duct, acute conges-
tion of the liver associated with congestive heart failure,
acute viral hepatitis, and the cholangiopathy of AIDS may
also mimic choledocholithiasis.
Diagnostic Approach
Laboratory Tests
In uncomplicated biliary colic and chronic cholecystitis,
there are usually no accompanying changes in hematologic
and biochemical tests. In acute cholecystitis, leukocytosis
is usually observed. Serum aminotransferase, alkaline
phosphatase, bilirubin, and amylase levels may also
increase.
Sonography
Ultrasonography is the modality of choice for examining
the biliary tract. Ultrasound can detect gallbladder stones
as small as 2 mm in diameter with sensitivity and specicity
rates exceeding 95%.
Sonography is also valuable in the diagnosis of acute
cholecystitis. Eliciting a sonographic Murphys sign (focal
gallbladder tenderness under the transducer) has a positive
predictive value of more than 90% for diagnosis of acute
cholecystitis when stones are seen. The presence of peri-
cholecystic uid in the absence of ascites and gallbladder
wall thickening to more than 4 mm are other nonspecic
ndings suggestive of acute cholecystitis.
Stones in the common bile duct are seen with sonogra-
phy in only half of cases. Thus, sonography conrms, but
does not exclude, common duct stones.
Hepatobiliary Scintigraphy
Hepatobiliary scintigraphy is most useful in evaluating
patients with suspected acute cholecystitis. A normal hepa-
tobiliary scan represents a patent cystic duct and virtually
rules out acute cholecystitis in patients who present with
abdominal pain. The sensitivity of the test is about 95%,
and the specicity is 90%. False-positive results occur pri-
marily in fasting or critically ill patients.
Endoscopic Retrograde
Cholangiopancreatography
Endoscopic retrograde cholangiopancreatography (ERCP)
is the standard for evaluating common duct stones and
pathology. Endoscopic therapeutic applications have revo-
lutionized the treatment of common duct stones and other
biliary tract disorders.
Computed Tomography and Magnetic
Resonance Imaging
Although not well suited for the evaluation of uncompli-
cated stones, standard computed tomography (CT) is an
excellent test to detect complications such as abscess for-
mation, perforation of the gallbladder or common bile
duct, or pancreatitis. Spiral CT and magnetic resonance
cholangiography may prove useful as a noninvasive means
of excluding common bile duct stones.
Management and Therapy
Optimum Treatment
Cholecystectomy remains the mainstay of treatment of
symptomatic gallstones.
Asymptomatic Cholelithiasis
Because up to 80% of all gallstones are asymptomatic and
the risk for developing symptoms or complications is low,
adult patients with silent or incidental gallstones should be
observed and treated expectantly.
Biliary Colic and Chronic Cholecystitis
The natural history of biliary colic is such that recurrent
biliary pain occurs in about 38% to 50% of patients per
year. The risk for serious biliary complications is relatively
low, estimated at 1% to 2% per year. A reasonable approach
is to offer cholecystectomy to those with recurring epi-
sodes of biliary colic. The laparoscopic approach to gall-
bladder removal is the treatment of choice for symptomatic
gallstones. Laparoscopy, unlike the traditional open opera-
tion, allows the surgery to be performed on an outpatient
basis with a marked reduction in postoperative pain and a
more rapid return to work and usual activities. Conversion
to open cholecystectomy is uncommon, averaging less than
3% in most institutions. The incidence of bile duct injury
associated with laparoscopic cholecystectomy has decreased
to less than 0.5%, and mortality rates are less than 0.1%.
Acute Cholecystitis
If acute cholecystitis is suspected, the patient should be
hospitalized for evaluation and treatment. Antibiotics may
be withheld in uncomplicated cases but are indicated in
toxic-appearing patients or when complications such as
perforation or emphysematous cholecystitis are suspected.
Denitive therapy is cholecystectomy performed within 24
to 48 hours of the onset of symptoms. Delaying the pro-
cedure potentially increases the difculty in performing
surgery, the complication rate, and the need to convert
to an open operation. Percutaneous cholecystostomy or
transpapillary endoscopic cholecystostomy can be used to
drain the inamed gallbladder for patients deemed to be
at high risk for surgery.

Choledocholithiasis
The optimal treatment for common duct stones depends
on the level of local expertise in endoscopy and surgery.
In general, the presence of obstructive jaundice with a
dilated common bile duct should lead promptly to preop-
erative ERCP with sphincterotomy and stone extraction.
Once the bile duct has been cleared, the patient can
undergo a routine laparoscopic cholecystectomy within 1
or 2 days.
Cholangitis
The management of sepsis in cholangitis is of paramount
importance. Drainage or decompression of the biliary
system is denitive. ERCP with stone extraction or at least
bile duct decompression with a stent is the treatment of
choice. Alternatively, access to the obstructed biliary tract
through percutaneous transhepatic cholangiography with
drainage catheter placement can temporize by draining the
infected obstructed bile duct. Once the patient has recu-
perated from the infectious insult, elective laparoscopic
cholecystectomy can be undertaken.
Gallstone Pancreatitis
For more than three fourths of patients, gallstone pancre-
atitis is mild, is self-limited, and resolves with conservative
management. Cholecystectomy should be performed
during the initial admission when the pancreatitis has
resolved. Delaying surgery increases the risk for recurrent
symptoms and further complications. An evaluation of the
biliary system for retained stones should be performed
with either a preoperative ERCP or intraoperative cholan-
giography. For patients with severe biliary pancreatitis,
early ERCP with sphincterotomy, if indicated, can be
benecial.
Avoiding Treatment Errors
The widespread use of CT, ultrasound, and nuclear scin-
tigraphy have greatly aided in the diagnosis of cholecystitis
and its complications. A team approach in its management
is always indicated because coordination of care among
primary care physicians, radiologists, gastroenterologists,
and surgeons is essential to ensure optimal patient care.
Future Directions
In light of the signicant public health impact of gall-
stones, ongoing research continues to focus on nding the
54  Cholelithiasis 393
medical means to prevent gallstone formation. Further
advances in nonsurgical therapy are expected. Perhaps the
most exciting developments will occur in biliary tract
imaging techniques with the application of improved reso-
lution ultrasound, endoscopic ultrasound, magnetic reso-
nance imaging, and cholangiography.
Additional Resources
Bellows CF, Berger DH: Management of gallstones. Am Fam Physician
72(4):637-642, 2005.
This concise, complete review article covers the diagnosis and management
of gallstones.
Browning JD, Sreenarasimhaiah J: Gallstone disease. In Feldman M,
Friedman LS, Sleisenger MH (eds): Sleisenger & Fordtrans Gastro-
intestinal and Liver Disease, 8th ed. Philadelphia, WB Saunders,
2006.
This is a superb chapter in the hands-down best reference book on gastro-
intestinal diseases. It is all inclusivehas everything in one source.
NIH Consensus Conference: Gallstones and laparoscopic cholecystec-
tomy. JAMA 269(8):1018-1024, 1993.
This is a great review, blessing the introduction of this landmark surgical
procedure.
EVIDENCE
1. Gurusamy KS, Samraj K: Early versus delayed laparoscopic cho-
lecystectomy for acute cholecystitis. Cochrane Database Syst Rev
4:CD005440, 2006.
Clinical trials comparing early versus late cholecystectomy for acute
cholecystitis are included in this analysis. Early laparoscopic cholecystec-
tomy during acute cholecystitis seems safe and shortens hospital stay.
2. Keus F, de Jong JA, Gooszen HG, van Laarhoven CJ: Laparo-
scopic versus open cholecystectomy for patients with symptomatic
cholecystolithiasis. Cochrane Database Syst Rev 4:CD006231,
2006.
Thirty-eight trials randomized 2338 patients. Meta-analysis suggests
less overall complications in the laparoscopic group with a shorter hospital
stay and convalescence.
3. Urbach DR, Stukel TA: Rate of elective cholecystectomy and the
incidence of severe gallstone disease. CMAJ 172:1015-1019,
2005.
Did the increase in the performance of elective cholecystectomies that
occurred after the introduction of laparoscopic cholecystectomy in 1991
result in a reduction in complications of gallstone disease? This study
concludes that, as a result of more elective cholecystectomies being per-
formed, there has been an overall reduction in the incidence of severe
gallstone disease that is entirely attributable to a reduction in the incidence
of acute cholecystitis.