US Pharm. 2013;38(3):33-41.
ABSTRACT: Gallbladder disease, particularly cholelithiasis
(gallstones), affects more than 20 million Americans each year. Patients
often go undiagnosed because cholelithiasis often does not present with
symptoms. Symptoms range from nausea or abdominal discomfort to biliary
colic and jaundice. Gallbladder diseases are diagnosed most accurately
via imaging techniques. However, laboratory values such as CBC,
liver-function testing, and serum amylase and lipase should be included
to help distinguish the type of gallbladder disease and/or identify
associated complications. The most effective treatment for patients with
gallbladder disease is surgery. Gallbladder disease is influenced by
diet, exercise, and nutrition, and patients should be encouraged to
incorporate these healthy habits into their lifestyle in order to reduce
their risk of gallbladder disorders.
The most common form of gallbladder disease is cholelithiasis (gallstones).1 Cholelithiasis affects more than 20 million Americans annually, resulting in a direct cost of more than $6.3 billion.2
Gallstones generally are asymptomatic and typically are discovered
during a surgical procedure for an unrelated condition or during
autopsy.1,2 In the United States, cholelithiasis is the most common inpatient diagnosis among gastrointestinal and liver diseases.3,4
Although gallstones are usually asymptomatic, some patients progress to
symptomatic disease. The primary clinical manifestation and
complication of cholelithiasis is cholecystitis (inflammation of the
gallbladder).1,2 Less commonly, patients with severe cases
may develop gallstone pancreatitis, gallbladder perforation, or other
gallbladder diseases (TABLE 1).1,5-8
Gallstones are hard, pebble-like structures that obstruct the cystic
duct. The formation of gallstones is often preceded by the presence of
biliary sludge, a viscous mixture of glycoproteins, calcium deposits,
and cholesterol crystals in the gallbladder or biliary ducts.5 In the U.S., most gallstones consist largely of bile supersaturated with cholesterol.1,2
This hypersaturation, which results from the cholesterol concentration
being greater than its solubility percentage, is caused primarily by
hypersecretion of cholesterol due to altered hepatic cholesterol
metabolism.1,3 A distorted balance between pronucleating
(crystallization-promoting) and antinucleating
(crystallization-inhibiting) proteins in the bile also can accelerate
crystallization of cholesterol in the bile.1-3,5 Mucin, a
glycoprotein mixture secreted by biliary epithelial cells, has been
documented as a pronucleating protein. It is the decreased degradation
of mucin by lysosomal enzymes that is believed to promote the formation
of cholesterol crystals.3
Loss of gallbladder muscular-wall motility and excessive sphincteric contraction also are involved in gallstone formation.1 This hypomotility leads to prolonged bile stasis (delayed gallbladder emptying), along with decreased reservoir function.3,5
The lack of bile flow causes an accumulation of bile and an increased
predisposition for stone formation. Ineffective filling and a higher
proportion of hepatic bile diverted from the gallbladder to the small
bile duct can occur as a result of hypomotility.1,5
Occasionally, gallstones are composed of bilirubin, a chemical that
is produced as a result of the standard breakdown of RBCs. Infection of
the biliary tract and increased enterohepatic cycling of bilirubin are
the suggested causes of bilirubin stone formation. Bilirubin stones,
often referred to as pigment stones, are seen primarily in patients with infections of the biliary tract or chronic hemolytic diseases (or damaged RBCs).1,3,6 Pigment stones are more frequent in Asia and Africa.3,6
The pathogenesis of cholecystitis most commonly involves the
impaction of gallstones in the bladder neck, Hartmann’s pouch, or the
cystic duct; gallstones are not always present in cholecystitis,
however.5 Pressure on the gallbladder increases, the organ
becomes enlarged, the walls thicken, the blood supply decreases, and an
exudate may form.2,5 Cholecystitis can be either acute or
chronic, with repeated episodes of acute inflammation potentially
leading to chronic cholecystitis. The gallbladder can become infected by
various microorganisms, including those that are gas forming. An
inflamed gallbladder can undergo necrosis and gangrene and, if left
untreated, may progress to symptomatic sepsis.1,2,5 Failure to properly treat cholecystitis may result in perforation of the gallbladder, a rare but life-threatening phenomenon.2,5,7
Cholecystitis also can lead to gallstone pancreatitis if stones
dislodge down to the sphincter of Oddi and are not cleared, thus
blocking the pancreatic duct.1
Genetic and environmental factors contribute to gallbladder disease.
Female gender, previous pregnancies, and family history of gallstone
disease are highly correlated with cholelithiasis.1,3 Approximately 60% of patients with acute cholecystitis are women; however, the disease tends to be more severe in men.2 Estrogen increases cholesterol and its saturation in bile and promotes gallbladder hypomotility.1 Diminished gallbladder motility is commonly seen during pregnancy.9
Other risk factors include a high dietary intake of fats and
carbohydrates, a sedentary lifestyle, type 2 diabetes mellitus, and
dyslipidemia (increased triglycerides and low HDL).3,9 A diet
high in fats and carbohydrates predisposes a patient to obesity, which
increases cholesterol synthesis, biliary secretion of cholesterol, and
cholesterol hypersaturation. However, a direct correlation between high
dietary intake of fats and cholelithiasis risk has not been established
because previous studies have yielded controversial results.9
Acute cholecystitis develops more frequently in symptomatic
cholelithiasis patients with type 2 diabetes mellitus than in
symptomatic patients without it.2 These patients also are more likely to have complications.
American Indians have the highest prevalence of cholelithiasis, with
the disease reaching epidemic proportions in this population. Gallstone
disease is also prevalent in Chilean and Mexican Hispanics.3,9
In addition to ethnicity, age plays a role in gallstone disease.
Patients who develop complicated symptomatic cholelithiasis tend to be
older, and the typical patient with gallstones is in her 40s.1,2
Gallstones are generally asymptomatic. In the uncommon event that a
patient develops symptomatic cholelithiasis, presentation can range from
mild nausea or abdominal discomfort to biliary colic and jaundice.1,5,10
Biliary colic, usually sharp in nature, is postprandial epigastric or
right-quadrant pain that lasts for several minutes to several hours. The
pain often radiates to the back or the right shoulder, and in more
intense cases it may be accompanied by nausea and vomiting.
Upper-right-quadrant tenderness and palpable infiltrate in the region of
the gallbladder are revealed upon physical examination.5,10
Cholecystitis presents in the same manner; however, the obstruction of
the cystic duct is persistent (rather than transient), and fever is
common.10 A patient with cholecystitis also may exhibit
Murphy’s sign (discomfort so severe that the patient stops inspiring
during palpation of the gallbladder) or jaundice. Jaundice, a
yellow discoloration of the skin and the sclera of the eyes, occurs
when the common bile duct is obstructed because of an impacted stone in
Hartmann’s pouch (Mirizzi’s syndrome). Other nonspecific symptoms, such
as indigestion, intolerance to fatty or fried foods, belching, and
flatulence, may also be present.1,5,10
Current techniques for diagnosing gallbladder disease are less
invasive and allow patients to recover more quickly than was the case
with earlier diagnostic procedures.10 Although the incidence of cholelithiasis is quite high in the U.S., few patients present with symptoms.4
This can complicate and prolong the diagnosis. CBC, liver-function
testing, and serum amylase and lipase should be included in the
laboratory tests to help discriminate between the various types of
gallbladder disease and/or identify complications caused by gallbladder
disease (TABLE 2).5,10
The diagnosis of cholelithiasis, cholecystitis, and other gallbladder
diseases can be confirmed via a number of different imaging techniques.
Ultrasonography and cholescintigraphy are the imaging studies most
commonly used to diagnose cholelithiasis and cholecystitis.10
Positive findings upon ultrasonography include stones, thickening of
the gallbladder wall, pericholecystic fluid, and Murphy’s sign (i.e.,
pain) upon contact with the ultrasonographic probe.10
Ultrasonography performed in the fasting state reveals the correct
diagnosis in more than 90% of cases, but bile-duct stones may be missed
in 50% of cases.3
Cholescintigraphy, also called hepatobiliary iminodiacetic acid (HIDA) scan,
is used to assess the function of the gallbladder and to diagnose acute
cholecystitis. HIDA scans are not helpful in identifying cholelithiasis
or chronic cholecystitis.11 In ambulatory patients,
cholescintigraphy provides a correct diagnosis more than 95% of the
time. However, cholescintigraphy may produce false-positive results in
30% to 40% of hospitalized patients, particularly those receiving
parenteral nutrition. Ultrasonography is the preferred diagnostic method
in these patients.10 Cholescintigraphy results are
considered abnormal when the radioactive tracer or dye does not
visualize the gallbladder, moves slowly through the bile ducts, or is
detected outside the biliary system.12
If choledocholithiasis is suspected, endoscopic retrograde
cholangiopancreatography (ERCP) may be beneficial. ERCP is used to
identify common bile-duct stones and also may be used to remove them.
ERCP is associated with complications such as pancreatitis. Noninvasive
techniques, such as endoscopic ultrasonography, may be used to detect
cholelithiasis, but not to remove the stones.4,11 CT may be used, but it is considered less accurate than other imaging methods, as it detects approximately 75% of gallstones.4,10
Magnetic resonance cholangiopancreatography (MRCP) is an imaging method
used to detect choledocholithiasis and other abnormalities of the
biliary tract. MRCP has a sensitivity of approximately 98%.4,11
Patients experiencing asymptomatic cholelithiasis do not require treatment.5
The treatment of choice for symptomatic cholelithiasis currently is
laparoscopic cholecystectomy, whereas previously it was open
cholecystectomy.3,10 Laparoscopic cholecystectomy is
associated with a shorter hospital stay and a faster recovery period
than open cholecystectomy is. Absolute contraindications to this
procedure include the inability to withstand general anesthesia, an
intractable bleeding disorder, and end-stage liver disease.3,5
In patients who are unable or unwilling to undergo surgery, endoscopic
decompression by internal gallbladder stent can help prevent
complications from developing and can serve as palliative long-term
treatment.5 Nonoperative therapy, which includes dissolution
of gallstones using oral bile acids and shock wave lithotripsy, may be
another option in such patients. However, nonoperative therapy is time
consuming and is associated with high cost, low effectiveness, and a
high recurrence rate.5,13
Oral bile acids used for the dissolution of gallstones include
chenodeoxycholic acid (chenodiol) and ursodeoxycholic acid (ursodiol) (TABLE 3).5,14
Oral bile acids are most effective for small gallstones (0.5-1 cm) and
may take up to 24 months to clear the stones. Ursodiol is the most
commonly used oral bile acid, secondary to its safer side-effect profile
compared with chenodiol. Chenodiol is associated with dose-dependent
diarrhea as well as with hepatotoxicity, hypercholesterolemia, and
leukopenia, all of which limit its use.14
Nutrition and lifestyle changes may be beneficial for the prevention
and treatment of cholelithiasis. Because obesity is associated with an
increased risk of cholelithiasis, weight loss may help prevent gallstone
formation.15 However, excessively rapid weight loss may
promote gallstone formation. Dietary factors that may help prevent
gallstone formation include polyunsaturated fat, monounsaturated fat,
fiber, and caffeine.15 Fish oil and moderate alcohol
consumption have been shown to lower triglycerides, lessen bile
cholesterol saturation, and increase HDL.3,9
Patients with acute cholecystitis require hospitalization for
complete bowel rest, parenteral fluids and nutrition, and IV
antibiotics.5 Surgical treatment options for cholecystitis
include percutaneous cholecystostomy, open cholecystostomy, and
Gallbladder diseases are most commonly secondary to cholelithiasis.
While most cases of gallstones are asymptomatic, some cases may progress
to a symptomatic disease. Factors that may increase the risk or
susceptibility to gallbladder disease include gender, ethnicity, medical
history, family history, and diet and nutrition. Gallbladder disease is
diagnosed primarily via imaging techniques. These diagnostic techniques
have their pros and cons, and, most important, their accuracy varies.
One technique may be preferred over another depending upon the type of
gallbladder disease or the presenting symptoms. Asymptomatic patients
generally do not require treatment. Surgery is the most common
treatment, but nonsurgical alternatives are available for patients who
cannot or are unwilling to undergo surgery. Pharmacists can play a role
in the treatment of gallbladder disease by educating patients about the
risk factors for gallbladder disease—particularly cholelithiasis—and
about how the risk can be reduced with proper nutrition, diet, and
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13. Ahmed A, Cheung RC, Keeffe EB. Management of gallstones and their complications. Am Fam Physician. 2000;61:1673-1680.
14. Nunes D. Dissolution therapy for the treatment of gallstones. UpToDate [by subscription]. www.uptodate.com/contents/dissolution-therapy-for-the-treatment-of-gallstones. Accessed February 4, 2013.
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