Diseases of the gall bladder and bile ducts.
S1
Physiology
Bile is produced
by the liver and channeled by the biliary ductal system into the intestinal
tract for the emulsification and absorption of fats. The liver determines the
chemical composition of bile, and this may be modified later by the gallbladder
and biliary epithelium. Cholesterol, ordinarily insoluble in water, comes into
solution by forming vesicles with phospholipids (principally lecithin) or mixed
micelles with bile salts and phospholipids.
S2
Table 1.
LIST OF DISEASES OF THE GALLBLADDER AND THE BILE DUCTS
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DISEASES OF
THE GALLBLADDER
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DISEASES OF THE BILE DUCTS
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CONGENITAL
ANOMALIES
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CONGENITAL
ANOMALIES
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GALLSTONES
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CHOLEDOCHOLITHIASIS
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ACUTE
CHOLECYSTITIS
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CHOLANGITIS
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ACALCULOUS
CHOLECYSTITIS
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PAPILLARY DYSFUNCTION
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PAPILLARY STENOSIS
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SPASM OF THE SPHINCTER OF
ODDI
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BILIARY DYSKINESIA
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EMPHYSEMATOUS
CHOLECYSTITIS
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PRIMARY BILIARY CIRRHOSIS
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CHRONIC
CHOLECYSTITIS
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AUTOIMMUNE
CHOLANGITIS
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GALLBLADDER CANCER
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NEOPLASMS
OF THE BILIARY TRACT
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HEPATOBILIARY PARASITISM
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SCLEROSING
CHOLANGITIS
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Frequency
Gallstone disease
is one of the most common and costly of all digestive diseases. In the United States
The incidence of
gallstones is 1 million new cases per year. The prevalence is 20 million cases
among Americans.
Approximately 2-7
cases per 100,000 population of primary sclerosing cholangitis (PSC) exist.
About 5% of patients with chronic ulcerative colitis develop PSC.
The incidence of
gallbladder cancer is 2.5 cases per 100,000 population.
DISEASES OF THE GALLBLADDER
Congenital
abnormalities.
Anomalies of the biliary tract
are not uncommon and include abnormalities in number, size, and form of the
gallbladder. Anomalies of position or suspension include left-sided
gallbladder, intrahepatic gallbladder, retrodisplacement of the gallbladder,
and “floating” gallbladder. The latter condition predisposes to acute torsion,
volvulus, or herniation of the gallbladder
Gallstones.
In about 80% of
patients, gallstones are clinically silent. Approximately 20% of patients
develop symptoms over 15-20 years, that is, about 1% per year, and almost all
become symptomatic before complications develop. Biliary-type pain, the typical
clinical presentation, is due to obstruction of the bile duct lumen. The
predictive value of intolerance to fatty food, indigestion may be clinically
helpful.
·
Two main types
of gallstones exist.
1.
Cholesterol stones (85%): These are divided into 2
subtypes—pure (90-100% cholesterol) or mixed (50-90% cholesterol). Pure
stones often are solitary, whitish, and larger than 2.5 cm in diameter. Mixed
stones usually are smaller, multiple in number, and occur in various shapes
and colors (cholesterol layers and
pigmented center).
2.
Pigment stones (15%) occur in 2 subtypes—brown and
black.
a.)
Brown stones are made up of calcium bilirubinate and
calcium-soaps. Bacteria are involved in their formation. The bacterial parths
aggregates with the bile pigment and precipitates out of solution.
b.)
Black stones typically form in the gallbladder and
result when excess bilirubin enters the bile and polymerizes into calcium
bilirubinate.
S2 The risk factors
associated with the development of cholesterol gallstones include obesity, a
high-calorie diet, clofibrate therapy, gastrointestinal disorders involving
major malabsorption of bile acids, cystic fibrosis with pancreatic
insufficiency, and female sex, use of oral contraceptives and other estrogenic
medications.
Coffee, ascorbic acid, has been shown to
reduce the risk of symptomatic cholesterol gallstones.
Pigment stones are
more common in patients with chronic hemolysis, alcoholic cirrhosis, and
advanced age.
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TABLE 1 Predisposing
Factors for Cholesterol and Pigment Gallstone Formation
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Symptoms of Gallstone Disease
Gallstones usually produce
symptoms by causing inflammation or obstruction following their migration into
the cystic duct or bile ducts.
The most specific and
characteristic symptom of gallstone disease is biliary colic. Visceral pain is characteristically a severe, steady
ache or fullness in the epigastrium or right upper quadrant (RUQ) of the
abdomen with frequent radiation to the interscapular area, right scapula, or
shoulder. Biliary colic begins quite suddenly and may persist with severe
intensity for 30 min to 5 h, subsiding gradually or rapidly. An episode of
biliary pain persisting beyond 5 h shows the development of acute
cholecystitis. Biliary colic may be precipitated by eating a fatty meal, by
consumption of a large meal following a period of prolonged fasting, or by
eating a normal meal; it is frequently nocturnal.
Nausea and vomiting frequently accompany episodes of biliary pain.
Fever or chills (rigors) with biliary pain usually imply a complication, i.e.,
cholecystitis, pancreatitis, or cholangitis.
Complaints of vague epigastric
fullness, dyspepsia, eructation, or flatulence, especially following a fatty
meal, should not be confused with biliary pain. Such symptoms are not specific
for biliary calculi.
S3 EXAMINATION
Ultrasonography of the gallbladder is very
accurate in the identification of cholelithiasis. Stones as small as 2 mm in diameter may be
confidently identified. Ultrasound can also be used to assess the emptying function
of the gallbladder.
Oral cholecystography (OCG) is a useful procedure
for the diagnosis of gallstones but has been changed to ultrasound. It may be
used to assess the patency of the cystic duct and gallbladder emptying
function. Further, OCG can also recognize and number of gallstones and
determine whether they are calcified.
Radiopharmaceuticals imagines have their greatest application in the
diagnosis of acute cholecystitis.
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TABLE
2 Diagnostic Evaluation of the Gallbladder
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TREATMENT
Surgical Therapy
In asymptomatic gallstone
patients, the risk of developing symptoms or complications requiring surgery is
quite small (in the range of 1 to 2% per year). Thus a recommendation for
cholecystectomy in a patient with gallstones should probably be based on
assessment of three factors: (1) the presence of symptoms that are frequent
enough or severe enough to interfere with the patient's general routine; (2)
the presence of a prior complication of gallstone disease, i.e., history of
acute cholecystitis, pancreatitis, gallstone fistula, etc.; or (3) the presence
of an underlying condition predisposing the patient to increased risk of
gallstone complications (e.g., calcified or porcelain gallbladder and/or a
previous attack of acute cholecystitis regardless of current symptomatic
status). Patients with very large gallstones (>3 cm in diameter) and patients
having gallstones in a congenitally anomalous gallbladder might also be
considered for prophylactic cholecystectomy. Although young age is a worrisome
factor in asymptomatic gallstone patients, few authorities would now recommend
routine cholecystectomy in all young patients with silent stones.
Laparoscopic cholecystectomy is a minimal-access approach for the removal of the
gallbladder together with its stones. Its advantages include a markedly
shortened hospital stay as well as decreased cost, and it is the procedure of
choice for most patients referred for elective cholecystectomy. Laparoscopic
cholecystectomy has become the “gold standard” for treating symptomatic
cholelithiasis.
Medical Therapy—Gallstone Dissolution
UDCA (Actigall,
URSO 250, URSO, Ursofalk, ursodeoxycholic acid) decreases cholesterol
saturation of bile and also help to dispersion of cholesterol from stones. UDCA
may also retard cholesterol crystal nucleation. In carefully selected patients
with a functioning gallbladder and with stones <10 mm in diameter, complete
dissolution can be achieved in about 50% of patients within 6 months to 2 years
with UDCA at a dose of 8 to 10 mg/kg per day. The highest success rate (i.e.,
>70%) occurs in patients with small (<5 mm ) floating radiolucent
gallstones. Probably no more than 10% of patients with symptomatic
cholelithiasis are candidates for such treatment.
Gallbladder stones may be
fragmented by extracorporeal shock
waves. While such shock wave
lithotripsy combined with medical litholytic therapy is safe and
effective in carefully selected patients with gallbladder calculi (radiolucent,
solitary stone <2 cm
in well-contracting gallbladder. The recurrence of gallstones is 30% of
patients within 5 years after lithotripsy combined with medical litholytic
therapy.
ACUTE AND CHRONIC CHOLECYSTITIS
ACUTE
CHOLECYSTITIS
Acute inflammation of the
gallbladder wall usually follows obstruction of the cystic duct by a stone.
Inflammatory response can be evoked by
three factors:
(1) mechanical
inflammation produced by increased intraluminal pressure and distention
with resulting ischemia of the gallbladder mucosa and wall,
(2) chemical
inflammation caused by the release of lysolecithin (due to the action of
phospholipase on lecithin in bile) and other local tissue factors,
(3) bacterial
inflammation, which may play a role in 50 to 85% of patients with acute
cholecystitis. The organisms most frequently isolated by culture of gallbladder
bile in these patients include Escherichia coli, Klebsiella spp., Streptococcus
spp., and Clostridium spp.
Acute cholecystitis often
begins as an attack of biliary pain
that progressively worsens. Approximately 60 to 70% of patients report having
experienced prior attacks that resolved spontaneously. As the episode
progresses, however, the pain of acute cholecystitis becomes more generalized
in the right upper abdomen. As with biliary colic, the pain of cholecystitis
may radiate to the interscapular area, right scapula, or shoulder. Peritoneal signs of inflammation
such as increased pain with jarring or on deep respiration may be apparent. The
patient is anorectic and often
nauseated. Vomiting is
relatively common and may produce symptoms and signs of vascular and
extracellular volume depletion. Jaundice
is unusual early in the course of acute cholecystitis but may occur
when edematous inflammatory changes involve the bile ducts and surrounding
lymph nodes. A low-grade fever
is characteristically present, but shaking chills or rigors are not uncommon.
The right upper qudrant of the
abdomen is almost invariably tender
to palpation (KERR’S SYMPTOM). An enlarged, tense
gallbladder is palpable in one-quarter to one-half of patients. Deep
inspiration or cough during subcostal palpation of the RUQ usually produces
increased pain and inspiratory arrest (Murphy's
sign). A light thump delivered to the right subcostal area may elicit a
marked increase in pain (Orthner’s
sign). Localized rebound tenderness in the RUQ is common, as are
abdominal distention and hypoactive bowel sounds from paralytic ileus, but
generalized peritoneal signs and abdominal rigidity are usually lacking, in the
absence of perforation.
The diagnosis of acute cholecystitis is usually made on the basis
of a characteristic history and physical examination. The triad of sudden onset of RUQ tenderness, fever, and leukocytosis
is highly suggestive. The serum bilirubin is mildly elevated
[<85.5 µmol/L (5 mg/dL)] in half of patients, while about one-fourth have
modest elevations in serum aminotransferases (usually less than a
fivefold elevation). The radionuclide (e.g., HIDA) biliary scan may be
confirmatory if bile duct imaging is seen without visualization of the
gallbladder. Ultrasound will demonstrate calculi in 90 to 95% of cases.
Outcomes. Approximately 75% of patients treated medically have
remission of acute symptoms within 2 to 7 days following hospitalization. In
25%, however, a complication of acute cholecystitis will occur despite
conservative. In this setting, prompt surgical intervention is required. Of the
75% of patients with acute cholecystitis who undergo remission of symptoms,
approximately one-quarter will experience a recurrence of cholecystitis within
1 year, and 60% will have at least one recurrent bout within 6 years. In view
of the natural history of the disease, acute cholecystitis is best treated by
early surgery whenever possible.
Mirrizzi's syndrome is a rare complication in which
a gallstone becomes impacted in the cystic duct or neck of the gallbladder
causing compression of the CBD, resulting in CBD obstruction and jaundice.
Ultrasound shows gallstone(s) lying outside the hepatic duct. Endoscopic
retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic
cholangiography (PTC) will usually demonstrate the characteristic extrinsic
compression of the CBD. Surgery consists of removing the cystic duct, diseased
gallbladder, and the impacted stone. The preoperative diagnosis of Mirrizzi's
syndrome is important to avoid CBD injury.
ACALCULOUS CHOLECYSTITIS
In 5 to 10% of patients with
acute cholecystitis, calculi obstructing the cystic duct are not found at
surgery. An increased risk for the development of acalculous cholecystitis is
especially associated with serious trauma or burns, with the postpartum period
following prolonged labor, and with orthopedic and other nonbiliary major
surgical operations in the postoperative period. It may possibly complicate
periods of prolonged parenteral hyperalimentation. For some of these cases,
biliary sludge in the cystic duct may be responsible. Other precipitating
factors include vasculitis, obstructing adenocarcinoma of the gallbladder,
diabetes mellitus, torsion of the gallbladder, “unusual” bacterial infections
of the gallbladder (e.g., Leptospira, Streptococcus, Salmonella, or Vibrio cholerae), and parasitic infestation of the
gallbladder. Acalculous cholecystitis may also be seen with a variety of other
systemic disease processes (sarcoidosis, cardiovascular disease, tuberculosis,
syphilis, actinomycosis, etc.).
Although the clinical manifestations of acalculous
cholecystitis are the same as calculous
cholecystitis, the setting of acute gallbladder inflammation complicating severe
underlying illness is characteristic of acalculous disease. Ultrasound,
computed tomography (CT) scanning, or radionuclide examinations demonstrating a
large, tense, static gallbladder without stones and with evidence of poor
emptying over a prolonged period may be diagnostically
useful in some cases. The complication rate
for acalculous cholecystitis exceeds that for calculous cholecystitis.
Successful management of acute
acalculous cholecystitis appears to depend primarily on early diagnosis and
surgical intervention, with meticulous attention to postoperative care.
EMPHYSEMATOUS CHOLECYSTITIS
So-called emphysematous
cholecystitis is thought to begin with acute cholecystitis (calculous or
acalculous) followed by ischemia or gangrene of the gallbladder wall and
infection by gas-producing organisms. Bacteria most frequently cultured in this
setting include anaerobes, such as C. perfringens, and
aerobes, such as E. coli. This condition occurs most
frequently in elderly men and in patients with diabetes mellitus. The clinical
manifestations are essentially undistinctive from those of nongaseous cholecystitis. The
diagnosis is usually made on plain abdominal film by finding gas within the
gallbladder lumen, dissecting within the gallbladder wall to form a gaseous
ring, or in the pericholecystic tissues. The morbidity and mortality rates with
emphysematous cholecystitis are considerable. Prompt surgical intervention
coupled with appropriate antibiotics is necessary.
CHRONIC
CHOLECYSTITIS
Chronic inflammation of the
gallbladder wall is almost always associated with the presence of gallstones
and is thought to result from repeated occurring of subacute or acute
cholecystitis or from persistent mechanical irritation of the gallbladder wall
by gallstones. The presence of bacteria in the bile occurs in more than
one-quarter of patients with chronic cholecystitis. The presence of infected
bile in a patient with chronic cholecystitis
undergoing elective cholecystectomy probably adds little to the operative risk.
Chronic cholecystitis may be asymptomatic for years, may
progress to symptomatic gallbladder disease or to acute cholecystitis, or may
present with complications.
Complications of Cholecystitis
EMPYEMA И HYDROPS
Empyema of the gallbladder
usually results from progression of acute cholecystitis with persistent cystic
duct obstruction to superinfection of the stagnant bile with a pus-forming
bacterial organism. The clinical picture resembles that of cholangitis with
high fever, severe RUQ pain, marked leukocytosis, and often, prostration.
Empyema of the gallbladder carries a high risk of gram-negative sepsis and/or
perforation. Emergency surgical intervention with proper antibiotic coverage is
required as soon as the diagnosis is suspected.
Hydrops or mucocele of the
gallbladder may also result from prolonged obstruction of the cystic duct,
usually by a large solitary calculus. In this instance, the obstructed
gallbladder lumen is progressively distended, over a period of time, by mucus
(mucocele) or by a clear transudate (hydrops) produced by mucosal epithelial
cells. A visible, easily palpable, nontender mass sometimes extending from the
RUQ into the right iliac fossa may be found on physical examination. The
patient with hydrops of the gallbladder frequently remains asymptomatic,
although chronic RUQ pain may also occur. Cholecystectomy is indicated, since
empyema, perforation, or gangrene may complicate the condition.
GANGRENE AND PERFORATION
Gangrene of the gallbladder
results from ischemia of the wall and patchy or complete tissue necrosis.
Underlying conditions often include marked distention of the gallbladder,
vasculitis, diabetes mellitus, empyema, or torsion resulting in arterial
occlusion. Gangrene usually predisposes to perforation of the gallbladder, but
perforation may also occur in chronic cholecystitis without premonitory warning
symptoms. Localized perforations are usually contained
by the omentum or by adhesions produced by recurrent inflammation of the
gallbladder. Bacterial superinfection of the walled-off gallbladder contents
results in abscess formation. Most patients are best treated with
cholecystectomy, but some seriously ill patients may be managed with
cholecystostomy and drainage of the abscess. Free perforation
is less common but is associated with a mortality rate of approximately 30%.
Such patients may experience a sudden transient relief of RUQ pain as the
distended gallbladder decompresses; this is followed by signs of generalized
peritonitis.
OTHER COMPLICATIONS:
FISTULA FORMATION AND
GALLSTONE ILEUS
LIMEY (MILK OF CALCIUM) BILE
AND PORCELAIN GALLBLADDER
PANCREATITIS
TREATMENT
Medical Therapy
Although surgical intervention
remains the mainstay of therapy for acute cholecystitis and its complications,
a period of in-hospital stabilization may be required before cholecystectomy.
Oral intake is eliminated,
nasogastric suction may be indicated, and extracellular volume depletion and
electrolyte abnormalities are repaired.
Nonsteroidal
anti-inflammatory drugs (NSAIDs) are usually employed for
analgesia because they may produce less spasm of the sphincter of Oddi than
drugs such as morphine. Intravenous
antibiotic therapy is usually indicated in patients with severe acute
cholecystitis even though bacterial superinfection of bile may not have
occurred in the early stages of the inflammatory process. Antibiotic therapy is
guided by the most common organisms likely to be present, which are E. coli, Klebsiella spp., and Streptococcus spp. Effective antibiotics include
ureidopenicillins such as piperacillin or mezlocillin, ampicillin sulbactam,
and third-generation cephalosporins. Anaerobic
coverage by a drug such as metronidazole should be added if gangrenous or
emphysematous cholecystitis is suspected. Similarly, combination therapy with
an aminoglycoside and other antibiotics may be considered in diabetic or
debilitated patients and in those with signs of gram-negative sepsis. Postoperative
complications of wound infection, abscess formation, or sepsis are reduced in
antibiotic-treated patients.
Surgical Therapy
The optimal timing of surgical
intervention in patients with acute cholecystitis depends on stabilization of
the patient. The clear trend is toward earlier surgery, and this is due in part
to requirements for shorter hospital stays. Urgent (emergency) cholecystectomy or cholecystostomy is
probably appropriate in most patients in whom a complication of acute
cholecystitis such as empyema, emphysematous cholecystitis, or perforation is
suspected or confirmed. In uncomplicated cases of acute cholecystitis, up to
30% of patients fail to resolve their symptoms on appropriate medical therapy,
and progression of the attack or a supervening complication leads to the
performance of early operation (within 24 to 72 h). Delayed surgical intervention is probably best reserved for
(1) patients with very high risk for early surgery and (2) patients in whom the
diagnosis of acute cholecystitis is in doubt. Early cholecystectomy is the
treatment of choice for most patients with acute cholecystitis. Mortality
figures for emergency cholecystectomy in most centers approach 3%, while the
mortality risk for elective or early cholecystectomy approximates 0.5% in
patients under age 60. Of course, the operative risks increase with age-related
diseases of other organ systems and with the presence of long- or short-term
complications of gallbladder disease. Seriously ill or debilitated patients
with cholecystitis may be managed with cholecystostomy and tube drainage of the
gallbladder. Elective cholecystectomy
may then be done at a later date.
Postcholecystectomy Complications
Early complications following
cholecystectomy include atelectasis and other pulmonary disorders, abscess formation
(often subphrenic), external or internal hemorrhage, biliary-enteric fistula,
and bile leaks. Jaundice may indicate absorption of bile from an intraabdominal
collection following a biliary leak or mechanical obstruction of the CBD by
retained calculi, intraductal blood clots, or extrinsic compression. Routine
performance of intraoperative cholangiography during cholecystectomy has helped
to reduce the incidence of these early complications.
In a small percentage of patients, however, a
disorder of the extrahepatic bile ducts may result in persistent
symptomatology. These so-called postcholecystectomy
syndromes may be due to (1) biliary strictures, (2) retained biliary
calculi, (3) cystic duct stump syndrome, (4) stenosis or dyskinesia of the
sphincter of Oddi, or (5) bile salt–induced diarrhea or gastritis.
Cystic Duct Stump Syndrome
In the absence of
cholangiographically demonstrable retained stones, symptoms resembling biliary
pain or cholecystitis in the postcholecystectomy patient have frequently been
attributed to disease in a long (>1 cm ) cystic duct remain
(cystic duct
stump syndrome). Careful analysis, however, reveals that postcholecystectomy
complaints are attributable to other causes in almost all patients in whom the
symptom complex was originally thought to result from the existence of a long
cystic duct stump. Accordingly, considerable care should be taken to
investigate the possible role of other factors in the production of
postcholecystectomy symptoms before attributing them to cystic duct stump
syndrome.
DISEASES OF THE BILE DUCTS
S4
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TABLE 3 Diagnostic Evaluation of the Bile
Ducts
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CONGENITAL ANOMALIES
Biliary Atresia and Hypoplasia
Atretic and hypoplastic
lesions of the extrahepatic and major intrahepatic bile ducts are the most
common biliary anomalies of clinical relevance encountered in infancy. The
clinical picture is one of severe obstructive jaundice during
the first month of life, with pale stools. When biliary atresia is suspected on
the basis of clinical, laboratory, and imaging findings the diagnosis is
confirmed by surgical exploration and operative cholangiography. The diagnosis
is confirmed by surgical exploration with operative cholangiography.
Approximately 10% of cases of biliary atresia are treatable with roux-en-Y
choledochojejunostomy, with the Kasai procedure
(hepatic portoenterostomy) being attempted in the remainder in an effort to
restore some bile flow. Most patients, even those having successful
biliary-enteric anastomoses, eventually develop chronic cholangitis, extensive
hepatic fibrosis, and portal hypertension.
Choledochal Cysts
Cystic dilatation may involve
the free portion of the CBD, i.e., choledochal cyst, or may present as
diverticulum formation in the intraduodenal segment. In the latter situation,
chronic reflux of pancreatic juice into the biliary tree can produce
inflammation and stenosis of the extrahepatic bile ducts leading to cholangitis
or biliary obstruction. Because the process may be gradual, approximately 50%
of patients present with onset of symptoms after age 10. The diagnosis may be
made by ultrasound, abdominal CT, MRC, or cholangiography. Only one-third of
patients show the classic triad of abdominal pain, jaundice, and an abdominal
mass. Surgical treatment involves excision of the “cyst” and biliary-enteric
anastomosis. Patients with choledochal cysts are at increased risk for the
subsequent development of cholangiocarcinoma.
Congenital Biliary Ectasia
Dilatation of intrahepatic
bile ducts may involve either the major intrahepatic radicles (Caroli's
disease), the inter- and intralobular ducts (congenital hepatic fibrosis), or
both. In Caroli's disease, clinical manifestations include recurrent
cholangitis, abscess formation in and around the affected ducts, and, often,
gallstone formation within portions of ectatic intrahepatic biliary radicles.
Ultrasound, MRC, and CT are of great diagnostic value in demonstrating cystic
dilatation of the intrahepatic bile ducts. Treatment with ongoing antibiotic
therapy is usually undertaken in an effort to limit the frequency and severity
of recurrent bouts of cholangitis. Progression to secondary biliary cirrhosis
with portal hypertension, extrahepatic biliary obstruction, cholangiocarcinoma,
or recurrent episodes of sepsis with hepatic abscess formation is common.
CHOLEDOCHOLITHIASIS
Passage of gallstones into the
CBD occurs in approximately 10 to 15% of patients with cholelithiasis. The
incidence of common duct stones increases with increasing age of the patient,
so that up to 25% of elderly patients may have calculi in the common duct at the
time of cholecystectomy. Undetected duct stones are left behind in
approximately 1 to 5% of cholecystectomy patients. The overwhelming majority of
bile duct stones are cholesterol stones formed in the gallbladder, which then
migrate into the extrahepatic biliary tree through the cystic duct. Primary
calculi arising de novo in the ducts are usually pigment stones developing in
patients with (1) hepatobiliary parasitism or chronic, recurrent cholangitis;
(2) congenital anomalies of the bile ducts (especially Caroli's disease); (3)
dilated, sclerosed, or strictured ducts; or (4) an MDR3
gene defect leading to impaired biliary phospholipids secretion. Common duct
stones may remain asymptomatic for years, may pass spontaneously into the
duodenum, or (most often) may present with biliary colic or a complication.
Complications
CHOLANGITIS
Cholangitis may be acute or
chronic, and symptoms result from inflammation, which usually requires at least
partial obstruction to the flow of bile. Bacteria are present on bile culture
in approximately 75% of patients with acute cholangitis early in the
symptomatic course. The
characteristic presentation of acute cholangitis involves biliary pain,
jaundice, and spiking fevers with chills (Charcot's triad). Blood
cultures are frequently positive, and leukocytosis is typical. Nonsuppurative acute cholangitis is most common and may
respond relatively rapidly to supportive measures and to treatment with
antibiotics. In suppurative acute cholangitis,
however, the presence of pus under pressure in a completely obstructed ductal
system leads to symptoms of severe toxicity—mental confusion, bacteremia, and
septic shock. Response to antibiotics alone in this setting is relatively poor,
multiple hepatic abscesses are often present, and the mortality rate approaches
100% unless prompt endoscopic or surgical relief of the obstruction and
drainage of infected bile are carried out. Endoscopic management of bacterial
cholangitis is as effective as surgical intervention. ERCP with endoscopic sphincterotomy
is safe and the preferred initial procedure for both establishing a definitive
diagnosis and providing effective therapy.
OBSTRUCTIVE JAUNDICE
Gradual obstruction of the CBD
over a period of weeks or months usually leads to initial manifestations of
jaundice or pruritus without associated symptoms of biliary colic or
cholangitis. Painless jaundice may occur in patients with choledocholithiasis,
but this manifestation is much more characteristic of biliary obstruction
secondary to malignancy of the head of the pancreas, bile ducts, or ampulla of
Vater.
In patients whose obstruction
is secondary to choledocholithiasis, associated chronic calculous cholecystitis
is very common, and the gallbladder in this setting may be relatively in distensible.
The absence of a palpable gallbladder in most patients with biliary obstruction
from duct stones is the basis for Courvoisier's law,
i.e., that the presence of a palpably enlarged gallbladder suggests that the
biliary obstruction is secondary to an underlying malignancy rather than to
calculous disease. Biliary obstruction causes progressive dilatation of the
intrahepatic bile ducts as intrabiliary pressures rise. Hepatic bile flow is
suppressed, and reabsorption and regurgitation of conjugated bilirubin into the
bloodstream lead to jaundice accompanied by dark urine (bilirubinuria) and
light-colored (acholic) stools.
CBD stones should be suspected
in any patient with cholecystitis whose serum bilirubin level exceeds 85.5
µmol/L (5 mg/dL). The maximum bilirubin level is seldom over 256.5 µmol/L (15.0
mg/dL) in patients with choledocholithiasis unless concomitant hepatic disease
or another factor leading to marked hyperbilirubinemia exists. Serum bilirubin
levels of 342.0 µmol/L (20 mg/dL) or more should suggest the possibility of
neoplastic obstruction. The serum alkaline phosphatase level is almost always
elevated in biliary obstruction. A rise in alkaline phosphatase often precedes
clinical jaundice and may be the only abnormality in routine liver function
tests. There may be a two- to tenfold elevation of serum aminotransferases,
especially in association with acute obstruction. Following relief of the
obstructing process, serum aminotransferase elevations usually return rapidly
to normal, while the serum bilirubin level may take 1 to 2 weeks to return to
normal. The alkaline phosphatase level usually falls slowly, lagging behind the
decrease in serum bilirubin.
PAPILLARY DYSFUNCTION, PAPILLARY STENOSIS, SPASM OF THE SPHINCTER OF
ODDI, AND BILIARY DYSKINESIA
Symptoms of biliary colic
accompanied by signs of recurrent, intermittent biliary obstruction may be
produced by papillary stenosis, papillary dysfunction, spasm of the sphincter
of Oddi, and biliary dyskinesia. Papillary stenosis is thought to result from acute
or chronic inflammation of the papilla of Vater or from glandular hyperplasia
of the papillary segment.
Five criteria have been used to define papillary
stenosis:
(1) upper abdominal pain, usually RUQ or
epigastric;
(2) abnormal liver tests;
(3) dilatation of the common
bile duct upon ERCP (ENDOSCOPIC
RETROGRADE CHOLANGIOPANCREATOGRAM) examination;
(4) delayed (>45 min)
drainage of contrast material from the duct;
(5) increased basal pressure
of the sphincter of Oddi, a finding that may be of only minor significance.
An alternative to ERCP is
magnetic resonance cholangiography (MRC) if ERCP and/or biliary manometry are
either unavailable or not feasible. In patients with papillary stenosis,
quantitative hepatobiliary scintigraphy has revealed delayed transit from the
common bile duct to the bowel, ductal dilatation, and abnormal time-activity
dynamics. This technique can also be used before and after sphincterotomy to
document improvement in biliary emptying. Treatment consists of endoscopic or
surgical sphincteroplasty to ensure wide patency of the distal portions of both
the bile and pancreatic ductsю
The factors usually considered
as indications for sphincterotomy include
(1) prolonged duration of
symptoms,
(2) lack of response to
symptomatic treatment,
(3) presence of severe
disability,
(4) the patient's choice of
sphincterotomy over surgery (given a clear understanding on his or her part of
the risks involved in both procedures).
Criteria for diagnosing dyskinesia of the sphincter of
Oddi are
even more controversial than those for papillary stenosis. Proposed mechanisms
include spasm of the sphincter, denervation sensitivity resulting in
hypertonicity, and abnormalities of the sequencing or frequency rates of
sphincteric contraction waves. When thorough evaluation has failed to
demonstrate another cause for the pain, and when cholangiographic and
manometric criteria suggest a diagnosis of biliary dyskinesia, medical
treatment with nitrites or anticholinergics to attempt pharmacologic relaxation
of the sphincter has been proposed. Endoscopic biliary sphincterotomy (EBS) or
surgical sphincteroplasty may be indicated in patients who fail to respond to a
2- to 3-month trial of medical therapy, especially if basal sphincter of Oddi
pressures are elevated. EBS has become the procedure of choice for removing
bile duct stones and for other biliary and pancreatic problems.
Primary biliary cirrhosis
PBC is a
progressive cholestatic biliary disease that presents with fatigue and itching
or asymptomatic elevation of the alkaline phosphatase. Jaundice develops with
progressive destruction of bile ductules that eventually leads to liver
cirrhosis and hepatic failure. This autoimmune illness has a familial
predisposition, in which even unaffected family members may have immunologic
abnormalities, especially an increased serum immunoglobulin M (IgM) and an
association with human leucocyte antigen (HLA)-DR8.
While numerous
autoantibodies have been identified, antimitochondrial antibodies (AMA) are
present in 95% of patients. Circulating immune complexes also have been
identified but are unlikely to play a pathogenic role. Circulating T lymphocyte
levels initially are within the reference range and decline as the disease
progresses. The histologic appearance of the bile duct destruction resembles
hepatic allograft rejection and appears to be mediated by cytotoxic T
lymphocytes.
Other Biliary Tract Diseases:
Autoimmune cholangitis represents a rare disease.
Neoplasms of the biliary tract: Carcinoma of the
biliary system manifests with clinical symptoms of weight loss (77%), nausea
(60%), anorexia (56%), abdominal pain (56%), fatigue (63%), pruritus (51%),
fever (21%), malaise (19%), diarrhea (19%), constipation (16%), and abdominal
fullness (16%). Symptomatic patients usually have advanced disease, with spread
to hilar lymph nodes before obstructive jaundice occurs. It is associated with a poor prognosis.
- Gallbladder
cancer.
- Cholangiocarcinoma
is an adenocarcinoma of the bile ducts.
- Ampullary
cancer accounts for 8% of biliary tract cancers. It most commonly presents
with painless jaundice or acute pancreatitis.
Biliary tract cysts: Cystic dilatation of the biliary
tree is an uncommon abnormality. About half of the patients present with some
combination of jaundice, abdominal pain, and an abdominal mass. The presence of
these cysts often is associated with anomalous union of the pancreatic and
biliary ductal system. This suggests that pancreatic juice enters the bile,
causes a proteolytic and inflammatory injury to the duct wall, and leads to
biliary cyst formation.
TRAUMA, STRICTURES, AND HEMOBILIA
Approximately 95% of benign strictures of the extrahepatic
bile ducts result from surgical trauma and occur in about 1 in 500 cholecystectomies.
The diagnosis is established by percutaneous or endoscopic cholangiography.
Endoscopic biopsy of biliary strictures may be helpful in establishing the
nature of the lesion. When positive exfoliative cytology is obtained, the
diagnosis of a neoplastic stricture is established. Successful operative
correction of bile duct strictures with duct-to-bowel anastomosis is usually
possible, although mortality rates from surgical complications, recurrent
cholangitis, or secondary biliary cirrhosis are high.
Hemobilia may follow traumatic or operative injury to the liver
or bile ducts, intraductal rupture of a hepatic abscess or aneurysm of the
hepatic artery, biliary or hepatic tumor hemorrhage, or mechanical
complications of choledocholithiasis or hepatobiliary parasitism. Diagnostic
procedures such as liver biopsy, PTC, and transhepatic biliary drainage
catheter placement may also be complicated by hemobilia. Patients often present
with a classic triad of biliary pain, obstructive jaundice, and melena or
occult blood in
the stools. The diagnosis is sometimes made by cholangiographic evidence of
blood clot in the biliary tree, but selective angiographic verification may be
required. Although minor episodes of hemobilia may resolve without operative
intervention, surgical ligation of the bleeding vessel is frequently required.
HEPATOBILIARY PARASITISM
Infestation of the biliary
tract by adult helminths or their ova may produce a chronic, recurrent pyogenic
cholangitis with or without multiple hepatic abscesses, ductal stones, or
biliary obstruction. This condition is relatively rare. The organisms most
commonly involved are trematodes or flukes, including Clonorchis
sinensis, Opisthorchis viverrini or O. felineus, and Fasciola hepatica.
The biliary tract also may be involved by intraductal migration of adult Ascaris lumbricoides from the duodenum or by intrabiliary
rupture of hydatid cysts of the liver produced by Echinococcus
spp. The diagnosis is made by cholangiography and the presence of
characteristic ova on stool examination. When obstruction is present, the
treatment of choice is laparotomy under antibiotic coverage, with common duct
exploration and a biliary drainage procedure.
SCLEROSING CHOLANGITIS
Primary or idiopathic
sclerosing cholangitis is characterized by a progressive, inflammatory,
sclerosing, and obliterative process affecting the extrahepatic and/or the
intrahepatic bile ducts. The disorder occurs in about 70% in association with
inflammatory bowel disease, especially ulcerative colitis. It may also be
associated (albeit rarely) with multifocal fibrosclerosis syndromes such as
retroperitoneal, mediastinal, and/or periureteral fibrosis; Riedel's struma; or
pseudotumor of the orbit.
Patients with primary
sclerosing cholangitis often present with signs and symptoms of chronic or
intermittent biliary obstruction: RUQ abdominal pain, pruritus, jaundice, or
acute cholangitis. Late in the course, complete biliary obstruction, secondary
biliary cirrhosis, hepatic failure, or portal hypertension with bleeding
varices may occur. The diagnosis is usually established by cholangiography.
When a diagnosis of sclerosing cholangitis has been established, a search for
associated diseases, especially for chronic inflammatory bowel disease, should
be carried out.
Secondary sclerosing
cholangitis may occur as a long-term complication of choledocholithiasis,
cholangiocarcinoma, operative or traumatic biliary injury, or contiguous
inflammatory processes.
Therapy with cholestyramine
may help control symptoms of pruritus, and antibiotics are useful when
cholangitis complicates the clinical picture. Vitamin D and calcium
supplementation may help prevent the loss of bone mass frequently seen in
patients with chronic cholestasis. Glucocorticoids, methotrexate, and
cyclosporine have not been shown to be efficacious in PSC. UDCA in high dosage
(20 mg/kg) improves serum liver tests, but an effect on survival has not been
documented. In cases where high-grade biliary obstruction (dominant strictures)
has occurred, balloon dilatation or stenting may be appropriate. Only rarely is
surgical intervention indicated. Efforts at biliary-enteric anastomosis or
stent placement may, however, be complicated by recurrent cholangitis and
further progression of the stenosing process. The prognosis is unfavorable. PSC is one of the most common
indications for liver transplantation.
DIFFERENTIAL DIAGNOSIS OF NONCHOLESTATIC JAUNDICE AND HYPERBILIRUBINEMIA
Jaundice
can result from increased formation of bilirubin or hepatobiliary disease
(hepatobiliary jaundice). Hepatobiliary jaundice can result from hepatocellular
dysfunction or cholestasis. Cholestasis can be intrahepatic or extrahepatic.
Increased formation and hepatocellular diseases
that impair liver uptake or decrease conjugation cause unconjugated
hyperbilirubinemia. Impaired biliary excretion produces conjugated
hyperbilirubinemia. Although these mechanisms seem distinct, in clinical
practice, jaundice, particularly jaundice due to hepatobiliary disease, almost
always produces multiple defects; the result is both unconjugated and
conjugated hyperbilirubinemia (mixed hyperbilirubinemia).
Rarely, certain disorders produce predominantly
unconjugated or conjugated hyperbilirubinemia. Unconjugated hyperbilirubinemia
due to increased bilirubin formation can result from hemolytic disorders; those
due to decreased conjugation can result from Gilbert syndrome (mild) and
Crigler-Najjar syndrome (severe).
Conjugated hyperbilirubinemia due to impaired
excretion can result from Dubin-Johnson syndrome. Conjugated hyperbilirubinemia
due to intrahepatic cholestasis can result from hepatitis, drug toxicity, and
alcoholic liver disease. Less common causes include primary biliary cirrhosis,
cholestasis of pregnancy, and metastatic cancer. Conjugated hyperbilirubinemia
due to extrahepatic cholestasis can result from a common bile duct stone or
pancreatic cancer. Less common causes include benign stricture of the common
duct (usually related to prior surgery), ductal carcinoma, pancreatitis or
pancreatic pseudocyst, and sclerosing cholangitis.
Liver disease and biliary obstruction usually
cause multiple defects, increasing both conjugated and unconjugated bilirubin.
Noncholestatic Conjugated
Hyperbilirubinemia
Disorders of bilirubin metabolism causing
conjugated hyperbilirubinemia without cholestasis produce no symptoms. Bilirubin
may appear in the urine. Aminotransferase and alkaline phosphatase levels are
usually normal. Treatment is unnecessary.
Dubin-Johnson
syndrome: This rare autosomal recessive disorder involves
impaired excretion of bilirubin glucuronides. It is usually diagnosed by liver
biopsy.
Rotor's
syndrome: This rare disorder is clinically similar to
Dubin-Johnson syndrome, but the liver is not pigmented, and other subtle
metabolic differences are present.
Unconjugated hyperbilirubinemia is a disorder
of bilirubin metabolism consisting of overproduction or defective conjugation
of bilirubin.
Hemolysis: RBC hemolysis is the most
frequent clinically important cause of increased bilirubin formation. Although
the normal liver can conjugate excess bilirubin, hemolysis may increase
bilirubin to an unmanageable amount.
Gilbert
syndrome: Gilbert syndrome is a presumably lifelong disorder
whose only significant abnormality is asymptomatic, mild, unconjugated hyperbilirubinemia.
It can be mistaken for chronic hepatitis or other liver disorders. Gilbert
syndrome may affect as many as 5% of people. Although family members may be
affected, a clear genetic pattern is difficult to establish.
Pathogenesis may involve complex defects in the
liver's uptake of bilirubin. Glucuronyl transferase activity is low. Liver
histology is normal.
Gilbert syndrome is most often detected in
young adults by finding an elevated bilirubin level, which usually fluctuates
between 2 and 5 mg/dL (34 and 86 μmol/L) and tends to increase
with fasting and other stresses.
Gilbert syndrome is differentiated from hepatitis by especially
increasing of unconjugated bilirubin, on the base of normal liver function test
results, and absence of urinary bilirubin. It is differentiated from hemolysis
by the absence of anemia and reticulocytosis. Treatment is unnecessary
Crigler-Najjar syndrome: This rare inherited disorder
is caused by deficiency of the enzyme glucuronyl transferase.
Patients with autosomal recessive type I (complete)
disease have severe hyperbilirubinemia. They usually die of kernicterus by age
1 yr but may survive into adulthood. "Kernicterus" refers to the
neurologic consequences of the deposition of unconjugated bilirubin in brain
tissue. Subsequent damage and scarring of the basal ganglia and brain-stem
nuclei may occur. Treatment may include phototherapy and liver transplantation.
Patients with autosomal dominant type II (partial)
disease (which has variable penetrance) often have less severe hyperbilirubinemia
(< 20 mg/dL [< 342 μmol/L]) and usually live into
adulthood without neurologic damage. Phenobarbital (LUMINAL)
1.5 to 2 mg/kg, which induces the partially deficient glucuronyl transferase, may be effective.
1.5 to 2 mg/kg, which induces the partially deficient glucuronyl transferase, may be effective.
