GB Flashcards
The majority (≈75%) of gallstones in the USA and Europe are cholesterol stones, which consist mainly of cholesterol monohydrate crystals and precipitates of amorphous calcium bilirubinate, often with calcium carbonate or phosphatein one of the crystalline polymorphs.
These stones are usually
subclassified as either pure cholesterol or mixed stones that contain at least 50% cholesterol by weight
The remaining gallstones are pigment stones that contain mostly calcium bilirubinate and are subclassified into 2 groups: black pigment stones (≈20%) and brown pigment stones (≈4.5%).
Rare gallstones (≈0.5%) include calcium carbonate stones and fatty acid–calcium stones
Gallstones also are classified by their location as intrahepatic, gallbladder, and bile duct (choledocholithiasis) stones.
Intrahepatic stones are predominantly brown pigment stones.
Gallbladder gallstones are mainly cholesterol stones, with a small group of black pigment stones.
Bile duct stones are composed mostly of mixed cholesterol stones
Most relevant studies have found that the prevalence of gallstones in women ranges from 5% to 20% between the ages of 20 and 55 years
25% to 30% after the age of 50 years
The prevalence in men is approximately half that of women of the same age
cholesterol gallstones occur infrequently in childhood and adolescence, and the prevalence of cholesterol gallstones increases linearly with age in both genders and approaches 50% at age 70 years in women
all ages, women are twice as likely as men to form cholesterol gallstones
estrogen increases the risk of cholesterol gallstones by augmenting hepatic secretion of biliary cholesterol, thereby leading to an increase in cholesterol saturation of bile
Pregnancy is a risk factor for the development of biliary sludge and gallstones
During pregnancy, bile becomes more lithogenic
because of a significant increase in estrogen levels, which result in increased hepatic cholesterol secretion and supersaturated bile.
gallbladder motility is impaired, with a
resulting increase in gallbladder volume and bile stasis. These alterations promote the formation of sludge and stones in the gallbladder
Increased progestogen concentrations also reduce
gallbladder motility. Because plasma concentrations of sex hormones, especially estrogen, increase linearly with duration of gestation, the risk of gallstone formation is high in the third trimester
of pregnancy
Increasing parity is probably a risk factor
for gallstones, especially in younger women
Rapid weight loss is a well-known risk factor for the formation of cholesterol gallstones.
As many as 50% of obese patients who undergo gastric bypass surgery form biliary sludge and eventually gallstones within 6 months after surgery
Gallstones also
develop in 25% of patients who undergo strict dietary restriction.
Gallstones may be prevented in this high-risk population by prophylactic administration of UDCA, which, in a dose of 600 mg/day, has been
TPN is associated with the development of cholelithiasis and acalculous cholecystitis.
As early as 3 weeks after initiation of TPN, biliary sludge often forms in the gallbladder because of
prolonged fasting In addition, the sphincter of Oddi may fail to relax, leading to preferential flow of bile into the gallbladder
Approximately 45% of adults and 43% of children form gallstones
after 3 to 4 months of TPN
prophylactic treatment to prevent gallstones should be prescribed if no contraindication exists
CCK octapeptide administered twice daily via an IV line to patients on long-term TPN has proved to be safe and cost effective and should be used routinely in TPN-treated patients
Biliary sludge is a crucial intermediate stage in the pathogenesis of both cholesterol and pigment gallstones because it facilitates crystallization and agglomeration of solid plate-like cholesterol monohydrate crystals, as well as precipitation of calcium bilirubinate, and ultimately develops into macroscopic stones
biliary sludge can induce acute cholecystitis, cholangitis, and acute pancreatitis.
associated with many conditions that predispose to gallstone formation, including pregnancy, rapid weight loss, spinal cord injury, longterm TPN, and treatment with octreotide
UDCA treatment of patients with persistent biliary
sludge decreases the frequency of clinical complications of biliary sludge
oral contraceptive steroids and conjugated estrogens in premenopausal women doubles the prevalence of cholesterol gallstones
Administration of estrogen to postmenopausal women and estrogen therapy to men with prostatic carcinoma have similar lithogenic effects
High levels of estrogen may induce gallbladder
hypomotility and consequently bile stasis
estrogen induces a decrease in plasma LDL cholesterol levels and an increase in plasma HDL cholesterol
concentrations.
Clofibrate is a lipid-lowering drug associated with
gallstone formation.
Clofibrate induces cholesterol supersaturation in bile and diminishes bile salt concentrations by reducing the activity of cholesterol 7α-hydroxylase
The 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors (statins) reduce the biliary cholesterol saturation index (CSI), but their role in the prevention or therapy of gallstone disease requires further investigation in humans
The somatostatin analog octreotide increases the prevalence of gallstones when administered to patients as treatment for acromegaly,
The third-generation cephalosporin ceftriaxone has a long duration of action, with much of the drug excreted in the urine.
Approximately 40% of the drug, however, is secreted in an unmetabolized form into bile, where its concentration reaches 100 to 200 times that of the concentration in plasma and exceeds its saturation level in bile.
Obesity is a well-known risk factor for cholelithiasis
Gallbladder bile is more lithogenic in obese than in non-obese persons, and a higher ratio of cholesterol to solubilizing lipids (bile acids and phospholipids)
Gallbladder motility is often impaired in obese persons, thereby promoting mucin secretion and accumulation, as well as cholesterol crystallization.
Patients with diabetes mellitus have long been considered to be at increased risk of developing gallstones because hypertriglyceridemia
and obesity are associated with diabetes mellitus and because gallbladder motility is often impaired in patients with diabetes mellitus
Disease or resection of the terminal ileum has been found to be a risk factor for gallstone formation
intestinal bile salt absorption is often impaired in patients with Crohn disease, who are at increased risk of gallstones
The loss of specific bile salt transporters in the terminal ileum may result in excessive bile salt
excretion in feces and a diminished bile salt pool size, presumably with a consequent increase in the risk of cholesterol gallstones
Spinal cord injuries are associated with a high prevalence of gallstones
Both gallstone disease and NAFLD are highly prevalent in the general population and often co-exist in the same populations
The prevalence of NAFLD was significantly higher in the group that underwent cholecystectomy (48.4%) and in the gallstone group (34.4%) than in the gallstone-free group (17.9%).
These findings suggest that both conditions are tightly associated with metabolic disturbances such as obesity, insulin resistance, dyslipidemia, and the metabolic syndrome.
Use of statins has been associated with a decreased risk of gallstone disease in 2 large case-control studies.
The observation that deficiency of ascorbic acid (vitamin C) is associated with the development of gallstones
subjects who consistently drank 2 to 3 cups of regular coffee per day were approximately 40% less likely to develop symptomatic gallstones
Drinking 4 or more cups per day was even more beneficial (relative risk 0.55), but there was no benefit to drinking decaffeinated coffee.
Cholesterol, phospholipids, and bile salts are the 3 major lipid species in bile, and bile pigments are minor solutes.
Celiac disease is a chronic, small intestinal, autoimmune enteropathy caused by an intolerance to dietary gluten in genetically predisposed individuals
Defective CCK release from the proximal small intestine caused by enteropathy in patients with celiac disease before they start a gluten-free diet, gallbladder emptying in response to a fatty meal is impaired.
The primary bile salts are hepatic catabolic products of cholesterol and are composed of cholate (a trihydroxy bile salt) and chenodeoxycholate (a dihydroxy bile salt
The most important of the conversion reactions is 7α-dehydroxylation of primary bile salts to produce deoxycholate from cholate and lithocholate from chenodoxycholate
Approximately 20% of the cholesterol in bile comes from de novo hepatic biosynthesis, and 80% is from pools of preformed cholesterol within the liver
De novo cholesterol synthesis in the liver uses acetate as a substrate and is mainly regulated by the rate-limited enzyme HMG-CoA reductase
5 primary defects that lead to
formation of cholesterol gallstones: (1) certain genetic factors, including LITH genes, (2) hepatic hypersecretion of biliary cholesterol,(3) gallbladder hypomotility, (4) rapid phase transitions of cholesterol, and (5) certain intestinal factors
Precholecystectomy treatment with the hydrophilic bile acid UDCA for 3 months prolongs the crystal detection time of bile in patients with cholesterol gallstones, thereby suggesting that UDCA could be an antinucleating factor.
Between meals, the gallbladder stores hepatic bile (with an average fasting volume of 25 to 30 mL in healthy subjects). Following a meal, depending on the degree of neurohormonal response, the gallbladder discharges a variable amount of bile.
Gallbladder hypomotility could precede gallstone formation. Gallbladder stasis induced by the hypofunctioning gallbladder could provide the time necessary to accommodate nucleation of cholesterol crystals and growth of gallstones within the mucin gel in the gallbladder
The high prevalence of cholelithiasis in patients receiving long-term TPN (see earlier) highlights the importance of gallbladder stasis in the formation of gallstones
Daily IV administration of CCK can completely prevent
gallbladder dysmotility and eliminate the inevitable risk of biliary sludge and gallstone formation
gallstones in patients with CF are generally black pigment stones (i.e., composed of calcium bilirubinate with an appreciable cholesterol admixture
Black pigment stones are formed in uninfected gallbladders, particularly in patients with chronic hemolytic anemia (e.g.,β-thalassemia, hereditary spherocytosis, sickle cell disease), ineffective erythropoiesis (e.g., pernicious anemia), ileal diseases (e.g., Crohn disease) with spillage of excess bile salts into the large intestine, extended ileal resections, and liver cirrhosis.
alterations promote formation of black pigment stones
because higher colonic bile salt concentrations enhance the solubilization of unconjugated bilirubin, thereby increasing bilirubin concentrations in bile.
The unifying predisposing factor in black
pigment stone formation is hepatic hypersecretion of bilirubin conjugates (especially monoglucuronides) into bile.
In the presence of hemolysis, hepatic secretion of these bilirubin conjugates increases 10-fold
Unconjugated monohydrogenated bilirubin is formed by the action of endogenous β-glucuronidase, which
coprecipitates with calcium as a result of supersaturation
Brown pigment stones are composed mainly of calcium salts of unconjugated bilirubin, with varying amounts of cholesterol, fatty acids, pigment fraction, and mucin glycoproteins, as well as small amounts of bile salts, phospholipids, and bacterial residues.
Brown pigment stones may be easily distinguished
grossly from black pigment stones by their reddish brown to dark brown color and lack of brightness.
Their shape is irregular or molded and occasionally spherical. Most of the stones are muddy in consistency, and some show facet formation
The cut surface is generally a stratified structure
(lamellation) or is amorphous without the radiating crystalline structure seen in cholesterol stones.
Brown pigment stones are formed not only in the gallbladder but also commonly in other portions of the biliary tract, especially in intrahepatic bile ducts.
Formation of brown pigment stones requires the presence of structural or functional stasis of bile associated with biliary infection, especially with Escherichia coli.
These stones are quite prevalent in Asia, where Clonorchis sinensis and roundworm infestations are common, and parasitic elements have been considered to be kernels of brown pigment stone formation
The cardinal symptom of gallstones is biliary pain (“colic”), which is described as pain in the RUQ often radiating to the back, with or without nausea and vomiting.
The pain is usually not true colic and is almost never associated with fever.
prophylactic cholecystectomy is not recommended in
patients with insulin-resistant diabetes mellitus and asymptomatic gallstones
Only 50% of pigment stones and 20% of cholesterol stones contain enough calcium to be visible on a plain abdominal film
Because 80% of gallstones in the Western world are of the cholesterol type, only 25% of stones can be detected by simple radiographs
Plain abdominal films have their greatest usefulness in
evaluating patients with some of the unusual complications of gallstones (e.g., emphysematous cholecystitis, cholecystenteric fistula, gallstone ileus) or in detecting a porcelain gallbladder
US requires only an overnight or 8-hour fast,
involves no ionizing radiation, is simple to perform, and provides accurate anatomic information
The diagnosis of gallstones relies on detection of echogenic objects within the lumen of the gallbladder that produce an acoustic shadow
The stones are mobile and generally congregate in the dependent portion of the gallbladder
Modern US can detect stones as small as 2 mm in diameter routinely
The sensitivity of US for detection of gallstones in the gallbladder is greater than 95% for stones larger than 2 mm.
The specificity is greater than 95% when stones produce acoustic shadows.
The contracted gallbladder filled with stones may give a “double arc shadow” or “wall-echo shadow” sign, with the gallbladder wall, echogenic stones, and acoustic shadowing seen in immediate proximity
Pericholecystic fluid (in the absence of ascites) and gallbladder wall thickening to more than 4 mm (in the absence of hypoalbuminemia) are suggestive of acute cholecystitis
A more specific finding is the so-called sonographic
Murphy sign, in which the ultrasonographer elicits focal gallbladder tenderness under the ultrasound transducer
Biliary pain
Intermittent obstruction of the cystic duct
No acute inflammation of the gallbladder
Severe, poorly localized, epigastric or RUQ visceral
pain growing in intensity over 15 min and remaining
constant for 1-6 h, often with nausea
Frequency of attacks varies from days to months
Gas, bloating, flatulence, and dyspepsia are not related to stones
Mild-to-moderate epigastric/ RUQ tenderness during an attack, with mild residual tenderness lasting days
After the initial attack, 30% of patients have no further
symptoms Symptoms develop in the remainder at a rate of 6% per year, and severe complications at a rate of 1%-2% per year
Acute cholecystitis
Impacted stone in the cystic duct
Acute inflammation of the gallbladder
Secondary bacterial infection in ≈ 50%
75% of cases are preceded by attacks of biliary pain
Visceral epigastric pain gives way to moderately severe localized pain in the RUQ, back, right
shoulder, or, rarely, chest Nausea with some vomiting is frequent
Pain lasting >6 h favors cholecystitis over biliary pain alone
Fever, but usually to <102°F unless complicated by gangrene or perforation
Right subcostal tenderness with inspiratory arrest (Murphy sign)
Leukocytosis with band forms is common
Serum bilirubin level may be 2-4 mg/dL, and aminotransferase and alkaline phosphatase levels may be elevated even in the absence of a BD stone or
hepatic infection
Mild serum amylase and lipase elevations are seen even in the absence of pancreatitis If serum bilirubin is >4 mg/dL or amylase or lipase is markedly elevated, a BD stone should be suspected
50% of cases resolve spontaneously in 7-10 days
without surgery
Left untreated, 10% of cases are
complicated by a localized perforation and 1% by a free perforation and peritonitis
Choledocholithiasis
Stone passed from the gallbladder via the cystic duct or formed in the BD
Intermitted obstruction of the BD
Often asymptomatic
Symptoms (when present) are indistinguishable from biliary pain
Predisposes to cholangitis and acute pancreatitis
Often findings are completely normal if the obstruction is
intermittent Jaundice with pain suggests stones; painless jaundice and a palpable gallbladder favor malignancy
Elevated serum bilirubin and alkaline phosphatase levels
are seen with BD obstruction Serum bilirubin level
>10 mg/dL suggests malignant obstruction or coexisting hemolysis
A transient “spike” in serum aminotransferase or amylase (or lipase) levels suggests the passage of a stone
The natural history is not well defined, but complications are more common and more severe than for asymptomatic stones in the gallbladder
Cholangitis
Charcot triad (pain, jaundice, and fever) is present in 70% of patients
Pain may be mild and transient and is often accompanied by chills
Mental confusion, lethargy, and delirium suggest sepsis
Fever in 95% RUQ tenderness in 90% Jaundice in 80%
Peritoneal signs in 15% Hypotension and mental confusion (forming Reynolds pentad in combination with Charcot triad) coexist in 15% and suggest gram negative sepsis
Leukocytosis in 80%, but the remainder may have a
normal WBC count with or without band forms
Serum bilirubin level is >2 mg/dL in 80%
Serum alkaline phosphatase level is usually elevated
Blood cultures are usually positive, especially during chills or a fever spike; 2 organisms are grown in cultures from half of patients
Acute cholecystitis Sonographic Murphy sign (focal gallbladder tenderness under the transducer) has a positive predictive value of >90% in detecting acute cholecystitis when stones are seen
Pericholecystic fluid (in the absence of ascites) and gallbladder wall thickening to >4 mm (in the absence of hypoalbuminemia) are nonspecific findings but are suggestive of acute cholecystitis
Cholescintigraphy (hepatobiliary scintigraphy; hydroxyiminodiacetic acid or diisopropyl iminodiacetic acid scan)
Acute cholecystitis
Assesses patency of the cystic duct
A normal scan shows radioactivity in the gallbladder, BD, and small bowel within 30-60 min
A positive result is defined as nonvisualization of the gallbladder, with preserved hepatic excretion of radionuclide into the BD or small bowel
A normal scan result virtually excludes acute cholecystitis
EUS is highly accurate for detecting choledocholithiasis.
More invasive and more expensive than standard US, EUS has the advantage of being able to visualize the bile duct from within the GI lumen and is comparable to ERCP in this respect
Cholescintigraphy (hepatobiliary scintigraphy) is a radionuclide imaging test of the gallbladder and biliary tract that is most useful for evaluating patients with suspected acute cholecystitis.
By demonstrating patency of the cystic duct, cholescintigraphy can exclude acute cholecystitis rapidly (within 90 minutes) in a patient who presents with abdominal pain
ERCP is one of the most effective modalities for detecting choledocholithiasis
The specificity of ERCP for the detection of bile duct
stones is approximately 95%.
Biliary pain is the most common presenting symptom of cholelithiasis, and about 75% of patients with symptomatic gallstone disease seek medical attention for episodic abdominal pain.
Biliary pain (conventionally referred to as biliary “colic,” a misnomer) is caused by intermittent obstruction of the cystic duct by one or more gallstones. Biliary pain does not require that inflammation of the gallbladder accompany the obstruction.
The term“chronic cholecystitis” to describe biliary pain should be avoided because it implies the presence of a chronic inflammatory infiltrate that may or may not be present in a given patient
The most common histologic changes observed in patients with biliary pain are mild fibrosis of the gallbladder wall with a chronic inflammatory cell infiltrate and intact mucosa
pain can also be associated with a scarred, shrunken gallbladder and Rokitansky-Aschoff sinuses (intramural diverticula).
Ingestion of a meal often precipitates pain,
but more commonly no inciting event is apparent.
The onset of biliary pain is more likely to occur during periods of weight reduction and marked physical inactivity such as prolonged bed rest than at other times.
The term “biliary colic,” used in the past, is a misnomer because the pain is steady rather than intermittent, as would be suggested by the word colic.
The pain increases gradually over a period of 15
minutes to an hour and then remains at a plateau for an hour or more before slowly resolving
one third of patients, the onset of pain may be more sudden, and on rare occasions, the pain may
cease abruptly.
Pain lasting more than 6 hours suggests acute cholecystitis rather than simple biliary pain
In order of decreasing frequency, biliary pain is felt maximally in the epigastrium, RUQ, LUQ, and various parts of the precordium or lower abdomen. Therefore, the notion that pain not located in the RUQ is atypical of gallstone disease is incorrect.
Radiation of the pain to the scapula, right shoulder, or lower abdomen occurs in half of patients
In general, the first, and often the only, imaging study recommended in patients with biliary pain is US of the RUQ
with recurrent uncomplicated biliary pain and documented gallstones are generally treated with elective laparoscopic cholecystectomy
Acute biliary pain improves with administration of meperidine, with or without ketorolac or diclofenac
Aspirin taken prophylactically has been reported to
prevent gallstone formation as well as acute attacks of biliary pain in patients with gallstones, but long-term use of other NSAIDs does not prevent gallstone formation
Acute cholecystitis is the most common complication of gallstone disease.
Inflammation of the gallbladder wall associated with abdominal pain, RUQ tenderness, fever, and leukocytosis is the hallmark of acute cholecystitis
Acute cholecystitis generally occurs when a stone becomes embedded in the cystic duct and causes chronic obstruction, rather than transient obstruction as in biliary pain.
Phospholipase A is believed to be released by gallstone-induced mucosal trauma and converts lecithin to lysolecithin.
Although normally absent from gallbladder
bile, lysolecithin is present in the gallbladder contents
of patients with acute cholecystitis
administration of IV indomethacin and oral ibuprofen to patients with acute cholecystitis has been shown to diminish both luminal pressure in the gallbladder and pain.
gallbladder is usually palpable lateral to its normal
anatomic location.
Mild jaundice is present in 20% of patients with acute cholecystitis and 40% of older adult patients.
Serum bilirubin levels are usually less than 4 mg/dL
The pain of untreated acute cholecystitis generally resolves in 7 to 10 days
acute cholecystitis often causes mild elevations in serum aminotransferase and alkaline phosphatase levels.
As noted earlier, the serum bilirubin level may also be mildly elevated (2 to 4 mg/dL), and even serum amylase and lipase values may be elevated nonspecifically.
A serum bilirubin value above 4 mg/dL or amylase value above 1000 U/L usually indicates co-existing bile duct obstruction or acute pancreatitis
US is the single most useful imaging study in acutely ill patients with RUQ pain and tenderness.
It accurately establishes the presence or absence of gallstones and serves as an extension of the physical examination.
The presence of a sonographic Murphy sign,
defined as focal gallbladder tenderness under the transducer, has a positive predictive value greater than 90% for detecting acute cholecystitis if gallstones are also present
US can detect nonspecific findings suggestive of acute cholecystitis, such as pericholecystic fluid and gallbladder wall thickening greater than 4 mm
Both findings lose specificity for acute cholecystitis if the patient has ascites or hypoalbuminemia.
A normal cholescintigraphy result shows radioactivity in
the gallbladder, bile duct, and small intestine within 30 to 60 minutes of injection of the isotope
sensitivity and specificity of scintigraphy
in the setting of acute cholecystitis are approximately 94%
However, sensitivity and specificity are reduced considerably in patients who have liver disease, are receiving parenteral nutrition, or are fasting. These conditions can lead to a false-positive result, defined as the absence of isotope in the gallbladder in a patient who does not have acute cholecystitis
a false-negative result is defined as filling of the gallbladder with isotope in the setting of acute cholecystitis, a situation that virtually never occurs
abdominal CT is highly sensitive for detecting pneumoperitoneum, acute pancreatitis, pancreatic pseudocysts, hepatic or intra-abdominal abscesses, appendicitis, and obstruction or perforation of a hollow viscus
Oral feeding should be withheld and an
NG tube inserted if the patient has a distended abdomen or persistent vomiting
In uncomplicated cases of acute cholecystitis, antibiotics need not be given. Antibiotics are warranted if the patient appears toxic or is suspected of having a complication such as perforation of the gallbladder or emphysematous cholecystitis
The most commonly used regimens include piperacillin-tazobactam, ceftriaxone plus metronidazole, or levofloxacin plus metronidazole
Definitive therapy of acute cholecystitis consists of cholecystectomy.
Cholesterol stones form only in the gallbladder, and any cholesterol stones found in the bile duct must have migrated there from the gallbladder.
Black pigment stones, which are associated with old age, hemolysis, alcoholism, and cirrhosis, also form in the gallbladder but only rarely migrate into the bile duct
The majority of pigment stones in the bile duct
are the softer brown pigment stones.
These stones form de novo in the bile duct as a result of bacterial action on phospholipid and bilirubin in bile
They are often proximal to a biliary stricture and are frequently associated with cholangitis.
Brown pigment stones are found in patients with hepatolithiasis and recurrent pyogenic cholangitis
The pressure in the bile duct is normally 10 to 15 cm H2O and rises to 25 to 40 cm H2O with complete obstruction.
When the pressure exceeds 15 cm H2O, bile flow decreases, and at 30 cm H2O, bile flow stops
Deep jaundice without pain, particularly with a palpable
gallbladder (Courvoisier sign), suggests neoplastic obstruction of the bile duct, even when the patient has stones in the gallbladder
With longstanding obstruction, secondary biliary cirrhosis may result, leading to physical findings of chronic liver disease
Bilirubin accumulates in serum because
of blocked excretion, whereas alkaline phosphatase levels rise because of increased synthesis of the enzyme by the canalicular epithelium
The rise in the alkaline phosphatase level is more
rapid than and precedes the rise in bilirubin level
The absolute height of the serum bilirubin level is proportional to the extent of obstruction, but the height of the alkaline phosphatase level bears no relation to either the extent of obstruction or its cause.
In cases of choledocholithiasis, the serum bilirubin level is typically in the range of 2 to 5 mg/dL and rarely exceeds 12 mg/dL.
Transient “spikes” in serum aminotransferase or amylase levels suggest passage of a bile duct stone into the duodenum.
In approximately 85% of cases, cholangitis is caused by a stone embedded in the bile duct, with resulting bile stasis. Other causes of bile duct obstruction that may result in cholangitis are neoplasms biliary strictures parasitic infections and congenital abnormalities of the bile ducts
The bacterial species most commonly cultured from the bile are E. coli, Klebsiella, Pseudomonas, Proteus, and enterococci
Anaerobic species such as Bacteroides fragilis and Clostridium perfringens are found in about 15% of appropriately cultured bile specimens.
Anaerobes usually accompany aerobes, especially E. coli. The fever and shaking chills of cholangitis are due to bacteremia from bile duct organisms.
The hallmark of cholangitis is Charcot triad, consisting of RUQ pain, jaundice, and fever
The full triad is present in only 70% of patients
The pain of cholangitis may be surprisingly mild and transient but is often accompanied by chills and rigors
Altered mental status and hypotension in combination with Charcot triad, known commonly as Reynolds pentad, occur in severe suppurative cholangitis.
On physical examination, fever is almost universal, occurring in 95% of patients, and usually greater than 102°F
RUQ tenderness is elicited in about 90% of patients, but jaundice is clinically detectable in only 80%.
Notably, peritoneal signs are found in only 15% of patients
The combination of hypotension and mental confusion indicates gram-negative septicemia. In overlooked cases of severe cholangitis, intrahepatic abscess may manifest as a
late complication
In particular, the serum bilirubin level exceeds 2 mg/dL in 80% of patients.
ERCP is the definitive test for the diagnosis of bile duct
stones and cholangitis.
Moreover, the ability of ERCP to establish drainage of infected bile under pressure can be lifesaving.
If ERCP is unsuccessful, percutaneous THC can be performed
In mild cases, initial therapy with a single drug (e.g., cefoxitin 2.0 g IV every 6 to 8 hours) is usually sufficient.
In severe cases, more intensive therapy (e.g., gentamicin, ampicillin, and metronidazole
or a broad-spectrum agent such as piperacillin-tazobactam 3.375 g IV every 6 hours or, if resistant organisms are suspected, meropenem 1 g IV every 8 hours) is indicated.
The patient’s condition should improve within 6 to 12 hours, and in most cases, the infection comes under control within 2 to 3 days, with defervescence, relief of discomfort, and a decline in WBC count.
emphysematous cholecystitis present with the
same clinical manifestations as patients with uncomplicated acute cholecystitis, but in the former, gas-forming organisms have secondarily infected the gallbladder wall. Pockets of gas are evident in the area of the gallbladder fossa on plain abdominal films, US,
and abdominal CT
Emphysematous cholecystitis often occurs in diabetic persons or older men who do not have gallstones, in whom atherosclerosis of the cystic artery with resulting ischemia may be the initiating event
A cholecystoenteric fistula occurs when a stone erodes through the gallbladder wall (usually the neck) and into a hollow viscus. The most common entry point into the bowel is the duodenum, followed in frequency by the hepatic flexure of the colon, the stomach, and the jejunum
Symptoms are initially similar to those of acute
cholecystitis, although at times the stone may pass into the bowel and may be excreted without causing any symptoms
the terminal ileum is the most common site of obstruction Gastric outlet obstruction (Bouveret syndrome) may occur rarely
An impacted stone in the gallbladder neck or cystic duct, with extrinsic compression of the common hepatic duct from
accompanying inflammation or fistula
Mirizzi syndrome
ERCP demonstrates dilated intrahepatic ducts and extrinsic compression of the common hepatic duct and possible fistula
Preoperative diagnosis is important to guide surgery and minimize the risk of BD injury
Porcelain gallbladder
Intramural calcification of the gallbladder wall, usually in association with stones
If the gallstone exceeds 25 mm in diameter, it may manifest (especially in older adult women) as a small intestinal obstruction (gallstone ileus); the ileocecal area is the most common site of obstruction.
plain abdominal film may show the pathognomonic features of pneumobilia, a dilated small bowel, and a large gallstone in the right lower quadrant
Bouveret syndrome is characterized by gastric outlet obstruction resulting from duodenal impaction of a large gallstone that has migrated through a cholecystoduodenal fistula.
Porcelain gallbladder, defined as intramural calcification of the gallbladder wall, is not a complication of gallstones but is mentioned here because of the remarkable tendency of carcinoma
to develop as a late complication of gallbladder calcification (specifically, a gallbladder with focal rather than diffuse wall calcification)
Prophylactic cholecystectomy, preferably through a laparoscopic approach, is indicated to prevent subsequent development of carcinoma, which may otherwise occur in up to 20% of cases
Laparoscopic cholecystectomy is the standard method for the management of
patients with biliary pain and complications of gallstone disease, such as acute cholecystitis, gallstone pancreatitis, and choledocholithiasis
The mainstay of current nonsurgical treatment of gallstone disease is oral dissolution with UDCA, with or without extracorporeal shock-wave lithotripsy
Nonsurgical treatments are effective only in patients with small, radiolucent cholesterol gallstones. Significant admixtures of pigment or calcium salts make stones indissoluble
The rationale for oral dissolution therapy is the reversal of the condition that led to formation of cholesterol gallstones, namely, the supersaturation of bile with cholesterol
Cholesterol stones dissolve if the surrounding medium can solubilize the cholesterol in the stones.
Both chenodeoxycholic acid and UDCA dissolve gallstones by decreasing biliary cholesterol secretion and desaturating bile
Chenodeoxycholic acid was the first bile acid used for gallstone dissolution but has been abandoned because of side effects, including diarrhea and increased serum aminotransferase and cholesterol levels.
Oral dissolution therapy should be considered for patients with uncomplicated gallstone disease, including those with mild, infrequent biliary pain.
Selection Criteria for Oral Bile Acid Dissolution
Therapy
STAGE OF GALLSTONE DISEASE
Symptomatic (biliary pain) without complications
GALLBLADDER FUNCTION
Opacification of gallbladder on oral cholecystography (patent cystic duct)
Normal result of stimulated cholescintigraphy (normal gallbladder emptying)
Normal result of functional US (normal gallbladder emptying after a test meal)
STONE CHARACTERISTICS
Radiolucent
Isodense or hypodense to bile and absence of calcification on CT Diameter ≤10 mm (<6 mm optimal)
Oral dissolution therapy works only on cholesterol stones. Although verifying the composition of gallstones can be difficult, the appearance of stones on plain films or CT images can be useful.
Cholesterol stones are radiolucent on plain films, and they are hypodense or isodense to bile and lack stone calcification on CT images
The number of stones does not influence the success of oral dissolution therapy; however,
only patients with stones that occupy less than half of the gallbladder volume should be considered for treatment.
Although oral dissolution therapy has been effective in stones up to 10 mm in diameter, results are best in stones less than 5 mm in size.
UDCA (ursodiol) is the preferred drug for oral dissolution treatment.
It is taken in a dose of 10 to 15 mg/kg of body weight per day. Night time dosing is more effective and is associated with better patient adherence than mealtime dosing
Treatment should continue until stone dissolution is documented by 2 consecutive negative ultrasonograms at least 1 month apart.
Treatment should be stopped if the patient does not tolerate the drug or experiences a complication of gallstones during therapy or if the stones fail to dissolve
after 6 months or dissolve only partially after 6 months with lack of progression to complete dissolution by 2 years
The rationale for shock-wave lithotripsy is to diminish the surface- to-volume ratio of a stone, thereby increasing the efficacy of oral dissolution therapy and decreasing stone size to allow small stones and debris to pass directly from the gallbladder into the
intestine without causing symptoms.
The technique involves the delivery of focused high-pressure sound waves to gallstones
Selection Criteria for Extracorporeal Shock-Wave
Lithotripsy
STAGE OF GALLSTONE DISEASE
Symptomatic (biliary pain) without complications
GALLBLADDER FUNCTION
Opacification of gallbladder on oral cholecystography (patent cystic duct)
Normal result of stimulated cholescintigraphy (normal gallbladder emptying)
Normal result of functional US (normal gallbladder emptying after a test meal)
STONE CHARACTERISTICS
Radiolucent
Isodense or hypodense to bile and absence of calcification on CT
Single Diameter <20 mm
Pregnant patients and patients on anticoagulants
should not undergo lithotripsy.
Shock-wave lithotripsy is reserved for patients with a solitary stone, measuring less than 2 cm in size.
Because only cholesterol stones are reliably cleared by
the addition of oral dissolution therapy, stones should have imaging features, such as radiolucency, suggestive of cholesterol stones
The energy of shock waves, number of shock waves per session, and number of sessions also influence the success rate.
UDCA, 10 to 15 mg/kg of body weight per day, is administered orally to dissolve stone fragments, especially when residual stone fragments are larger than 2 mm in size, gallbladder function is poor, or the gallbladder has not cleared small fragments within 3 to 6 months of lithotripsy
Recurrence is most often related to the presence of lithogenic bile and gallbladder dysmotility, rather than patient variables such as gender, age, and weight.
Factors that predict higher rates of treatment failure include stone size larger than 16 mm, multiple stones, and stones with a CT density greater than 84 Hounsfield units
Lithotripsy is more cost-effective in older adults than in the young and less cost-effective in patients with multiple stones than in those with a single stone
When lithotripsy is compared with laparoscopic
cholecystectomy, patients who undergo laparoscopic cholecystectomy experience a greater incremental improvement in quality of life at 6 months,
The triangle of Calot is the space bordered by
the cystic duct, cystic artery, and inferior edge of the gallbladder.
Dissection and identification of these structures permits safe division of the cystic duct and minimizes the chance of bile duct injury. The abdominal incision is then closed. Closed suction drains are rarely indicated after cholecystectomy
The risk of death is several-fold higher when cholecystectomy is performed as an emergency for acute cholecystitis and when bile duct exploration is required
Prophylactic antibiotics are not administered routinely to patients with uncomplicated gallstone disease, including biliary pain
In this approach, the entire hepatocystic triangle is dissected, exposing the cystic duct and artery, infundibulum of the gallbladder, and junction of the gallbladder and cystic duct, before a cholangiogram is performed or the cystic duct and artery are divided
Cholangiography during laparoscopic cholecystectomy has 2 main purposes.
First, the cholangiogram may detect unsuspected bile duct stones.
Second, the cholangiogram confirms the surgeon’s
impression of the anatomy of the biliary tract
Perihilar cholangiocarcinomas, also referred to as
Klatskin tumor
Cholangiocarcinoma is an epithelial carcinoma with differentiated features of biliary epithelium that arises from the intra- and extrahepatic biliary tract.
It is the most common bile duct tumor and second most common primary hepatic malignancy
The majority of cholangiocarcinomas are either perihilar
(50% to 60%) or distal (20% to 30%) tumors, whereas intrahepatic cholangiocarcinomas account for only approximately 20% of all cholangiocarcinomas
Type I cholangiocarcinomas involve the common hepatic duct distal to the union of the right and left hepatic ducts
type II tumors
involve the union of the right and left hepatic ducts;
type IIIa
tumors involve the union of the right and left hepatic ducts and extend up the right hepatic duct;
type IIIb tumors involve the union of the right and left hepatic ducts and extend up the left hepatic duct; and
type IV tumors are multifocal or involve the
biliary confluence and extend up the right and left hepatic ducts.
The natural course of cholangiocarcinoma is aggressive, with a median survival of less than 24 months following diagnosis.
The mass-forming type is the most common type of intrahepatic cholangiocarcinoma, accounting for more than 85% of cases
High levels of CA 19-9 levels (>1000 U/mL) have been associated with metastatic cholangiocarcinoma
Risk Factors for Cholangiocarcinoma DEFINITE Caroli disease Choledochal cyst Hepatolithiasis Opisthorchis viverrini infection PSC Thorotrast
PROBABLE Biliary-enteric drainage procedures Cirrhosis Clonorchis sinensis infection Heavy alcohol consumption Hepatitis C Toxins (dioxins, polyvinyl chloride)
The only curative treatment option for cholangiocarcinoma is surgical extirpation.
Surgical resection is also the treatment of choice for perihilar and distal cholangiocarcinomas in the absence of PSC
Criteria for Unresectability of Perihilar Cholangiocarcinoma
Atrophy of one liver lobe with encasement of the contralateral portal vein branch
Atrophy of one liver lobe with contralateral secondary biliary radicle involvement
Bilateral portal vein branch encasement
Bilateral hepatic artery encasement
Distant lymph node metastases
Hilar cholangiocarcinoma, Bismuth-Corlette type IV
Intrahepatic or distant metastases
PSC
Significant comorbid conditions
Retrograde injection of dye without drainage
carries a high risk of iatrogenic bacterial cholangitis, which can be severe.
Early intervention in a patient with malignant biliary
obstruction is recommended because the time to normalization of the serum bilirubin level doubles from 3 to 6 weeks when the serum total bilirubin level is greater than 10 mg/dL
Gallbladder carcinoma is the second most common primary biliary malignancy and the fifth most common malignancy of the GI tract.
Gallbladder carcinoma is not amenable
to medical or radiation therapy, and surgical resection is the only potentially curative treatment.
prognosis of gallbladder carcinoma is dismal, with 5-year survival rates of 0% to 10% and a median survival of less than 6 months. More aggressive surgical approaches have been advocated.
distribution of gallbladder carcinoma is geographically heterogeneous, and is 2 to 3 times as common in females as males
The average age at diagnosis is 65 years, and the peak incidence is observed in the seventh and eighth decades of life
The primary risk factor for gallbladder carcinoma is cholelithiasis
Gallstones are found in 65% to 90% of patients with gallbladder carcinoma
Risk Factors for Gallbladder Carcinoma
Aflatoxin Carcinogens* Cholangiocarcinoma Cholelithiasis (stone size >1 cm) Chronic Salmonella Typhi or Paratyphi carrier status First-degree relative with gallbladder cancer IBD Intrahepatic biliary dysplasia Lynch syndrome Pancreaticobiliary malunion Porcelain gallbladder PSC Segmental adenomyomatosis in patients ≥60 years of age
prophylactic cholecystectomy in an asymptomatic
patient with gallstones to prevent gallbladder carcinoma cannot be recommended.
positive correlation between the risk of gallbladder
carcinoma and the size and number of gallstones has been reported but likely reflects the duration of cholelithiasis
Porcelain gallbladder (extensive calcification of the gallbladder wall) is a classic, albeit controversial, risk factor for gallbladder carcinoma
Adenomatous polyps of the gallbladder constitute another risk factor for gallbladder carcinoma
The risk correlates positively with the size, type, and growth rate of the polyps.
Patients with adenomatous polyps that are greater than 1 cm in size, sessile, and associated with gallstones, exhibit a rapid increase in size, demonstrate arterial flow on Doppler US, or are symptomatic are at increased risk of malignant transformation and warrant
prophylactic cholecystectomy
PSC has been associated with gallbladder carcinoma, and studies have reported that adenocarcinoma of the gallbladder
Adenomyomatosis of the gallbladder is characterized by microscopic invaginations (Rokitansky-Aschoff sinuses) of the mucosa with cyst formation in the muscularis propria
Chronic carriers of Salmonella Typhi or Paratyphi have
been shown to be at increased risk for the development of gallbladder carcinoma
papillary form of gallbladder carcinoma has a lower potential for invasion and metastatic spread to lymph nodes
Gallbladder carcinoma spreads via direct invasion, lymphatic or hematogenous metastasis, perineural invasion, and intraperitoneal or intraductal invasion
CEA and CA 19-9 are the most commonly used tumor markers for gallbladder carcinoma
Typical imaging presentations of gallbladder
carcinoma include focal or diffuse mural thickening of the gallbladder, an intraluminal mass greater than 2 cm in size that originates in the gallbladder wall, and a subhepatic mass that replaces or obscures the gallbladder and often invades adjacent organs
Findings indicative of the malignant nature of a gallbladder lesion include
irregular, asymmetrical mural thickening greater
than 1 cm in depth and a nodular or smooth intraluminal mass greater than 1 cm in size, with fixation to the gallbladder wall, that is not displaced by the patient’s movements and has no acoustic shadow.
TNM and AJCC/UICC Staging Systems for Gallbladder Carcinoma
T1a Tumor invades lamina propria
T1b Tumor invades muscularis propria
T2 Tumor invades perimuscular connective tissue
T3 Tumor perforates the serosa
T4 Tumor invades the portal vein or hepatic artery
N1 Regional lymph node metastases (≤3 lymph nodes)
Surgery is the only potentially curative therapeutic option for gallbladder carcinoma
Contraindications to resection include multiple hepatic or distant metastases, gross vascular invasion or encasement of major vessels, malignant ascites, and poor functional status
Direct invasion of the colon, duodenum, or liver is not considered an absolute contraindication to surgical resection.
The goal of surgical treatment is an R0 resection, defined as negative margins and nodal dissection one
level past microscopically involved lymph nodes.
Invasion of the muscularis propria, as in stage T2 tumors,
requires radical cholecystectomy
ampullary carcinomas are often diagnosed earlier than the others and, therefore, at a resectable stage, thereby resulting in a better prognosis
Peak incidence is in the 7th decade of life. There
is a slight male predominance, with a male-to-female ratio of 1.48:1
Familial adenomatous polyposis (FAP) is an important risk factor for the development of ampullary carcinomas
Periampullary carcinoma is the second most common cause of death (after colon cancer) in patients with FAP
Ampullary carcinomas are classified into the following 3 types:
(1) intramural protruding (intra-ampullary),
(2) extramural protruding (periampullary),
and (3) ulcerating ampullary
Seventy-five percent of all ampullary
neoplasms are adenocarcinomas, 20% are benign adenomas, and 5% are neuroendocrine tumors
Like the other periampullary and biliary malignancies, ampullary carcinomas present initially with obstructive jaundice
Anicteric patients may present with bacterial cholangitis.
Rare patients have “silver stools” as a result of the combination of acholic stools that result from bile duct obstruction and bleeding of the tumor
Immunohistochemical analysis has shown high
expression of CEA and CA 19-9 in the tumor
Frequently, dilatation of both the bile
and pancreatic ducts (“double-duct sign”) or only the bile duct is seen; dilatation of the pancreatic duct alone is rarely seen
Surgical resection is the only curative treatment for ampullary carcinomas.
In contrast to the other biliary malignancies, however,
77% to 93% of ampullary carcinomas are resectable at the time of diagnosis
The standard surgical approach is pancreaticoduodenectomy
Hepatobiliary ascariasis also can be treated conservatively with fluid resuscitation, bowel rest, and antibiotics
Worms in the bile duct are not effectively treated with albendazole because the drug is poorly absorbed and not concentrated in bile.
This feature of albendazole is advantageous because were paralyzed worms within the duct unable to pass out through the sphincter of Oddi, they could become trapped in the bile duct.
Patientsm with hepatobiliary ascariasis should be treated with albendazole each day for several days because the worms only become susceptible to the drug after they migrate out of the bile duct
Worms also can invade the pancreatic duct and intrapancreatic Ascaris can be treated just as hepatobiliary ascariasis.
Ascending cholangitis, acute obstructive jaundice, or acute pancreatitis requires emergent ERCP with worm extraction from the ducts by balloon, basket, or forceps—preferably without sphincterotomy.
Ampullary sphincterotomy permits worms easier access to the ducts and can increase the risk of recurrent pancreaticobiliary ascariasis
PBC is an autoimmune liver disease that generally affects middle-aged women and is the most common chronic cholestatic liver disease in adults in the USA.
PBC is characterized by progressive intrahepatic bile duct destruction, which leads to cholestasis, complications, and symptoms related to cholestasis, cirrhosis, and portal hypertension.
The presence of an elevated alkaline phosphatase
level and AMA in the serum is highly characteristic
UDCA is the only medication shown to improve LT-free survival.
Obeticholic acid (OBA) was approved for patients intolerant of UDCA or those who do not have an adequate biochemical response to UDCA
PBC occurs worldwide and predominantly in women, with a female-to-male ratio of 9:1.
The diagnosis of PBC usually is made between the ages of 40 and 60 years
Although the etiology of PBC remains unknown, it is likely an immune-mediated process that occurs as a result of complex interactions between the environment and genetically susceptible individuals.
In the early biliary lesions of PBC, eosinophilic infiltration and granulomas often are seen.
PBC is principally a disease of the small intrahepatic bile ducts, with loss of biliary epithelial cells that line these ducts and resulting cholestatic damage.
AMA continue to be regarded as the most sensitive and specific immunologic hallmark of the disease
AMA do not appear to be cytotoxic: (1) They persist after LT without evidence of disease recurrence; (2) disease severity is unrelated to antibody titer; (3) they are not always present in PBC
ANA are present in nearly one half of patients with PBC and in up to 85% of patients with AMA-negative PBC
The typical patient with symptomatic disease is a middle-aged woman with a complaint of fatigue or pruritus.
Other symptoms include RUQ abdominal pain, anorexia, and jaundice
Pruritus generally is intermittent during the day and is most troublesome in the evening and at night. Pruritus often resolves as the disease progresses, but in some patients, severe, intractable pruritus can develop in earlier stages of the disease and may require LT for effective management.
Pruritus in cholestatic liver disease may be partially mediated by lysophosphatidic acid and the enzyme autotaxin
Most patients with PBC do not have jaundice at the time of diagnosis. Jaundice occurs later in the course of the disease and usually is persistent and associated with a worse prognosis
HCC is an important malignancy associated with PBC, and the risk is nearly 19-fold higher than that in the general
population
The diagnosis of PBC is established when 2 out of 3 of the following criteria are met: chronic cholestatic liver test elevation (typically with alkaline phosphatase ≥1.5 times the upper limit of normal [ULN]), elevated serum AMA (titers ≥1:40), or a liver biopsy specimen consistent with PBC. A liver biopsy is typically not required
Almost all patients have increased serum levels of alkaline phosphatase and GGTP.
Serum aminotransferase (AST, ALT) levels are mildly elevated (usually less than 3 times the ULN); marked elevations (more than 5 times the ULN) are distinctly unusual and may suggest PBC-autoimmune hepatitis overlap syndrome
One of the earliest histologic changes associated with PBC may be a loss of the canals of Hering
Damage to the epithelial cells of the small bile ducts can also be appreciated early in the disease course
The most important and only diagnostic clue in many cases is ductopenia, defined as the absence of interlobular bile ducts in greater than 50% of portal tracts.
The florid duct lesion, in which the epithelium of the interlobular and segmental bile ducts degenerates segmentally, with formation of poorly defined, noncaseating epithelioid granulomas, is nearly diagnostic of PBC but is found in a relatively small number of cases, mainly in early stages
Ludwig stage 1 disease is characterized by inflammatory destruction of the intrahepatic septal and interlobular bile ducts that range up to 100 μm in diameter.
These lesions often are focal and described as florid duct lesions, characterized by marked inflammation and necrosis around a bile duct.
The portal tracts usually are expanded by lymphocytes, with only sparse neutrophils or eosinophils seen.
stage 2 disease the inflammation extends from the portal tract into the hepatic parenchyma, a lesion called interface hepatitis, or formerly, piecemeal necrosis.
Destruction of bile ducts with proliferation of bile ductules can be seen.
Stage 3 disease is characterized by scarring and fibrosis. hallmark of this stage is the presence of fibrosis without regenerative nodules.
Stage 4 disease is characterized by cirrhosis with fibrous septa and regenerative nodules
person with AMA, the combination of a serum alkaline
phosphatase level greater than 1.5 times the ULN and a serum AST level less than 5 times the ULN is highly predictive for a diagnosis of PBC
Nearly two thirds can have a periportal “halo” sign (T1-and T2-weighted hypointensity centered around portal venous branches) on MRI and intraabdominal lymphadenopathy
Both the serum bilirubin and alkaline phosphatase levels are important surrogate markers that can predict transplant-free survival
Most persons with AMA-negative PBC have antinuclear (perinuclear/rim-like or multiple nuclear dots pattern) or smooth muscle antibodies (or both).
Although these patients may be distinguished by the lack of AMA in serum
The most cost-effective dose of UDCA in patients with PBC is 13 to 15 mg/kg/day, which can be given in divided doses taken with meals
Obeticholic acid (OBA) is a first-in-class farnesoid X receptor (FXR) agonist.
FXR is a nuclear receptor expressed in the liver, kidneys, adrenal glands, and intestine and plays a key role in bile acid metabolism, liver regeneration, and inflammation
fenofibrate and bezafibrate can improve liver biochemical test levels, even in UDCA nonresponders
Prednisolone and prednisone may improve serum alkaline phosphatase and aminotransferase levels and liver histologic features in patients with PBC, at least in the short term
Budesonide is a glucocorticoid structurally related to 16α hydroxyprednisolone, with extensive first-pass hepatic metabolism and minimal systemic availability
Vitamin K deficiency occurs with severe cholestasis and is manifested by a prolonged prothrombin time.
A trial of oral vitamin K, 5 to 10 mg daily, should be given to determine if the prothrombin time improves.
If it does, the patient should be maintained on a water-soluble vitamin K, 5 mg per day
Cholestyramine is successful in a majority of patients who can tolerate the unpleasant side effects of bad taste, bloating, and occasional constipation.
The recommended total dose is 3 to 12 g/day orally, and the drug is most effective when one half of the dose is given 30 minutes before and one half is given 30 minutes after breakfast, to permit maximal bile acid binding as the gallbladder empties.
All drugs that can potentially bind to cholestyramine (including UDCA) should be taken several hours before or after the cholestyramine.
Colesevelam has a higher bile acid-binding capacity and fewer side effects than cholestyramine
The best therapeutic alternative for patients with end-stage PBC is LT.
The antibiotic rifampin also is effective in relieving the pruritus of PBC.
A majority of patients respond to rifampin, and benefit occurs within one week of the start of therapy. The starting dose is 150 mg twice daily orally; occasionally, higher doses are
needed.
Rifampin induces drug-metabolizing enzymes, so caution is needed when concurrent drugs are administered. Rifampin has been associated with reversible liver injury
type I cysts, accounting for 80% to 90% of cases, exhibit segmental or diffuse fusiform dilatation of the bile duct.
Type II cysts consist of a true choledochal diverticulum
Type III cysts consist of dilatation of the intraduodenal portion of the bile duct, or choledochocele
Type IVa, or multiple intrahepatic and extrahepatic
cysts
Type IVb or multiple extrahepatic cysts
The type IVb variant is either uncommon or may overlap with type I
type V, or Caroli disease, which consists of single or
multiple dilatations of the intrahepatic ductal system, should be viewed as a form of choledochal cyst is unsettled
Ia, Common type;
Ib, segmental dilatation;
Ic, diffuse dilatation;
II, diverticulum;
III, choledochocele;
IVa, multiple cysts (intra and extrahepatic);
IVb, multiple cysts (extrahepatic)
V, single or multiple dilatations of the intrahepatic ducts
(Caroli disease
The classic triad of abdominal pain, jaundice, and a palpable abdominal mass is observed in less than 20% of patients
The diagnosis of a choledochal malformation is best established by US
Caroli disease is a rare disorder characterized by congenital nonobstructive gross dilatation of the segmental intrahepatic bile ducts
and may occur in association with medullary sponge kidney (in 60% to 80% of patients) or congenital hepatic fibrosis
The human liver is formed from 2 primordia: the liver diverticulum and the septum transversum
The septum transversum consists of mesenchymal cells and a capillary plexus formed by the branches of the 2 vitelline veins.
At the 3- to 4-mm stage, between the third
and fourth weeks of gestation, the growing diverticulum projects as an epithelial plug into the septum transversum
The characteristic folds of the gallbladder are formed toward the end of gestation and are moderately developed in the neonate.
Bile secretion starts at the beginning of the fourth month of gestation;
The adult human liver has more than 2 km of bile ductules and ducts
These bile ducts are initially 30 to 40 μm in diameter and are lined by a layer of cuboidal or columnar epithelium that displays a microvillar architecture on its luminal surface
The common hepatic duct emerges from the porta hepatis after the union of the right and left hepatic ducts, each of which is 0.5 to 2.5 cm long
The confluence of the right and left hepatic ducts is outside the liver in some 95% of cases
In the adult, the common hepatic duct is about 3 cm long and is joined by the cystic duct, usually at its right side, to form the common bile duct (or simply bile duct).
The length and angle of junction of the cystic duct with the common hepatic duct are variable
The cystic duct enters the common hepatic duct directly in 70% of patients; alternatively, the cystic duct may run anterior or posterior to the bile duct and spiral around it before joining the bile duct on its medial side
The cystic duct may also course parallel to the common hepatic duct for 5 to 6 cm and enter it after running posterior to the first portion of the duodenum
Mucus-secreting tubular glands can be found at regular intervals in the submucosa, with openings to the surface of the mucosa.
The common bile duct is 6.0 to 8.0 cm long, runs between layers of the lesser omentum, and lies anterior to the portal vein and to the right of the hepatic artery
The bile duct is normally 0.5 to 1.5 cm in diameter
wall of the extrahepatic bile duct is supported
by a layer of connective tissue with an admixture of occasional smooth muscle fibers. The smooth muscle component is conspicuous only at the neck of the gallbladder and at the lower end of the bile duct. The bile duct passes retroperitoneally behind the
first portion of the duodenum in a notch on the back of the head of the pancreas and enters the second part of the duodenum
the sphincter choledochus—circular muscle fibers that
surround the intramural portion of the bile duct immediately
before its junction with the pancreatic duct;
(2) the sphincter pancreaticus, which is present in approximately one third of persons and surrounds the intraduodenal portion of the pancreatic duct
before its juncture with the ampulla;
(3) the fasciculi longitudinales— longitudinal muscle bundles that span intervals between the bile and pancreatic ducts; and (4) the sphincter ampullae—
longitudinal muscle fibers that surround a sparse layer of circular fibers around the ampulla of Vater
The sphincter choledochus constricts the lumen of the bile duct and, thus, prevents bile flow.
Contraction of the fasciculi longitudinales shortens the length of the bile duct and, thus, promotes the flow of bile into the duodenum.
The contraction of the sphincter ampullae shortens the
ampulla and approximates the ampullary folds to prevent reflux of intestinal contents into the bile and pancreatic ducts.
When both ducts end in the ampulla, however, contraction of the sphincter may cause reflux of bile into the pancreatic duct
The intrahepatic and extrahepatic bile ducts are highly dependent on arterial blood supply for oxygenation.
An abundant anastomotic network of blood vessels from branches of the hepatic and gastroduodenal arteries supplies the bile duct
The supraduodenal portion of the duct is supplied by vessels running along its wall inferiorly from the retroduodenal artery and superiorly from the right hepatic artery. Injury to these blood vessels
can result in bile duct ischemia and stricturing
The gallbladder is a storage reservoir that allows bile acids to be delivered in a high concentration and in a controlled manner to the duodenum for the solubilization of dietary lipid
It lies in a fossa on the undersurface of the right lobe of the liver
This distensible pear-shaped structure
is 3 cm wide and 7 cm long in the adult and has a capacity of 30 to 50 mL
The gallbladder has a thin muscular layer with the
smooth muscle cells largely oriented around the circumference of the gallbladder. The absorptive surface of the gallbladder is enhanced by numerous prominent folds. The gallbladder is covered
anteriorly by an adventitia that is fused with the capsule of the liver.
The portions of the gallbladder are the
fundus, body, infundibulum, and neck.24 The anterior portion of the fundus is located at the level of the right lateral border of the musculus rectus abdominis and the ninth costal cartilage.
The infundibulum is an area of tapering between the gallbladder body and neck.
Hartmann pouch is a bulging of the inferior surface of the infundibulum that lies close to the neck of the gallbladder.
Gallstones can become impacted in Hartmann pouch,
thereby obstructing the cystic duct and producing cholecystitis
Extensive inflammation in Hartmann pouch can lead to obstruction of the adjacent common hepatic duct (Mirizzi syndrome)
The gallbladder is connected at its neck to the cystic duct, which empties into the bile duct (see Fig. 62.3).29
The cystic duct is about 4 cm long and maintains continuity with the surface columnar epithelium, lamina propria, muscularis, and serosa of the gallbladder
The mucous membrane of the gallbladder neck
forms the spiral valve of Heister, which is involved in regulating flow into and out of the gallbladder.
The gallbladder is supplied by the cystic artery, which usually arises from the right hepatic artery
The artery divides into 2 branches near the neck of the gallbladder: a superficial branch that supplies the serosal surface and a deep branch that supplies the interior layers of the gallbladder wall
gallbladder is particularly susceptible
to ischemic injury and necrosis that result from inflammation or interruption of hepatic arterial flow.
triangular cord or band-like periportal echogenicity (≥3 mm in thickness), which represents a cone-shaped fibrotic mass cranial to the portal vein, appears to be a specific ultrasonographic finding in the early diagnosis of biliary atresia.
The gallbladder “ghost” triad, defined as gallbladder
length less than 1.9 cm, lack of smooth or complete echogenic mucosal lining with an indistinct wall, and irregular or lobular contour, has been proposed as an additional criterion for biliary atresia.
Choledochal cysts are not familial, and female children
are affected more commonly than male children
PSC is a rare progressive disease of the biliary tract characterized by inflammation and fibrosis of the intrahepatic and extrahepatic biliary ductal systems, leading eventually to biliary cirrhosis
PSC is a pathologic process that occurs in the absence of choledocholithiasis or a history of bile duct surgery
The diagnosis of PSC is established by cholangiography.
MRCP is the method of choice for visualizing the intrahepatic and extrahepatic bile ducts and is comparable to ERCP findings and significantly less invasive than ERCP
Irregularities of the intrahepatic and extrahepatic ducts can be found, including alternating strictures and areas of dilatation that produce a beaded appearance.
Involvement of the intrahepatic bile ducts
predominates in patients whose condition appears after the neonatal period. Occasionally, a dominant stricture of the extrahepatic ducts or papillary stenosis is found.
The sphincter of Oddi (SO) is composed of layers of
smooth muscle that are embedded in, but functionally separate from, the muscle of the duodenal wall and that serve as a 4- to 10-mm high-pressure zone
The SO comprises 3 parts: a small segment (sphincter ampullae) that covers the common channel formed by the union of the bile and pancreatic ducts (when a common channel is present); a second small portion (sphincter pancreaticus) that surrounds the beginning of the main pancreatic duct; and the largest portion (sphincter choledochus) that covers the distal bile duct
In addition, the fasciculi longitudinales
are muscle bundles that span intervals between the bile and pancreatic ducts. The SO functions primarily as a resistor, with tonic contraction that limits bile flow during the interdigestive period.
The SO functions primarily as a resistor,
with tonic contraction that limits bile flow during the interdigestive period.
It also serves as a pump, with phasic contractions that facilitate the flow of bile into the duodenum,
perhaps serving a housekeeping function for the distal bile duct.
The SO participates in the migrating motor complex,
with motilin-induced increases in the frequency and amplitude of sphincter contractions shortly before and during bursts of intense duodenal contractions.
SOD is a benign, noncalculous obstructive disorder that occurs
at the level of the SO. The pathogenesis of SOD can be divided into 2 subtypes:
SO stenosis, which results from passive obstruction at the SO caused by fibrosis, inflammation, or both; and SO dyskinesia, which results from intermittent obstruction caused
by sphincter muscle spasm
Clinical Associations with SOD
Definite Biliary-type pain after cholecystectomy
Probable
Biliary-type pain in a patient with an intact gallbladder
Possible After LT AIDS-associated viral and protozoal infections Chronic pancreatitis Hyperlipidemia Idiopathic recurrent acute pancreatitis Opium use
SOD has been associated with 3 clinical conditions:
(1) persistent or recurrent biliary-type pain following cholecystectomy;
(2) recurrent idiopathic (unexplained) pancreatitis; and (3) biliary- type pain in patients with an intact gallbladder but without cholelithiasis. SOD generally occurs spontaneously but has also
been described with increased frequency in patients who have undergone LT
The pain is typical of biliary
pain; it is severe and occurs in the epigastrium or the RUQ and may radiate to the back or right shoulder blade.
The pain is generally episodic, lasts more than 30 minutes, and occurs at least once a year.31 The Rome Consensus Committee has proposed diagnostic criteria for SO disorder, based predominantly
on expert opinion
Because ERCP remains the only reliable diagnostic and therapeutic intervention for SOD, and brings with it substantial risks, defining the clinical characteristics that reliably predict the presence of SOD and the response to sphincter ablation is of paramount
importance.
Mod Milwaukee=Biliary type I Rome IV= SO stenosis Biliary pain Duct diameter >9 mm Serum ALT or AST elevation
Biliary type II Functional biliary sphincter disorder Biliary pain One of the objective criteria noted above
Biliary type III Functional pain Biliary pain only
Noninvasive diagnostic tests for SOD include biliary scintigraphy; fatty meal, CCK, or secretin-stimulated US; secretinstimulated MRI; and secretin-stimulated EUS.
The performance characteristics of these tests have largely been validated by SOM, which has been recognized increasingly as an inadequate gold
standard
ERCP remains the gold standard for the diagnosis and treatment of SOD, although patients in whom this diagnosis is suspected have the highest rates of procedural complications. Such patients
have a three-fold increase in the risk of post-ERCP pancreatitis
Patients with a basal SO pressure >40 mm Hg had a clinical response rate of 91%, compared with a 25% rate in patients with a high basal pressure in whom a sham sphincterotomy was performed
The most common reason for considering the diagnosis of SOD is biliary-type pain in a postcholecystectomy patient
The volume of hepatic bile secreted is estimated to range from 500 to 600 mL per day, and bile acids are the most abundant organic components.
During digestion of a large meal, the gallbladder remains contracted, and bile acids secreted by
the liver bypass the gallbladder and empty directly into the duodenum.
During this period, the intraluminal bile acid concentration in the small intestine is 5 to 10 mmol/L, well above the threshold concentration of approximately 1.5 mmol/L that is required for micelle formation
During the interdigestive period, the sphincter
of Oddi contracts and the gallbladder relaxes, causing a larger fraction of the bile acids secreted into bile to enter the gallbladder for storage.
In adult humans, the enterohepatic circulation maintains a bile acid pool size of approximately 2 to 4 g. The bile acid pool cycles 2 to 3 times per meal, and the intestine may reabsorb between 10 and 30 g of bile acid per day.
Approximately 0.2 to 0.6 g of bile acid escapes
reabsorption and is eliminated in the stool each day
More than 90% of the bile acids secreted into bile are derived from the recirculating pool. To maintain this process, hepatocytes must transport bile acids efficiently from the portal blood into bile
In the fasting state, uptake of bile acids is highest in the periportal hepatocytes (closest to the portal venules), whereas during feeding, more distal hepatocytes in the liver acinus are recruited to participate
The concentration of bile acids in the portal blood of healthy humans is 20 to 50 μmol/L.
The hepatic fractional extraction is related to bile acid structure and albumin binding and is highest (80% to 90%) for hydrophilic conjugated bile acids such as conjugated CA and lowest (50% to 60%) for unconjugated hydrophobic protein-bound bile acids such as CDCA
In healthy humans, the kidney filters approximately 100 μmol of bile acids each day. Remarkably, only 1 to 2 μmol are excreted in the urine because of highly efficient tubular reabsorption
Cholestasis is defined as interruption of the normal process of bile formation and is classically subdivided into intrahepatic cholestasis, a functional defect in bile formation at the level of the hepatocyte, and extrahepatic cholestasis, an obstruction to bile flow within the biliary tract.
Although serum GGTP levels are elevated in some
other forms of cholestasis, GGTP levels are typically normal in the cholestatic patient with a bile acid biosynthesis defect because the block occurs prior to canalicular secretion
In the absence of a gallbladder, the bile
acid pool is stored in the small intestine during the fasting state.
After ingestion of a meal, the bile acid pool moves to the terminal ileum, where it is actively absorbed and returned to the liver via the portal circulation
Increased dehydroxylation of CA to DCA
has been reported and may be secondary to an increased enterohepatic cycling of bile acids in the fasting state. Diarrhea is one of the most common symptoms after cholecystectomy
Resection of the terminal ileum causes intestinal bile acid malabsorption.
If the resection is short (<100 cm), the effect on bile
acid metabolism is minimal because increased hepatic bile acid biosynthesis balances fecal loss.
Excess amounts of unabsorbed bile acids enter the colon and act to inhibit water absorption or induce secretion, thereby resulting in mild, watery diarrhea
When 100 cm or more of ileum is
resected, including the ileocecal valve, hepatic bile acid secretion diminishes because maximal synthesis is considerably less than the normal hepatic secretion rate
In PBC, UDCA appears to stimulate biliary bicarbonate secretion to protect against bile acid-induced ductular damage, delay the progression of fibrosing
cholangiopathy, reduce the need for LT, and improve survival
Sclerosing cholangitis encompasses a spectrum of cholestatic conditions that are characterized by patchy inflammation, fibrosis, and destruction of the intrahepatic and extrahepatic biliary tract.
These conditions are typically chronic, progressive
disorders in which persistent biliary damage may lead to biliary obstruction, biliary cirrhosis, and hepatic failure, with associated complications
The most common and best described is PSC, a disorder that usually occurs in association
with IBD, either UC or Crohn colitis. PSC may also be associated with a wide variety of fibrotic, autoimmune, and infiltrative disorders,
The term secondary sclerosing cholangitis (SSC) refers to a syndrome that is similar to PSC but develops as a consequence of a known disease or injury
The original description of PSC was of an “obliterative cholangitis” of the extrahepatic biliary tract with diffuse thickening of the wall and narrowing of the lumen
predominance of men in the third and fourth decades of life and the association with UC
The classic form of PSC, now often referred
to as large-duct PSC, occurs predominantly in men (male:female ratio 3:2), is co-existent with IBD in 60% to 80% of cases
Large-duct PSC is the most common and
best described type and is strongly associated with the HLA A01, B08, DRB1*03 haplotype
Small-duct PSC is a term used to describe a small group of patients who present with clinical, biochemical, and histologic features compatible with PSC but who lack the typical cholangiographic
findings of PSC
Depending on the criteria used, from 1% to 53.8% of patients with PSC may be diagnosed with overlapping features of autoimmune hepatitis (AIH
Although PSC has been diagnosed in neonates and as late as the eighth decade of life, most patients present between the ages of 25 and 45 years, with a median age of diagnosis ranging from 36 to 39 years
Approximately two thirds of patients with PSC are
men, but in the subset of patients without IBD, the male-to-female
ratio is lower.
Women with PSC are generally older at diagnosis.
PSC is also associated with nonsmoking, but whether this effect is independent of IBD remains controversial.
Coffee consumption and, among women, the use of hormone therapy have been associated with a reduced risk of PSC.
Although early studies suggested that
approximately 80% of patients with PSC had concomitant IBD, subsequent data have shown that the frequency of IBD in patients with PSC is 65% to 70%.
The association with IBD is stronger with more
extensive colonic involvement; the frequency of PSC is approximately 5.5% in those with pancolitis, in contrast to 0.5% in those with only distal colitis.86 PSC is not thought to occur in association
with Crohn disease isolated to the small intestine
PSC typically progresses independently
of IBD,88 and, in fact, PSC may be diagnosed years after total proctocolectomy for UC
The colitis of PSC is often extensive, although clinically quiescent, regardless of whether it is classified as UC or Crohn disease
Inflammation is more pronounced in the right than left colon. In addition, PSC patients
who have undergone proctocolectomy and ileal pouch-anal anastomosis
have a higher frequency of pouchitis.
Crohn disease associated with PSC is not typically associated with strictures or fistulas but is restricted to the colon. In fact, the lower frequency
of pancolitis in Crohn disease versus UC could explain the apparent lower frequency of PSC in Crohn disease compared with UC
Patients with concurrent UC have a much earlier age of onset and much higher rates of hepatobiliary cancer, LT, and death
Most Common Symptoms and Signs at the Time of
Diagnosis of PSC
Symptom
Fatigue 65-75
Abdominal pain 24-72
Sign
Jaundice 30-73
Hepatomegaly 34-62
Chronic elevation of serum alkaline phosphatase levels, typically 3 to 5 times the upper limit of normal, is the biochemical hallmark of PSC.
A normal alkaline phosphatase level, however, may be
found in up to 6% of patients with cholangiographically proved PSC.
Serum aminotransferase levels are
typically elevated, although rarely above 4 to 5 times the upper limit of normal, except in the pediatric population, in the setting of acute cholangitis, or in overlap with AIH
Several immunologic markers and serum autoantibodies are found in most patients with PSC, although none is specific for the disease.
Hyperglobulinemia is frequent; serum IgM levels are elevated in up to 50% of patients, and IgG and IgA levels may also be elevated
Autoantibodies are commonly detected in patients
with PSC
ANA, often in low titer, may be detected in 24% to
53% of patients. SMA are found in 13% to 20% of patients, but AMA are found in less than 10%.
Most commonly found in patients with PSC are ANCA (specifically perinuclear ANCA, or pANCA), which are detected in 65% to 88% of patients and appear to react to a heterogeneous group of antigens.
ANCA positivity has been associated with younger age
at the diagnosis of PSC, lower frequency of cholangiocarcinoma, and higher prevalence of HLA-B08 and DDRB103
The characteristic cholangiographic findings include
multifocal stricturing and ectasia of the biliary tract.
Areas of narrowing are interspersed with areas of normal or near-normal caliber and areas of poststenotic dilatation. The result is a classic “beaded” appearance to the biliary tract
The strictured segments are usually short, annular, or band-like in appearance although longer confluent strictures may be seen in more advanced disease. Localized segments of dilated ducts may have a saccular or diverticular appearance.
Major areas of focal, tight narrowing known as dominant strictures, may be seen and often involve the bifurcation of the hepatic duct
diffuse involvement of the intrahepatic biliary tract may give a pruned appearance that is difficult to distinguish from the diffuse intrahepatic
duct attenuation seen in patients with cirrhosis of any cause
MRI with MRCP is considered the modality of choice for
the diagnosis of PSC
stage 1 (portal stage) changes are confined to the portal tracts and consist of portal inflammation, connective tissue expansion, and cholangitis.
Stage 2 (periportal stage) is characterized by expansion of inflammatory and fibrotic processes beyond the confines of the limiting plate, resulting in interface hepatitis (“piecemeal necrosis”) and periportal fibrosis. Depending on the degree of biliary obstruction, ductular proliferation and cholangitis may be of varying severity.
Stage 3 (septal stage) is characterized by agreement was substantial
Stage 4 (cirrhotic stage) implies progression to biliary cirrhosis. The degree of inflammatory activity may subside as the stage of the disease progresses, and focal bile ductular proliferation may be striking
Dominant strictures, defined as strictures with a diameter of less than 1.5 mm of the common bile duct or less than 1.0 mm of a hepatic duct within 2 cm of the bifurcation,
Patients with IBD and a cholestatic pattern of liver biochemical test elevations should undergo imaging of the hepatobiliary system by MRC due to the relatively high pretest probability
of PSC
Cholangiographic findings in patients with cirrhosis from causes other than PSC may at times be mistaken for PSC; however, cholangiography in cirrhotic patients without PSC typically shows diffuse intrahepatic attenuation of bile ducts without the ductal irregularity or stricturing seen in patients with PSC
PBC is a chronic cholestatic condition that shares some clinical features with PSC
however, PBC predominantly
affects middle-aged women, has no association with IBD, and is associated strongly with high titers of AMA
Acute bacterial cholangitis
Multifocal intrahepatic and extrahepatic bile duct strictures, slight biliary dilatation, diverticular outpouchings, “pruned tree” appearance
AIDS-related cholangiopathy
Multiple intrahepatic bile duct strictures, stones, biliary abscesses
Subclinical phase: Patients may have cholangiographic evidence of PSC but normal serum liver biochemical values and no symptoms. These patients are typically identified as a result
of incidental findings on imaging studies or through screening of individuals w`ith long-standing IBD
Asymptomatic phase: Patients remain asymptomatic but have biochemical abnormalities, typically elevation of serum alkaline phosphatase levels with variable elevations of serum bilirubin and aminotransferase levels.
Symptomatic phase: Symptoms of cholestasis or liver injury, or both, develop. Pruritus, fatigue, symptoms of cholangitis, and jaundice may occur, often in combination.
Decompensated cirrhosis: The final phase is characterized by worsening symptoms and complications of end-stage liver disease,
such as ascites, encephalopathy, and variceal bleeding
Cholelithiasis and choledocholithiasis are more common in patients with PSC than in the general population.
Gallstones, often pigmented calcium bilirubinate stones, are found in approximately 25% of patients with PSC
Cholangiocarcinoma is a feared complication of PSC arising from bile duct epithelium (see Chapter 69). PSC is a premalignant condition of the biliary tract, analogous to the relationship between UC and carcinoma of the colon.
The lifetime risk of developing cholangiocarcinoma in patients with PSC ranges between 5% and 20% with the greatest risk in the first year following the diagnosis of PSC
Tumors are most commonly found in the
common hepatic duct and perihilar region but may involve only the bile duct, intrahepatic ducts, and cystic duct
Since the introduction of LT, cholangiocarcinoma has become the leading cause of death in patients with PSC.
Risk factors for the development of cholangiocarcinoma in patients with PSC include older age, male sex, large-duct PSC, and UC, whereas small-duct PSC and Crohn disease or absence of IBD appear to be protective
Carbohydrate antigen 19-9 (CA19-9) has been the most
extensively tested potential serum marker for cholangiocarcinoma.
The development of cholangiocarcinoma is an ominous sign, with a median survival of 5 months after diagnosis
Due to the high rate of recurrence of cholangiocarcinoma after LT, few patients with cholangiocarcinoma are considered candidates to LT
A growing body of evidence suggests that patients with concomitant PSC and UC are at significantly higher risk for developing colonic neoplasia (dysplasia or carcinoma) than patients with UC alone
This theory is supported by the higher frequency of right-sided colon cancer in patients with UC and PSC than in those with UC alone
Patients with PSC who have UC should undergo surveillance for the detection of colonic dysplasia or cancer every N1 to 2 years, beginning at the time of diagnosis of PSC.
Except for LT, no specific therapy has proved effective for treating PSC. The objectives of management prior to liver decompensation should be the treatment of complications, such as bacterial
cholangitis and pruritus, prevention of osteoporosis and nutritional deficiencies, and early diagnosis of malignancies, including cholangiocarcinoma,
gallbladder cancer, and colon cancer
Although the majority of clinical trials have demonstrated improvement
in serum liver biochemical test levels, none has demonstrated a survival benefit or delay in the requirement for LT. In addition, there have been no benefits to UDCA with regard to fatigue, pruritus,
or development of cholangiocarcinoma
The results of a prospective, placebo-controlled randomized trial of UDCA in a dose of 25 to 30 mg/kg/day for 6 years, however, demonstrated a higher risk of death, need for LT
risk of spontaneous bacterial cholangitis, patients with PSC are at high risk of cholangitis following biliary instrumentation and should receive antibiotic prophylaxis following any biliary procedure, usually with a 5- to 7-day course of a fluoroquinolone, cephalosporin, or a beta-lactamase inhibitor
The role of biliary surgery in PSC has diminished considerably with improvements in endoscopic therapy and the advent of LT.
LT is the only therapy that has been shown conclusively to improve the natural history of PSC
Infection with C. sinensis, Opisthorchis species, and A. lumbricoides is endemic in the same geographic region where RPC is prevalent, suggesting an important role of these infections
RPC has also been called “oriental cholangiohepatitis,” “Hong Kong disease,” “biliary obstruction syndrome of the Chinese,” and hepatolithiasis
RPC are characteristic, with the majority of patients (75% to 80%) having intrahepatic stones, with predominant involvement of the left hepatic duct
MRCP is the preferred diagnostic test
Antibiotic therapy should be initiated promptly, once cultures of blood and bile (if accessible) have been obtained
Although gallstones and their complications account for most cholecystectomies, a consistent 15% of these operations are performed in patients without gallstones
In these patients, the majority of cholecystectomies are performed as treatment for 1 of 2 distinct clinical syndromes: acalculous biliary pain and acalculous cholecystitis.
Acute acalculous cholecystitis is typically a disease of immobilized and critically ill
older men with coexisting vascular disease
Biliary pain (or biliary “colic”) is typically characterized by intense epigastric or right upper quadrant pain that starts suddenly, rises in intensity over a 15-minute period, and continues at a steady plateau for 30 minutes or more before slowly subsiding. The localization of pain to the right hypochondrium or radiation to the right shoulder is the most specific finding for a biliary tract origin
The attacks of pain are frequently precipitated by ingestion of a meal and may be accompanied by restlessness, nausea, or vomiting.
Between attacks, the physical findings are usually normal, with the possible exception of residual upper abdominal tenderness
Acalculous biliary pain is predominantly a disorder
of young women
Acalculous Biliary Pain
Female preponderance (80%)
Young to middle-aged ambulatory patient
Risk factors are similar to those for cholelithiasis (i.e., obesity and multiparity
Episodic RUQ or epigastric pain identical to calculous biliary pain
Physical findings are usually normal
Laboratory findings are usually normal
US shows no stones and usually a normal gallbladder
Stimulated cholescintigraphy using CCK to measure the GBEF may identify patients who are likely to improve after cholecystectomy
Male preponderance (80%)
A critically ill older adult patient in an ICU
Risk factors are preexisting atherosclerosis, recent surgery, and hemodynamic instability
Unexplained sepsis with few localizing signs; rapid
progression to gangrene and perforation
Physical examination may show fever; RUQ tenderness is
present in only 25%
Leukocytosis and hyperamylasemia may be present
Diagnostic Criteria for Acute Acalculous Cholecystitis
RUQ tenderness, if present, supports the diagnosis
but is lacking in 75% of cases
Unexplained fever, hypotension, leukocytosis, or
hyperamylasemia is frequently the only finding
Thickened gallbladder wall (>4 mm) in the absence of
ascites and hypoalbuminemia (serum albumin <3.2
g/dL) Sonographic Murphy’s sign (maximum tenderness
over the US-localized gallbladder)
Pericholecystic fluid collection
Thickened gallbladder wall (>4 mm) in the absence of
ascites and hypoalbuminemia
Pericholecystic fluid, subserosal edema (in the
absence of ascites), intramural gas, or sloughed mucosa
Nonvisualization of the gallbladder with normal
excretion of radionuclide into the bile duct and
duodenum indicates a positive result for acute
cholecystitis
Results in critically ill, immobilized patients may be
falsely positive because of viscous bile
Better at excluding than confirming acute cholecystitis
acalculous biliary pain are likely to
benefit from cholecystectomy involves calculation of a gallbladder ejection fraction (GBEF) using cholescintigraphy
with a slow IV infusion of CCK over 30 minutes
Cholecystectomy has not typically been recommended for patients with acalculous pain and a normal GBEF,
acute acalculous cholecystitis may occur
in the absence of antecedent trauma or stress, especially in children, older adult patients with coexisting vascular disease, bone marrow transplant recipients, patients receiving
chemotherapy, and patients with AIDS
Salmonella spp. Staphylococcus aureus, CMV, Zika virus in immunocompromised patients, and EBV in children
Most cases of acute acalculous cholecystitis occur in the setting of prolonged fasting, immobility, and hemodynamic instability
Infection of the gallbladder mucosa with bacteria, usually Gram-negative enteric organisms and manaerobes, is thought to be a secondary event in acute acalculous cholecystitis, following rather than causing the initial injury.
The clinical features of acute acalculous cholecystitis often differ from those of acute cholecystitis caused by stone disease.
Symptoms or signs referable to the RUQ are initially
absent in 75% of cases.
Unexplained fever, hypotension, leukocytosis, or hyperamylasemia may be the only clue that something is amiss.
Compared with the clinical course of typical calculous cholecystitis, that of acute acalculous cholecystitis is more fulminant.
By the time the diagnosis has been made, at least half of the patients have experienced a complication of cholecystitis, such as gangrene or a confined perforation of the gallbladder
acute acalculous cholecystitis
Three US findings indicative of gallbladder disease are
(1) thickened gallbladder wall (defined as > 4 mm) in the absence of ascites or hypoalbuminemia,
(2) sonographic Murphy’s sign (defined as maximum tenderness over the US-localized gallbladder),
and
(3) pericholecystic fluid collection.
thickened gallbladder wall is not specific for cholecystitis but in the proper clinical setting is suggestive of gallbladder involvement and should prompt further evaluation.
A pericholecystic fluid collection indicates advanced disease.
Two points are given for distention of the gallbladder or thickening of the gallbladder wall,
one point each is given for “striated” thickening (alternating hypoechoic and hyperechoic layers) of the
gallbladder wall, sludge, and pericholecystic fluid.
Scores of 6 or higher accurately predict acalculous cholecystitis.
CT findings suggestive of cholecystitis are similar to US findings and include gallbladder wall thickening (>4 mm), pericholecystic fluid, subserosal edema (in the absence of ascites), intramural gas, and sloughed gallbladder mucosa
Hepatobiliary scintigraphy may be useful for excluding cystic duct obstruction in patients with clinical features suggestive of acute cholecystitis
Cholesterolosis is an acquired histologic abnormality of the gallbladder epithelium characterized by excessive accumulation of cholesterol esters and TG within epithelial macrophages
Unlike the small intestine, the gallbladder has no muscularis mucosa, and the lamina propria abuts directly on the muscular layer.
the gallbladder ages, the valleys of the epithelial layer may deepen so that they penetrate into the muscular
layer and form Rokitansky-Aschoff sinuses.
These sinuses are acquired lesions present in about 90% of resected gallbladders. If Rokitansky-Aschoff sinuses are deep and branching and
are accompanied by thickening (hypertrophy) of the muscular layer, a diagnosis of adenomyomatosis can be made
Rupture of Rokitansky-Aschoff sinuses is thought to underlie the rare entity xanthogranulomatous cholecystitis, in which the gallbladder is involved in an inflammatory process with lipid-laden macrophages
Adenomyomatosis may involve the entire gallbladder (diffuse or generalized adenomyomatosis) or, more commonly, may be localized to the gallbladder fundus, in which case the lesion is often termed adenomyoma
luminal narrowing and a “dumbbell-shaped” gallbladder
involved portion of the gallbladder wall is thickened to 10 mm or more, and the muscle layer is 3 to 5 times its normal thickness.
Increased intraluminal pressure in the gallbladder from mechanical obstruction has been postulated to result in cystic dilatation of the Rokitansky-Aschoff sinuses, subsequent hyperplasia of the muscle layer, and adenomyomatosis.
Like pressurerelated colonic diverticula, Rokitansky-Aschoff sinuses are most likely to be found where the muscle layer is weakest (at the site of a penetrating blood vessel
On oral cholecystography , the mural diverticula
that constitute Rokitansky-Aschoff sinuses may fill with
contrast material and produce characteristic radiopaque dots that parallel the margin of the gallbladder lumen
Cholesterol polyps are the most common type of gallbladder polyp
Cholesterol polyps are typically small (<10 mm in diameter), pedunculated polyps that are attached to the mucosa by a thin, fragile stalk
Frequently, detached tiny cholesterol polyps are found floating in the bile when the gallbladder is opened after cholecystectomy
