Saturday, 2 November 2013


Diseases of the gall bladder and bile ducts.



Bile is produced by the liver and channeled by the biliary ductal system into the intestinal tract for the emulsification and absorption of fats. The liver determines the chemical composition of bile, and this may be modified later by the gallbladder and biliary epithelium. Cholesterol, ordinarily insoluble in water, comes into solution by forming vesicles with phospholipids (principally lecithin) or mixed micelles with bile salts and phospholipids.
Table 1.





Gallstone disease is one of the most common and costly of all digestive diseases. In the United States, 6.3 million men and 14.2 million women aged 20-74 years had gallbladder disease.
The incidence of gallstones is 1 million new cases per year. The prevalence is 20 million cases among Americans.
Approximately 2-7 cases per 100,000 population of primary sclerosing cholangitis (PSC) exist. About 5% of patients with chronic ulcerative colitis develop PSC.
The incidence of gallbladder cancer is 2.5 cases per 100,000 population.

Congenital abnormalities.
Anomalies of the biliary tract are not uncommon and include abnormalities in number, size, and form of the gallbladder. Anomalies of position or suspension include left-sided gallbladder, intrahepatic gallbladder, retrodisplacement of the gallbladder, and “floating” gallbladder. The latter condition predisposes to acute torsion, volvulus, or herniation of the gallbladder

In about 80% of patients, gallstones are clinically silent. Approximately 20% of patients develop symptoms over 15-20 years, that is, about 1% per year, and almost all become symptomatic before complications develop. Biliary-type pain, the typical clinical presentation, is due to obstruction of the bile duct lumen. The predictive value of intolerance to fatty food, indigestion may be clinically helpful.
·   Two main types of gallstones exist.
1.                Cholesterol stones (85%): These are divided into 2 subtypes—pure (90-100% cholesterol) or mixed (50-90% cholesterol). Pure stones often are solitary, whitish, and larger than 2.5 cm in diameter. Mixed stones usually are smaller, multiple in number, and occur in various shapes and colors (cholesterol layers and  pigmented center).
2.                Pigment stones (15%) occur in 2 subtypes—brown and black.
a.)                 Brown stones are made up of calcium bilirubinate and calcium-soaps. Bacteria are involved in their formation. The bacterial parths aggregates with the bile pigment and precipitates out of solution.
b.)                 Black stones typically form in the gallbladder and result when excess bilirubin enters the bile and polymerizes into calcium bilirubinate.
S2 The risk factors associated with the development of cholesterol gallstones include obesity, a high-calorie diet, clofibrate therapy, gastrointestinal disorders involving major malabsorption of bile acids, cystic fibrosis with pancreatic insufficiency, and female sex, use of oral contraceptives and other estrogenic medications.
 Coffee, ascorbic acid, has been shown to reduce the risk of symptomatic cholesterol gallstones.
Pigment stones are more common in patients with chronic hemolysis, alcoholic cirrhosis, and advanced age.
TABLE 1 Predisposing Factors for Cholesterol and Pigment Gallstone Formation
Cholesterol Stones
1.   Demographic/genetic factors

a.   Prevalence highest in North American Indians, Chilean Indians, and Chilean Hispanics, greater in Northern Europe and North America than in Asia, lowest in Japan; familial disposition; hereditary aspects
2.   Obesity

a.   Normal bile acid pool and secretion but increased biliary secretion of cholesterol
3.   Weight loss

a.   Mobilization of tissue cholesterol leads to increased biliary cholesterol secretion while enterohepatic circulation of bile acids is decreased
4.   Female sex hormones

a.   Estrogens stimulate hepatic lipoprotein receptors, increase uptake of dietary cholesterol, and increase biliary cholesterol secretion

b.   Natural estrogens, other estrogens, and oral contraceptives lead to decreased bile salt secretion and decreased conversion of cholesterol to cholesteryl esters
5.   Increasing age

a.   Increased biliary secretion of cholesterol, decreased size of bile acid pool, decreased secretion of bile salts
6.   Gallbladder hypomotility leading to stasis and formation of sludge

a.   Prolonged parenteral nutrition

b.   Fasting

c.   Pregnancy

d.   Drugs such as octreotide
7.   Clofibrate therapy

a.   Increased biliary secretion of cholesterol
8.   Decreased bile acid secretion

a.   Primary biliary cirrhosis

b.   Genetic defect of the CYP7A1 gene
9.   Decreased phospholipid secretion

a.   Genetic defect of the MDR3 gene
10.   Miscellaneous

a.   High-calorie, high-fat diet

b.   Spinal cord injury
Pigment Stones
1.   Demographic/genetic factors: Asia, rural setting
2.   Chronic hemolysis
3.   Alcoholic cirrhosis
4.   Pernicious anemia
5.   Cystic fibrosis
6.   Chronic biliary tract infection, parasite infections
7.   Increasing age
8.   Ileal disease, ileal resection or bypass
Symptoms of Gallstone Disease
Gallstones usually produce symptoms by causing inflammation or obstruction following their migration into the cystic duct or bile ducts.
The most specific and characteristic symptom of gallstone disease is biliary colic. Visceral pain is characteristically a severe, steady ache or fullness in the epigastrium or right upper quadrant (RUQ) of the abdomen with frequent radiation to the interscapular area, right scapula, or shoulder. Biliary colic begins quite suddenly and may persist with severe intensity for 30 min to 5 h, subsiding gradually or rapidly. An episode of biliary pain persisting beyond 5 h shows the development of acute cholecystitis. Biliary colic may be precipitated by eating a fatty meal, by consumption of a large meal following a period of prolonged fasting, or by eating a normal meal; it is frequently nocturnal.
Nausea and vomiting frequently accompany episodes of biliary pain.
Fever or chills (rigors) with biliary pain usually imply a complication, i.e., cholecystitis, pancreatitis, or cholangitis.
Complaints of vague epigastric fullness, dyspepsia, eructation, or flatulence, especially following a fatty meal, should not be confused with biliary pain. Such symptoms are not specific for biliary calculi.
Ultrasonography of the gallbladder is very accurate in the identification of cholelithiasis. Stones as small as 2 mm in diameter may be confidently identified. Ultrasound can also be used to assess the emptying function of the gallbladder.
Oral cholecystography (OCG) is a useful procedure for the diagnosis of gallstones but has been changed to ultrasound. It may be used to assess the patency of the cystic duct and gallbladder emptying function. Further, OCG can also recognize and number of gallstones and determine whether they are calcified.
Radiopharmaceuticals  imagines have their greatest application in the diagnosis of acute cholecystitis.
TABLE 2 Diagnostic Evaluation of the Gallbladder

Diagnostic Advantages
Diagnostic Limitations

·       Rapid
·       Accurate identification of gallstones (>95%)
·       Simultaneous scanning of GB, liver, bile ducts, pancreas
·       “Real-time” scanning allows assessment of GB volume, contractility
·       Not limited by jaundice, pregnancy
·       May detect very small stones
·       Bowel gas
·       Massive obesity
·       Ascites
Procedure of choice for detection of stones

·       Accurate identification of cystic duct obstruction
·       Simultaneous assessment of bile ducts
·       Contraindicated in pregnancy
·       Serum bilirubin >103–205 µmol/L (6–12 mg/dL)
·       Cholecystogram of low resolution
·  Indicated for confirmation acute cholecystitis;
·  less sensitive in chronic cholecystitis;
·  useful in diagnosis of acalculous cholecystopathy.
·       Low cost
·       Readily available
·       Relatively low yield
·       Contraindicated in pregnancy
Pathognomonic findings in:
·       Calcified gallstones
·       Limey bile, porcelain GB
·       Emphysematous cholecystitis
·       Gallstone ileus

Largely replaced by GBUS
Surgical Therapy
In asymptomatic gallstone patients, the risk of developing symptoms or complications requiring surgery is quite small (in the range of 1 to 2% per year). Thus a recommendation for cholecystectomy in a patient with gallstones should probably be based on assessment of three factors: (1) the presence of symptoms that are frequent enough or severe enough to interfere with the patient's general routine; (2) the presence of a prior complication of gallstone disease, i.e., history of acute cholecystitis, pancreatitis, gallstone fistula, etc.; or (3) the presence of an underlying condition predisposing the patient to increased risk of gallstone complications (e.g., calcified or porcelain gallbladder and/or a previous attack of acute cholecystitis regardless of current symptomatic status). Patients with very large gallstones (>3 cm in diameter) and patients having gallstones in a congenitally anomalous gallbladder might also be considered for prophylactic cholecystectomy. Although young age is a worrisome factor in asymptomatic gallstone patients, few authorities would now recommend routine cholecystectomy in all young patients with silent stones.
Laparoscopic cholecystectomy is a minimal-access approach for the removal of the gallbladder together with its stones. Its advantages include a markedly shortened hospital stay as well as decreased cost, and it is the procedure of choice for most patients referred for elective cholecystectomy. Laparoscopic cholecystectomy has become the “gold standard” for treating symptomatic cholelithiasis.
Medical Therapy—Gallstone Dissolution
UDCA (Actigall, URSO 250, URSO, Ursofalk, ursodeoxycholic acid) decreases cholesterol saturation of bile and also help to dispersion of cholesterol from stones. UDCA may also retard cholesterol crystal nucleation. In carefully selected patients with a functioning gallbladder and with stones <10 mm in diameter, complete dissolution can be achieved in about 50% of patients within 6 months to 2 years with UDCA at a dose of 8 to 10 mg/kg per day. The highest success rate (i.e., >70%) occurs in patients with small (<5 mm) floating radiolucent gallstones. Probably no more than 10% of patients with symptomatic cholelithiasis are candidates for such treatment.
Gallbladder stones may be fragmented by extracorporeal shock waves. While such shock wave lithotripsy combined with medical litholytic therapy is safe and effective in carefully selected patients with gallbladder calculi (radiolucent, solitary stone <2 cm in well-contracting gallbladder. The recurrence of gallstones is 30% of patients within 5 years after lithotripsy combined with medical litholytic therapy.

Acute inflammation of the gallbladder wall usually follows obstruction of the cystic duct by a stone. Inflammatory response can be evoked by three factors:
(1) mechanical inflammation produced by increased intraluminal pressure and distention with resulting ischemia of the gallbladder mucosa and wall,
(2) chemical inflammation caused by the release of lysolecithin (due to the action of phospholipase on lecithin in bile) and other local tissue factors,
(3) bacterial inflammation, which may play a role in 50 to 85% of patients with acute cholecystitis. The organisms most frequently isolated by culture of gallbladder bile in these patients include Escherichia coli, Klebsiella spp., Streptococcus spp., and Clostridium spp.
Acute cholecystitis often begins as an attack of biliary pain that progressively worsens. Approximately 60 to 70% of patients report having experienced prior attacks that resolved spontaneously. As the episode progresses, however, the pain of acute cholecystitis becomes more generalized in the right upper abdomen. As with biliary colic, the pain of cholecystitis may radiate to the interscapular area, right scapula, or shoulder. Peritoneal signs of inflammation such as increased pain with jarring or on deep respiration may be apparent. The patient is anorectic and often nauseated. Vomiting is relatively common and may produce symptoms and signs of vascular and extracellular volume depletion. Jaundice is unusual early in the course of acute cholecystitis but may occur when edematous inflammatory changes involve the bile ducts and surrounding lymph nodes. A low-grade fever is characteristically present, but shaking chills or rigors are not uncommon.
The right upper qudrant of the abdomen is almost invariably tender to palpation     (KERR’S SYMPTOM). An enlarged, tense gallbladder is palpable in one-quarter to one-half of patients. Deep inspiration or cough during subcostal palpation of the RUQ usually produces increased pain and inspiratory arrest (Murphy's sign). A light thump delivered to the right subcostal area may elicit a marked increase in pain (Orthner’s sign). Localized rebound tenderness in the RUQ is common, as are abdominal distention and hypoactive bowel sounds from paralytic ileus, but generalized peritoneal signs and abdominal rigidity are usually lacking, in the absence of perforation.
The diagnosis of acute cholecystitis is usually made on the basis of a characteristic history and physical examination. The triad of sudden onset of RUQ tenderness, fever, and leukocytosis is highly suggestive. The serum bilirubin is mildly elevated [<85.5 µmol/L (5 mg/dL)] in half of patients, while about one-fourth have modest elevations in serum aminotransferases (usually less than a fivefold elevation). The radionuclide (e.g., HIDA) biliary scan may be confirmatory if bile duct imaging is seen without visualization of the gallbladder. Ultrasound will demonstrate calculi in 90 to 95% of cases.
Outcomes. Approximately 75% of patients treated medically have remission of acute symptoms within 2 to 7 days following hospitalization. In 25%, however, a complication of acute cholecystitis will occur despite conservative. In this setting, prompt surgical intervention is required. Of the 75% of patients with acute cholecystitis who undergo remission of symptoms, approximately one-quarter will experience a recurrence of cholecystitis within 1 year, and 60% will have at least one recurrent bout within 6 years. In view of the natural history of the disease, acute cholecystitis is best treated by early surgery whenever possible.
Mirrizzi's syndrome is a rare complication in which a gallstone becomes impacted in the cystic duct or neck of the gallbladder causing compression of the CBD, resulting in CBD obstruction and jaundice. Ultrasound shows gallstone(s) lying outside the hepatic duct. Endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) will usually demonstrate the characteristic extrinsic compression of the CBD. Surgery consists of removing the cystic duct, diseased gallbladder, and the impacted stone. The preoperative diagnosis of Mirrizzi's syndrome is important to avoid CBD injury.

In 5 to 10% of patients with acute cholecystitis, calculi obstructing the cystic duct are not found at surgery. An increased risk for the development of acalculous cholecystitis is especially associated with serious trauma or burns, with the postpartum period following prolonged labor, and with orthopedic and other nonbiliary major surgical operations in the postoperative period. It may possibly complicate periods of prolonged parenteral hyperalimentation. For some of these cases, biliary sludge in the cystic duct may be responsible. Other precipitating factors include vasculitis, obstructing adenocarcinoma of the gallbladder, diabetes mellitus, torsion of the gallbladder, “unusual” bacterial infections of the gallbladder (e.g., Leptospira, Streptococcus, Salmonella, or Vibrio cholerae), and parasitic infestation of the gallbladder. Acalculous cholecystitis may also be seen with a variety of other systemic disease processes (sarcoidosis, cardiovascular disease, tuberculosis, syphilis, actinomycosis, etc.).
Although the clinical manifestations of acalculous cholecystitis are  the same as calculous cholecystitis, the setting of acute gallbladder inflammation complicating severe underlying illness is characteristic of acalculous disease. Ultrasound, computed tomography (CT) scanning, or radionuclide examinations demonstrating a large, tense, static gallbladder without stones and with evidence of poor emptying over a prolonged period may be diagnostically useful in some cases. The complication rate for acalculous cholecystitis exceeds that for calculous cholecystitis. Successful management of acute acalculous cholecystitis appears to depend primarily on early diagnosis and surgical intervention, with meticulous attention to postoperative care.

So-called emphysematous cholecystitis is thought to begin with acute cholecystitis (calculous or acalculous) followed by ischemia or gangrene of the gallbladder wall and infection by gas-producing organisms. Bacteria most frequently cultured in this setting include anaerobes, such as C. perfringens, and aerobes, such as E. coli. This condition occurs most frequently in elderly men and in patients with diabetes mellitus. The clinical manifestations are essentially undistinctive from those of nongaseous cholecystitis. The diagnosis is usually made on plain abdominal film by finding gas within the gallbladder lumen, dissecting within the gallbladder wall to form a gaseous ring, or in the pericholecystic tissues. The morbidity and mortality rates with emphysematous cholecystitis are considerable. Prompt surgical intervention coupled with appropriate antibiotics is necessary.

Chronic inflammation of the gallbladder wall is almost always associated with the presence of gallstones and is thought to result from repeated occurring of subacute or acute cholecystitis or from persistent mechanical irritation of the gallbladder wall by gallstones. The presence of bacteria in the bile occurs in more than one-quarter of patients with chronic cholecystitis. The presence of infected bile in a patient with chronic cholecystitis undergoing elective cholecystectomy probably adds little to the operative risk. Chronic cholecystitis may be asymptomatic for years, may progress to symptomatic gallbladder disease or to acute cholecystitis, or may present with complications.
Complications of Cholecystitis
Empyema of the gallbladder usually results from progression of acute cholecystitis with persistent cystic duct obstruction to superinfection of the stagnant bile with a pus-forming bacterial organism. The clinical picture resembles that of cholangitis with high fever, severe RUQ pain, marked leukocytosis, and often, prostration. Empyema of the gallbladder carries a high risk of gram-negative sepsis and/or perforation. Emergency surgical intervention with proper antibiotic coverage is required as soon as the diagnosis is suspected.
Hydrops or mucocele of the gallbladder may also result from prolonged obstruction of the cystic duct, usually by a large solitary calculus. In this instance, the obstructed gallbladder lumen is progressively distended, over a period of time, by mucus (mucocele) or by a clear transudate (hydrops) produced by mucosal epithelial cells. A visible, easily palpable, nontender mass sometimes extending from the RUQ into the right iliac fossa may be found on physical examination. The patient with hydrops of the gallbladder frequently remains asymptomatic, although chronic RUQ pain may also occur. Cholecystectomy is indicated, since empyema, perforation, or gangrene may complicate the condition.

Gangrene of the gallbladder results from ischemia of the wall and patchy or complete tissue necrosis. Underlying conditions often include marked distention of the gallbladder, vasculitis, diabetes mellitus, empyema, or torsion resulting in arterial occlusion. Gangrene usually predisposes to perforation of the gallbladder, but perforation may also occur in chronic cholecystitis without premonitory warning symptoms. Localized perforations are usually contained by the omentum or by adhesions produced by recurrent inflammation of the gallbladder. Bacterial superinfection of the walled-off gallbladder contents results in abscess formation. Most patients are best treated with cholecystectomy, but some seriously ill patients may be managed with cholecystostomy and drainage of the abscess. Free perforation is less common but is associated with a mortality rate of approximately 30%. Such patients may experience a sudden transient relief of RUQ pain as the distended gallbladder decompresses; this is followed by signs of generalized peritonitis.

Medical Therapy
Although surgical intervention remains the mainstay of therapy for acute cholecystitis and its complications, a period of in-hospital stabilization may be required before cholecystectomy.
Oral intake is eliminated, nasogastric suction may be indicated, and extracellular volume depletion and electrolyte abnormalities are repaired.
 Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually employed for analgesia because they may produce less spasm of the sphincter of Oddi than drugs such as morphine. Intravenous antibiotic therapy is usually indicated in patients with severe acute cholecystitis even though bacterial superinfection of bile may not have occurred in the early stages of the inflammatory process. Antibiotic therapy is guided by the most common organisms likely to be present, which are E. coli, Klebsiella spp., and Streptococcus spp. Effective antibiotics include ureidopenicillins such as piperacillin or mezlocillin, ampicillin sulbactam, and third-generation cephalosporins. Anaerobic coverage by a drug such as metronidazole should be added if gangrenous or emphysematous cholecystitis is suspected. Similarly, combination therapy with an aminoglycoside and other antibiotics may be considered in diabetic or debilitated patients and in those with signs of gram-negative sepsis. Postoperative complications of wound infection, abscess formation, or sepsis are reduced in antibiotic-treated patients.
Surgical Therapy
The optimal timing of surgical intervention in patients with acute cholecystitis depends on stabilization of the patient. The clear trend is toward earlier surgery, and this is due in part to requirements for shorter hospital stays. Urgent (emergency) cholecystectomy or cholecystostomy is probably appropriate in most patients in whom a complication of acute cholecystitis such as empyema, emphysematous cholecystitis, or perforation is suspected or confirmed. In uncomplicated cases of acute cholecystitis, up to 30% of patients fail to resolve their symptoms on appropriate medical therapy, and progression of the attack or a supervening complication leads to the performance of early operation (within 24 to 72 h). Delayed surgical intervention is probably best reserved for (1) patients with very high risk for early surgery and (2) patients in whom the diagnosis of acute cholecystitis is in doubt. Early cholecystectomy is the treatment of choice for most patients with acute cholecystitis. Mortality figures for emergency cholecystectomy in most centers approach 3%, while the mortality risk for elective or early cholecystectomy approximates 0.5% in patients under age 60. Of course, the operative risks increase with age-related diseases of other organ systems and with the presence of long- or short-term complications of gallbladder disease. Seriously ill or debilitated patients with cholecystitis may be managed with cholecystostomy and tube drainage of the gallbladder. Elective cholecystectomy may then be done at a later date.
Postcholecystectomy Complications
Early complications following cholecystectomy include atelectasis and other pulmonary disorders, abscess formation (often subphrenic), external or internal hemorrhage, biliary-enteric fistula, and bile leaks. Jaundice may indicate absorption of bile from an intraabdominal collection following a biliary leak or mechanical obstruction of the CBD by retained calculi, intraductal blood clots, or extrinsic compression. Routine performance of intraoperative cholangiography during cholecystectomy has helped to reduce the incidence of these early complications.
 In a small percentage of patients, however, a disorder of the extrahepatic bile ducts may result in persistent symptomatology. These so-called postcholecystectomy syndromes may be due to (1) biliary strictures, (2) retained biliary calculi, (3) cystic duct stump syndrome, (4) stenosis or dyskinesia of the sphincter of Oddi, or (5) bile salt–induced diarrhea or gastritis.
Cystic Duct Stump Syndrome
In the absence of cholangiographically demonstrable retained stones, symptoms resembling biliary pain or cholecystitis in the postcholecystectomy patient have frequently been attributed to disease in a long (>1 cm) cystic duct remain (cystic duct stump syndrome). Careful analysis, however, reveals that postcholecystectomy complaints are attributable to other causes in almost all patients in whom the symptom complex was originally thought to result from the existence of a long cystic duct stump. Accordingly, considerable care should be taken to investigate the possible role of other factors in the production of postcholecystectomy symptoms before attributing them to cystic duct stump syndrome.

TABLE 3 Diagnostic Evaluation of the Bile Ducts
Diagnostic Advantages
Diagnostic Limitations
·       Rapid
·       Simultaneous scanning of GB, liver, bile ducts, pancreas
·       Accurate identification of dilated bile ducts
·       Not limited by jaundice, pregnancy
·       Guidance for fine-needle biopsy
·       Bowel gas
·       Massive obesity
·       Ascites
·       Barium
·       Partial bile duct obstruction
·       Poor visualization of distal CBD
·       None
·       None
·       Initial procedure of choice in investigating possible biliary tract obstruction
·       Simultaneous scanning of GB, liver, bile ducts, pancreas
·       Accurate identification of dilated bile ducts, masses
·       Not limited by jaundice, gas, obesity, ascites
·       High-resolution image
·       Guidance for fine-needle biopsy
·       Extreme cachexia
·       Movement artifact
·       Ileus
·       Partial bile duct obstruction
·       Pregnancy
·       Reaction to iodinated contrast, if used
·       Indicated for evaluation of hepatic or pancreatic masses
·       Procedure of choice in investigating possible biliary obstruction if diagnostic limitations prevent HBUS
·            Useful modality for visualizing pancreatic and biliary ducts
·            Has excellent sensitivity for bile duct dilatation, biliary stricture, and intraductal abnormalities
·            Can identify pancreatic duct dilatation or stricture, pancreatic duct stenosis, and pancreas divisum
·            Cannot offer therapeutic intervention
·            High cost
·            Claustrophobia
·            Certain metals (iron)
·            None

·            Extremely successful when bile ducts dilated
·            Best visualization of proximal biliary tract
·            Bile cytology/culture
·            Percutaneous transhepatic drainage
·            Nondilated or sclerosed ducts
·            Pregnancy
·            Uncorrectable coagulopathy
·            Massive ascites
·            ?Hepatic abscess
·            Bleeding
·            Hemobilia
·            Bile peritonitis
·            Bacteremia, sepsis
·            Indicated when ERCP is contraindicated or failed
·       Simultaneous pancreatography
·       Best visualization of distal biliary tract
·       Bile or pancreatic cytology
·       Endoscopic sphincterotomy and stone removal
·       Biliary manometry
·       Gastroduodenal obstruction
·       ? Roux en Y biliary-enteric anastomosis
·       Pregnancy
·       ? Acute pancreatitis
·       ? Severe cardiopulmonary disease
·       Pancreatitis
·       Cholangitis, sepsis
·       Infected pancreatic pseudocyst
·       Perforation (rare)
·       Hypoxemia, aspiration
·       Cholangiogram of choice in:
·       Absence of dilated ducts
·       ? Pancreatic, ampullary or gastroduodenal disease
·       Prior biliary surgery
·       Endoscopic sphincterotomy a treatment possibility
·       Most sensitive method to detect ampullary stones
·       Can be used in pregnancy

Biliary Atresia and Hypoplasia
Atretic and hypoplastic lesions of the extrahepatic and major intrahepatic bile ducts are the most common biliary anomalies of clinical relevance encountered in infancy. The clinical picture is one of severe obstructive jaundice during the first month of life, with pale stools. When biliary atresia is suspected on the basis of clinical, laboratory, and imaging findings the diagnosis is confirmed by surgical exploration and operative cholangiography. The diagnosis is confirmed by surgical exploration with operative cholangiography. Approximately 10% of cases of biliary atresia are treatable with roux-en-Y choledochojejunostomy, with the Kasai procedure (hepatic portoenterostomy) being attempted in the remainder in an effort to restore some bile flow. Most patients, even those having successful biliary-enteric anastomoses, eventually develop chronic cholangitis, extensive hepatic fibrosis, and portal hypertension.
Choledochal Cysts
Cystic dilatation may involve the free portion of the CBD, i.e., choledochal cyst, or may present as diverticulum formation in the intraduodenal segment. In the latter situation, chronic reflux of pancreatic juice into the biliary tree can produce inflammation and stenosis of the extrahepatic bile ducts leading to cholangitis or biliary obstruction. Because the process may be gradual, approximately 50% of patients present with onset of symptoms after age 10. The diagnosis may be made by ultrasound, abdominal CT, MRC, or cholangiography. Only one-third of patients show the classic triad of abdominal pain, jaundice, and an abdominal mass. Surgical treatment involves excision of the “cyst” and biliary-enteric anastomosis. Patients with choledochal cysts are at increased risk for the subsequent development of cholangiocarcinoma.
Congenital Biliary Ectasia
Dilatation of intrahepatic bile ducts may involve either the major intrahepatic radicles (Caroli's disease), the inter- and intralobular ducts (congenital hepatic fibrosis), or both. In Caroli's disease, clinical manifestations include recurrent cholangitis, abscess formation in and around the affected ducts, and, often, gallstone formation within portions of ectatic intrahepatic biliary radicles. Ultrasound, MRC, and CT are of great diagnostic value in demonstrating cystic dilatation of the intrahepatic bile ducts. Treatment with ongoing antibiotic therapy is usually undertaken in an effort to limit the frequency and severity of recurrent bouts of cholangitis. Progression to secondary biliary cirrhosis with portal hypertension, extrahepatic biliary obstruction, cholangiocarcinoma, or recurrent episodes of sepsis with hepatic abscess formation is common.

Passage of gallstones into the CBD occurs in approximately 10 to 15% of patients with cholelithiasis. The incidence of common duct stones increases with increasing age of the patient, so that up to 25% of elderly patients may have calculi in the common duct at the time of cholecystectomy. Undetected duct stones are left behind in approximately 1 to 5% of cholecystectomy patients. The overwhelming majority of bile duct stones are cholesterol stones formed in the gallbladder, which then migrate into the extrahepatic biliary tree through the cystic duct. Primary calculi arising de novo in the ducts are usually pigment stones developing in patients with (1) hepatobiliary parasitism or chronic, recurrent cholangitis; (2) congenital anomalies of the bile ducts (especially Caroli's disease); (3) dilated, sclerosed, or strictured ducts; or (4) an MDR3 gene defect leading to impaired biliary phospholipids secretion. Common duct stones may remain asymptomatic for years, may pass spontaneously into the duodenum, or (most often) may present with biliary colic or a complication.
Cholangitis may be acute or chronic, and symptoms result from inflammation, which usually requires at least partial obstruction to the flow of bile. Bacteria are present on bile culture in approximately 75% of patients with acute cholangitis early in the symptomatic course. The characteristic presentation of acute cholangitis involves biliary pain, jaundice, and spiking fevers with chills (Charcot's triad). Blood cultures are frequently positive, and leukocytosis is typical. Nonsuppurative acute cholangitis is most common and may respond relatively rapidly to supportive measures and to treatment with antibiotics. In suppurative acute cholangitis, however, the presence of pus under pressure in a completely obstructed ductal system leads to symptoms of severe toxicity—mental confusion, bacteremia, and septic shock. Response to antibiotics alone in this setting is relatively poor, multiple hepatic abscesses are often present, and the mortality rate approaches 100% unless prompt endoscopic or surgical relief of the obstruction and drainage of infected bile are carried out. Endoscopic management of bacterial cholangitis is as effective as surgical intervention. ERCP with endoscopic sphincterotomy is safe and the preferred initial procedure for both establishing a definitive diagnosis and providing effective therapy.
Gradual obstruction of the CBD over a period of weeks or months usually leads to initial manifestations of jaundice or pruritus without associated symptoms of biliary colic or cholangitis. Painless jaundice may occur in patients with choledocholithiasis, but this manifestation is much more characteristic of biliary obstruction secondary to malignancy of the head of the pancreas, bile ducts, or ampulla of Vater.
In patients whose obstruction is secondary to choledocholithiasis, associated chronic calculous cholecystitis is very common, and the gallbladder in this setting may be relatively in distensible. The absence of a palpable gallbladder in most patients with biliary obstruction from duct stones is the basis for Courvoisier's law, i.e., that the presence of a palpably enlarged gallbladder suggests that the biliary obstruction is secondary to an underlying malignancy rather than to calculous disease. Biliary obstruction causes progressive dilatation of the intrahepatic bile ducts as intrabiliary pressures rise. Hepatic bile flow is suppressed, and reabsorption and regurgitation of conjugated bilirubin into the bloodstream lead to jaundice accompanied by dark urine (bilirubinuria) and light-colored (acholic) stools.
CBD stones should be suspected in any patient with cholecystitis whose serum bilirubin level exceeds 85.5 µmol/L (5 mg/dL). The maximum bilirubin level is seldom over 256.5 µmol/L (15.0 mg/dL) in patients with choledocholithiasis unless concomitant hepatic disease or another factor leading to marked hyperbilirubinemia exists. Serum bilirubin levels of 342.0 µmol/L (20 mg/dL) or more should suggest the possibility of neoplastic obstruction. The serum alkaline phosphatase level is almost always elevated in biliary obstruction. A rise in alkaline phosphatase often precedes clinical jaundice and may be the only abnormality in routine liver function tests. There may be a two- to tenfold elevation of serum aminotransferases, especially in association with acute obstruction. Following relief of the obstructing process, serum aminotransferase elevations usually return rapidly to normal, while the serum bilirubin level may take 1 to 2 weeks to return to normal. The alkaline phosphatase level usually falls slowly, lagging behind the decrease in serum bilirubin.

Symptoms of biliary colic accompanied by signs of recurrent, intermittent biliary obstruction may be produced by papillary stenosis, papillary dysfunction, spasm of the sphincter of Oddi, and biliary dyskinesia. Papillary stenosis is thought to result from acute or chronic inflammation of the papilla of Vater or from glandular hyperplasia of the papillary segment.
Five criteria have been used to define papillary stenosis:
 (1) upper abdominal pain, usually RUQ or epigastric;
(2) abnormal liver tests;
(3) dilatation of the common bile duct upon ERCP (ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAM) examination;
(4) delayed (>45 min) drainage of contrast material from the duct;
(5) increased basal pressure of the sphincter of Oddi, a finding that may be of only minor significance.
An alternative to ERCP is magnetic resonance cholangiography (MRC) if ERCP and/or biliary manometry are either unavailable or not feasible. In patients with papillary stenosis, quantitative hepatobiliary scintigraphy has revealed delayed transit from the common bile duct to the bowel, ductal dilatation, and abnormal time-activity dynamics. This technique can also be used before and after sphincterotomy to document improvement in biliary emptying. Treatment consists of endoscopic or surgical sphincteroplasty to ensure wide patency of the distal portions of both the bile and pancreatic ductsю
The factors usually considered as indications for sphincterotomy include
(1) prolonged duration of symptoms,
(2) lack of response to symptomatic treatment,
(3) presence of severe disability,
(4) the patient's choice of sphincterotomy over surgery (given a clear understanding on his or her part of the risks involved in both procedures).

Criteria for diagnosing dyskinesia of the sphincter of Oddi are even more controversial than those for papillary stenosis. Proposed mechanisms include spasm of the sphincter, denervation sensitivity resulting in hypertonicity, and abnormalities of the sequencing or frequency rates of sphincteric contraction waves. When thorough evaluation has failed to demonstrate another cause for the pain, and when cholangiographic and manometric criteria suggest a diagnosis of biliary dyskinesia, medical treatment with nitrites or anticholinergics to attempt pharmacologic relaxation of the sphincter has been proposed. Endoscopic biliary sphincterotomy (EBS) or surgical sphincteroplasty may be indicated in patients who fail to respond to a 2- to 3-month trial of medical therapy, especially if basal sphincter of Oddi pressures are elevated. EBS has become the procedure of choice for removing bile duct stones and for other biliary and pancreatic problems.

Primary biliary cirrhosis
PBC is a progressive cholestatic biliary disease that presents with fatigue and itching or asymptomatic elevation of the alkaline phosphatase. Jaundice develops with progressive destruction of bile ductules that eventually leads to liver cirrhosis and hepatic failure. This autoimmune illness has a familial predisposition, in which even unaffected family members may have immunologic abnormalities, especially an increased serum immunoglobulin M (IgM) and an association with human leucocyte antigen (HLA)-DR8.
While numerous autoantibodies have been identified, antimitochondrial antibodies (AMA) are present in 95% of patients. Circulating immune complexes also have been identified but are unlikely to play a pathogenic role. Circulating T lymphocyte levels initially are within the reference range and decline as the disease progresses. The histologic appearance of the bile duct destruction resembles hepatic allograft rejection and appears to be mediated by cytotoxic T lymphocytes.

Other Biliary Tract Diseases:
Autoimmune cholangitis represents a rare disease.
Neoplasms of the biliary tract: Carcinoma of the biliary system manifests with clinical symptoms of weight loss (77%), nausea (60%), anorexia (56%), abdominal pain (56%), fatigue (63%), pruritus (51%), fever (21%), malaise (19%), diarrhea (19%), constipation (16%), and abdominal fullness (16%). Symptomatic patients usually have advanced disease, with spread to hilar lymph nodes before obstructive jaundice occurs. It is associated with a poor prognosis.
  • Gallbladder cancer.
  • Cholangiocarcinoma is an adenocarcinoma of the bile ducts.
  • Ampullary cancer accounts for 8% of biliary tract cancers. It most commonly presents with painless jaundice or acute pancreatitis.
Biliary tract cysts: Cystic dilatation of the biliary tree is an uncommon abnormality. About half of the patients present with some combination of jaundice, abdominal pain, and an abdominal mass. The presence of these cysts often is associated with anomalous union of the pancreatic and biliary ductal system. This suggests that pancreatic juice enters the bile, causes a proteolytic and inflammatory injury to the duct wall, and leads to biliary cyst formation.
Approximately 95% of benign strictures of the extrahepatic bile ducts result from surgical trauma and occur in about 1 in 500 cholecystectomies. The diagnosis is established by percutaneous or endoscopic cholangiography. Endoscopic biopsy of biliary strictures may be helpful in establishing the nature of the lesion. When positive exfoliative cytology is obtained, the diagnosis of a neoplastic stricture is established. Successful operative correction of bile duct strictures with duct-to-bowel anastomosis is usually possible, although mortality rates from surgical complications, recurrent cholangitis, or secondary biliary cirrhosis are high.
Hemobilia may follow traumatic or operative injury to the liver or bile ducts, intraductal rupture of a hepatic abscess or aneurysm of the hepatic artery, biliary or hepatic tumor hemorrhage, or mechanical complications of choledocholithiasis or hepatobiliary parasitism. Diagnostic procedures such as liver biopsy, PTC, and transhepatic biliary drainage catheter placement may also be complicated by hemobilia. Patients often present with a classic triad of biliary pain, obstructive jaundice, and melena or occult blood in the stools. The diagnosis is sometimes made by cholangiographic evidence of blood clot in the biliary tree, but selective angiographic verification may be required. Although minor episodes of hemobilia may resolve without operative intervention, surgical ligation of the bleeding vessel is frequently required.
Infestation of the biliary tract by adult helminths or their ova may produce a chronic, recurrent pyogenic cholangitis with or without multiple hepatic abscesses, ductal stones, or biliary obstruction. This condition is relatively rare. The organisms most commonly involved are trematodes or flukes, including Clonorchis sinensis, Opisthorchis viverrini or O. felineus, and Fasciola hepatica. The biliary tract also may be involved by intraductal migration of adult Ascaris lumbricoides from the duodenum or by intrabiliary rupture of hydatid cysts of the liver produced by Echinococcus spp. The diagnosis is made by cholangiography and the presence of characteristic ova on stool examination. When obstruction is present, the treatment of choice is laparotomy under antibiotic coverage, with common duct exploration and a biliary drainage procedure.
Primary or idiopathic sclerosing cholangitis is characterized by a progressive, inflammatory, sclerosing, and obliterative process affecting the extrahepatic and/or the intrahepatic bile ducts. The disorder occurs in about 70% in association with inflammatory bowel disease, especially ulcerative colitis. It may also be associated (albeit rarely) with multifocal fibrosclerosis syndromes such as retroperitoneal, mediastinal, and/or periureteral fibrosis; Riedel's struma; or pseudotumor of the orbit.
Patients with primary sclerosing cholangitis often present with signs and symptoms of chronic or intermittent biliary obstruction: RUQ abdominal pain, pruritus, jaundice, or acute cholangitis. Late in the course, complete biliary obstruction, secondary biliary cirrhosis, hepatic failure, or portal hypertension with bleeding varices may occur. The diagnosis is usually established by cholangiography. When a diagnosis of sclerosing cholangitis has been established, a search for associated diseases, especially for chronic inflammatory bowel disease, should be carried out.
Secondary sclerosing cholangitis may occur as a long-term complication of choledocholithiasis, cholangiocarcinoma, operative or traumatic biliary injury, or contiguous inflammatory processes.
Therapy with cholestyramine may help control symptoms of pruritus, and antibiotics are useful when cholangitis complicates the clinical picture. Vitamin D and calcium supplementation may help prevent the loss of bone mass frequently seen in patients with chronic cholestasis. Glucocorticoids, methotrexate, and cyclosporine have not been shown to be efficacious in PSC. UDCA in high dosage (20 mg/kg) improves serum liver tests, but an effect on survival has not been documented. In cases where high-grade biliary obstruction (dominant strictures) has occurred, balloon dilatation or stenting may be appropriate. Only rarely is surgical intervention indicated. Efforts at biliary-enteric anastomosis or stent placement may, however, be complicated by recurrent cholangitis and further progression of the stenosing process. The prognosis is unfavorable. PSC is one of the most common indications for liver transplantation.

Jaundice can result from increased formation of bilirubin or hepatobiliary disease (hepatobiliary jaundice). Hepatobiliary jaundice can result from hepatocellular dysfunction or cholestasis. Cholestasis can be intrahepatic or extrahepatic.
Increased formation and hepatocellular diseases that impair liver uptake or decrease conjugation cause unconjugated hyperbilirubinemia. Impaired biliary excretion produces conjugated hyperbilirubinemia. Although these mechanisms seem distinct, in clinical practice, jaundice, particularly jaundice due to hepatobiliary disease, almost always produces multiple defects; the result is both unconjugated and conjugated hyperbilirubinemia (mixed hyperbilirubinemia).
Rarely, certain disorders produce predominantly unconjugated or conjugated hyperbilirubinemia. Unconjugated hyperbilirubinemia due to increased bilirubin formation can result from hemolytic disorders; those due to decreased conjugation can result from Gilbert syndrome (mild) and Crigler-Najjar syndrome (severe).
Conjugated hyperbilirubinemia due to impaired excretion can result from Dubin-Johnson syndrome. Conjugated hyperbilirubinemia due to intrahepatic cholestasis can result from hepatitis, drug toxicity, and alcoholic liver disease. Less common causes include primary biliary cirrhosis, cholestasis of pregnancy, and metastatic cancer. Conjugated hyperbilirubinemia due to extrahepatic cholestasis can result from a common bile duct stone or pancreatic cancer. Less common causes include benign stricture of the common duct (usually related to prior surgery), ductal carcinoma, pancreatitis or pancreatic pseudocyst, and sclerosing cholangitis.
Liver disease and biliary obstruction usually cause multiple defects, increasing both conjugated and unconjugated bilirubin.
Noncholestatic Conjugated Hyperbilirubinemia
Disorders of bilirubin metabolism causing conjugated hyperbilirubinemia without cholestasis produce no symptoms. Bilirubin may appear in the urine. Aminotransferase and alkaline phosphatase levels are usually normal. Treatment is unnecessary.
Dubin-Johnson syndrome: This rare autosomal recessive disorder involves impaired excretion of bilirubin glucuronides. It is usually diagnosed by liver biopsy.
Rotor's syndrome: This rare disorder is clinically similar to Dubin-Johnson syndrome, but the liver is not pigmented, and other subtle metabolic differences are present.
Unconjugated Hyperbilirubinemia
Unconjugated hyperbilirubinemia is a disorder of bilirubin metabolism consisting of overproduction or defective conjugation of bilirubin.
Hemolysis: RBC hemolysis is the most frequent clinically important cause of increased bilirubin formation. Although the normal liver can conjugate excess bilirubin, hemolysis may increase bilirubin to an unmanageable amount.
Gilbert syndrome: Gilbert syndrome is a presumably lifelong disorder whose only significant abnormality is asymptomatic, mild, unconjugated hyperbilirubinemia. It can be mistaken for chronic hepatitis or other liver disorders. Gilbert syndrome may affect as many as 5% of people. Although family members may be affected, a clear genetic pattern is difficult to establish.
Pathogenesis may involve complex defects in the liver's uptake of bilirubin. Glucuronyl transferase activity is low. Liver histology is normal.
Gilbert syndrome is most often detected in young adults by finding an elevated bilirubin level, which usually fluctuates between 2 and 5 mg/dL (34 and 86 μmol/L) and tends to increase with fasting and other stresses.
Gilbert syndrome is differentiated from hepatitis by especially increasing of unconjugated bilirubin, on the base of normal liver function test results, and absence of urinary bilirubin. It is differentiated from hemolysis by the absence of anemia and reticulocytosis. Treatment is unnecessary
Crigler-Najjar syndrome: This rare inherited disorder is caused by deficiency of the enzyme glucuronyl transferase.
Patients with autosomal recessive type I (complete) disease have severe hyperbilirubinemia. They usually die of kernicterus by age 1 yr but may survive into adulthood. "Kernicterus" refers to the neurologic consequences of the deposition of unconjugated bilirubin in brain tissue. Subsequent damage and scarring of the basal ganglia and brain-stem nuclei may occur. Treatment may include phototherapy and liver transplantation.
Patients with autosomal dominant type II (partial) disease (which has variable penetrance) often have less severe hyperbilirubinemia (< 20 mg/dL [< 342 μmol/L]) and usually live into adulthood without neurologic damage. Phenobarbital (LUMINAL)
1.5 to 2 mg/kg, which induces the partially deficient glucuronyl transferase, may be effective.

Primary shunt hyperbilirubinemia: This rare, familial, benign condition is associated with overproduction of early-labeled bilirubin.