Diseases of the Gallbladder and Bile
Physiology of Bile Production and Flow
Bile Secretion and Composition
Bile formed in the hepatic lobules is secreted into a complex network of canaliculi, small bile ductules, and larger bile ducts that run with lymphatics and branches of the portal vein and hepatic artery in portal tracts situated between hepatic lobules. These interlobular bile ducts coalesce to form larger septal bile ducts that join to form the right and left hepatic ducts, which in turn unite to form the common hepatic duct. The common hepatic duct is joined by the cystic duct of the gallbladder to form the common bile duct (CBD), which enters the duodenum (often after joining the main pancreatic duct) through the ampulla of Vater.
Hepatic bile is an isotonic fluid with an electrolyte composition resembling blood plasma. The electrolyte composition of gallbladder bile differs from that of hepatic bile because most of the inorganic anions, chloride and bicarbonate, have been removed by reabsorption across the gallbladder epithelium.
Major components of bile by weight include water (82%), bile acids (12%), lecithin and other phospholipids (4%), and unesterified cholesterol (0.7%). Other constituents include conjugated bilirubin, proteins (IgA, metabolites of hormones, and other proteins metabolized in the liver), electrolytes, mucus, and, often, drugs and their metabolites.
The total daily basal secretion of hepatic bile is approximately 500 to 600 mL. Many substances taken up or synthesized by the hepatocyte are secreted into the bile canalculi. The canalicular membrane forms microvilli and is associated with microfilaments of actin, microtubules, and other contractile elements. Prior to their secretion into the bile, many substances that are taken up into the hepatocyte are conjugated, while others such as phospholipids, a portion of primary bile acids, and some cholesterol are synthesized de novo in the hepatocyte. Three mechanisms are important in regulating bile flow: (1) active transport of bile acids from hepatocytes into the bile canaliculi, (2) active transport of other organic anions, and (3) cholangiocellular secretion. The last is a secretin-mediated and cyclic AMP-dependent mechanism that ultimately results in the secretion of a sodium- and bicarbonate-rich fluid into the bile ducts.
Active vectorial secretion of biliary constituents from the portal blood into the bile canaliculi is driven by a distinct set of polarized transport systems at the basolateral (sinusoidal) and the canalicular plasma membrane domains of the hepatocyte. Two sinusoidal bile salt uptake systems have been cloned in humans, the Na+/taurocholate cotransporter and the organic anion transporting protein, which also transports a large variety of non-bile salt organic anions. Four ATP-dependent canalicular transport systems ("export pumps") have been identified: a bile salt export pump (BSEP), which was formerly called "sister of P-glycoprotein"; a conjugate export pump (MRP2), also called the canalicular multispecific organic anion transporter, which mediates the canalicular excretion of various amphiphilic conjugates formed by phase II conjugation (e.g., bilirubin diglucuronide); a multidrug export pump (MDR1) for hydrophobic cationic compounds; and a phospholipid export pump (MDR3). The canalicular membrane also contains ATP-independent transport systems such as the Cl-/HCO3- anion exchanger isoform 2 for canalicular bicarbonate secretion. For some of these transporters, genetic defects have been identified that are associated with various forms of cholestasis or defects of biliary excretion. BSEP is defective in progressive familial intrahepatic cholestasis (PFIC) type 2. Mutations of MRP2 cause the Dubin-Johnson syndrome, an inherited form of conjugated hyperbilirubinemia. A defective MDR3 results in PFIC-3. The cystic fibrosis transmembrane regulator located on bile duct epithelial cells is defective in cystic fibrosis, which may be associated with impaired cholangiocellular bile formation and chronic cholestatic liver disease.
The Bile Acids
The primary bile acids, cholic acid and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver, conjugated with glycine or taurine, and excreted into the bile. Secondary bile acids, including deoxycholate and lithocholate, are formed in the colon as bacterial metabolites of the primary bile acids. However, lithocholic acid is much less efficiently absorbed from the colon than deoxycholic acid. Another secondary bile acid, found in low concentration is ursodeoxycholic acid (UDCA), a stereoisomer of CDCA. In normal bile, the ratio of glycine to taurine conjugates is about 3:1.
Bile acids are detergents that in aqueous solutions and above a critical concentration of about 2 mM form molecular aggregates called micelles. Cholesterol alone is poorly soluble in aqueous environments, and its solubility in bile depends on both the total lipid concentration and the relative molar percentages of bile acids and lecithin. Normal ratios of these constituents favor the formation of solubilizing mixed micelles, while abnormal ratios promote the precipitation of cholesterol crystals in bile.
In addition to facilitating the biliary excretion of cholesterol, bile acids are necessary for the normal intestinal absorption of dietary fats via a micellar transport mechanism (Chap. 286). Bile acids also serve as a major physiologic driving force for hepatic bile flow and aid in water and electrolyte transport in the small bowel and colon.
Bile acids are efficiently conserved under normal conditions. Unconjugated, and to a lesser degree also conjugated, bile acids are absorbed by passive diffusion along the entire gut. Quantitatively much more important for bile salt recirculation, however, is the active transport mechanism for conjugated bile acids in the distal ileum (Chap. 286). The reabsorbed bile acids enter the portal bloodstream and are taken up rapidly by hepatocytes, reconjugated, and resecreted into bile (enterohepatic circulation).
The normal bile acid pool size is approximately 2 to 4 g. During digestion of a meal, the bile acid pool undergoes at least one or more enterohepatic cycles, depending on the size and composition of the meal. Normally, the bile acid pool circulates approximately 5 to 10 times daily. Intestinal absorption of the pool is about 95% efficient, so fecal loss of bile acids is in the range of 0.3 to 0.6 g/d. This fecal loss is compensated by an equal daily synthesis of bile acids by the liver, and thus the size of the bile acid pool is maintained. Bile acids returning to the liver suppress de novo hepatic synthesis of primary bile acids from cholesterol by inhibiting the rate-limiting enzyme cholesterol 7-hydroxylase. While the loss of bile salts in stool is usually matched by increased hepatic synthesis, the maximum rate of synthesis is approximately 5 g/d, which may be insufficient to replete the bile acid pool size when there is pronounced impairment of intestinal bile salt reabsorption.
Gallbladder and Sphincteric Functions
In the fasting state, the sphincter of Oddi offers a high-pressure zone of resistance to bile flow from the common bile duct into the duodenum. This tonic contraction serves to (1) prevent reflux of duodenal contents into the pancreatic and bile ducts and (2) promote bile filling of the gallbladder. The major factor controlling the evacuation of the gallbladder is the peptide hormone cholecystokinin (CCK), which is released from the duodenal mucosa in response to the ingestion of fats and amino acids. CCK produces (1) powerful contraction of the gallbladder, (2) decreased resistance of the sphincter of Oddi, (3) increased hepatic secretion of bile, and thus (4) enhanced flow of biliary contents into the duodenum.
Hepatic bile is "concentrated" within the gallbladder by energy-dependent transmucosal absorption of water and electrolytes. Almost the entire bile acid pool may be sequestered in the gallbladder following an overnight fast for delivery into the duodenum with the first meal of the day. The normal capacity of the gallbladder is 30 to 50 mL of bile.
Diseases of the Gallbladder
Anomalies of the biliary tract may be found in 10 to 20% of the population, including abnormalities in number, size, and shape (e.g., agenesis of the gallbladder, duplications, rudimentary or oversized "giant" gallbladders, and diverticula). Phrygian cap is a clinically innocuous entity in which a partial or complete septum (or fold) separates the fundus from the body. Anomalies of position or suspension are not uncommon and include left-sided gallbladder, intrahepatic gallbladder, retrodisplacement of the gallbladder, and "floating" gallbladder. The latter condition predisposes to acute torsion, volvulus, or herniation of the gallbladder.
Gallstones are quite prevalent in most western countries. In the United States, autopsy series have shown gallstones in at least 20% of women and in 8% of men over the age of 40. It is estimated that 16 to 20 million persons in the United States have gallstones and that approximately 1 million new cases of cholelithiasis develop each year.
Gallstones are formed by concretion or accretion of normal or abnormal bile constituents. They are divided into three major types; cholesterol and mixed stones account for 80% of the total, with pigment stones comprising the remaining 20%. Mixed and cholesterol gallstones usually contain more than 50% cholesterol monohydrate plus an admixture of calcium salts, bile pigments, proteins, and fatty acids. Pigment stones are composed primarily of calcium bilirubinate; they contain less than 20% cholesterol.
Cholesterol and Mixed Stones and Biliary Sludge
Cholesterol is essentially water insoluble and requires aqueous dispersion into either micelles or vesicles, both of which require the presence of a second lipid to "liquefy" the cholesterol. Cholesterol and phospholipids are secreted into bile as unilamellar bilayered vesicles, which are converted into mixed micelles consisting of bile acids, phospholipids, and cholesterol by the action of bile acids. If there is an excess of cholesterol in relation to phospholipids and bile acids, unstable cholesterol-rich vesicles remain, which aggregate into large multilamellar vesicles from which cholesterol crystals precipitate (Fig. 302-1).
There are several important mechanisms in the formation of lithogenic (stone-forming) bile. The most important is increased biliary secretion of cholesterol. This may occur in association with obesity, high-caloric and cholesterol-rich diets, or drugs (e.g., clofibrate) and may result from increased activity of HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis, and increased hepatic uptake of cholesterol from blood. In patients with gallstones, dietary cholesterol increases biliary cholesterol secretion. This does not occur in non-gallstone patients on high-cholesterol diets. In addition to environmental factors such as high-caloric and cholesterol-rich diets, genetic factors play an important role in cholesterol hypersecretion and gallstone formation. A high prevalence of gallstones is found among first-degree relatives of gallstone carriers and in certain ethnic populations such as American Indians as well as Chilean Indians and Chilean Hispanics. A common genetic trait has been identified for some of these populations by mitochondrial DNA analysis. A genetic defect in the control of cholesterol secretion also exists in certain strains of inbred mice who develop gallstones under a lithogenic diet. In some patients, impaired hepatic conversion of cholesterol to bile acids may also occur, resulting in an increase of the lithogenic cholesterol/bile acid ratio. Lithogenic bile may also result from conditions affecting the enterohepatic circulation of bile acids (e.g., prolonged parenteral alimentation or ileal disease or resection). In addition, most patients with gallstones may have reduced activity of hepatic cholesterol 7-hydroxylase, the rate-limiting enzyme for primary bile acid synthesis.
Thus an excess of biliary cholesterol in relation to bile acids and phospholipids is primarily due to hypersecretion of cholesterol, but hyposecretion of bile acids may contribute. Two additional disturbances of bile acid metabolism that are likely to contribute to supersaturation of bile with cholesterol are (1) reduction of the bile acid pool and (2) enhanced conversion of cholic acid to deoxycholic acid, with replacement of the cholic acid pool by an expanded deoxycholic acid pool. The first disorder may be caused by more rapid loss of primary bile acid from the small intestine into the colon. The second disturbance may result from enhanced dehydroxylation of cholic acid and increased absorption of newly formed deoxycholic acid. An increased deoxycholate secretion is associated with hypersecretion of cholesterol into bile. While supersaturation of bile with cholesterol is an important prerequisite for gallstone formation, it is not sufficient by itself to produce cholesterol precipitation in vivo. Most people with supersaturated bile do not develop stones because the time required for cholesterol crystals to nucleate and grow is longer than the time bile spends in the gallbladder.
A second important mechanism is nucleation of cholesterol monohydrate crystals, which is greatly accelerated in human lithogenic bile; it is this feature rather than the degree of cholesterol supersaturation that distinguishes lithogenic from normal gallbladder bile. Accelerated nucleation of cholesterol monohydrate in bile may be due to either an excess of pronucleating factors or a deficiency of antinucleating factors. Mucin and certain non-mucin glycoproteins appear to be pronucleating factors, while apolipoproteins AI and AII and other glycoproteins appear to be antinucleating factors. Cholesterol monohydrate crystal nucleation and crystal growth probably occur within the mucin gel layer. Vesicle fusion leads to liquid crystals, which, in turn, nucleate into solid cholesterol monohydrate crystals. Continued growth of the crystals occurs by direct nucleation of cholesterol molecules from supersaturated unilamellar or multilamellar biliary vesicles.
A third important mechanism in cholesterol gallstone formation is gallbladder hypomotility. If the gallbladder emptied all supersaturated or crystal-containing bile completely, stones would not be able to grow. A high percentage of patients with gallstones exhibits abnormalities of gallbladder emptying. Ultrasonographic studies show that gallstone patients have an increased gallbladder volume during fasting and also after a test meal (residual volume) and that fractional emptying after gallbladder stimulation is decreased. Gallbladder emptying is a major determinant of gallstone recurrence in patients who underwent biliary lithotripsy. Within 3 years, only 13% of patients with good but 53% of patients with poor gallbladder emptying form recurrent stones.
Biliary sludge is a thick mucous material that upon microscopic examination reveals lecithin-cholesterol crystals, cholesterol monohydrate crystals, calcium bilirubinate, and mucin thread or mucous gels. Biliary sludge typically forms a crescent-like layer in the most dependent portion of the gallbladder and is recognized by characteristic echoes on ultrasonography (see below). The presence of biliary sludge implies two abnormalities: (1) the normal balance between gallbladder mucin secretion and elimination has become deranged and (2) nucleation of biliary solutes has occurred. That biliary sludge may be a precursor form of gallstone disease is evident from several observations. In one study, 96 patients with gallbladder sludge were followed prospectively by serial ultrasound studies. In 18%, biliary sludge disappeared and did not recur for at least 2 years. In 60%, biliary sludge disappeared and reappeared; in 14%, gallstones (8% asymptomatic, 6% symptomatic) developed, and in 6%, severe biliary pain with or without acute pancreatitis occurred. In 12 patients, cholecystectomies were performed, 6 for gallstone-associated biliary pain and 3 in symptomatic patients with sludge but without gallstones who had prior attacks of pancreatitis; the latter did not recur after cholecystectomy. It should be emphasized that biliary sludge can develop with disorders that cause gallbladder hypomotility, i.e., surgery, burns, total parenteral nutrition, pregnancy, and oral contraceptives-all of which are associated with gallstone formation.
Two other conditions are associated with cholesterol stone or biliary sludge formation: pregnancy and very low calorie diet. There appear to be two key changes during pregnancy that contribute to a "cholelithogenic state." First, the composition of the bile acid pool and the cholesterol-carrying capacity of bile change, with a resultant marked increase in cholesterol saturation during the third trimester. Second, ultrasonographic studies have demonstrated that gallbladder contraction in response to a standard meal is sluggish, resulting in impaired gallbladder emptying. That these changes are related to pregnancy per se is supported by several studies that show reversal of these abnormalities after delivery. During pregnancy, gallbladder sludge develops in 20 to 30% of women and gallstones in 5 to 12%. While biliary sludge is a common finding during pregnancy, it is usually asymptomatic and often resolves spontaneously after delivery. Gallstones, which are less common than sludge and frequently associated with biliary colic, may also disappear after delivery because of spontaneous dissolution related to bile becoming unsaturated with cholesterol post partum.
From 10 to 20% of people having rapid weight reduction through very low calorie dieting develop gallstones. In a study involving 600 patients who completed a 16-week, 520-kcal/d diet, UDCA in a dosage of 600 mg/d proved highly effective in preventing gallstone formation; gallstones developed in only 3% of UDCA recipients compared to 28% of placebo-treated patients.
To summarize, cholesterol gallstone disease occurs because of several defects, which include (1) bile supersaturation with cholesterol, (2) nucleation of cholesterol monohydrate with subsequent crystal retention and stone growth, and (3) abnormal gallbladder motor function with delayed emptying and stasis. Other important factors known to predispose to cholesterol stone formation are summarized in Table 302-1.
Gallstones composed largely of calcium bilirubinate are much more common in the Far East than in western countries. The presence of increased amounts of unconjugated, insoluble bilirubin in bile results in the precipitation of bilirubin, which may aggregate to form pigment stones or may form the nidus for growth of mixed cholesterol gallstones. In western countries, chronic hemolytic states (with increased conjugated bilirubin in bile) or alcoholic liver disease are associated with an increased incidence of pigment stones. Deconjugation of an excess of soluble bilirubin mono- and diglucuronide may be mediated by endogenous -glucuronidase but may also occur by spontaneous alkaline hydrolysis. Sometimes, the enzyme is also produced when bile is chronically infected by bacteria. Pigment stone formation is especially prominent in Asians and is often associated with infections in the biliary tree (Table 302-1).
Procedures of potential use in the diagnosis of cholelithiasis and other diseases of the gallbladder are detailed in Table 302-2. The plain abdominal film may detect gallstones containing sufficient calcium to be radiopaque (10 to 15% of cholesterol and mixed stones and approximately 50% of pigment stones). Plain radiography may also be of use in the diagnosis of emphysematous cholecystitis, porcelain gallbladder, limey bile, and gallstone ileus.
Ultrasonography of the gallbladder is very accurate in the identification of cholelithiasis and has several advantages over oral cholecystography (Fig. 302-2A). The gallbladder is easily visualized with the technique, and in fact, failure to image the gallbladder successfully in a fasting patient correlates well with the presence of underlying gallbladder disease. Stones as small as 2 mm in diameter may be confidently identified provided that firm criteria are used [e.g., acoustic "shadowing" of opacities that are within the gallbladder lumen and that change with the patient's position (by gravity)]. In major medical centers, the false-negative and false-positive rates for ultrasound in gallstone patients are about 2 to 4%. Biliary sludge is material of low echogenic activity that typically forms a layer in the most dependent position of the gallbladder. This layer shifts with postural changes but fails to produce acoustic shadowing; these two characteristics distinguish sludges from gallstones. 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 largely replaced by ultrasound. However, OCG is still useful for the selection of patients for nonsurgical therapy of gallstone disease such as lithotripsy or bile acid dissolution therapy. In both these settings, OCG is used to assess the patency of the cystic duct and gallbladder emptying function. Further, OCG can also delineate the size and number of gallstones and determine whether they are calcified. Factors that may produce nonvisualization of the OCG are summarized in Table 302-2.
Radiopharmaceuticals such as 99mTc-labeled N-substituted iminodiacetic acids (HIDA, DIDA, DISIDA, etc.) are rapidly extracted from the blood and are excreted into the biliary tree in high concentration even in the presence of mild to moderate serum bilirubin elevations. Failure to image the gallbladder in the presence of biliary ductal visualization may indicate cystic duct obstruction, acute or chronic cholecystitis, or surgical absence of the organ. Such scans have their greatest application in the diagnosis of acute cholecystitis.
Symptoms of Gallstone Disease
Gallstones usually produce symptoms by causing inflammation or obstruction following their migration into the cystic duct or CBD. The most specific and characteristic symptom of gallstone disease is biliary colic. Obstruction of the cystic duct or CBD by a stone produces increased intraluminal pressure and distention of the viscus that cannot be relieved by repetitive biliary contractions. The resultant visceral pain is characteristically a severe, steady ache or pressure 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 is sometimes followed by a residual mild ache or soreness in the RUQ, which may persist for 24 h or so. Nausea and vomiting frequently accompany episodes of biliary colic. An elevated level of serum bilirubin and/or alkaline phosphatase suggests a common duct stone. Fever or chills (rigors) with biliary colic 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 colic. Such symptoms are frequently elicited from patients with gallstone disease but are not specific for biliary calculi. 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.
Gallstone disease discovered in an asymptomatic patient or in a patient whose symptoms are not referable to cholelithiasis is a common clinical problem. The natural history of "silent" or asymptomatic gallstones has occasioned much debate. A study of predominantly male silent gallstone patients suggests that the cumulative risk for the development of symptoms or complications requiring surgery is relatively low-10% at 5 years, 15% at 10 years, and 18% at 15 years. Patients remaining asymptomatic for 15 years were found to be unlikely to develop symptoms during further follow-up, and most patients who did develop complications from their gallstones experienced prior warning symptoms. Similar conclusions apply to diabetic patients with silent gallstones. Decision analysis has suggested that (1) the cumulative risk of death due to gallstone disease while on expectant management is small, and (2) prophylactic cholecystectomy is not warranted.
Complications requiring cholecystectomy are much more common in gallstone patients who have developed symptoms of biliary colic. Patients found to have gallstones at a young age are more likely to develop symptoms from cholelithiasis than are patients older than 60 years at the time of initial diagnosis. Patients with diabetes mellitus and gallstones may be somewhat more susceptible to septic complications, but the magnitude of risk of septic biliary complications in diabetic patients is incompletely defined. In addition, asymptomatic gallstone patients with nonvisualization of the gallbladder on OCG appear to have an increased tendency to develop symptoms and complications.
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 (over 2 cm in diameter) and patients having gallstones in a congenitally anomalous gallbladder might also be considered for prophylactic cholecystectomy. Although age under 50 years 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.
From several studies involving over 4000 patients undergoing laparoscopic cholecystectomy, the following key points emerge: (1) complications develop in about 4% of patients, (2) conversion to laparotomy occurs in 5%, (3) the death rate is remarkably low (i.e., <0.1%), and (4) bile duct injuries are unusual (i.e., 0.2 to 0.5%). These data indicate why laparoscopic cholecystectomy has become the "gold standard" for treating symptomatic cholelithiasis.
Medical Therapy-Gallstone Dissolution
UDCA decreases cholesterol saturation of bile and also appears to produce a lamellar liquid crystalline phase in bile that allows a dispersion of cholesterol from stones by physiochemical means. UDCA may also retard cholesterol crystal nucleation. In carefully selected patients with a functioning gallbladder and with radiolucent 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. However, in addition to the vexing problem of recurrent stones (30 to 50% over 3 to 5 years of follow-up), there is also the factor of taking an expensive drug for an indefinite period of time. The advantages and success of laparoscopic cholecystectomy have largely reduced the role of gallstone dissolution to patients who wish to avoid or are not candidates for elective cholecystectomy.
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 procedure is employed infrequently because of the emergence of laparoscopic cholystectomy as the procedure of choice for symptomatic cholelithiasis, the recurrence of gallstones in 30% of patients within 5 years after lithotripsy combined with medical litholytic therapy, and the cost of taking UDCA for a variable period after the procedure.
Acute and Chronic Cholecystitis
Acute inflammation of the gallbladder wall usually follows obstruction of the cystic duct by a stone. Inflammatory response can be evoked by three factors: (1) mechanical inflammation produced by increased intraluminal pressure and distention with resulting ischemia of the gallbladder mucosa and wall, (2) chemical inflammation caused by the release of lysolecithin (due to the action of phospholipase on lecithin in bile) and other local tissue factors, and (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., group D Streptococcus, Staphylococcus spp., and Clostridium spp.
Acute cholecystitis often begins as an attack of biliary colic 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 RUQ of the abdomen is almost invariably tender to palpation. 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 blow delivered to the right subcostal area may elicit a marked increase in pain. 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, absent 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. Typically, leukocytosis in the range of 10,000 to 15,000 cells per microliter with a left shift on differential count is found. The serum bilirubin is mildly elevated [<85.5 mol/L (5 mg/dL)] in 45% of patients, while 25% 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.
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 treatment (see below). 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.
In 5 to 10% of patients with acute cholecystitis, calculi obstructing the cystic duct are not found at surgery. In over 50% of such cases, an underlying explanation for acalculous inflammation is not found. 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. 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.) and may possibly complicate periods of prolonged parenteral hyperalimentation.
Although the clinical manifestations of acalculous cholecystitis are indistinguishable from those of 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.
Disordered motility of the gallbladder can produce recurrent biliary pain in patients without gallstones. Infusion of an octapeptide of CCK can be used to measure the gallbladder ejection fraction during cholescintigraphy. In a representative study, CCK cholescintigraphy using 99mTc-diisopropyl iminodiacetic acid (DIDA) identified 21 patients with an abnormal gallbladder ejection fraction (<40% at 45 min); 10 of 11 patients who underwent surgery became asymptomatic; all 10 showed abnormalities, i.e., chronic cholecystitis, gallbladder muscle hypertrophy, and/or a markedly narrowed cystic duct. From this and other similar studies, the following criteria can be used to identify patients with acalculous cholecystopathy: (1) recurrent episodes of typical RUQ pain characteristic of biliary tract pain, (2) abnormal CCK cholescintigraphy demonstrating a gallbladder ejection fraction of less than 40%, and (3) infusion of CCK reproduces the patient's pain. An additional clue would be the identification of a large gallbladder on ultrasound examination. Finally, it should be noted that sphincter of Oddi dysfunction can also give rise to recurrent RUQ pain and CCK-scintigraphic abnormalities.
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. welchii or 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 indistinguishable from those of nongaseous cholecystitis. The diagnosis is usually made on plain abdominal film by the finding of 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 mandatory.
Chronic inflammation of the gallbladder wall is almost always associated with the presence of gallstones and is thought to result from repeated bouts of subacute or acute cholecystitis or from persistent mechanical irritation of the gallbladder wall. The presence of bacteria in the bile occurs in more than one-quarter of patients with chronic cholecystitis. Although the presence of infected bile in a patient with chronic cholecystitis undergoing elective cholecystectomy probably adds little to the operative risk, intraoperative Gram's staining and routine culturing of bile have been advocated to identify those patients whose gallbladder is colonized with Clostridium spp. Appropriate antibiotics intra- and postoperatively are recommended in such patients because colonization with these organisms may be associated with devastating septic complications following surgery. Chronic cholecystitis may be asymptomatic for years, may progress to symptomatic gallbladder disease or to acute cholecystitis, or may present with complications (see below).
Complications of Cholecystitis
Empyema and Hydrops
Empyema of the gallbladder usually results from progression of acute cholecystitis with persistent cystic duct obstruction to superinfection of the stagnant bile with a pus-forming bacterial organism. The clinical picture resembles that of cholangitis with high fever, severe RUQ pain, marked leukocytosis, and often, prostration. Empyema of the gallbladder carries a high risk of gram-negative sepsis and/or perforation. Emergency surgical intervention with proper antibiotic coverage is required as soon as the diagnosis is suspected.
Hydrops or mucocele of the gallbladder may also result from prolonged obstruction of the cystic duct, usually by a large solitary calculus. In this instance, the obstructed gallbladder lumen is progressively distended, over a period of time, by mucus (mucocele) or by a clear transudate (hydrops) produced by mucosal epithelial cells. A visible, easily palpable, nontender mass sometimes extending from the RUQ into the right iliac fossa may be found on physical examination. The patient with hydrops of the gallbladder frequently remains asymptomatic, although chronic RUQ pain may also occur. Cholecystectomy is indicated, since empyema, perforation, or gangrene may complicate the condition.
Gangrene and Perforation
Gangrene of the gallbladder results from ischemia of the wall and patchy or complete tissue necrosis. Underlying conditions often include marked distention of the gallbladder, vasculitis, diabetes mellitus, empyema, or torsion resulting in arterial occlusion. Gangrene usually predisposes to perforation of the gallbladder, but perforation may also occur in chronic cholecystitis without premonitory warning symptoms. Localized perforations are usually contained by the omentum or by adhesions produced by recurrent inflammation of the gallbladder. Bacterial superinfection of the walled-off gallbladder contents results in abscess formation. Most patients are best treated with cholecystectomy, but some seriously ill patients may be managed with cholecystostomy and drainage of the abscess. Free perforation is less common but is associated with a mortality rate of approximately 30%. Such patients may experience a sudden transient relief of RUQ pain as the distended gallbladder decompresses; this is followed by signs of generalized peritonitis.
Fistula Formation and Gallstone Ileus
Fistulization into an adjacent organ adherent to the gallbladder wall may result from inflammation and adhesion formation. Fistulas into the duodenum are most common, followed in frequency by those involving the hepatic flexure of the colon, stomach or jejunum, abdominal wall, and renal pelvis. Clinically "silent" biliary-enteric fistulas occurring as a complication of chronic cholecystitis have been found in up to 5% of patients undergoing cholecystectomy. Asymptomatic cholecystoenteric fistulas may sometimes be diagnosed by finding gas in the biliary tree on plain abdominal films. Barium contrast studies or endoscopy of the upper gastrointestinal tract or colon may demonstrate the fistula. Treatment in the symptomatic patient usually consists of cholecystectomy, CBD exploration, and closure of the fistulous tract.
Gallstone ileus refers to mechanical intestinal obstruction resulting from the passage of a large gallstone into the bowel lumen. The stone customarily enters the duodenum through a cholecystoenteric fistula at that level. The site of obstruction by the impacted gallstone is usually at the ileocecal valve, provided that the more proximal small bowel is of normal caliber. The majority of patients do not give a history of either prior biliary tract symptoms or complaints suggestive of acute cholecystitis or fistulization. Large stones over 2.5 cm in diameter are thought to predispose to fistula formation by gradual erosion through the gallbladder fundus. Diagnostic confirmation may occasionally be found on the plain abdominal film (e.g., small-intestinal obstruction with gas in the biliary tree and a calcified, ectopic gallstone) or following an upper gastrointestinal series (cholecystoduodenal fistula with small-bowel obstruction at the ileocecal valve). Laparotomy with stone extraction (or propulsion into the colon) remains the procedure of choice to relieve obstruction. Evacuation of large stones within the gallbladder should also be performed. In general, the gallbladder and its attachment to the intestines should be left alone.
Limey (Milk of Calcium) Bile and Porcelain Gallbladder
Calcium salts may be secreted into the lumen of the gallbladder in sufficient concentration to produce calcium precipitation and diffuse, hazy opacification of bile or a layering effect on plain abdominal roentgenography. This so-called limey bile, or milk of calcium bile, is usually clinically innocuous, but cholecystectomy is recommended because limey bile most often occurs in a hydropic gallbladder. In the entity called porcelain gallbladder, calcium salt deposition within the wall of a chronically inflamed gallbladder may be detected on the plain abdominal film. Cholecystectomy is advised in all patients with porcelain gallbladder because in a high percentage of cases this finding appears to be associated with the development of carcinoma of the gallbladder.
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. Meperidine or nonsteroidal antiinflammatory 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. Postoperative complications of wound infection, abscess formation, or sepsis are reduced in antibiotic-treated patients. Effective antibiotics include ureidopenicillins, ampicillin, metronidazole, and cephalosporins. Combination with an aminoglycoside or other antibiotics may be considered in diabetic or debilitated patients and in those with signs of gram-negative sepsis (Chap. 134).
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). The technical complications of surgery are not increased in patients undergoing early as opposed to delayed cholecystectomy. Delayed surgical intervention is probably best reserved for (1) patients in whom the overall medical condition imposes an unacceptable 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.
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.
Overall, cholecystectomy is a very successful operation that provides total or near-total relief of preoperative symptoms in 75 to 90% of patients. The most common cause of persistent postcholecystectomy symptoms is an overlooked extrabiliary disorder (e.g., reflux esophagitis, peptic ulceration, pancreatitis, or-most often-irritable bowel syndrome). 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 colic or cholecystitis in the postcholecystectomy patient have frequently been attributed to disease in a long (>1 cm) cystic duct remnant (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.
Papillary dysfunction, papillary stenosis, spasm of the sphincter of Oddi, and biliary dyskinesia
Symptoms of biliary colic accompanied by signs of recurrent, intermittent biliary obstruction may be produced by papillary stenosis, papillary dysfunction, spasm of the sphincter of Oddi, and biliary dyskinesia. Papillary stenosis is thought to result from acute or chronic inflammation of the papilla of Vater or from glandular hyperplasia of the papillary segment. Five criteria have been used to define papillary stenosis: (1) upper abdominal pain, usually RUQ or epigastric; (2) abnormal liver tests; (3) dilatation of the common bile duct upon endoscopic retrograde cholangiopancreatography (ERCP) examination; (4) delayed (>45 min) drainage of contrast material from the duct; and (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 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 ducts. The greater the number of the preceding criteria present, the greater the likelihood that a patient does have a degree of papillary stenosis sufficient to justify correction. 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, and (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 a well-established procedure for removing bile duct stones and for other biliary and pancreatic problems. Approximately 150,000 such procedures are performed annually in the United States. Key findings in a recent study of EBS include: (1) Dysfunction of the sphincter of Oddi was the most frequent patient-related risk factor for complications; (2) pancreatitis was more frequent in young patients; (3) difficulty in cannulating the bile duct and the use of "precut" sphincterotomy were important technique-related risk factors for complications; and (4) experience in the volume of procedures proved to be important; endoscopists who perform more than one EBS per week had lower complication rates than endoscopists who performed a smaller number of procedures.
Bile Salt-Induced Diarrhea and Gastritis
Postcholecystectomy patients may develop symptoms and signs of gastritis, which has been attributed to duodenogastric reflux of bile. However, firm data linking an increased incidence of bile gastritis with surgical removal of the gallbladder are lacking. Cholecystectomy induces persistent changes in gut transit, and these changes effect a noticeable modification of bowel habits. Cholecystectomy shortens gut transit time by accelerating passage of the fecal bolus through the colon with marked acceleration in the right colon, thus causing an increase in colonic bile acid output and a shift in bile acid composition toward the more diarrheagenic secondary bile acids. Diarrhea that is severe enough, i.e., three or more watery movements per day, can be classified as postcholecystectomy diarrhea, and this occurs in 8 to 12% of patients undergoing elective cholecystectomy. Treatment with a bile acid sequestering agent, such as cholestyramine, is often effective in ameliorating troublesome diarrhea.
The Hyperplastic Cholecystoses
The term hyperplastic cholecystoses is used to denote a group of disorders of the gallbladder characterized by excessive proliferation of normal tissue components.
Adenomyomatosis is characterized by a benign proliferation of gallbladder surface epithelium with glandlike formations, extramural sinuses, transverse strictures, and/or fundal nodule ("adenoma" or "adenomyoma") formation. Outpouchings of mucosa termed Rokitansky-Aschoff sinuses may be seen on oral cholecystography in conjunction with hyperconcentration of contrast medium. Characteristic dimpled filling defects also may be seen.
Cholesterolosis is characterized by abnormal deposition of lipid, especially cholesterol esters, in the lamina propria of the gallbladder wall. In its diffuse form ("strawberry gallbladder"), the gallbladder mucosa is brick red and speckled with bright yellow flecks of lipid. The localized form shows solitary or multiple "cholesterol polyps" studding the gallbladder wall. Cholesterol stones of the gallbladder are found in nearly half the cases. Cholecystectomy is indicated in both adenomyomatosis and cholesterolosis when symptomatic or when cholelithiasis is present.
Diseases of the Bile Ducts
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. 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.
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, or cholangiography. Only one-third of patients show the classic triad of abdominal pain, jaundice, and an abdominal mass. Ultrasonographic detection of a cyst separate from the gallbladder should suggest the diagnosis of choledochal cyst, which can be confirmed by demonstrating the entrance of extrahepatic bile ducts into the cyst. 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
Cystic dilatation of the 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, sometimes, gallstone formation within portions of ectatic intrahepatic biliary radicles. The CT scan and cholangiographic patterns are usually diagnostic, and 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, amyloidosis, extrahepatic biliary obstruction, cholangiocarcinoma, or recurrent episodes of sepsis with hepatic abscess formation is common.
Pathophysiology and Clinical Manifestations
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 or mixed 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) chronic hemolytic diseases; (2) hepatobiliary parasitism or chronic, recurrent cholangitis; (3) congenital anomalies of the bile ducts (especially Caroli's disease); or (4) dilated, sclerosed, or strictured ducts. 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 colic, 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 indistensible. 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 regurgitation of conjugated bilirubin into the bloodstream leads 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 mol/L (5 mg/dL). The maximum bilirubin level is seldom over 256.5 mol/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 mol/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.
The most common associated entity discovered in patients with nonalcoholic acute pancreatitis is biliary tract disease. Biochemical evidence of pancreatic inflammation complicates acute cholecystitis in 15% of cases and choledocholithiasis in over 30%, and the common factor appears to be the passage of gallstones through the common duct. Coexisting pancreatitis should be suspected in patients with symptoms of cholecystitis who develop (1) back pain or pain to the left of the abdominal midline, (2) prolonged vomiting with paralytic ileus, or (3) a pleural effusion, especially on the left side. Surgical treatment of gallstone disease is usually associated with resolution of the pancreatitis.
Secondary Biliary Cirrhosis
Secondary biliary cirrhosis may complicate prolonged or intermittent duct obstruction with or without recurrent cholangitis. Although this complication may be seen in patients with choledocholithiasis, it is more common in cases of prolonged obstruction from stricture or neoplasm. Once established, secondary biliary cirrhosis may be progressive even after correction of the obstructing process, and increasingly severe hepatic cirrhosis may lead to portal hypertension or to hepatic failure and death. Prolonged biliary obstruction may also be associated with clinically relevant deficiencies of the fat-soluble vitamins A, D, and K.
Diagnosis and Treatment
The diagnosis of choledocholithiasis is usually made by cholangiography (Table 302-3), either preoperatively by ERCP or intraoperatively at the time of cholecystectomy. As many as 15% of patients undergoing cholecystectomy will prove to have CBD stones. With the advent of laparoscopic cholecystectomy, the management of CBD stones in the presence of gallstones is gradually being clarified. Preoperative ERCP with endoscopic papillotomy and stone extraction is the preferred approach. It not only provides stone clearance but also defines the anatomy of the biliary tree in relationship to the cystic duct. ERCP is indicated in gallstone patients who have any of the following risk factors: (1) a history of jaundice or pancreatitis, (2) abnormal tests of liver function, and (3) ultrasonographic evidence of a dilated CBD or stones in the duct. Alternatively, if intraoperative cholangiography reveals retained stones, postoperative ERCP can be carried out. The need for preoperative ERCP is expected to decrease further as laparoscopic techniques improve.
The widespread use of laparoscopic cholecystectomy and ERCP has decreased the incidence of complicated biliary tract disease and the need for choledocholithotomy and T-tube drainage of the bile ducts. EBS followed by spontaneous passage or stone extraction is the treatment of choice in the management of patients with common duct stones, especially in elderly or poor-risk patients.
Trauma, Strictures, and Hemobilia
Benign strictures of the extrahepatic bile ducts result from surgical trauma in approximately 95% of cases and occur in about 1 in 500 cholecystectomies. Strictures may present with bile leak or abscess formation in the immediate postoperative period or with biliary obstruction or cholangitis as long as 2 years or more following the inciting trauma. The diagnosis is established by percutaneous or endoscopic cholangiography. Endoscopic brushing of biliary strictures is an effective way to establish the nature of the lesion and is more accurate than bile cytology alone. When positive exfoliative cytology is obtained, the diagnosis of a neoplastic stricture is established. This procedure is especially important in patients with primary sclerosing cholangitis who are predisposed to the development of cholangiocarcinomas. Successful operative correction by a skillful surgeon 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, percutaneous transhepatic cholangiography (PTHC), and transhepatic biliary drainage catheter placement may also be complicated by hemobilia. Patients often present with a classic triad of biliary colic, 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.
Extrinsic Compression of the Bile Ducts
Partial or complete biliary obstruction may sometimes be produced by extrinsic compression of the ducts. The most common cause of this form of obstructive jaundice is carcinoma of the head of the pancreas. Biliary obstruction may also occur as a complication of either acute or chronic pancreatitis or involvement of lymph nodes in the porta hepatis by lymphoma or metastatic carcinoma. The latter should be distinguished from cholestasis resulting from massive replacement of the liver by tumor.
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 but does occur in inhabitants of southern China and elsewhere in Southeast Asia. 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. It should be emphasized that in the Far East, one also sees cholangiohepatitis associated with pigment lithiasis, which may, in fact, be more common than cholangitis due to parasites.
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. In patients with AIDS, cholangiopancreatography may demonstrate a broad range of biliary tract changes as well as pancreatic duct obstruction and occasionally pancreatitis (Chap. 309). Further, biliary tract lesions in AIDS include infection and cholangiopancreatographic changes similar to primary sclerosing cholangitis. Changes noted include: (1) diffuse involvement of intrahepatic bile ducts alone, (2) involvement of both intra- and extrahepatic bile ducts, (3) ampullary stenosis, (4) stricture of the intrapancreatic portion of the common bile duct, and (5) pancreatic duct involvement. Associated infectious organisms include Cryptosporidium, Mycobacterium avium-intracellulare, cytomegalovirus, Microsporidia, and Isospora. In addition, acalculous cholecystitis occurs in up to 10% of patients. ERCP sphincterotomy, while not without risk, provides significant pain reduction in patients with AIDS-associated papillary stenosis. Secondary sclerosing cholangitis may occur as a long-term complication of choledocholithiasis, cholangiocarcinoma, operative or traumatic biliary injury, or contiguous inflammatory processes.
Patients with primary sclerosing cholangitis often present with signs and symptoms of chronic or intermittent biliary obstruction: jaundice, pruritus, RUQ abdominal pain, 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 finding multifocal, diffusely distributed strictures with intervening segments of normal or dilated ducts, producing a beaded appearance on cholangiography (Fig. 302-2D). The cholangiographic technique of choice in suspected cases is ERCP, since intrahepatic ductal involvement may make PTHC difficult. When a diagnosis of sclerosing cholangitis has been established, a search for associated diseases, especially for chronic inflammatory bowel disease, should be carried out.
A recent study describes the natural history and outcome for 305 patients of Swedish descent with primary sclerosing cholangitis; 134 (44%) of the patients were asymptomatic at the time of diagnosis and, not surprisingly, had a significantly higher survival rate with a median follow-up time of 63 months. The independent predictors of a bad prognosis were age, serum bilirubin concentration, and liver histologic changes. Cholangiocarcinoma was found in 24 patients (8%). Inflammatory bowel disease was closely associated with primary sclerosing cholangitis and had a prevalence of 81% in this study population.
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. UDCA improves serum liver tests, but an effect on survival has not been documented. In cases where complete or high-grade biliary obstruction (dominant strictures) has occurred, balloon dilatation, stenting, or (rarely) surgical intervention may be appropriate. Efforts at biliary-enteric anastomosis or stent placement may, however, be complicated by recurrent cholangitis and further progression of the stenosing process. The role of colectomy in patients with sclerosing cholangitis complicating chronic ulcerative colitis is uncertain. The prognosis is unfavorable, with a median survival of 9 to 12 years following the diagnosis, regardless of therapy. Four variables (age, serum bilirubin level, histologic stage, and splenomegaly) predict survival in patients with primary sclerosing cholangitis and serve as the basis for a risk score. Primary sclerosing cholangitis is one of the most common indications for liver transplantation.
In two large studies involving 627 and 3147 patients, the prevalence of gallbladder polyps was 6.7 and 6.9%, respectively, with a marked male predominance. Few significant changes occurred over a 5-year period in asymptomatic patients in whom gallbladder polyps <10 mm in diameter were found. If polyps >10 mm are present and show rapid growth, cholecystectomy should be considered.