369 |
Diseases of the Gallbladder and Bile Ducts |
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. As a result of water reabsorption, total solute concentration of bile increases from 3–4 g/dL in hepatic bile to 10–15 g/dL in gallbladder bile.
Major solute components of bile by moles percent include bile acids (80%), lecithin and traces of other phospholipids (16%), and unesterified cholesterol (4.0%). In the lithogenic state, the cholesterol value can be as high as 8–10%. Other constituents include conjugated bilirubin; proteins (all immunoglobulins, albumin, 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 ~500–600 mL. Many substances taken up or synthesized by the hepatocyte are secreted into the bile canaliculi. 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 are taken up into the hepatocyte, 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 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 set of polarized transport systems at the basolateral (sinusoidal) and the canalicular apical plasma membrane domains of the hepatocyte. Two sinusoidal bile salt uptake systems have been cloned in humans, the Na+/taurocholate cotransporter (NTCP, SLC10A1) and the organic anion–transporting proteins (OATPs), which also transport a large variety of non-bile salt organic anions. Several ATP-dependent canalicular transport systems, “export pumps,” (ATP-binding cassette transport proteins, also known as ABC transporters) have been identified, the most important of which are: the bile salt export pump (BSEP, ABCB11); the anionic conjugate export pump (MRP2, ABCC2), which mediates the canalicular excretion of various amphiphilic conjugates formed by phase II conjugation (e.g., bilirubin mono- and diglucuronides and drugs); the multidrug export pump (MDR1, ABCB1) for hydrophobic cationic compounds; and the phospholipid export pump (MDR3, ABCB4). Two hemitransporters ABCG5/G8, functioning as a couple, constitute the canalicular cholesterol and phytosterol transporter. F1C1 (ATP8B1) is an aminophospholipid transferase (“flippase”) essential for maintaining the lipid asymmetry of the canalicular membrane. The canalicular membrane also contains ATP-independent transport systems such as the Cl/HCO3 anion exchanger isoform 2 (AE2, SLC4A2) for canalicular bicarbonate secretion. For most of these transporters, genetic defects have been identified that are associated with various forms of cholestasis or defects of biliary excretion. F1C1 is defective in progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) and results in ablation of all other ATP-dependent transporter functions. BSEP is defective in PFIC2 and BRIC2. Mutations of MRP2 (ABCC2) cause the Dubin-Johnson syndrome, an inherited form of conjugated hyperbilirubinemia (Chap. 359). A defective MDR3 (ABCB4) results in PFIC3. ABCG5/G8, the canalicular half transporters for cholesterol and other neutral sterols, are defective in sitosterolemia. The cystic fibrosis transmembrane regulator (CFTR, ABCC7) located on bile duct epithelial cells but not on canalicular membranes is defective in cystic fibrosis, which is associated with impaired cholangiocellular pH regulation during ductular bile formation and chronic cholestatic liver disease, occasionally resulting in biliary cirrhosis.
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 secreted 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 healthy subjects, the ratio of glycine to taurine conjugates in bile is ~3:1.
Bile acids are detergent-like molecules that in aqueous solutions and above a critical concentration of about 2 mM form molecular aggregates called micelles. Cholesterol alone is sparingly 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 via an intermediate liquid crystal phase.
In addition to facilitating the biliary excretion of cholesterol, bile acids facilitate the normal intestinal absorption of dietary fats, mainly cholesterol and fat-soluble vitamins, via a micellar transport mechanism (Chap. 349). 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.
ENTEROHEPATIC CIRCULATION
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. 349). 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 2–4 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 ~5–10 times daily. Intestinal reabsorption of the pool is about 95% efficient; therefore, fecal loss of bile acids is in the range of 0.2–0.4 g/d. In the steady state, 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 in the intestine release fibroblast growth factor 19 (FGF19) into the circulation, which is transported to the liver where it suppresses synthesis of bile acids from cholesterol by inhibiting the rate-limiting enzyme cytochrome P450 7A1 (CYP7A1) and also promotes gallbladder relaxation. While the loss of bile salts in stool is usually matched by increased hepatic synthesis, the maximum rate of synthesis is ~5 g/d, which may be insufficient to replete the bile acid pool size when there is pronounced impairment of intestinal bile salt reabsorption.
The expression of ABC transporters in the enterohepatic circulation and of the rate-limiting enzymes of bile acid and cholesterol synthesis are regulated in a coordinated fashion by nuclear receptors, which are ligand-activated transcription factors. The hepatic BSEP (ABCB11) is upregulated by the farnesoid × receptor (FXR), a bile acid sensor that also represses bile acid synthesis. The expression of the cholesterol transporter, ABCG5/G8, is upregulated by the liver × receptor (LXR), which is an oxysterol sensor.
GALLBLADDER AND SPHINCTERIC FUNCTIONS
In the fasting state, the sphincter of Oddi offers a high-pressure zone of resistance to bile flow from the CBD into the duodenum. Its tonic contraction serves to (1) prevent reflux of duodenal contents into the pancreatic and bile ducts and (2) promote 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, and (3) 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 mL of bile.
DISEASES OF THE GALLBLADDER
CONGENITAL ANOMALIES
Anomalies of the biliary tract are not uncommon and include 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
Epidemiology and Pathogenesis Gallstones are quite prevalent in most Western countries. Gallstone formation increases after age 50. In the United States, the third National Health and Nutrition Examination Survey (NHANES III) has revealed an overall prevalence of gallstones of 7.9% in men and 16.6% in women. The prevalence was high in Mexican Americans (8.9% in men, 26.7% in women), intermediate for non-Hispanic whites (8.6% in men, 16.6% in women), and low for African Americans (5.3% in men, 13.9% in women).
Gallstones are formed because of abnormal bile composition. They are divided into two major types: cholesterol stones and pigment stones. Cholesterol stones account for more than 90% of all gallstones in Western industrialized countries. Cholesterol gallstones usually contain >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 <20% cholesterol and are classified into “black” and “brown” types, the latter forming secondary to chronic biliary infection.
CHOLESTEROL 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 solubilize 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. 369-1).
FIGURE 369-1 Scheme showing pathogenesis of cholesterol gallstone formation. Conditions or factors that increase the ratio of cholesterol to bile acids and phospholipids (lecithin) favor gallstone formation. ABCB4, ATP-binding cassette transporter; ABCG5/8, ATP-binding cassette (ABC) transporter G5/G8; CYP7A1, cytochrome P450 7A1; MDR3, multidrug resistance protein 3, also called phospholipid export pump.
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, the metabolic syndrome, high-caloric and cholesterol-rich diets, or drugs (e.g., clofibrate) and may result from increased activity of hydroxymethylglutaryl-coenzyme A (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 gallstone disease. A large study of symptomatic gallstones in Swedish twins provided strong evidence for a role of genetic factors in gallstone pathogenesis. Genetic factors accounted for 25%, shared environmental factors for 13%, and individual environmental factors for 62% of the phenotypic variation among monozygotic twins. A single nucleotide polymorphism of the gene encoding the hepatic cholesterol transporter ABCG5/G8 has been found in 21% of patients with gallstones, but only in 9% of the general population. It is thought to cause a gain of function of the cholesterol transporter and to contribute to cholesterol hypersecretion. A high prevalence of gallstones is found among first-degree relatives of gallstone carriers and in certain ethnic populations such as American Indians, Chilean Indians, and Chilean Hispanics. A common genetic trait has been identified for some of these populations by mitochondrial DNA analysis. 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. Although most cholesterol stones have a polygenic basis, there are rare monogenic (Mendelian) causes. Recently, a mutation in the CYP7A1 gene has been described that results in a deficiency of the enzyme cholesterol 7-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. The homozygous state is associated with hypercholesterolemia and gallstones. Because the phenotype is expressed in the heterozygote state, mutations in the CYP7A1 gene may contribute to the susceptibility to cholesterol gallstone disease in the population. Mutations in the MDR3 (ABCB4) gene, which encodes the phospholipid export pump in the canalicular membrane of the hepatocyte, may cause defective phospholipid secretion into bile, resulting in cholesterol supersaturation of bile and formation of cholesterol gallstones in the gallbladder and in the bile ducts. 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 or phospholipids may contribute. An additional disturbance of bile acid metabolism that is likely to contribute to supersaturation of bile with cholesterol is enhanced conversion of cholic acid to deoxycholic acid, with replacement of the cholic acid pool by an expanded deoxycholic acid pool. It 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 generally not sufficient by itself to produce cholesterol precipitation in vivo. Most individuals with supersaturated bile do not develop stones because the time required for cholesterol crystals to nucleate and grow is longer than the time bile remains in the gallbladder.
An important mechanism is nucleation of cholesterol monohydrate crystals, which is greatly accelerated in human lithogenic 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 nonmucin glycoproteins, principally immunoglobulins, appear to be pronucleating factors, while apolipoproteins A-I and A-II and other glycoproteins appear to be antinucleating factors. Pigment particles may possibly play a role as nucleating factors. In a genome-wide analysis of serum bilirubin levels, the uridine diphosphate-glucuronyltransferase 1A1 (UGT1A1) Gilbert’s syndrome gene variant was associated with the presence of gallstone disease. Because most gallstones associated with the UGT1A1 variant were cholesterol stones, this finding points to the role of pigment particles in the pathogenesis of gallbladder stones. 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 exhibit abnormalities of gallbladder emptying. Ultrasonographic studies show that gallstone patients display an increased gallbladder volume during fasting and also after a test meal (residual volume) and that fractional emptying after gallbladder stimulation is decreased. The incidence of gallstones is increased in conditions associated with infrequent or impaired gallbladder emptying such as fasting, parenteral nutrition, or pregnancy and in patients using drugs that inhibit gallbladder motility.
Biliary sludge is a thick, mucous material that, upon microscopic examination, reveals lecithin-cholesterol liquid crystals, cholesterol monohydrate crystals, calcium bilirubinate, and mucin 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. However, the presence of biliary sludge implies supersaturation of bile with either cholesterol or calcium bilirubinate.
Two other conditions are associated with cholesterol-stone or biliary-sludge formation: pregnancy and rapid weight reduction through a very-low-calorie diet. There appear to be two key changes during pregnancy that contribute to a “cholelithogenic state”: (1) a marked increase in cholesterol saturation of bile during the third trimester and (2) sluggish gallbladder contraction in response to a standard meal, 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 quite rapidly after delivery. During pregnancy, gallbladder sludge develops in 20–30% of women and gallstones in 5–12%. Although 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 postpartum.
Approximately 10–20% of persons with rapid weight reduction achieved through very-low-calorie dieting develop gallstones. In a study involving 600 patients who completed a 3-month, 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. In obese patients treated by gastric banding, 500 mg/d of UDCA reduced the risk of gallstone formation from 30% to 8% within a follow-up of 6 months.
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 369-1.
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PREDISPOSING FACTORS FOR CHOLESTEROL AND PIGMENT GALLSTONE FORMATION |
PIGMENT STONES Black pigment stones are composed of either pure calcium bilirubinate or polymer-like complexes with calcium and mucin glycoproteins. They are more common in patients who have chronic hemolytic states (with increased conjugated bilirubin in bile), liver cirrhosis, Gilbert’s syndrome, or cystic fibrosis. Gallbladder stones in patients with ileal diseases, ileal resection, or ileal bypass generally are also black pigment stones. Enterohepatic recycling of bilirubin in ileal disease states contributes to their pathogenesis. Brown pigment stones are composed of calcium salts of unconjugated bilirubin with varying amounts of cholesterol and protein. They are caused by the presence of increased amounts of unconjugated, insoluble bilirubin in bile that precipitates to form stones. Deconjugation of an excess of soluble bilirubin mono- and diglucuronides may be mediated by endogenous β-glucuronidase but may also occur by spontaneous hydrolysis. Sometimes, the enzyme is also produced when bile is chronically infected by bacteria, and such stones are brown. Pigment stone formation is frequent in Asia and is often associated with infections in the gallbladder and biliary tree (Table 369-1).
Diagnosis Procedures of potential use in the diagnosis of cholelithiasis and other diseases of the gallbladder are detailed in Table 369-2. Ultrasonography of the gallbladder is very accurate in the identification of cholelithiasis and has replaced oral cholecystography (Fig. 369-2A). Stones as small as 1.5 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 ~2–4%. 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.
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DIAGNOSTIC EVALUATION OF THE GALLBLADDER |
FIGURE 369-2 Examples of ultrasound and radiologic studies of the biliary tract. A. An ultrasound study showing a distended gallbladder (GB) containing a single large stone (arrow), which casts an acoustic shadow. B. Endoscopic retrograde cholangiopancreatogram (ERCP) showing normal biliary tract anatomy. In addition to the endoscope and large vertical gallbladder filled with contrast dye, the common hepatic duct (CHD), common bile duct (CBD), and pancreatic duct (PD) are shown. The arrow points to the ampulla of Vater. C. Endoscopic retrograde cholangiogram (ERC) showing choledocholithiasis. The biliary tract is dilated and contains multiple radiolucent calculi. D. ERCP showing sclerosing cholangitis. The common bile duct shows areas that are strictured and narrowed.
The plain abdominal film may detect gallstones containing sufficient calcium to be radiopaque (10–15% of cholesterol and ~50% of pigment stones). Plain radiography may also be of use in the diagnosis of emphysematous cholecystitis, porcelain gallbladder, limey bile, and gallstone ileus.
Oral cholecystography (OCG) has historically been a useful procedure for the diagnosis of gallstones but has been replaced by ultrasound and is regarded as obsolete. It may be 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.
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 some 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 that is a constant and often long-lasting pain (see below). 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 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. It is steady rather than intermittent, as would be suggested by the word colic, which must be regarded as a misnomer, although it is in widespread use. An episode of biliary pain persisting beyond 5 h should raise the suspicion of acute cholecystitis (see below). Nausea and vomiting frequently accompany episodes of biliary pain. An elevated level of serum bilirubin and/or alkaline phosphatase suggests a common duct stone. Fever or chills (rigors) with biliary pain usually imply a complication, i.e., cholecystitis, pancreatitis, or cholangitis. Complaints of short-lasting, vague epigastric fullness, dyspepsia, eructation, or flatulence, especially following a fatty meal, should not be confused with biliary pain. Such symptoms are frequently elicited from patients with or without 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; it is frequently nocturnal, occurring within a few hours of retiring.
Natural History Gallstone disease discovered in an asymptomatic patient or in a patient whose symptoms are not referable to cholelithiasis is a common clinical problem. Sixty to 80% of persons with asymptomatic gallstones remain asymptomatic over follow-up periods of up to 25 years. The probability of developing symptoms within 5 years after diagnosis is 2–4% per year and decreases in the years thereafter to 1–2%. The yearly incidence of complications is about 0.1–0.3%. 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 pain. Patients found to have gallstones at a young age are more likely to develop symptoms from cholelithiasis than are patients >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.
ACUTE AND CHRONIC CHOLECYSTITIS
Acute Cholecystitis Acute inflammation of the gallbladder wall usually follows obstruction of the cystic duct by a stone. Inflammatory response can be evoked by three factors: (1) mechanical inflammation produced by increased intraluminal pressure and distention with resulting ischemia of the gallbladder mucosa and wall, (2) chemical inflammation caused by the release of lysolecithin (due to the action of phospholipase on lecithin in bile) and other local tissue factors, and (3) bacterial inflammation, which may play a role in 50–85% 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 60–70% 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 25–50% of patients. Deep inspiration or cough during subcostal palpation of the RUQ usually produces increased pain and inspiratory arrest (Murphy’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. Typically, leukocytosis in the range of 10,000–15,000 cells per microliter with a left shift on differential count is found. The serum bilirubin is mildly elevated (<85.5 μmol/L [5 mg/dL]) in fewer than half of patients, whereas about one-fourth have modest elevations in serum aminotransferases (usually less than a fivefold elevation). Ultrasound will demonstrate calculi in 90–95% of cases and is useful for detection of signs of gallbladder inflammation including thickening of the wall, pericholecystic fluid, and dilatation of the bile duct. The radionuclide (e.g., HIDA) biliary scan may be confirmatory if bile duct imaging is seen without visualization of the gallbladder.
Approximately 75% of patients treated medically have remission of acute symptoms within 2–7 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, ~25% 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.
Mirizzi’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) (Fig. 369-2B), percutaneous transhepatic cholangiography (PTC), or magnetic resonance cholangiopancreatography (MRCP) 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 Mirizzi’s syndrome is important to avoid CBD injury.
ACALCULOUS CHOLECYSTITIS In 5–10% of patients with acute cholecystitis, calculi obstructing the cystic duct are not found at surgery. In >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. 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 (e.g., sarcoidosis, cardiovascular disease, tuberculosis, syphilis, actinomycosis).
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 or computed tomography (CT) 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.
ACALCULOUS CHOLECYSTOPATHY 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. The surgical findings have included abnormalities such as chronic cholecystitis, gallbladder muscle hypertrophy, and/or a markedly narrowed cystic duct. Some of these patients may well have had antecedent gallbladder disease. 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 <40%, and (3) infusion of CCK reproducing 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.
EMPHYSEMATOUS CHOLECYSTITIS So-called emphysematous cholecystitis is thought to begin with acute cholecystitis (calculous or acalculous) followed by ischemia or gangrene of the gallbladder wall and infection by gas-producing organisms. Bacteria most frequently cultured in this setting include anaerobes, such as Clostridium welchii or Clostridium 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 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 mandatory.
Chronic Cholecystitis 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 by gallstones. The presence of bacteria in the bile occurs in >25% 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 (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, because 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 ~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 Fistula formation 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 acute 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 fistula formation. Large stones, >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 in the lumen of the gallbladder in sufficient concentration may 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, especially when it 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.
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.
Overall, cholecystectomy is a very successful operation that provides total or near-total relief of preoperative symptoms in 75–90% of patients. The most common cause of persistent postcholecystectomy symptoms is an overlooked symptomatic nonbiliary 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 pain 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 acalculous cholecystopathy, 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 CBD upon 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 (MRC) if ERCP and/or biliary manometry are either unavailable or not feasible. After exclusion of acalculous cholecystopathy, 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 is 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 the procedure of choice for removing bile duct stones and for other biliary and pancreatic problems.
BILE SALT–INDUCED DIARRHEA AND GASTRITIS Postcholecystectomy patients may develop symptoms of dyspepsia, which have been attributed to duodenogastric reflux of bile. However, firm data linking these symptoms to bile gastritis after 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, i.e. deoxycholic acid. Diarrhea that is severe enough, i.e., three or more watery movements per day, can be classified as postcholecystectomy diarrhea, and this occurs in 5–10% of patients undergoing elective cholecystectomy. Treatment with bile acid–sequestering agents such as cholestyramine or colestipol 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.
Cholesterolosis is characterized by abnormal deposition of lipid, especially cholesteryl esters, within macrophages 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.
The prevalence of gallbladder polyps in the adult population is ~5%, with a marked male predominance. Few significant changes have been found over a 5-year period in asymptomatic patients with gallbladder polyps <10 mm in diameter. Cholecystectomy is recommended in symptomatic patients, as well as in asymptomatic patients >50 years of age, or in those whose polyps are >10 mm in diameter or associated with gallstones or polyp growth on serial ultrasonography.
DISEASES OF THE BILE DUCTS
CONGENITAL ANOMALIES
Biliary Atresia and Hypoplasia Atretic and hypoplastic lesions of the extrahepatic and large 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. 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, ~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. 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 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, brown pigment gallstone formation within portions of ectatic intrahepatic biliary radicles. Ultrasound, MRC, and CT are of great diagnostic value in demonstrating cystic dilatation of the intrahepatic bile ducts. Treatment with ongoing antibiotic therapy is usually undertaken in an effort to limit the frequency and severity of recurrent bouts of cholangitis. Progression to secondary biliary cirrhosis with portal hypertension, extrahepatic biliary obstruction, cholangiocarcinoma, or recurrent episodes of sepsis with hepatic abscess formation is common.
CHOLEDOCHOLITHIASIS
Pathophysiology and Clinical Manifestations Passage of gallstones into the CBD occurs in ~10–15% 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 ~1–5% 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 brown 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 (ABCB4) gene defect leading to impaired biliary phospholipids secretion (low phospholipid–associated cholesterol cholelithiasis). Common duct stones may remain asymptomatic for years, may pass spontaneously into the duodenum, or (most often) may present with biliary colic or a complication.
Complications • CHOLANGITIS Cholangitis may be acute or chronic, and symptoms result from inflammation, which usually is caused by at least partial obstruction to the flow of bile. Bacteria are present on bile culture in ~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.
