Age and Gender

Epidemiologic and clinical studies have reported that cholesterol gallstones occur infrequently in childhood and adolescence, and the prevalence of cholesterol gallstones increases linearly with age in both genders and approaches 50% at age 70 in women.^14,15 Furthermore, elderly persons are at higher risk for complications of gallstones, and mortality from surgery is often unacceptably high in patients older than age 65. Cholesterol saturation of bile is significantly higher in elderly Swedes and Chilean women than in younger controls, and age correlates positively with an increased hepatic secretion rate of biliary cholesterol.^16,17 In animals, aging has been shown to be associated with increased cholesterol gallstone formation as a result of increased biliary secretion and intestinal absorption of cholesterol, decreased hepatic synthesis and secretion of bile salts, and reduced gallbladder contractility (see later).¹⁸

Epidemiologic investigations have found, and clinical studies have confirmed, that at all ages, women are twice as likely as men to form cholesterol gallstones. The difference between women and men begins during puberty and continues through the childbearing years because of the effects of female sex hormones⁸ and differences between the sexes in how the liver metabolizes cholesterol in response to estrogen. Human and animal studies have suggested that estrogen increases the risk of cholesterol gallstones by augmenting the hepatic secretion of biliary cholesterol, thereby leading to an increase in cholesterol saturation of bile.^19–22

Diet

Epidemiologic investigations have shown that cholesterol cholelithiasis is prevalent in populations that consume a Western diet that consists of high amounts of total calories, cholesterol, saturated fatty acids, refined carbohydrates, proteins, and salt, as well as a low amount of fiber. The incidence of cholesterol gallstones is significantly higher in North and South American as well as European populations than in Asian and African populations.^3,23 Several clinical studies have found an association between the increased incidence of cholesterol gallstones in China and westernization of the traditional Chinese diet.²⁴ In Japan, cholesterol cholelithiasis was once rare, but since the 1970s, the adoption of Western-type dietary habits has led to a markedly increased incidence.²⁵

Pregnancy and Parity

Pregnancy is a risk factor for the development of biliary sludge and gallstones.²⁶ During pregnancy, bile becomes more lithogenic as a result of increased estrogen levels, which result in increased cholesterol secretion and supersaturated bile. In addition, gallbladder motility is reduced, with a resulting increase in gallbladder volume and bile stasis. These alterations promote sludge and stone formation.²⁷ Increased plasma levels of progestogen also reduce gallbladder motility. Because plasma hormone concentrations increase linearly with duration of gestation, the risk of gallstone formation is especially hazardous in the third trimester of pregnancy. Increasing parity is probably a risk factor for gallstones, especially in younger women.

Rapid Weight Loss

Rapid weight loss is a well-known risk factor for the formation of cholesterol gallstones.²⁸ As many as 50% of obese patients who undergo gastric bypass surgery form biliary sludge and eventually gallstones within six months after surgery. Gallstones also develop in 25% of patients who undergo strict dietary restriction. Furthermore, 40% of these patients display symptoms related to gallstones within the same six-month period. The mechanisms by which rapid weight loss causes gallstone formation include increased hepatic secretion of biliary cholesterol during caloric restriction, increased production of mucin by the gallbladder, and impaired gallbladder motility. Gallstones could be prevented in this high-risk population by prophylactic administration of ursodeoxycholic acid (UDCA). UDCA in a dose of 600 mg/day has been reported to reduce the frequency of gallstones from 28% to 3% in obese patients on a very-low-calorie diet.²⁹

Total Parenteral Nutrition

Total parenteral nutrition (TPN) is associated with the development of cholelithiasis and of acalculous cholecystitis. As early as three weeks after the initiation of TPN, biliary sludge often forms in the gallbladder because of prolonged fasting. In addition, the sphincter of Oddi may fail to relax, leading to preferential flow of bile into the gallbladder. Finally, approximately 45% of adults and 43% of children form gallstones after three to four months of TPN.^30,31 Because patients receiving TPN often have serious medical problems and are not good candidates for abdominal surgery, prophylactic treatment to prevent gallstones should be prescribed if no contraindication exists. Cholecystokinin (CCK) octapeptide administered twice daily via an intravenous line to patients on long-term TPN has proved to be safe and cost effective³² and should be used routinely in TPN-treated patients.

Biliary Sludge

Biliary sludge is a crucial intermediate stage in the pathogenesis of both cholesterol and pigment gallstones because it facilitates crystallization and agglomeration of solid cholesterol crystals, as well as precipitation of calcium bilirubinate, and leads ultimately to the development into macroscopic stones.^33,34 In addition, biliary sludge can induce acute cholecystitis, cholangitis, and acute pancreatitis. Furthermore, biliary sludge is associated with many conditions that predispose to gallstone formation, including pregnancy, rapid weight loss, spinal cord injury, long-term TPN, and treatment with octreotide.³ Although biliary sludge is reversible in most cases, it persists or disappears and reappears in 12% to 20% of affected persons and eventually leads to gallstones.³⁵ Treatment of patients with persistent biliary sludge with UDCA decreases the frequency of clinical complications of biliary sludge.

Drugs

Lipid Abnormalities

Epidemiologic investigations have shown that plasma HDL cholesterol levels are inversely correlated with the frequency of cholesterol gallstones.⁴³ By contrast, hypertriglyceridemia is positively associated with an increased frequency of gallstones.⁴⁴ These seemingly independent variables are actually interrelated because high plasma triglyceride levels tend to increase with increasing body mass and are inversely correlated with plasma HDL levels. Interestingly, high plasma total and LDL cholesterol levels are not likely to be risk factors for the formation of gallstones.

Systemic Diseases

Chemical Composition of Bile

Cholesterol, phospholipids, and bile salts are the three major lipid species in bile; bile pigments are minor solutes. Cholesterol accounts for up to 95% of the sterols in bile and gallstones; the remaining 5% of the sterols are cholesterol precursors and dietary sterols from plant and shellfish sources. Concentrations of cholesteryl esters are negligible in bile; they account for less than 0.02% of total sterols in gallstones. The major phospholipids are lecithins (phosphatidylcholines), which account for more than 95% of total phospholipids; the remainder consists of cephalins (phosphatidylethanolamines) and a trace amount of sphingomyelin. Phospholipids constitute 15% to 25% of total lipids in bile. Lecithins are insoluble amphiphilic molecules with a hydrophilic, zwitterionic phosphocholine head group and hydrophobic tails that include two long fatty acyl chains. Biliary lecithins possess a saturated C-16 acyl chain in the sn-1 position and an unsaturated C-18 or C-20 acyl chain in the sn-2 position. The major molecular species of lecithins (with corresponding frequencies) in bile are 16 : 0 to 18 : 2 (40% to 60%), 16 : 0 to 18 : 1 (5% to 25%), 18 : 0 to 18 : 2 (1% to 16%), and 16 : 0 to 20 : 4 (1% to 10%). Lecithins are synthesized principally in the endoplasmic reticulum of the liver from diacylglycerol through the cytidine diphosphate-choline pathway. The common bile salts typically contain a steroid nucleus of four fused hydrocarbon rings with polar hydroxyl functions and an aliphatic side chain conjugated in amide linkage with glycine or taurine. In bile, more than 95% of bile salts are 5β,C-24 hydroxylated acidic steroids that are amide-linked to glycine or taurine in an approximate ratio of 3 : 1. Bile salts constitute approximately two thirds of the solute mass of normal human bile by weight. The hydrophilic (polar) areas of bile salts are the hydroxyl groups and conjugated side chain of either glycine or taurine, and the hydrophobic (nonpolar) area is the ringed steroid nucleus. Because they possess both hydrophilic and hydrophobic surfaces, bile salts are highly soluble, detergent-like, amphiphilic molecules. Their high aqueous solubility is attributable to their capacity to self-assemble into micelles when a critical micellar concentration is exceeded.

The primary bile salts are hepatic catabolic products of cholesterol and are composed of cholate (a trihydroxy bile salt) and chenodeoxycholate (a dihydroxy bile salt) (see Chapter 64). The secondary bile salts are derived from the primary bile salt species by the action of intestinal bacteria in the ileum and colon and include deoxycholate, ursodeoxycholate, and lithocholate. The most important of the conversion reactions is 7α-dehydroxylation of primary bile salts to produce deoxycholate from cholate and lithocholate from chenodoxycholate. Another important conversion reaction is the 7α-dehydrogenation of chenodeoxycholate to form 7α-oxo-lithocholate. This bile salt does not accumulate in bile but is metabolized by hepatic or bacterial reduction to form the tertiary bile salt chenodeoxycholate (mainly in the liver) or its 7β-epimer ursodeoxycholate (primarily by bacteria in the colon).

Bile pigments are minor solutes and account for approximately 0.5% of total lipids in bile by weight. They are mainly bilirubin conjugates with traces of porphyrins and unconjugated bilirubin. In human bile, bilirubin monoglucuronides and diglucuronides are the major bile pigments. Other bile pigments are monoconjugates and diconjugates of xylose, glucose, and glucuronic acid and various homoconjugates and heteroconjugates of them.

Proteins and elements are also found in bile. Albumin appears to be the most abundant protein in bile, followed by immunoglobulins G and M, apolipoproteins AI, AII, B, CI, and CII, transferrin, and α₂-macroglobin. Other proteins that have been identified but not quantitated in bile include epidermal growth factor, insulin, haptoglobin, cholecystokinin, lysosomal hydrolase, and amylase. Elements detected in bile include sodium, phosphorus, potassium, calcium, copper, zinc, iron, manganese, molybdenum, magnesium, and strontium.

Physical States of Biliary Lipids

Cholesterol is nearly insoluble in water, and the mechanism by which cholesterol is solubilized in bile is complex because bile is an aqueous solution. The two main types of macromolecular aggregates in bile are micelles and vesicles.

Bile salts are soluble in an aqueous solution because they are amphiphilic, in that they have both hydrophilic and hydrophobic areas. This unique property of bile salts is dependent on the number and characteristics of the hydroxyl groups and side chains as well as the composition of the particular aqueous solution. When bile salt concentrations exceed the critical micellar concentration, their monomers can aggregate spontaneously to form simple micelles. The simple micelles (∼3 nm in diameter) are small, disk-like, and thermodynamically stable aggregates that can solubilize cholesterol. They can also solubilize and incorporate phospholipids to form mixed micelles that are capable of solubilizing at least triple the amount of cholesterol compared with that solubilized by simple micelles. Mixed micelles (∼4-8 nm in diameter) are large, thermodynamically stable aggregates that are composed of bile salts, phospholipids, and cholesterol. Their size depends on the relative proportion of bile salts and phospholipids. The mixed micelle is a lipid bilayer with the hydrophilic groups of the bile salts and phospholipids aligned on the “outside” of the bilayer, interfacing with the aqueous bile, and the hydrophobic groups on the “inside.” Therefore, cholesterol molecules can be solubilized on the inside of the bilayer away from the aqueous areas on the outside. The amount of cholesterol that can be solubilized is dependent on the relative proportions of bile salts, and the maximal solubility of cholesterol occurs when the molar ratio of phospholipids to bile salts is between 0.2 and 0.3. Furthermore, solubility of cholesterol in mixed micelles is enhanced when the concentration of total lipids in bile is increased.

Observations by quasi-elastic light-scattering spectroscopy and electron microscopy used to examine model and native biles reveal that in addition to micelles, vesicles solubilize cholesterol in bile. Biliary vesicles are unilamellar spherical structures that contain phospholipids, cholesterol, and little, if any, bile salts. Vesicles are substantially larger than either simple or mixed micelles (40 to 100 nm in diameter) but much smaller than liquid crystals (∼500 nm in diameter) that are composed of multilamellar spherical structures. Because vesicles are present in large quantities in hepatic bile, they presumably are secreted by hepatocytes. Unilamellar vesicles are often detected in freshly collected samples of unsaturated bile and are physically indistinguishable from those identified in supersaturated bile. Dilute hepatic bile, in which cholesterol crystals and gallstones never form, is always supersaturated with cholesterol because vesicles solubilize biliary cholesterol in excess of what could be solubilized in mixed micelles. Cholesterol-rich vesicles are remarkably stable in dilute bile, consistent with the absence of cholesterol crystallization in hepatic bile. The unilamellar vesicles can fuse and form large multilamellar vesicles (also known as liposomes or liquid crystals). Solid cholesterol crystals may nucleate from multilamellar vesicles in concentrated gallbladder bile.

Vesicles are relatively static structures that are affected by several factors, including biliary lipid concentrations and the relative ratios of cholesterol, phospholipids, and bile salts. The relative concentrations of these three important lipids in bile are influenced by their hepatic secretion rates, which vary with fasting and feeding. For example, during fasting, biliary bile salt output is relatively low. As a result, the ratio of cholesterol to bile salts is increased, and more cholesterol is carried in vesicles than in micelles. By contrast, with feeding, biliary bile salt output increases and more cholesterol is solubilized in micelles than in vesicles. In addition, when the concentration of bile salts is relatively low, especially in dilute hepatic bile, vesicles are relatively stable, and only some vesicles convert to micelles. By contrast, with increasing bile salt concentrations in concentrated gallbladder bile, vesicles may transform or convert completely to mixed micelles. Because relatively more phospholipids than cholesterol can be transferred from vesicles to mixed micelles, the residual vesicles are remodeled and may be enriched in cholesterol relative to phospholipids. If the remaining vesicles have a relatively low cholesterol-to-phospholipid ratio (less than 1), they are relatively stable, but if the cholesterol-to-phospholipid ratio in vesicles is greater than 1, vesicles become increasingly unstable. These cholesterol-rich vesicles may transfer some cholesterol to less cholesterol-rich vesicles or to micelles or may fuse or aggregate to form larger (∼500 nm in diameter) multilamellar vesicles (i.e., liposomes or liquid crystals). Liquid crystals are visible by polarizing light microscopy as lipid circular droplets with characteristic birefringence in the shape of a Maltese cross. Liquid crystals are inherently unstable and may form solid plate-like cholesterol monohydrate crystals, a process termed cholesterol nucleation. Therefore, nucleation of cholesterol monohydrate crystal results in a decrease in the amount of cholesterol contained in vesicles but not in micelles, and vesicles may serve as the primary source of cholesterol for nucleation.

Under normal physiologic conditions, bile is concentrated gradually within the biliary tree so that the bile salt concentration approaches its critical micellar concentration. When this occurs, bile salts begin to modify the structure of phospholipid-rich vesicles that are secreted into bile by hepatocytes. These interactions signify the start of a complex series of molecular rearrangements that ultimately lead to formation of simple and mixed micelles. In supersaturated bile, two pathways result in the formation of cholesterol-rich vesicles from phospholipid-rich vesicles at the canalicular membrane. Because bile salts solubilize phospholipids more efficiently than cholesterol, cholesterol-rich vesicles may form when bile salts preferentially extract phospholipid molecules directly from phospholipid-rich vesicles. The alternative pathway is the rapid dissolution of phospholipid-rich vesicles by bile salts with the production of unstable mixed micelles that contain excess cholesterol. Structural rearrangements of these unstable micellar particles result in the formation of cholesterol-rich vesicles.

Phase Diagrams and Cholesterol Solubility in Bile

In the 1960s, Small and colleagues defined the maximal solubility (saturation) limits for cholesterol in model quaternary bile systems that consisted of varying proportions of cholesterol, phospholipids, bile salts, and water.^49,50 The relative proportions (as molar percentages) of the three lipids in bile play a critical role in determining the maximal solubility of cholesterol. When the relative proportions of the three lipids at a fixed total lipid concentration are plotted in a triangular coordinate, the solubility of cholesterol for any given solute concentration can be determined.⁵¹ The triangular coordinate diagram also illustrates the physical phases of cholesterol in bile. For example, the phase diagram shown in Figure 65-3 is specific for a total lipid concentration of 7.5 g/dL, which is typical of human gallbladder bile.^52,53 For hepatic bile, with a typical total lipid concentration of 3 g/dL, the phase boundaries would be different, with a smaller micellar zone, all phase boundaries shifted to the left, and an expanded two-phase zone on the right (i.e., region E in Figure 65-3). The effect of the total lipid content on cholesterol solubilization in the micellar zone explains why hepatic bile tends to be more saturated with cholesterol than is gallbladder bile in the same subject. Because hepatic bile contains cholesterol-phospholipid vesicles that are relatively stable, solid cholesterol monohydrate crystals never occur in hepatic bile.

Figure 65-3. Equilibrium phase diagram of cholesterol-phospholipid (lecithin)–mixed bile salt system (37°C, 0.15 M NaCl, pH 7.0, total lipid concentration 7.5 g/dL) showing positions and configuration of crystallization regions. The components are expressed in moles percent. The one-phase micellar zone at the bottom is enclosed by a solid angulated line, and above it, two solid lines divide the two-phase zones from a central three-phase zone. Based on the solid and liquid crystallization sequences present in the bile, the left two-phase and central three-phase regions are divided by dashed lines into regions A to D. The number of phases given represents the equilibrium state. The phases are cholesterol monohydrate crystals and saturated micelles for crystallization regions A and B; cholesterol monohydrate crystals, saturated micelles, and liquid crystals for regions C and D; and liquid crystals of variable composition and saturated micelles for region E. Of note is that decreases in temperature (37°C→4°C), total lipid concentration (7.5 g/dL→2.5 g/dL), and bile salt hydrophobicity (3α,12α→3α,7α→3α,7α,12α→3α,7β hydroxylated taurine conjugates) progressively shift all crystallization pathways to lower phospholipid contents, retard crystallization, and reduce micellar cholesterol solubilities. These changes generate a series of new condensed-phase diagrams with an enlarged region E.

(Reproduced with permission from Wang DQ, Carey MC. Complete mapping of crystallization pathways during cholesterol precipitation from model bile: Influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems. J Lipid Res 1996; 37:606-30.)

Equilibrium phase diagrams can also be used to predict the phases in which cholesterol crystals can be found at equilibrium. Although the equilibration process starts after bile is secreted from hepatocytes and flows into the biliary tree, the evolution to cholesterol monohydrate crystals occurs only in the gallbladder. For example, in unsaturated bile, all cholesterol can be solubilized in both simple and mixed micelles, and relative lipid compositions are located in the micellar zone of the phase diagram. By contrast, in supersaturated bile, cholesterol cannot be completely solubilized by simple and mixed micelles, and relative lipid compositions are located outside the micellar zone of the phase diagram. Under these circumstances, high vesicle cholesterol concentrations and high total lipid concentrations in bile work together to produce the solid crystalline phase. Therefore, with typical physiologic lipid ratios, at equilibrium, cholesterol monohydrate crystals are present with saturated simple and mixed micelles or with saturated micelles plus vesicles that have become multilamellar liquid crystals. The final physical chemical state of bile is also influenced by the ratio of the concentration of bile salts to that of phospholipids and the overall hydrophilic-hydrophobic balance of both bile salt and phospholipid species.

Within the micellar zone (see Fig. 65-3), bile is a visually clear, stable solution that is considered unsaturated because all cholesterol can be solubilized in thermodynamically stable simple and mixed micelles. At the boundary line of the micellar zone, bile is saturated because all the solubilizing capacity for cholesterol is utilized and no further cholesterol can be carried in micelles. Outside the micellar zone, bile is supersaturated because excess cholesterol cannot be solubilized by micelles^51,54 and exists in more than one phase (micelles, liquid crystals, and solid monohydrate crystals); the solution is visually cloudy. Obviously, relatively stable unilamellar cholesterol-phospholipid vesicles solubilize a significant proportion of cholesterol outside the micellar zone. The term metastable zone refers to the area in the phase diagram (above but near the micellar zone) in which bile is supersaturated with cholesterol but may not form solid cholesterol crystals even after many days. The diagram also suggests that when the quantity of cholesterol in bile exceeds that which can be solubilized by the available bile salts and phospholipids, solid cholesterol crystals precipitate in bile. Furthermore, the proportional distance outside the micellar zone directed along an axis joined to the cholesterol apex is often calculated as the cholesterol saturation index (CSI) (or lithogenic index).⁵⁴ Therefore, the degree of saturation of bile with cholesterol can be quantitated. A CSI for a sample of bile can be estimated directly from the diagram or calculated by using a formula. The CSI is the ratio of the actual amount of cholesterol present in a bile sample to the maximal amount of cholesterol that can be dissolved in it. Bile that has a CSI of 1 is saturated; bile with a saturation index less than 1 is unsaturated; and bile with a saturation index greater than 1 is supersaturated. The degree of saturation can also be expressed as percent saturation by multiplying the saturation index by 100. For example, at the boundary of the micellar zone, bile is saturated, and the CSI is 100%. Supersaturated bile has a CSI above 100%, and unsaturated bile has a CSI below 100%. The CSI values are also useful for predicting the proportion of lipid particles and the metastable and equilibrium physical-chemical states in bile.

Source of Lipids Secreted in Bile

The supply of hepatic cholesterol molecules that can be recruited for biliary secretion depends on the balance of input and output of cholesterol and its catabolism in the liver (see also Chapter 72) (Fig. 65-4). Input is related to the amount of cholesterol (both unesterified and esterified) taken up by the liver from plasma lipoproteins (LDL > HDL > chylomicron remnants) plus de novo hepatic cholesterol synthesis. Output is related to the amount of cholesterol disposed of within the liver by conversion to cholesteryl ester (to form new very-low-density lipoprotein [VLDL] and for storage) minus the amount of cholesterol converted to primary bile salts. An appreciable fraction of cholesterol in bile also may be derived from the diet via apolipoprotein E–dependent delivery of chylomicron remnants to the liver. Under low or no dietary cholesterol conditions, bile contains newly synthesized cholesterol from the liver and preformed cholesterol that reaches the liver in several different ways. Approximately 20% of the cholesterol in bile comes from de novo hepatic biosynthesis, and 80% is from pools of preformed cholesterol within the liver. De novo cholesterol synthesis in the liver uses acetate as a substrate and is regulated mainly by the rate-limited enzyme HMG-CoA reductase. This enzyme can be up- or down-regulated depending on the overall cholesterol balance in the liver. An increase in the activity of this rate-limiting enzyme leads to excessive cholesterol secretion in bile. The major sources of preformed cholesterol are hepatic uptake of plasma lipoproteins (mainly HDL and LDL through their receptors on the basolateral membrane of hepatocytes). Consistent with their central role in reverse cholesterol transport, HDL particles are the main lipoprotein source of cholesterol that is targeted for biliary secretion. Under conditions of a diet high in cholesterol, dietary cholesterol reaches the liver through the intestinal lymphatic pathways as chylomicrons and then chylomicron remnants, after chylomicrons are hydrolyzed by plasma lipoprotein lipase and hepatic lipase. The synthesis of new cholesterol in the liver is reduced and comprises only approximately 5% of biliary cholesterol. Overall, the liver can systematically regulate the total amount of cholesterol within it, and any excess cholesterol is handled efficiently.

Figure 65-4. Uptake, biosynthesis, catabolism, and biliary secretion of cholesterol at the hepatocyte level. The hepatic uptake of cholesterol is mediated by the low-density lipoprotein (LDL) receptor (LDLR) for LDL, by scavenger receptor class B type I (SR-BI) for high-density lipoprotein (HDL), and by the chylomicron remnant receptor (CMRR) for chylomicron remnants (CMR). Biosynthesis of hepatic cholesterol (CH) from acetate is regulated by the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Part of the cholesterol is esterified by acyl-coenzyme A:cholesterol acyltransferase (ACAT) for storage in the liver. Some of the cholesterol is used for the formation of very-low-density lipoprotein (VLDL), which is secreted into the blood. The ATP-binding cassette (ABC) transporter ABCA1 may translocate, either directly or indirectly, cholesterol and phospholipids to the cell surface, where they appear to form lipid domains that interact with amphipathic α-helices in apolipoproteins. This interaction solubilizes these lipids and generates nascent HDL particles that dissociate from the cell. A proportion of cholesterol is used for the synthesis of bile salts via the “neutral” and the “acidic” pathways, as regulated by two rate-limiting enzymes cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), respectively. Hepatic secretion of biliary cholesterol (CH), bile salts (BS), and phospholipids (PL) across the canalicular membrane is determined by three lipid transporters, ABCG5/G8, ABCB11, and ABCB4, respectively. A vesicle is shown in the canaliculus.

Although biliary phospholipid is derived from the cell membranes of hepatocytes, the composition of biliary phospholipid differs markedly from that of hepatocyte membranes. The membranes of hepatocytes contain phosphatidylcholines (lecithins), phosphatidylethanolamines, phosphatidylinositols, phosphatidylserines, and sphingomyelins. The major source of phosphatidylcholine molecules destined for secretion into bile is hepatic synthesis. A fraction of biliary phosphatidylcholines may also originate in the phospholipid coat of HDL particles. Approximately 11 g of phospholipids are secreted into bile each day in humans.

More than 95% of bile salt molecules, after secretion into bile, return to the liver through the enterohepatic circulation by absorption mostly from the distal ileum via an active transport system (see also Chapter 64). Consequently, newly synthesized bile salts in the liver contribute only a small fraction (<5%) to biliary secretion and compensate for bile salts that escape intestinal absorption and are lost in feces. The fecal excretion of bile salts is increased when the enterohepatic circulation of bile salts is partially or completely interrupted by surgery, disease states, or drugs (e.g., bile salt-binding resins such as cholestyramine). Complete interruption of the enterohepatic circulation results in up-regulation of bile salt synthesis in the liver, which restores bile salt secretion rates to approximately 25% of their usual values. Cholesterol from two sources serves as substrate for de novo bile salt synthesis—cholesterol that is newly synthesized in the smooth endoplasmic reticulum and cholesterol that is preformed outside the smooth endoplasmic reticulum. The first step in this process is catalyzed by cholesterol 7α-hydroxylase. In the basal state, de novo bile salt synthesis uses principally newly synthesized cholesterol as substrate. When de novo cholesterol biosynthesis is suppressed by long-term therapy with a HMG-CoA reductase inhibitor, preformed cholesterol originating from plasma lipoprotein substitutes for newly synthesized cholesterol.

Biliary Lipid Secretion

Bile salts have been shown to stimulate secretion of vesicles, which are always detected in freshly collected hepatic bile.^55,56 When cultured under specified conditions, rat hepatocytes form couplets with isolated “bile canaliculi” at the interface between adjoining cells. With the use of laser light-scattering techniques, vesicle formation can be observed within these bile canaliculi after exposure to bile salts. In addition, rapid fixation techniques and electronic microscopy have provided direct morphologic evidence of vesicle formation at the outer surface of the canalicular membrane.^57,58 Most, if not all, bile salts are thought to enter canalicular spaces as monomers, whereas biliary phospholipids and cholesterol enter as unilamellar vesicles (see Fig. 65-4). A study of the molecular genetics of sitosterolemia (see Chapter 64) has shown that efflux of biliary cholesterol from the canalicular membrane is protein mediated. Two plasma membrane proteins—adenosine triphosphate (ATP)-binding cassette (ABC) transporters ABCG5 and ABCG8—promote cellular efflux of cholesterol. The significance of this process for bile formation has been examined in genetically modified mice, in which overexpression of abcg5 and abcg8 in the liver was shown to increase the cholesterol content of gallbladder bile.^59–63 Despite a reduced frequency of gallstones, the formation of gallstones is still observed in abcg5/g8 double-knockout mice, as well as in abcg5 or abcg8 single-knockout mice, challenged with a lithogenic diet.^59–63 These findings strongly suggest the existence of an ABCG5/G8-independent pathway for hepatic secretion of biliary cholesterol and its role in the formation of cholesterol gallstones. In addition, scavenger receptor class B type I (SR-BI) is localized in sinusoidal, and possibly, canalicular, membranes of the hepatocyte, and in transgenic and knockout mice fed a chow diet, biliary secretion of cholesterol varies in proportion to hepatic expression of SR-BI and to the contribution of SR-BI to sinusoidal uptake of HDL cholesterol destined for secretion into bile.^64,65

Deletion of the Abcb4 gene completely inhibits hepatic secretion of biliary phospholipids in mice,⁶⁶ suggesting that ABCB4 could be responsible for the translocation, or “flip,” of phosphatidylcholine from the endoplasmic (inner) to ectoplasmic (outer) leaflet of the canalicular membrane bilayer and that the action of ABCB4 may form phosphatidylcholine-rich microdomains within the outer membrane leaflet. Although the ectoplasmic leaflet of the canalicular membrane is cholesterol- and sphingomyelin-rich and is relatively resistant to penetration by bile salts, bile salts may promote vesicular secretion of biliary cholesterol and phosphatidylcholine. Bile salts may partition preferentially into these areas to destabilize the membrane and release phosphatidylcholine-rich vesicles because detergent-like bile salt molecules within the canalicular space could interact with canalicular membrane. Mutations of the ABCB4 gene in humans result in the molecular defect underlying type 3 progressive familial intrahepatic cholestasis (see Chapter 76).⁶⁷

Biliary bile salts include those that are newly synthesized in the liver and those that undergo enterohepatic cycling. The precise molecular mechanism of bile salt secretion is not known, although it probably involves ABCB11, a bile salt export pump (see Chapter 64).^68–70 Although hepatic secretion of biliary bile salts directly affects cholesterol-phospholipid vesicle secretion, whether bile salt secretion is coupled to cholesterol and phospholipid secretion at a molecular level is not known. The relationship between bile salt secretion and cholesterol secretion is curvilinear: At low bile salt secretion rates (usually less than 10 µmol/hr/kg), more cholesterol is secreted per molecule of bile salt than at higher rates. Although bile salt secretion rates are not low in normal subjects, they could diminish during prolonged fasting, during the overnight period, and with substantial bile salt losses, as occur with a biliary fistula or ileal resection when the liver cannot compensate sufficiently by increasing bile salt synthesis. At high bile salt secretion rates, for example, during and after eating, biliary cholesterol saturation is less than that during interprandial periods. In laboratory animals, biliary secretion of organic anions does not influence bile salt secretion but does inhibit secretion of phospholipid and cholesterol into bile because organic anions bind bile salts within bile canaliculi and prevent interactions with the canalicular membrane.

Ultrasonography

Since its introduction in the 1970s, ultrasonographic examination of the biliary tract has become the principal imaging modality for the diagnosis of cholelithiasis. Ultrasonography requires only an overnight or eight-hour fast, involves no ionizing radiation, is simple to perform, and provides accurate anatomic information. It has the additional advantage of being portable and thus available at the bedside of a critically ill patient.¹⁹⁴

The diagnosis of gallstones relies on the detection of echogenic objects within the lumen of the gallbladder that produce an acoustic shadow (Fig. 65-8A). The stones are mobile and generally congregate in the dependent portion of the gallbladder. Modern ultrasonography is able to detect stones as small as 2 mm in diameter routinely. Smaller stones may be missed or may be confused with biliary sludge (layering echogenic material that does not cast acoustic shadows).¹⁹⁷

Figure 65-8. A, Typical ultrasonographic appearance of cholelithiasis. A gallstone is present within the lumen of the gallbladder (GB), casting an acoustic shadow. With repositioning of the patient, the stones will move, thereby excluding the possibility of a gallbladder polyp. B, Cholelithiasis in the setting of acute cholecystitis. Multiple gallstones can be seen within the gallbladder lumen with associated acoustic shadowing. In addition, the gallbladder wall is thickened (arrowheads).

(Courtesy of Julie Champine, MD, Dallas, Tex.)

The sensitivity of ultrasonography for the detection of gallstones in the gallbladder is more than 95% for stones larger than 2 mm.¹⁹⁸ The specificity is greater than 95% when stones produce acoustic shadows. Rarely, advanced scarring and contraction of the gallbladder around gallstones make it impossible to locate the gallbladder or the stones; this finding should also raise the possibility of gallbladder cancer. The contracted gallbladder filled with stones may give a “double-arc shadow” or “wall-echo shadow” sign, with the gallbladder wall, echogenic stones, and acoustic shadowing seen in immediate proximity. If the gallbladder cannot be identified ultrasonographically, then a complementary imaging modality such as oral cholecystography or abdominal computed tomography (CT) is warranted.

Ultrasonography is the standard for the diagnosis of stones in the gallbladder but is distinctly less sensitive for the detection of stones in the bile duct (previously termed common bile duct).¹⁹⁹ Because of the proximity of the distal bile duct to the duodenum, luminal bowel gas often interferes with the ultrasonographic image, and the entire length of the bile duct cannot be examined.²⁰⁰ As a result, only approximately 50% of bile duct stones are actually seen on ultrasonography.¹⁹⁴ The presence of an obstructing bile duct stone, however, can be inferred when a dilated duct is found. Now that endoscopic retrograde cholangiopancreatography (ERCP) has uncovered a rising frequency of falsely negative ultrasonograms, the upper limit of normal of the diameter of the bile duct has declined from 10 mm to 6 mm. Even so, inferring choledocholithiasis from a dilated bile duct on ultrasonography has a sensitivity of only 75%.

Finally, ultrasonography is quite useful for diagnosing acute cholecystitis.²⁰¹ Pericholecystic fluid (in the absence of ascites) and gallbladder wall thickening to more than 4 mm (in the absence of hypoalbuminemia) are suggestive of acute cholecystitis (see Fig. 65-8B). Unfortunately, in the critical care setting, these nonspecific findings are seen frequently in patients with no other evidence of gallbladder disease.²⁰¹ A more specific finding is the so-called sonographic Murphy’s sign, in which the ultrasonographer elicits focal gallbladder tenderness under the ultrasound transducer. Eliciting a sonographic Murphy’s sign is somewhat operator dependent and requires an alert patient. Presence of the sign has a positive predictive value of greater than 90% for detecting acute cholecystitis if gallstones are present.²⁰²

Because it provides accurate anatomic localization of biliary tract abnormalities, ultrasonography may help localize other abdominal diseases, such as abscesses or pseudocysts, that may be in the differential diagnosis.

Endoscopic Ultrasonography

Endoscopic ultrasonography (EUS) is highly accurate for detecting choledocholithiasis. Inherently more invasive and more expensive than standard ultrasonography, EUS has the advantage of being able to visualize the bile duct from within the gastrointestinal lumen and is reported to be comparable to ERCP in this respect. Intraluminal imaging provides several advantages over transabdominal ultrasonography, including closer proximity to the bile duct, higher resolution, and lack of interference by bowel gas or abdominal wall layers (Fig. 65-9). In several studies, EUS had a positive predictive value of 99%, a negative predictive value of 98%, and an accuracy rate of 97% for the diagnosis of bile duct stones compared with ERCP.^203,204 If bile duct stones are found on EUS, endoscopic removal of the stones is necessary, and it can be argued that ERCP should be the initial study if choledocholithiasis is strongly suspected. Nonetheless, several studies that compared EUS with ERCP have found both techniques to be accurate for confirming or excluding choledocholithiasis, with EUS having advantages in both safety and cost.^205–207

Figure 65-9. Endoscopic ultrasonography, with a radial sector scanning endoscope, demonstrating choledocholithiasis. The bile duct (BD) is shown extending to the level of the gallbladder (GB) (top) and distally (middle and bottom pictures). The greatest diameter of the BD is 12 mm (middle), and the duct tapers distally to a diameter of 7 mm (bottom). Within the distal BD a gallstone is clearly visualized (bottom). Note the proximity of adjacent structures to the bile duct and the ease with which these structures are resolved by endoscopic ultrasonography. Conf, confluence of the portal and splenic veins; PD, pancreatic duct; PV, portal vein.

EUS also has been found to be superior to magnetic resonance cholangiopancreatography (MRCP) (or simply magnetic resonance cholangiography [MRC]) in detecting the presence or absence of bile duct stones (see later). The major benefit of EUS in patients with a clinical suspicion of choledocholithiasis is the ability to avoid unnecessary ERCP and sphincterotomy, which is not without risk. Therefore, EUS is currently considered an appropriate modality for excluding bile duct stones, especially if the pretest probability of finding stones is low to intermediate.

Oral Cholecystography

Once the mainstay of imaging studies of the gallbladder, oral cholecystography (OCG) now has limited application as a secondary approach to identifying stones in the gallbladder.¹⁹⁴ The ease, reliability, and rapidity with which it can detect stones, along with the absence of ionizing radiation, have made ultrasonography the imaging study of choice. In unusual cases in which the gallbladder cannot be identified ultrasonographically (as when the gallbladder is contracted and full of stones),²⁰⁸ OCG is complementary to ultrasonography for demonstrating cholelithiasis. Additionally, when medical dissolution of stones or lithotripsy is being considered, visualization of the gallbladder on OCG excludes cystic duct obstruction (see Chapter 66).²⁰⁹ Because of the time required to complete the test (48 hours), OCG is not useful in patients with suspected acute cholecystitis or other complications of gallstone disease. On occasion, OCG may detect unsuspected disease of the gallbladder, such as adenomyomatosis or cholesterolosis (see Chapter 67).

Cholescintigraphy

Cholescintigraphy (hepatobiliary scintigraphy) is a radionuclide imaging test of the gallbladder and biliary tract that is most useful for evaluating patients with suspected acute cholecystitis. By demonstrating patency of the cystic duct, cholescintigraphy can exclude acute cholecystitis rapidly (within 90 minutes) from the differential diagnosis in a patient who presents with abdominal pain.^210,211

The procedure can be performed on an emergency basis in a nonfasting patient after intravenous administration of gamma-emitting 99mTc-labeled hydroxyl iminodiacetic acid (HIDA) or diisopropyl iminodiacetic acid (DISIDA), which is taken up rapidly by the liver and secreted into bile. As shown in Figure 65-10, serial scans after injection normally should show radioactivity in the gallbladder, bile duct, and small intestine within 30 to 60 minutes.¹⁶⁷ In the past, imaging of jaundiced patients with this technique was limited, but use of DISIDA may allow imaging of the biliary tree in a patient with a serum bilirubin value as high as 20 mg/dL.

Figure 65-10. Cholescintigraphy demonstrating an obstructed cystic duct characteristic of acute cholecystitis. The gamma-emitting radioisotope diisopropyl iminodiacetic acid (DISIDA) is injected intravenously, rapidly (at 5 min) taken up by the liver, and excreted into bile (at 20 min). Sequential images show the isotope quickly entering the duodenum (at 45 min) and passing distally in the small intestine without ever being concentrated in the gallbladder. The failure of the gallbladder to be visualized as a hot spot within 30 to 60 minutes constitutes a positive result and implies obstruction of the cystic duct.

An abnormal or “positive” scan result is defined as nonvisualization of the gallbladder with preserved excretion into the bile duct or small intestine. The accuracy of the test for detecting acute cholecystitis is 92%, superior to that for ultrasonography. False-positive results occur primarily in fasting or critically ill patients, in whom gallbladder motility is decreased. The reduction in gallbladder motility leads to greater water resorption, which results in a gelatinous bile. In critically ill patients, cholestasis and hepatocyte dysfunction result in reduced clearance of radionuclide imaging agents. Although nonvisualization of the gallbladder because of cystic duct obstruction is the hallmark of acute cholecystitis, pericholecystic hepatic uptake of radionuclide is a useful secondary sign.²¹²

In some patients (e.g., those with chronic cholecystitis, liver disease, or choledocholithiasis), imaging of the gallbladder on a radionuclide scan is delayed for several hours, and scanning must be repeated in four or more hours to confirm absence of acute cholecystitis. This delay in visualization of the gallbladder is problematic in the acutely ill patient but has largely been overcome with the administration of intravenous morphine sulfate to patients in whom the gallbladder fails to be visualized within 60 minutes. Morphine raises the pressure within the sphincter of Oddi, thereby leading to the preferential flow of bile into the gallbladder if the cystic duct is not obstructed. Another scan is obtained 30 minutes after injection of morphine, and if the gallbladder is visualized, cystic duct obstruction and, hence, acute cholecystitis, is excluded. The gallbladder may not be visualized in approximately half of critically ill patients even after injection of morphine, thereby leading to false-positive cholescintigraphy results.

Although primarily a tool for evaluating acutely ill patients with suspected acute cholecystitis, cholescintigraphy after administration of CCK may be useful in identifying patients with chronic acalculous biliary pain who are likely to benefit from empirical cholecystectomy (see Chapter 67). An additional important role for cholescintigraphy is the noninvasive and clear detection of bile leakage from the cystic duct as a complication of cholecystectomy (see Chapter 66).²¹³

Endoscopic Retrograde Cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) is one of the most effective modalities for detecting choledocholithiasis. The technique of this procedure is discussed in more detail in Chapter 70. Stones within the bile duct appear as filling defects and can be detected with a sensitivity of approximately 95% (Fig. 65-11). Care should be taken to avoid inadvertent injection of air into the biliary tract²¹⁴ because bubbles may mimic gallstones. The specificity of ERCP for the detection of bile duct stones is approximately 95%.

Figure 65-11. An endoscopic retrograde cholangiogram demonstrating dilatation of the bile duct to 15 mm with multiple filling defects representing choledocholithiasis (arrows).

(Courtesy of Steve Burdick, MD, Dallas, Tex.)

The therapeutic applications of ERCP have revolutionized the treatment of patients with choledocholithiasis²¹⁵ and other bile duct disorders (see Chapter 70). Because ERCP is invasive and is associated with potential complications such as pancreatitis and postsphincterotomy bleeding, however, the role of ERCP has been challenged by other modalities that exclude choledocholithiasis more safely and accurately in patients in whom the clinical suspicion of choledocholithiasis is not high. As the use of EUS and MRC has increased, the role of ERCP in the diagnosis of choledocholithiasis has changed considerably. A National Institutes of Health consensus conference has recommended the use of ERCP only when the clinical probability for choledocholithiasis is high (i.e., when the need for therapeutic intervention is likely). For diagnosis of choledocholithiasis alone, EUS and MRC are equal in accuracy to ERCP.²¹⁶

Computed Tomographic Cholangiography and Magnetic Resonance Cholangiography

In patients with cholelithiasis or choledocholithiasis, CT has been used principally for detecting complications such as pericholecystic fluid in acute cholecystitis, gas in the gallbladder wall suggesting emphysematous cholecystitis, gallbladder perforation, and abscesses (Fig. 65-12). Spiral CT cholangiography (CTC) with use of an oral cholecystographic contrast agent has been studied for the detection of choledocholithiasis.^217,218 Although CTC is still inferior to ERCP imaging for detecting bile duct stones, it may reveal other surrounding pathologic abnormalities.²¹⁷

Figure 65-12. Abdominal computed tomography demonstrating emphysematous cholecystitis with associated cholelithiasis. Pockets of gas (yellow arrow), resulting from a secondary infection with gas-forming organisms, are present within the wall of the gallbladder (GB).

(Courtesy of Julie Champine, MD, Dallas, Tex.)

MRC is highly useful for imaging the bile duct and detecting gallstones. This modality is especially useful for detecting abnormalities in the most distal extrahepatic portion of the bile duct when the duct is not dilated; this region often is not well visualized by transabdominal ultrasonography.¹⁹⁵ With the advent of laparoscopic cholecystectomy, an easy, quick, and, preferably, noninvasive method of excluding bile duct stones is needed. MRC permits the construction of a three-dimensional image of the bile duct with a high sensitivity for detecting bile duct stones (Fig. 65-13).^219,220 In a systematic review that compared MRC with diagnostic ERCP for the detection of choledocholithiasis, MRC had a sensitivity of 93% and a specificity of 94%.²²¹

Figure 65-13. Magnetic resonance cholangiography demonstrating choledocholithiasis. Within the bile duct (BD) are two filling defects representing gallstones. GB, gallbladder.

(Courtesy of Charles Owen, III, MD, Dallas, Tex.)

CTC and MRC are noninvasive but, unlike ERCP, have no therapeutic application. They are most useful for excluding choledocholithiasis (either preoperatively or postoperatively) in patients who undergo cholecystectomy and in whom the probability of bile duct stones is believed to be low. ERCP is now reserved for patients with a higher probability of bile duct stones and thus the need for therapeutic intervention.

Pathogenesis

Biliary pain (conventionally referred to as biliary “colic,” a misnomer) is caused by intermittent obstruction of the cystic duct by one or more gallstones. Biliary pain does not require that inflammation of the gallbladder accompany the obstruction. The term chronic cholecystitis to describe biliary pain should be avoided because it implies the presence of a chronic inflammatory infiltrate that may or may not be present in a given patient. Indeed, the severity and frequency of biliary pain and the pathologic changes in the gallbladder do not correlate significantly.²²² The most common histologic changes observed in patients with biliary pain are mild fibrosis of the gallbladder wall with a chronic inflammatory cell infiltrate and an intact mucosa. Recurrent episodes of biliary pain also can be associated with a scarred, shrunken gallbladder and Rokitansky-Aschoff sinuses (intramural diverticula). Bacteria can be cultured from gallbladder bile or gallstones themselves in about 10% of patients with biliary pain, but bacterial infection is not believed to contribute to the symptoms (see also Chapter 67).

Clinical Features

Biliary pain is visceral in nature and, thus, poorly localized.²²³ In a typical case, the patient experiences episodes of upper abdominal pain, usually in the epigastrium or right upper quadrant (RUQ) but sometimes in other abdominal locations. Ingestion of a meal often can precipitate pain, but more commonly no inciting event is apparent. The onset of biliary pain is more likely to occur during periods of weight reduction and marked physical inactivity such as prolonged bed rest than at other times.

The term biliary colic, used in the past, is a misnomer because the pain is steady rather than intermittent as would be suggested by the word “colic.” The pain increases gradually over a period of 15 minutes to an hour and then remains at a plateau for an hour or more before slowly resolving. In one third of patients, the onset of pain may be more sudden, and on rare occasions, the pain may cease abruptly. Pain lasting more than six hours suggests acute cholecystitis rather than simple biliary pain.

In order of decreasing frequency, biliary pain is felt maximally in the epigastrium, RUQ, left upper quadrant, and various parts of the precordium or lower abdomen. Therefore, the notion that pain not located in the RUQ is atypical of gallstone disease is incorrect. Radiation of the pain to the scapula, right shoulder, or lower abdomen occurs in one half of patients. Diaphoresis and nausea with some vomiting are common, although vomiting is not as protracted as in intestinal obstruction or acute pancreatitis. Like patients with other kinds of visceral pain, the patient with biliary pain is usually restless and active during an episode.

Complaints of gas, bloating, flatulence, and dyspepsia, which are common in patients with gallstones, are probably not related to the stones themselves. These nonspecific symptoms are found with similar frequencies in persons without gallstones. Accordingly, patients with gallstones whose only symptoms are dyspepsia and other nonspecific upper gastrointestinal tract complaints are not candidates for cholecystectomy. Physical findings are usually normal, with only mild to moderate gallbladder tenderness during an attack and perhaps mild residual tenderness lasting several days after an attack.

Natural History

Biliary pain is cause for concern but not alarm. Approximately 30% of patients who have an attack of classic biliary pain will experience no additional attacks over the next 24 months. Therefore, a reasonable approach would be to offer cholecystectomy to patients with recurring episodes of biliary pain.²²⁴ In the remaining 70%, the frequency of recurrent attacks varies widely from patient to patient, but the pattern remains relatively constant for an individual patient over time. In patients monitored after an initial attack of biliary pain, symptoms sufficient to warrant cholecystectomy develop on average at a rate of approximately 6% per year. The cumulative risk that symptoms that require therapy will develop in asymptomatic persons with gallstones who are followed up for five years is 7.6%.²²⁵ The probability that a patient with a history of biliary pain will experience a complication of gallstones that requires urgent surgical intervention is only 1% to 2% per year.²²⁴

Diagnosis

In a patient with uncomplicated biliary pain, laboratory parameters are usually normal. Elevations of serum bilirubin, alkaline phosphatase, or amylase levels suggest coexisting choledocholithiasis.

In general, the first, and often the only, imaging study recommended in patients with biliary pain is ultrasound of the RUQ. Ultrasonography is rapid, noninvasive, highly sensitive, and highly specific for detecting stones in the gallbladder. Despite the impressive diagnostic accuracy of ultrasonography, a clinically important stone is occasionally missed and the correct diagnosis delayed because of the large number of patients who undergo ultrasonography for any reason.¹⁹⁵ Given the relatively benign natural history of biliary pain, patients with suspected gallstones but a negative ultrasonography result can safely be observed, further diagnostic testing being reserved for those in whom symptoms recur.²²⁶

Oral cholecystography is generally viewed as a secondary imaging study of the gallbladder and is reserved for patients in whom medical dissolution therapy or lithotripsy of gallstones is planned (see Chapter 66). In such cases, patency of the cystic duct must be confirmed by OCG before therapy. On rare occasions, OCG may demonstrate small floating gallstones that were missed by ultrasonography.

Differential Diagnosis

The differential diagnosis of recurrent, episodic upper abdominal symptoms includes reflux esophagitis, peptic ulcer, pancreatitis, renal colic, diverticulitis, carcinoma of the colon, irritable bowel syndrome, radiculopathy, and angina pectoris. Usually, a carefully taken history assists in narrowing the differential diagnosis. For example, relief of pain with food, antacids, or antisecretory drugs suggests peptic ulcer, whereas pain of a cramping nature suggests an intestinal disorder. The pain of angina pectoris usually is precipitated by exercise and does not last for hours, and the pain of renal stones usually is associated with abnormal findings on urinalysis. Like biliary pain, irritable bowel syndrome is common in young women, but pain is associated with altered bowel habits. The pain of shingles or a radiculopathy from osteoarthritis occasionally may resemble biliary pain.

Treatment

Patients with recurrent, uncomplicated biliary pain and documented gallstones are generally treated with elective laparoscopic cholecystectomy, as discussed in Chapter 66. Acute biliary pain improves with administration of meperidine, with or without ketorolac or diclofenac. Aspirin taken prophylactically has been reported to prevent gallstone formation as well as acute attacks of biliary pain in patients with gallstones, but long-term use of NSAIDs does not prevent gallstone formation.^227,228

Pathogenesis

Acute cholecystitis generally occurs when a stone becomes embedded in the cystic duct and causes chronic obstruction, rather than transient obstruction as in biliary pain.²²⁹ Stasis of bile within the gallbladder lumen results in damage of the gallbladder mucosa with consequent release of intracellular enzymes and activation of a cascade of inflammatory mediators.

In animal studies, if the cystic duct is ligated, the usual result is gradual absorption of the gallbladder contents without the development of inflammation²³⁰; the additional instillation of a luminal irritant, such as concentrated bile or lysolecithin, or trauma from an indwelling catheter is required to cause acute cholecystitis in an obstructed gallbladder.

Phospholipase A is believed to be released by gallstone-induced mucosal trauma and converts lecithin to lysolecithin. Although normally absent from gallbladder bile, lysolecithin is present in the gallbladder contents of patients with acute cholecystitis.²³¹ In animal models, installation of lysolecithin into the gallbladder produces acute cholecystitis associated with increased protein secretion, decreased water absorption, and evidence of white blood cell (WBC) invasion associated with elevated production of prostaglandins E and F_1α. Administration of indomethacin, a cyclooxygenase inhibitor, has been shown to block this inflammatory response.

Studies of human tissue obtained at cholecystectomy have demonstrated enhanced prostaglandin production in the inflamed gallbladder. Additionally, administration of intravenous indomethacin and oral ibuprofen to patients with acute cholecystitis has been shown to diminish both luminal pressure in the gallbladder and pain.²³¹

Supporting evidence for the role of prostaglandins in the development of acute cholecystitis comes from a prospective study in which patients who presented with biliary pain were randomized to receive diclofenac, a prostaglandin synthetase inhibitor, or placebo.²³² Ultimately, acute cholecystitis developed in 9 of 40 patients who received placebo, whereas episodes of biliary pain resolved in all 20 patients who received diclofenac. These data suggest a chain of events in which obstruction of the cystic duct in association with one or more intraluminal factors damages the gallbladder mucosa and stimulates prostaglandin synthetase. The resulting fluid secretion and inflammatory changes promote a cycle of further mucosal damage and inflammation.²³²

Enteric bacteria can be cultured from gallbladder bile in approximately one half of patients with acute cholecystitis.²³³ Bacteria are not believed, however, to trigger the actual onset of acute cholecystitis.

Pathology

If examined in the first few days of an attack of acute cholecystitis, the gallbladder usually is distended and contains a stone embedded in the cystic duct.²³⁴ After the gallbladder is opened, inflammatory exudate and, rarely, pus are present. Later in the attack, the bile pigments that are normally present are absorbed, having been replaced by thin mucoid fluid, pus, or blood. If the attack of acute cholecystitis is left untreated for a long period but the cystic duct remains obstructed, the lumen of the gallbladder may become distended with clear mucoid fluid, a condition known as hydrops of the gallbladder.

Histologic changes range from mild acute inflammation with edema to necrosis and perforation of the gallbladder wall. Surprisingly, the severity of histologic changes correlates little with the patient’s symptoms.²³⁴ If the gallbladder is resected for acute cholecystitis and no stones are found, the specimen should be carefully examined histologically for evidence of vasculitis or cholesterol emboli because these systemic disorders may manifest as acalculous cholecystitis (see Chapter 35).

Clinical Features

Approximately 75% of patients with acute cholecystitis report prior attacks of biliary pain (see Table 65-2).²³⁵ Often, such a patient is alerted to the possibility that more than simple biliary pain is occurring by the prolonged duration of the pain. If biliary pain has been constant for more than six hours, uncomplicated biliary pain is increasingly unlikely, and acute cholecystitis should be suspected.

As inflammation in the gallbladder wall progresses, poorly localized visceral pain gives way to moderately severe parietal pain that localizes to the RUQ.²³⁵ Less commonly the back or rarely the chest may be the site of maximal pain. Nausea with some vomiting is characteristic of acute cholecystitis, but these symptoms almost invariably follow, rather than precede, the onset of pain. Vomiting is not as persistent or as severe as that with intestinal obstruction or acute pancreatitis.

In some patients, the symptoms of acute cholecystitis are nonspecific, with only a mild ache and anorexia, whereas other patients may present with toxic manifestations, including fever and severe RUQ pain with guarding and localized rebound tenderness.

In contrast to uncomplicated biliary pain, the physical findings can, in many cases, suggest the diagnosis of acute cholecystitis. Fever is common, but body temperature is usually less than 102°F unless the gallbladder has become gangrenous or has perforated (Fig. 65-14). Mild jaundice is present in 20% of patients with acute cholecystitis and 40% of elderly patients. Serum bilirubin levels usually are less than 4 mg/dL.²³⁶ Bilirubin levels above this value suggest the possibility of bile duct stones, which may be found in 50% of jaundiced patients with acute cholecystitis. Another cause of pronounced jaundice in patients with acute cholecystitis is Mirizzi’s syndrome, which is associated with inflammatory obstruction of the common hepatic duct (see later).

Figure 65-14. Ultrasonography demonstrating a complex fluid collection adjacent to the gallbladder (GB), consistent with gallbladder perforation.

(Courtesy of Julie Champine, MD, Dallas, Tex.)

The abdominal examination often demonstrates right subcostal tenderness, with a palpable gallbladder in one third of patients. A palpable gallbladder is more common in patients having a first attack of acute cholecystitis because repeated attacks usually result in a scarred, fibrotic gallbladder that is unable to distend. For unclear reasons, the gallbladder is usually palpable lateral to its normal anatomic location.

A relatively specific finding of acute cholecystitis is Murphy’s sign.²³⁵ During palpation in the right subcostal region, pain and inspiratory arrest may occur when the patient takes a deep breath that brings the inflamed gallbladder into contact with the examiner’s hand. The presence of Murphy’s sign in the appropriate clinical setting is a reliable predictor of acute cholecystitis, although gallstones should still be confirmed by ultrasonography.

Natural History

The pain of untreated acute cholecystitis generally resolves in 7 to 10 days.²³⁷ Not uncommonly, symptoms remit within 48 hours of hospitalization. One study has shown that acute cholecystitis resolves without complications in approximately 83% of patients but results in gangrenous cholecystitis in 7%, gallbladder empyema in 6%, perforation in 3%, and emphysematous cholecystitis in fewer than 1%.²³⁸

Diagnosis

Perhaps because it is so common, acute cholecystitis is often at the top of the differential diagnosis of abdominal symptoms and is actually overdiagnosed when clinical criteria alone are considered. In a prospective series of 100 patients with RUQ pain and tenderness and suspected acute cholecystitis, this diagnosis was correct in only two thirds of cases. The clinician must therefore use laboratory and imaging studies to confirm the presence of acute cholecystitis, exclude complications such as gangrene and perforation, and look for alternative causes of the clinical findings.

Table 65-3 details the most common laboratory findings in acute cholecystitis.²³⁷ Leukocytosis with a shift to immature neutrophils is common. Because a diagnosis of bile duct stones with cholangitis usually is in the differential diagnosis, attention is directed to results of liver biochemical tests.²³⁶ Even without any detectable bile duct obstruction, acute cholecystitis often causes mild elevations in serum aminotransferase and alkaline phosphatase levels. As noted earlier, the serum bilirubin level may also be mildly elevated (2 to 4 mg/dL), and even serum amylase and lipase values may be elevated nonspecifically. A serum bilirubin value greater than 4 mg/dL or amylase value greater than 1000 U/L usually indicates coexisting bile duct obstruction or acute pancreatitis and warrants further evaluation.

When the level of leukocytosis exceeds 15,000 cells/mm³, particularly in the setting of worsening pain, high fever (temperature > 102°F), and chills, suppurative cholecystitis (empyema) or perforation should be suspected, and urgent surgical intervention may be required. Such advanced gallbladder disease may be present even if local and systemic manifestations are unimpressive.

Ultrasonography is the single most useful imaging study in acutely ill patients with RUQ pain and tenderness. It accurately establishes the presence or absence of gallstones and serves as an extension of the physical examination. Presence of sonographic Murphy’s sign, defined as focal gallbladder tenderness under the transducer, has a positive predictive value greater than 90% for detecting acute cholecystitis if gallstones are also present, the operator is skillful, and the patient is alert.²³⁹ Additionally, ultrasonography can detect nonspecific findings suggestive of acute cholecystitis, such as pericholecystic fluid and gallbladder wall thickening greater than 4 mm. Both findings lose specificity for acute cholecystitis if the patient has ascites or hypoalbuminemia.^195,240

Because the prevalence of gallstones is high in the population, many patients with nonbiliary tract diseases that manifest as acute abdominal pain (such as acute pancreatitis and complications of peptic ulcer) may have incidental and clinically irrelevant gallstones. The greatest usefulness of cholescintigraphy in these patients is its ability to exclude acute cholecystitis and allow the clinician to focus on nonbiliary causes of the patient’s acute abdominal pain.¹⁸⁸ A normal cholescintigraphy scan result shows radioactivity in the gallbladder, bile duct, and small intestine within 30 to 60 minutes of injection of the isotope. With rare exceptions, a normal result excludes acute cholecystitis caused by gallstones. Several studies have suggested that the sensitivity and specificity of scintigraphy in the setting of acute cholecystitis are approximately 94% each. Its sensitivity and specificity are reduced considerably, however, in patients who have liver disease, are receiving parenteral nutrition, or are fasting. These conditions can lead to a false-positive scan result, defined as the absence of isotope in the gallbladder in a patient who does not have acute cholecystitis. If a positive scan result is defined as the absence of isotope in the gallbladder, then a false-negative scan result would be defined as filling of the gallbladder with isotope in the setting of acute cholecystitis, a situation that virtually never occurs. Therefore, scintigraphy should not be used as the initial imaging study in a patient with suspected cholecystitis but rather should be used as a secondary imaging study in patients who already are known to have gallstones and in whom a nonbiliary cause of acute abdominal pain is possible.²⁴¹

In an effort to reduce the occurrence of false-positive cholescintigraphy scan results, morphine can be administered to the patient if the gallbladder has failed to be visualized after 60 minutes. As discussed earlier, by increasing pressure within the sphincter of Oddi, administration of morphine directs bile into the gallbladder unless the cystic duct is obstructed. Additional scans obtained 30 minutes after the injection of morphine occasionally show filling of the gallbladder with isotope, thereby excluding cystic duct obstruction. Unfortunately, despite the use of morphine augmentation, cholescintigraphy continues to have a false-positive rate of 60% in critically ill patients.

The greatest usefulness of abdominal CT in patients with acute cholecystitis is to detect complications such as emphysematous cholecystitis and perforation of the gallbladder. At the same time, CT can exclude other intra-abdominal processes that may engender a similar clinical picture. For example, abdominal CT is highly sensitive for detecting pneumoperitoneum, acute pancreatitis, pancreatic pseudocysts, hepatic or intra-abdominal abscesses, appendicitis, and obstruction or perforation of a hollow viscus. An abdominal CT scan usually is not warranted in patients with obvious acute cholecystitis, but if the diagnosis is uncertain or the optimal timing of surgery is in doubt, CT may be invaluable.

Differential Diagnosis

The principal conditions to consider in the differential diagnosis of acute cholecystitis are appendicitis, acute pancreatitis, pyelonephritis or renal calculi, peptic ulcer, acute hepatitis, pneumonia, hepatic abscess or tumor, and gonococcal or chlamydial perihepatitis. These possibilities should be considered before a cholecystectomy is recommended.

Acute appendicitis is the disease most often confused with acute cholecystitis because the initial diagnostic impression is based largely on localized right-sided abdominal tenderness, which may be lower than expected in cholecystitis or higher than expected in appendicitis. In general, fever, leukocytosis, and tenderness progress more inexorably in appendicitis. Abdominal CT usually can distinguish these two entities (see Chapter 116).

Acute pancreatitis also may be difficult to distinguish from acute cholecystitis on the basis of the history and physical examination alone. Generally, vomiting is a more prominent feature of acute pancreatitis, and affected persons are more uncomfortable in a supine position. Hyperamylasemia is more profound in pancreatitis than cholecystitis, and an elevated serum lipase value is more specific (see Chapter 58).

Diseases of the right kidney may produce pain and tenderness that mimic findings in acute cholecystitis, but urinalysis and ultrasonography can usually differentiate renal disease from cholecystitis. The pain of an uncomplicated peptic ulcer is usually chronic and seldom confused with that of acute cholecystitis, but a perforated ulcer, at least initially, may mimic severe acute cholecystitis. Signs of generalized peritonitis or pneumoperitoneum strongly suggest a perforated viscus, necessitating emergency laparotomy (see Chapters 10 and 52).

Pneumonia with pleurisy may cause abdominal pain and tenderness, but the pleuritic nature of the pain and the chest radiograph findings should suggest the correct diagnosis.

In some instances, acute hepatitis, especially when caused by alcohol, may manifest as severe RUQ pain and tenderness, fever, and leukocytosis and may be confused diagnostically with acute cholecystitis. In such cases, careful assessment of the liver biochemical values over time in combination with ultrasonography or cholescintigraphy may exclude a diagnosis of acute cholecystitis. Rarely, liver biopsy may be warranted (see Chapters 77 to 81 and 84).

Gonococcal perihepatitis (Fitz-Hugh–Curtis syndrome) produces RUQ pain and tenderness, which often overshadow any pelvic complaints, as well as leukocytosis. Nevertheless, adnexal tenderness is found on physical examination, and a Gram stain of the cervical smear should show gonococci (see Chapter 37).

Hepatic abscesses and tumors usually can be differentiated from acute cholecystitis on the basis of ultra-sonographic findings. Prior undiagnosed gallbladder perforation may manifest with fever from a subhepatic abscess. Pseudolithiasis due to ceftriaxone therapy, most often in children, has caused symptoms resembling those of acute cholecystitis, although the gallbladder is histologically normal (see Chapters 82 and 94).

Treatment

The patient in whom acute cholecystitis is suspected should be hospitalized. The patient is often hypovolemic from vomiting and poor oral intake, and fluid and electrolytes should be administered intravenously. Oral feeding should be withheld and a nasogastric tube inserted if the patient has a distended abdomen or is vomiting persistently.

In uncomplicated cases of acute cholecystitis, antibiotics need not be given. Antibiotics are warranted if the patient appears particularly toxic or a complication such as perforation of the gallbladder or emphysematous cholecystitis is suspected. Antibiotics that cover gram-negative enteric bacteria are effective. Coverage with a single agent such as cefoxitin is appropriate in mild cases, but more severely ill patients should receive broad-spectrum coverage with ampicillin and an aminoglycoside or with a third-generation cephalosporin and metronidazole.

Definitive therapy of acute cholecystitis consists of cholecystectomy. The safety and effectiveness of using a laparoscopic approach in the setting of acute cholecystitis have been demonstrated (see Chapter 66).²⁴²

Etiology

Gallstones may pass from the gallbladder into the bile duct or can form de novo in the duct. Generally, all gallstones from one patient, whether from the gallbladder or bile duct, are of one type, either cholesterol or pigment. Cholesterol stones form only in the gallbladder, and any cholesterol stones found in the bile duct must have migrated there from the gallbladder. Black pigment stones, which are associated with old age, hemolysis, alcoholism, and cirrhosis, also form in the gallbladder and only rarely migrate into the bile duct. The majority of pigment stones in the bile duct are the softer brown pigment stones. These stones form de novo in the bile duct as a result of bacterial action on phospholipid and bilirubin in bile (see earlier).²⁴³ They are often found proximal to biliary strictures and are frequently associated with cholangitis. Brown pigment stones are found in patients with hepatolithiasis and recurrent pyogenic cholangitis (see Chapter 68).²⁴⁴

Fifteen percent of patients with gallbladder stones also have bile duct stones. Conversely, of patients with ductal stones, 95% also have gallbladder stones.²⁴⁵ In patients who present with choledocholithiasis months or years after a cholecystectomy, determining whether the stones were overlooked at the earlier operation or have subsequently formed may be impossible. In fact, formation of pigment stones in the bile duct is also a late complication of endoscopic sphincterotomy.²⁴⁶ In a study of the long-term consequences of endoscopic sphincterotomy in more than 400 patients, the cumulative frequency of recurrent bile duct stones was 12%; all the recurrent stones were of the brown pigment type, irrespective of the chemical composition of the original gallstones. This observation suggests that sphincterotomy permits chronic bacterial colonization of the bile duct that results in deconjugation of bilirubin and precipitation of pigment stones.

Stones in the bile duct usually come to rest at the lower end of the ampulla of Vater. Obstruction of the bile duct raises bile pressure proximally and causes the ducts to dilate. Pressure in the bile duct is normally 10 to 15 cm H₂O and rises to 25 to 40 cm H₂O with complete obstruction. When pressure exceeds 15 cm H₂O, bile flow decreases, and at 30 cm H₂O, bile flow stops.

The bile duct dilates to the point that dilatation can be detected on either ultrasonography or abdominal CT in approximately 75% of cases. In the patient who has had recurrent bouts of cholangitis, the bile duct may become fibrotic and thus unable to dilate. Moreover, dilatation of the duct is sometimes absent in patients with choledocholithiasis because the obstruction is low-grade and intermittent.

Clinical Features

The morbidity of choledocholithiasis stems principally from biliary obstruction, which raises biliary pressure and diminishes bile flow. The rate of onset of obstruction, its extent, and the amount of bacterial contamination of the bile are the major factors that determine the resulting symptoms. Acute obstruction usually causes biliary pain and jaundice, whereas obstruction that develops gradually over several months may manifest initially as pruritus or jaundice alone.²⁴⁷ If bacteria proliferate, life-threatening cholangitis may result (see later).

The physical findings are usually normal if obstruction of the bile duct is intermittent. Mild to moderate jaundice may be noted when obstruction has been present for several days to a few weeks. Deep jaundice without pain, particularly with a palpable gallbladder (Courvoisier’s sign), suggests neoplastic obstruction of the bile duct, even when the patient has stones in the gallbladder. With longstanding obstruction, secondary biliary cirrhosis may result, leading to physical findings of chronic liver disease.

As shown in Table 65-2, results of laboratory studies may be the only clue to the presence of choledocholithiasis.²⁴⁸ With bile duct obstruction, serum bilirubin and alkaline phosphatase levels both increase. Bilirubin accumulates in serum because of blocked excretion, whereas alkaline phosphatase levels rise because of increased synthesis of the enzyme by the canalicular epithelium. The rise in the alkaline phosphatase level is more rapid than and precedes the rise in bilirubin level.²⁴⁹ The absolute height of the serum bilirubin level is proportional to the extent of obstruction, but the height of the alkaline phosphatase level bears no relation to either the extent of obstruction or its cause. In cases of choledocholithiasis, the serum bilirubin level is typically in the range of 2 to 5 mg/dL²⁰⁵ and rarely exceeds 12 mg/dL. Transient “spikes” in serum aminotransferase or amylase levels suggest passage of a bile duct stone into the duodenum. The overall sensitivity of liver biochemical testing for detecting choledocholithiasis is reported to be 94%; serum levels of gamma glutamyl transpeptidase are elevated most commonly but may not be assessed in clinical practice.²⁴⁹

Natural History

Little information is available on the natural history of asymptomatic bile duct stones. In many patients such stones remain asymptomatic for months or years, but available evidence suggests that the natural history of asymptomatic bile duct stones is less benign than that of asymptomatic gallstones.^247,250

Diagnosis

Ultrasonography actually visualizes bile duct stones in only about 50% of cases,¹⁹⁹ whereas dilatation of the bile duct to a diameter greater than 6 mm is seen in about 75% of cases. Ultrasonography can confirm, or at least suggest, the presence of bile duct stones but cannot exclude choledocholithiasis definitively. EUS, although clearly more invasive than standard ultrasonography, has the advantage of visualizing the bile duct more accurately. In preliminary studies, EUS has excluded or confirmed choledocholithiasis with sensitivity and specificity rates of approximately 98% as compared with ERCP.²⁰³

ERCP is the standard method for the diagnosis and therapy of bile duct stones,²⁵¹ with sensitivity and specificity rates of approximately 95%. When the clinical probability of choledocholithiasis is low, however, less invasive studies, such as EUS and MRCP, should be performed first.²¹⁶

Percutaneous transhepatic cholangiography (percutaneous THC) is also an accurate test for confirming the presence of choledocholithiasis. The procedure is most readily accomplished when the intrahepatic bile ducts are dilated and now is performed primarily when ERCP is unavailable or has been technically unsuccessful.

Laparoscopic ultrasonography may be used in the surgical suite immediately before mobilization of the gallbladder during cholecystectomy. Laparoscopic ultrasonography may be as accurate as surgical cholangiography in detecting bile duct stones and may thereby obviate the need for the latter.²⁵²

Differential Diagnosis

Symptoms caused by obstruction of the bile duct cannot be distinguished from those caused by obstruction of the cystic duct. Therefore, biliary pain is always in the differential diagnosis in patients with an intact gallbladder. The presence of jaundice or abnormal liver biochemical test results strongly points to the bile duct rather than the gallbladder as the source of the pain.

In patients who present with jaundice, malignant obstruction of the bile duct or obstruction from a choledochal cyst may be indistinguishable clinically from choledocholithiasis (see Chapters 62 and 69).

Acute passive congestion of the liver, associated with cardiac decompensation, may cause intense RUQ pain, tenderness, and even jaundice with serum bilirubin levels higher than 10 mg/dL (see Chapter 83); however, fever is usually absent, and the WBC count is normal or only slightly elevated. The patient typically has other obvious signs of cardiac decompensation. Constrictive pericarditis and cor pulmonale also may cause acute congestion of the liver with only subtle cardiac findings.

Acute viral hepatitis rarely may cause severe RUQ pain with tenderness and fever. The WBC count, however, usually is not elevated, whereas serum alanine aminotransferase and aspartate aminotransferase levels are markedly elevated.

Acquired immunodeficiency syndrome (AIDS)-associated cholangiopathy²⁵³ and papillary stenosis must be considered in human immunodeficiency virus–positive patients with RUQ pain and abnormal liver biochemical test results (see Chapter 33).

Treatment

Because of its propensity to result in serious complications such as cholangitis and acute pancreatitis, choledocholithiasis warrants treatment in nearly all cases.²⁵⁴ The optimal therapy for a given patient depends on the severity of symptoms, presence of coexisting medical problems, availability of local expertise, and presence or absence of the gallbladder.

Bile duct stones discovered at the time of a laparoscopic cholecystectomy present a dilemma to the surgeon. Some surgeons may attempt laparoscopic exploration of the bile duct. In other cases, the operation can be converted to an open cholecystectomy with bile duct exploration, but this approach results in greater morbidity and a more prolonged hospital stay. Alternatively, the laparoscopic cholecystectomy can be carried out as planned, and the patient can return for ERCP with removal of the bile duct stones. Such an approach, if successful, cures the disease but runs the risk of necessitating a third procedure, namely a bile duct exploration, if the stones cannot be removed at ERCP. In general, the greater the expertise of the therapeutic endoscopist, the more inclined the surgeon should be to complete the laparoscopic cholecystectomy and have the bile duct stones removed endoscopically.²⁵⁴

In especially high-risk patients, endoscopic removal of bile duct stones may be performed without cholecystectomy. This approach is particularly appropriate for elderly patients with other severe illnesses.²⁵⁵ Cholecystectomy is required subsequently for recurrent symptoms in only 10% of patients. The surgical management and endoscopic treatment of gallstones are discussed in detail in Chapters 66 and 70, respectively.

Etiology and Pathophysiology

In approximately 85% of cases, cholangitis is caused by a stone embedded in the bile duct, with resulting bile stasis.²⁵⁷ Other causes of bile duct obstruction that may result in cholangitis are neoplasms (see Chapters 60 and 69), biliary strictures (see Chapters 68 and 70), parasitic infections (see Chapters 68 and 82), and congenital abnormalities of the bile ducts (see Chapter 62). This discussion deals specifically with cholangitis caused by gallstones in the bile duct.

Bile duct obstruction is necessary, but not sufficient, to cause cholangitis. Cholangitis is relatively common in patients with choledocholithiasis and nearly universal in patients with a post-traumatic bile duct stricture but is seen in only 15% of patients with neoplastic obstruction of the bile duct. It is most likely to result when a bile duct that already contains bacteria becomes obstructed, as is the case in most patients with choledocholithiasis and stricture but in few patients with neoplastic obstruction. Malignant obstruction is more often complete than obstruction by a stricture or a bile duct stone and less commonly permits the reflux of bacteria from duodenal contents into the bile ducts.²⁵⁸

The bacterial species most commonly cultured from the bile are E. coli, Klebsiella, Pseudomonas, Proteus, and enterococci. Anaerobic species such as Bacteroides fragilis and Clostridium perfringens are found in about 15% of appropriately cultured bile specimens. Anaerobes usually accompany aerobes, especially E. coli. The shaking chills and fever of cholangitis are caused by bacteremia from bile duct organisms. The degree of regurgitation of bacteria from bile into hepatic venous blood is directly proportional to the biliary pressure and, hence, the degree of obstruction.²⁵⁸ For this reason, decompression alone often effectively treats the illness.

Clinical Features

The hallmark of cholangitis is Charcot’s triad, consisting of RUQ pain, jaundice, and fever (see Table 65-2). The full triad is present in only 70% of patients.²⁵⁸ The pain of cholangitis may be surprisingly mild and transient but is often accompanied by chills and rigors. Elderly patients in particular may present solely with mental confusion, lethargy, and delirium. Altered mental status and hypotension in combination with Charcot’s triad, known commonly as Reynolds’ pentad, occur in severe suppurative cholangitis.

On physical examination, fever is almost universal, occurring in 95% of patients. RUQ tenderness is elicited in approximately 90% of patients, but jaundice is clinically detectable in only 80%. Notably, peritoneal signs are found in only 15% of patients. The combination of hypotension and mental confusion indicates gram-negative septicemia. In overlooked cases of severe cholangitis, intrahepatic abscess may manifest as a late complication (see Chapter 82).

Laboratory study results are often helpful in pointing to the biliary tract as the source of sepsis. In particular, the serum bilirubin level exceeds 2 mg/dL in 80% of patients. When the bilirubin level is normal initially, the diagnosis of cholangitis may not be suspected.²⁴⁹ The WBC count is elevated in 80% of patients. In many patients who have a normal WBC count, examination of the peripheral blood smear reveals a dramatic shift to immature neutrophil forms. The serum alkaline phosphatase level is usually elevated, and the serum amylase level may also be elevated if pancreatitis is also present.

In the majority of cases, blood culture results are positive for enteric organisms, especially if culture specimens are obtained during chills and fever spikes. The organism found in the blood is invariably the same as that found in the bile.

Diagnosis

The principles of radiologic diagnosis of cholangitis are the same as those for choledocholithiasis. As shown in Table 65-3, stones in the bile duct are seen ultrasonographically in only about 50% of cases¹⁵⁵ but can be inferred by detection of a dilated bile duct in about 75% of cases. Normal ultrasonography findings do not exclude the possibility of choledocholithiasis in a patient in whom the clinical presentation suggests cholangitis.²⁴¹

An abdominal CT is an excellent test for excluding complications of gallstones such as acute pancreatitis and abscess, but a standard abdominal CT scan is not capable of excluding bile duct stones. EUS and MRC, as noted earlier, have a much higher accuracy rate than CT for detecting and excluding stones in the bile duct.

ERCP is the standard test for the diagnosis of bile duct stones and cholangitis. Moreover, the ability of ERCP to establish drainage of infected bile under pressure can be life-saving. If ERCP is unsuccessful, percutaneous THC can be performed (see Chapter 70).

Treatment

In cases of suspected bacterial cholangitis, blood culture specimens should be obtained immediately and therapy started with antibiotics effective against the likely causative organisms.²⁵⁹ In mild cases, initial therapy with a single drug, such as cefoxitin, 2.0 g intravenously every six to eight hours, is usually sufficient. In severe cases, more intensive therapy (e.g., gentamicin, ampicillin, and metronidazole or a broad-spectrum agent such as piperacillin-tazobactam 3.375 g intravenously every six hours or, if resistant organisms are suspected, meropenem 1 g intravenously every eight hours) is indicated.

The patient’s condition should improve within 6 to 12 hours, and in most cases, the infection comes under control within 2 to 3 days, with defervescence, relief of discomfort, and a decline in the WBC count. In these cases, definitive therapy can be planned on an elective basis. If, however, after 6 to 12 hours of careful observation, the patient’s clinical status declines with worsening fever, pain, mental confusion, or hypotension, the bile duct must be decompressed immediately.²⁵⁹ If available, ERCP with stone extraction, or at least decompression of the bile duct with an intrabiliary stent, is the treatment of choice. Controlled studies in which ERCP and decompression of the bile duct were compared with emergency surgery and bile duct exploration have shown dramatically lower morbidity and mortality rates in patients treated endoscopically.²⁵⁴ The surgical treatment and endoscopic management of cholangitis are discussed in detail in Chapters 66 and 70, respectively.