Investigators have used many different definitions of biliary sludge, and this has made it difficult to compare various studies. On ultrasonography, sludge appears as low-level echoes that layer in the dependent portion of the gallbladder without acoustic shadowing (Figure 1) (2). It generally shifts slowly with positioning. On microscopy, sludge has been defined as a mixture of particulate matter and bile that occurs when various solutes in bile precipitate (3-5). The criteria for differentiating between particulate matter and small stones are not entirely clear, but it has been suggested that a stone be defined as a particle with a diameter greater than 2 mm that cannot be crushed by digital compression (4). Clinically, biliary sludge is almost always an ultrasonographic diagnosis.

View larger version (85K): [in this window] [in a new window]   Figure 1. Biliary sludge on ultrasonography. Top. Biliary sludge appears as low-amplitude echoes without postacoustic shadowing. Bottom. The echoes layer in the dependent portion of the gallbladder and shift slowly with positioning. (Courtesy of Dr. Tom Winter, University of Washington, Seattle, Washington.).

In this review, we focus on the diagnosis, clinical significance, and treatment of biliary sludge and suggest a protocol for diagnostic bile microscopy.

Methods

Top Methods Author & Article Info References

We identified studies by performing MEDLINE searches for English-language articles published between 1966 and 1998, reviewing citations from selected publications, and examining abstracts from selected meetings. Basic science and clinical studies on sludge and gallstones were selected by consensus. Each study was examined with careful attention to methods, and data were abstracted for further analysis. The agency funding our study had no role in the conception of this work or the decision to submit it for publication.

Chemical Composition

Biliary sludge is most commonly composed of cholesterol monohydrate crystals, calcium bilirubinate granules, or other calcium salts embedded in strands of gallbladder mucus (3). Proteins and xenobiotics, such as ceftriaxone, are also important components. Sludge contains a large proportion of undefined residue, protein-lipid complexes, and mucin (6). Calcium bilirubinate granules are almost invariably present, and bilirubin is usually found in its unconjugated, least soluble form (5). The source of the unconjugated bilirubin is controversial. Bilirubin is excreted by the liver mainly in its diglucuronide form, but small amounts of the monoglucuronide and unconjugated forms are also seen. The enzyme ß-glucuronidase, which deconjugates bilirubin, may be important. Conditions in which the activity of this enzyme is increased, such as chronic low-grade biliary infection, are associated with pigment gallstones. ß-glucuronidase has also been identified in uninfected bile, probably having originated in the biliary epithelium (7, 8). Nonenzymatic hydrolysis of bilirubin may occur (9).

The chemical composition of sludge varies with the clinical situation. In the general population, sludge is composed of calcium bilirubinate and cholesterol monohydrate crystals in various proportions (5). In patients receiving total parenteral nutrition, sludge consists primarily of calcium bilirubinate (3); in pregnant women, cholesterol monohydrate predominates (Lee SP. Unpublished data). In patients receiving high-dose ceftriaxone therapy, sludge is composed of calcium-ceftriaxone complexes (10).

Pathogenesis

Bile is a complex solution with many constituents, including lipids, proteins, bilirubin, and inorganic anions. Sludge formation depends on the physical-chemical interactions of all of these constituents, abnormalities of gallbladder mucosal function, and gallbladder dysmotility. It has been hypothesized that gallstones are formed from sludge by further precipitate aggregation, and it is generally thought that sludge is a necessary precursor to gallstones. For example, after chemical dissolution of gallstones, gallbladder sludge is usually seen on ultrasonography before gallstone recurrence (11). Thus, most investigators think that the pathogenesis of sludge is similar to that of gallstones; this topic is reviewed elsewhere (12-16). However, controversy remains about the fact that sludge resolves spontaneously in most persons and that gallstones form in only a small minority of persons with sludge. This suggests to some that sludge is not a precursor to gallstones and that the pathogenesis of the two entities differs. Nevertheless, it is difficult to imagine that gallstones could form from clear bile without the intermediate formation of microprecipitates. How the microprecipitates aggregate and grow to form well-ordered, structured gallstones remains to be determined.

Diagnosis

Clinically, sludge is most often diagnosed ultrasonographically, according to the criteria defined above (17). The ultrasonographic pattern can be produced by calcium bilirubinate granules or cholesterol monohydrate crystals as small as 0.5 to 1 mm in diameter mixed with bile and mucus, independent of bile viscosity (2). Other entities, including blood, necrotic debris, multiple small gallstones, or pus, can also have an appearance similar to that of sludge. However, the sensitivity of transabdominal ultrasonography for sludge is only about 55%, and this procedure cannot define the chemical composition of the microprecipitates. The appearance of sludge on endoscopic ultrasonography is similar to that on transabdominal ultrasonography, and the sensitivity of endoscopic ultrasonography is approximately 96% (18, 19). On computed tomography, sludge has greater attenuation than normal bile and layers within the gallbladder (20, 21). Its appearance on magnetic resonance imaging has not been well characterized.

Direct microscopic examination of the contents of the gallbladder is more sensitive than ultrasonography in the detection of sludge. Thus, even though it is less clinically applicable than ultrasonography, the microscopic examination of bile is considered the diagnostic gold standard. In addition, microscopy allows the chemical composition of sludge to be defined by precipitate structure (Figure 2).

View larger version (95K): [in this window] [in a new window]   Figure 2. Biliary sludge on microscopy. Left. Cholesterol monohydrate crystals appear as rhomboid plates. Right. Pigment granules appear as reddish-brown, amorphous clumps.

Many different protocols for bile microscopy have been described, and some measures can maximize the sensitivity of this procedure. It should be recognized that gallbladder bile is preferred, if not essential, for examination. Although hepatic bile can be supersaturated with cholesterol, rapid transit through the biliary ductal system rarely allows enough time for hepatic bile to form a solid crystal large enough to be detectable on microscopy (22-25). Hepatic bile is invariably yellow and free of precipitate, even when the gallbladder contains sludge and stones. Thus, using ductal bile to look for sludge in patients with intact gallbladders is inappropriate.

We suggest a protocol for the microscopic examination of bile for crystals. The first step is to obtain the necessary sample of gallbladder bile. For patients undergoing endoscopy, aspiration of the duodenal contents after cholecystokinin infusion, 0.05 to 0.1 mg/kg of body weight intravenously over 10 minutes, is acceptable. Cholecystokinin promotes gallbladder emptying by stimulating contraction of the gallbladder and relaxation of the sphincter of Oddi. Sampling for 10 to 20 minutes after the infusion usually yields 5 to 15 mL of dark duodenal contents that include gallbladder bile. Radiologic contrast used in endoscopic retrograde cholangiopancreatography does not interfere with subsequent examination. For patients not undergoing endoscopy, a nasogastric tube may be placed in the duodenum under fluoroscopic guidance. A cholecystokinin infusion is started, and intermittent mild negative suction (–5 to –10 mm Hg) is applied for 20 minutes, yielding 5 to 15 mL of duodenal fluid that contains gallbladder bile.

Next, the sample is spun in a bench centrifuge at 3000 g for 15 minutes. Whether the temperature should be controlled at 37 °C is a subject of debate. In our experience, this control is difficult to achieve and does not improve accuracy. However, if bile samples are frozen and examined later, many false-positive results can occur. With freezing, cholesterol crystals may form that will not redissolve. If fresh bile cannot be examined immediately, it should be centrifuged. The sediment collected can be safely frozen and examined later. Whole bile samples cannot be simply refrigerated because bacterial contamination may occur.

The sediment is transferred to a glass slide with a drop of distilled water and is examined under light or polarizing microscopy. Gallbladder bile is normally brown and clear without precipitates. Cholesterol monohydrate crystals appear as rhomboid plates, often with a median notch (Figure 2, left). They can be present as simple crystals, in clumps, in stacks, or as small spherules of crystalline materials (26). Calcium bilirubinate granules appear as brownish or reddish-brown clumps (Figure 2, right) (4).

Bile microscopy is a qualitative assay; thus, quantification of the crystals (the amount of which depends on the sampling method) is not strictly necessary. In addition, it is not clear that the number of crystals correlates with clinical symptoms. In our studies, we regard more than two crystals per 100x field or more than four crystals per sample as a positive test result. Each sample is examined in triplicate with positive and negative controls.

Clinical Course and Complications

The reported prevalence of biliary sludge varies widely. Most studies have examined patients in specific clinical situations, such as pregnancy or critical illness. Natural history studies are usually based on ultrasonographic diagnoses, without microscopic confirmation or determination of chemical composition. It is therefore not known whether the natural history of calcium bilirubinate-predominant sludge differs from that of cholesterol monohydrate-predominant sludge.

Studies of the natural history of biliary sludge are few, and many of them are limited by inadequate follow-up (Table 1) (11, 27, 28). Only one large study (11) has been done with a well-defined follow-up protocol. In this study, three clinical outcomes were seen: complete resolution, a waxing and waning course, and gallstone formation. From this and other, less rigorous studies, it seems that sludge found in patients with abdominal pain spontaneously disappears in about 50% of cases and persists asymptomatically in about 20% of cases over a 3-year period. Over the same period, symptoms may develop in 10% to 15% of patients and stones may develop in 5% to 15% of patients. If a specific precipitating cause for sludge exists, sludge usually resolves upon the removal of that cause. If the precipitating event recurs or persists, gallstones can form (27). For instance, sludge and gallstones often coexist after multiple pregnancies (32) or prolonged administration of total parenteral nutrition (33).

Like gallstones, sludge is most often asymptomatic. However, in addition to predisposing to gallstone formation, sludge can lead to such complications as biliary colic (11, 28, 34). About 31% of patients with nonalcoholic pancreatitis have sludge, and up to 74% of patients with "idiopathic" pancreatitis (in which excess alcohol use, gallstones, metabolic abnormalities, and drug-related causes have been excluded) have been shown to have sludge (35, 36). Other reported complications of sludge include cholangitis and acute "acalculous" cholecystitis (37, 38).

In contrast, some studies have shown no complications of sludge other than gallstone formation. These have generally varied, shorter-term studies of asymptomatic patients in specific clinical situations. In addition, protocols and follow-up in these studies have varied, and the results may not be generalizable (29-31). Thus, the overall rate of complications from sludge is difficult to estimate, and factors predicting the development of complications are unknown. Nevertheless, approximately 10% of persons with sludge develop biliary colic, and a smaller percentage develop other complications, including acute pancreatitis.

If one accepts that sludge can cause problems, then a more provocative hypothesis is that the pain and inflammation seen in gallstone disease are mediated by the presence of sludge. For example, symptomatic patients with gallstones who received ursodeoxycholic acid treatment had resolution of their symptoms in 3 months, although the number and size of their gallstones did not change (39). It is likely that cholesterol crystals in their bile dissolved before the gallstones did. Asymptomatic patients with gallstones who are receiving shock-wave lithotripsy can develop biliary colic, cholecystitis, or acute pancreatitis (40-43). In these patients, sludge may have been created iatrogenically.

Specific Clinical Situations

Biliary sludge has been reported in many diverse clinical settings, including pregnancy (44, 45), rapid weight loss (46), critical illness (47), prolonged fasting (48), and long-term administration of total parenteral nutrition (33, 29, 49). It has also been reported in patients receiving ceftriaxone (50-52) or octreotide (53-55) and in recipients of bone marrow or solid organ transplants (30, 56-59) (Table 2). The pathophysiology and chemical composition of sludge differ in each of these settings.

Pregnancy

Epidemiologic studies show a high prevalence of sludge in the peripartum period (44, 45). In pregnant women, the incidence of sludge is 26% to 31% and the incidence of gallstones is 2% to 5%. Most of the women studied were asymptomatic throughout pregnancy and the peripartum period. Although age, obesity, and cumulative months of oral contraceptive use are risk factors for gallstones, no clear risk factors for sludge have been identified. Stones and sludge resolve in many women during the first year after delivery. However, it is hypothesized that women with multiple or closely spaced pregnancies may form gallstones as sludge recurs or persists.

Sludge in pregnancy consists of cholesterol monohydrate crystals. The high prevalence of sludge and gallstones in pregnant women may be due to greater bile lithogenicity and gallbladder hypomotility. The higher estrogen levels seen in pregnancy indirectly increase cholesterol saturation of bile (60-63). Higher progesterone levels may inhibit gallbladder contractility (64, 65).

Rapid Weight Loss

Numerous studies have documented an excess incidence of gallstones during rapid weight loss. Few have specifically studied the incidence of sludge. Shiffman and colleagues (46) found gallbladder sludge in 13% and gallstones in 26% of previously asymptomatic patients 6 to 18 months after proximal gastric bypass surgery (46). No risk factors for the development of sludge or gallstones were identified.

Sludge and gallstones associated with weight loss are composed primarily of cholesterol. During weight loss, the amount of cholesterol secreted into bile increases as excess cholesterol is mobilized from peripheral adipose tissue (46, 66-69). Thus, the degree of cholesterol saturation of bile increases, on average (66, 67, 69, 70), although this is not seen uniformly in all persons. Gallbladder stasis is also a contributing factor because gallbladder motility decreases with low-calorie diets, with prolonged fasting, or after major abdominal surgery (48, 71-74). This effect may be negated by including adequate calories or dietary fat to maximally stimulate gallbladder contraction (75, 76).

Critical Illness, Prolonged Fasting, and Total Parenteral Nutrition

Critically ill patients can develop sludge after 5 to 10 days of fasting (47, 48). A potential etiologic factor is the administration of total parenteral nutrition. Of patients without preexisting hepatobiliary disease who receive total parenteral nutrition, sludge forms in 6% after 3 weeks, in 50% after 4 to 6 weeks, and in 100% after 6 weeks of therapy (33). Twenty-six percent may develop gallstones during or after total parenteral nutrition therapy and may require cholecystectomy. Sludge generally persists while patients are receiving total parenteral nutrition but resolves with discontinuation of this therapy.

Sludge in this setting is composed primarily of calcium bilirubinate. Total parenteral nutrition induces changes in bile composition that increase lithogenicity, including higher bilirubin, calcium, and phospholipid concentrations (77, 78). In addition, cholesterol saturation increases and nucleation time (the time to initial precipitate formation) decreases (78, 79). Gallbladder dysmotility is also postulated as an important factor in these patients. Dysmotility may occur after major abdominal surgery, prolonged fasting, or total parenteral nutrition (74, 78, 80). Therefore, biliary sludge induced by total parenteral nutrition forms as a result of a combination of increased bile lithogenicity and gallbladder stasis.

Ceftriaxone

Between 25% and 46% of initially asymptomatic patients treated with ceftriaxone develop sludge, but symptoms occur in only a minority of these patients (81). Precipitates form after approximately 9 days of treatment but resolve after the discontinuation of ceftriaxone therapy in most cases. However, cases of ceftriaxone-associated gallstones, biliary colic, and acute cholecystitis have been reported (82). Of patients receiving long-term ceftriaxone therapy for Lyme disease, 2% developed gallbladder disease, and more than half of these patients required cholecystectomy. Risk factors for the development of gallbladder disease include younger age and higher daily dosages of ceftriaxone (52). Together, these findings suggest that long-term ceftriaxone therapy predisposes to formation of sludge, which may later evolve into stones.

Ceftriaxone is excreted into bile as a divalent anion (83). In the gallbladder, its concentration in bile can exceed serum concentrations 20- to 150-fold (38). Like bilirubin, ceftriaxone can precipitate with calcium. Thus, sludge in patients receiving ceftriaxone is composed mainly of calcium-ceftriaxone complexes, with small amounts of cholesterol crystals and bilirubinate granules. Microscopically, the precipitates appear as fine, granular-crystalline material. On ultrasonography, these precipitates produce high-amplitude echoes with prominent postacoustic shadows, an appearance that can be confused with that of gallstones (83).

Octreotide

Octreotide is a synthetic analogue of the gut peptide somatostatin. It is used to treat acromegaly, neuroendocrine tumors, and secretory diarrheas. Of patients with acromegaly who receive octreotide, 67% develop sludge and 24% develop gallstones after 1 year of treatment (53-55). The risk for development of sludge or gallstones depends only on the length of treatment, not on the daily dosage. Sludge in patients receiving octreotide is composed primarily of cholesterol crystals (84).

Octreotide has several physiologic actions that may contribute to sludge formation. Like somatostatin, it inhibits hepatic bile secretion and promotes absorption of sodium and water by the gallbladder, leading to increases in bile concentration (85-90). Octreotide and somatostatin inhibit motility of the sphincter of Oddi and emptying of the gallbladder, possibly contributing to bile stasis (91-95). Acromegalic patients with octreotide-associated stones have greater bile cholesterol saturation and shorter crystal nucleation times (96).

Bone Marrow or Solid Organ Transplantation

Sludge can develop within 3 to 5 days after bone marrow transplantation (30, 56), and it is found in as many as 67% of recipients 28 days after transplantation. It resolves in most patients but can evolve into gallstones in up to 25%. In the studies done to date (30, 56), patients remained asymptomatic during follow-up. After cardiac transplantation, biliary sludge and gallstones develop in 2% and 18% of patients, respectively (50). Up to 89% of patients with sludge or stones may require biliary tract surgery for associated symptoms and complications (97). Similar findings have been noted in kidney transplant recipients (57).

After bone marrow transplantation, sludge is composed primarily of calcium bilirubinate (6). The composition of sludge after solid organ transplantation has not been determined, but calcium bilirubinate probably predominates. The cause of sludge or stones in transplant recipients has not been determined but is probably multifactorial. Patients may be critically ill, may receive total parenteral nutrition, or may require prolonged administration of narcotics. Immunosuppression with cyclosporine may be another risk factor, and duration of cyclosporine therapy may be a risk factor for gallstone formation in kidney transplant recipients (98). Cyclosporine therapy can induce cholestasis, possibly predisposing to sludge formation (99-104).

Clinical Evaluation of Suspected Biliary Sludge

In a patient presenting with abdominal pain, true biliary colic should be distinguished from nonspecific abdominal discomfort. A cholecystectomy done for true biliary colic is usually curative, but symptoms often persist if the procedure is done in patients with nonspecific dyspepsia and cholelithiasis (105, 106). Nevertheless, despite the availability of many imaging techniques that can be used to demonstrate sludge or gallstones, the diagnosis of biliary colic is ultimately based on clinical judgment.

For a patient in whom sludge is suspected, the choice of diagnostic method must be based on the clinical setting and the sensitivity, specificity, and cost of the diagnostic tests available. In general, given its relatively low cost and noninvasiveness, transabdominal ultrasonography should be the initial test. However, because the sensitivity of this test is only about 55% to 60%, further testing should be considered if the test result is negative and clinical suspicion remains high (for example, in a patient with recurring attacks of idiopathic pancreatitis). If the diagnosis is to be pursued, either endoscopic ultrasonography or bile microscopy may be chosen.

Generally, bile microscopy is considered the gold standard for diagnosis. The reported sensitivity of this test for sludge or gallstones varies from 67% to 86%, and the specificity ranges from 88% to 100% (26, 34, 107, 108). The sensitivity is 83% when bile is obtained directly from the common bile duct during endoscopic retrograde cholangiopancreatography (109). One recent study (110) reported higher sensitivity if bile was obtained through duodenal intubation than through endoscopy, but it is not clear that bile from the gallbladder was sampled during endoscopy in this study. The sensitivity of bile microscopy is probably similar for all sampling methods if gallbladder bile is collected.

Endoscopic ultrasonography has been less widely studied than bile microscopy. Dahan and coworkers (18) reported a sensitivity of endoscopic ultrasonography of 96% compared with a sensitivity of 67% for duodenal drainage. The specificities of the two methods were similar: 86% to 91% (18). The sensitivity of endoscopic ultrasonography and bile microscopy combined is approximately 92% (19).

Thus, for patients with suspected biliary sludge who have a negative result on transabdominal ultrasonography, further testing depends on the clinical situation. We recommend bile sampling for patients in whom the clinical suspicion of sludge is high and in whom further treatment, such as cholecystectomy, would be considered. The choice of a method of bile sampling depends on the clinical situation. For example, if upper gastrointestinal tract disorders remain in the differential diagnosis, an upper gastrointestinal endoscopy could be done and bile could be aspirated for microscopy during this procedure. If the patient has no indication for upper gastrointestinal endoscopy, a bile sample could be obtained through duodenal intubation. Patients with recurrent episodes of idiopathic acute pancreatitis generally undergo endoscopic retrograde cholangiopancreatography, and bile can be sampled from the duodenum or the common bile duct during this procedure (Figure 3). Patients who have an indication for endoscopic ultrasonography, such as evaluation of abnormalities seen on previous imaging studies, should undergo this procedure first; if sludge is not identified on imaging, bile can be collected for microscopy. We do not recommend endoscopic ultrasonography for patients without another indication for the test, given the test's relatively low availability and high cost.

View larger version (29K): [in this window] [in a new window]   Figure 3. Suggested algorithm for diagnosis in patients with recurrent episodes of acute pancreatitis in whom biliary sludge is suspected. ERCP = endoscopic retrograde cholangiopancreatography.

Prevention

Specific measures to prevent the development of sludge are not practical or cost-effective in the general population. However, two potential preventive strategies—use of ursodeoxycholic acid and use of cholecystokinin—have undergone preliminary study. At this time, neither of these methods can be recommended routinely for clinical use, even in high-risk populations.

Ursodeoxycholic Acid

Ursodeoxycholic acid is an orally administered bile acid that has been extensively studied for the dissolution of gallstones and the treatment of primary biliary cirrhosis. It decreases cholesterol secretion into bile and prolongs crystal nucleation time. However, few studies have examined ursodeoxycholic acid for the treatment of biliary sludge. In patients who were rapidly losing weight, ursodeoxycholic acid decreased the incidence of gallstones by 50% to 100% (111, 112). In patients with idiopathic pancreatitis and sludge, Ros and coworkers (35) found that after initial treatment with ursodeoxycholic acid to dissolve cholesterol crystals, ongoing maintenance therapy successfully prevented the recurrence of sludge and pancreatitis.

Cholecystokinin

Sitzmann and colleagues (113) have proposed that cholecystokinin be used for prophylaxis against the development of sludge in patients in whom gallbladder stasis is an underlying cause of sludge (such as patients receiving prolonged total parenteral nutrition). In their study (113), patients initially free of sludge or stones were randomly assigned to receive a daily intravenous infusion of cholecystokinin or placebo. None of the patients receiving cholecystokinin but 62% of the placebo recipients developed sludge or gallstones. Few side effects were seen. The safety and efficacy of cholecystokinin in other clinical settings have not been studied.

Treatment

In general, patients should be evaluated specifically for sludge or stones only after they develop symptoms. Regularly monitoring asymptomatic patients for the development of sludge or stones has not been generally done, even in high-risk patients. However, sludge is often found incidentally on imaging studies done for other reasons, and its management in these circumstances has been debated. If a specific precipitating cause of sludge is present, attempts should be made to eliminate it. For management purposes, sludge and gallstones should be considered similar in almost all respects. Thus, asymptomatic patients with sludge should be observed and managed expectantly (Figure 4).

View larger version (28K): [in this window] [in a new window]   Figure 4. Suggested algorithm for treatment in patients with a diagnosis of biliary sludge. UDCA = ursodeoxycholic acid.

In contrast, if symptoms or complications of sludge occur, therapy should be considered (Figure 3 and Figure 4). Patients with uncomplicated biliary colic are at moderate risk for future pain and more serious complications, but up to 30% of patients have no further symptoms. Thus, clinical judgment must be used in deciding whether to proceed with therapy in these patients. If more serious complications, such as acute pancreatitis, have occurred, therapy should be considered more strongly. The definitive therapy for sludge is cholecystectomy, done by using either the laparoscopic or the open route. However, if the patient is a poor surgical candidate, nonsurgical interventions, such as oral bile acid dissolution or percutaneous cholecystostomy with drainage, can be considered. The long-term efficacy of these methods has not been proven; thus, these methods should be used only in patients who require therapy but are not good surgical candidates. The recurrence rate of sludge after oral bile acid dissolution is not known, but gallstones recur in up to 50% of patients. The efficacy of percutaneous cholecystostomy and drainage in the treatment of sludge has not been well established.

Conclusions

Biliary sludge is found in diverse clinical situations but is not well understood. Its clinical course varies: Progression to gallstones, a waxing and waning course, and complete resolution are all possible outcomes. In itself, sludge may cause complications normally associated with gallstones, including biliary colic, acute pancreatitis, and acute cholecystitis. It is most often diagnosed on ultrasonography, although bile microscopy may be considered the gold standard for diagnosis. If patients with sludge are asymptomatic, they can be managed expectantly. If patients develop symptoms or complications, cholecystectomy should be considered as the definitive therapy.

Much is still to be learned about biliary sludge and gallstones. Ongoing controversies surround the natural history of biliary sludge, risk factors for its formation, and its true place in the spectrum of biliary tract disease. Future prospective clinical studies may help clarify these issues and further our understanding of biliary tract abnormalities.