Journal of Gastroenterology and Hepatology (1992) 7, 618-621

SPECIAL ARTICLE

Gall-bladder sludge: Lessons from ceftriaxone Y. S . K I M , M. F. K E S T E L L AND S . P. L E E Department of Medicine, University of Washington and the VA Medical Center, Seattle, Washington, USA.

CEFTRIAXONE A N D CEFTRIAXONEASSOCIATED S L U D G E

power of bile acid mixed micelles and phospholipid vesicles is o~erwhelmed.’~-’’ Bilirubin is excreted as the soluble diglucuronide. Deconjugation, either by nonenzymatic hydrolysis or by P-glucuronidase results in free Ceftriaxone, a third generation cephalosporin with a wide bilirubin. When the solubility product of calcium and and effective range of antimicrobial activity’ has been the unconjugated bilirubin is exceeded, calcium bilirubinate antibiotic of choice in several infectious diseases, includprecipitate^."^'^ While this may be simple clear logic, the ing biliary Ceftriaxone is excreted in the urine, real life scenario is much more complicated. First, there but a substantial amount (3O-6O0/o) is also excreted in is a wide range of metastability around the solubility bile. The antibiotic is excreted predominantly in an limits. This is true for cholesterol,zO~z’ as well as for unmetabolized form. In 1986, Schaad et al. first described calcium salts. ‘*,19 The absolute numerical solubility prodthe development of gall-bladder sludge in a patient uct does not accurately predict the propensity to form precipitates. This led to a search for factors which would receiving ceftriaxone.6 ‘This was followed b other case affect the nucleation and precipitation of cholesterol reports of ceftriaxone inducing cholecystitis Y and biliary monohydrate crystals. Recent studies have greatly exp a h a Subsequently, prospective studies have shown that panded this field of research. There are now putative unusual echogenic sludge appears in 25-43% of proteins which are r o n u c l e a t o r ~ and ~ ~ -proteins ~~ which patients.’-’ This form of gall-bladder sludge is interestare antinucleatorsZP of cholesterol monohydrate crystal ing in several aspects: it can be relatively common; it has formation. In the case of calcium salts, likewise, there are unusual acoustic characteristics and resembles gallstones; promotersz7and inhibitor^'^,'^ of precipitation. Second, a it can cause symptoms; and it disappears after stopping gall-bladder seems to be important, if not essential, for ceftriaxone. Because of these seemingly confusing obserthese precipitates and gallstones to form.I4 If the surgeon vations, various terms such as ‘pseudolithiasis’ or ‘reversdoes a good job with an elective cholecystectomy, the ible cholelithiasis’ have been c o i r ~ e d . ~The . ~ chemical patient is ‘cured’ of the gallstone disease despite the liver composition of the gall-bladder sludge has been unequivocontinuing to secrete cholesterol ‘supersaturated’ bile cally identified as calcium-ceftriaxone,l 2 Apart from beafter the operation. Similarly, a patient with haemolysis ing a fascinating clinical entity, this iatrogenic biliary and pigment gallstones seldom has recurrence of primary precipitate can teach us a great deal about the pathophysiductal stones. The contractile and mucosal function ology of gallstone disease.I3 of the gall-bladder both contribute to the formation of ~ l u d g e . ’ This ~ , ~ ~is reflected in that, when there is gallbladder stasis, sludge develops. Patients on total parenteral PATHOGENESIS OF GALL-BLADDER nutrition or after major operations have a tendency to SLUDGE form pigment sludge of calcium b i l i r ~ b i n a t e . ~ ’Preg.~~ nant women, with apparently sluggish gall-bladder contraction, develop sludge of cholesterol crystals.33 Bile is a transparent aqueous solution. When precipitates What then about ceftriaxone? T h e antibiotic is excreted occur, the sediments are referred to as biliary sludge. into bile and concentrated in the gall-bladder. From Sludge occurs mainly in the gall-bladder and can be physico-chemical considerations, it is expected that, diagnosed by direct microscopic examination of W e or by when the solubility product of calcium and ceftriaxone ultrasonography.’3 The most commonly observed precipiis exceeded, precipitation should follow. Precipitation of a tates are cholesterol monohydrate and calcium bilirubidrug or xenobiotic in the biliary system is rare, and nate. The formation of these precipitates, the crucial, although a number of antibiotics are excreted in bile, first, and prerequisite step of gallstone formation can be explained by the principles of physical ~ h e m i s t r y . ’ ~ none is an organic anion like ceftriaxone. Ceftriaxone exists in solution as a divalent anion, and behaves like Cholesterol precipitates when the cholesterol-solubilizing



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Correspondence: Sum P. Lee, Professor of Medicine, Chief, Gastroenterology Section ( 1 1 lGI), VA Medical Center, 1660 South Columbian Way, Seattle, Washington 98108, USA. Accepted for publication 2 5 June 1992.

Ceftriaxone-associated sludge other calcium-sensitive anions in bile (carbonate, bilirubinate, phosphate, palmitate) that are implicated in the pathogenesis of gallstones. Animal and in viiro studies of ceftriaxone have shown that it is secreted in high concentrations far exceeding the calculated solubility p r o d ~ c t .Parallel ~ ~ , ~ ~studies in the rat and guinea pig showed that the rat has a much higher transport maximum for ceftriaxone with the result that biliary ceftriaxone concentration is many times that of the guinea pig. However the rat, which is without a gallbladder, never has any precipitation in vivo. In contrast, the guinea pig, despite a much lower biliary ceftriaxone output in the hepatic bile, forms gall-bladder sludge of calcium ~ e f t r i a x o n e This . ~ ~ emphasizes that in gallstone formation, kinetic (gall-bladder) factors are just as important as thermodynamic (hepatic) factors.

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suggest that if gall-bladder sludge is causally related to a specific precipitating factor, it usually disappears after the aetiological factor is removed. In total parenteral nutrition, therefore, the majority (> 90%) of gall-bladder sludge would disappear after resumption of enteral feedi ~ ~ gIn. ~pregnant ' women, most sludge would clear after delivery.33 There are no comprehensive studies designed to examine the fate of ceftriaxone-associated sludge. Most reports indicate that after stopping the drug, the sludge disappears in a matter of Gall-bladder sludge, however, is not always benign. Acalculous cholecystitis may complicate total parenteral nutrition patients and pregnant women. Both groups run a higher risk of having gallstones. Sludge can precipitate acute p a n c r e a t i t i ~ . ' ~In, ~a~ 4-year follow-up study of 96 patients with functional abdominal pain and gall-bladder sludge, 13% developed symptoms of biliary tract dise a ~ e . ~With ~ , ~ ultrasound ' monitoring, sludge can disappear, disappear and reappear, or evolve to gallstones. ULTRASON OG R APH I C FEATURES 0F Most cases of ceftriaxone-associated sludge run a benign CEFTRIAXONE-ASSOCIATED S L U D G E course. However there are patients who had symptoms of biliary pain or cholecystitis, and cholecystectomies were performed. Although no formal long-term follow-up has Ultrasound identifies precipitates of cholesterol crystals been done on ceftriaxone-associated sludge the evolution and clumps of calcium bilirubinate as low amplitude ' ceftriaxone has echoes without producing post-acoustic ~hadowing.~' to gallstones has been r e p ~ r t e d . ~Because become a widely prescribed antibiotic, clinicians will see Gallstones, on the other hand, give rise to high amplitude patients with gall-bladder sludge. We believe that ultraechoes with a prominent shadow effect. The reason for sonography should not be routinely performed in patients this differentiation is understandable. If the ultrasound treated with this but used only when there wave strikes a loose aggregate of particulate matter, some are clinical suspicions of hepatobiliary symptoms. One of the ultrasound energy will be reflected (low amplitude should also beware of the unusual sonographic features of echoes), but some will travel through the matrix of the ceftriaxone-associated sludge. If the presence of sludge is aggregate (no shadowing). Replace the sludge with a associated with signs, symptoms or laboratory findings of stone and all the ultrasound wave striking the rock will be cholecystitis, cholangitis or pancreatitis, the drug should reflected (high amplitude echoes) and nothing will reach be stopped. Cholecystectomy is considered only if the the other side of the rock (shadowing). patient does not improve. Ceftriaxone-associated sludge produces anomalous ultrasound features compared with 'conventional' sludge. Although the sludge is present as a layer of fine powdery SUMMARY granules, it produces high amplitude echoes and has prominent shadows. Whether this is due to a denselypacked collection of precipitated calcium ceftriaxone, or Ceftriaxone-associated sludge has been a fascinating is a result of the acoustic impedance and sound-scattering story.43 The occurrence is novel and unique. It has characteristics of the compound, is not known. For the produced a model of gall-bladder sludge in humans. This clinician, however, it is important to recognize this phenomenon has taught us a great deal about biliary lipid finding. It occurs commonly in patients treated with and organic anion excretion by the liver,34 and the ceftriaxone, and it can be misdiagnosed as gallstone physical chemistry of calcium and calcium sensitive disease. anions.35It has added further insights into the pathophysiology of gall-bladder sludge formation. It points to a combination of a hepatic effect where the liver secretes a biochemically abnormal bile, and a gall-bladder effect CLINICAL COURSE O F CEFTRIAXONEwhich provides an environment for precipitation, in order ASSOCIATED S L U D G E for sludge to develop.36 T h e precipitated calcium ceftriaxone has prompted us to re-evaluate the imaging criteria for the diagnosis of gall-bladder sludge versus gallOur inadequate understanding of the pathogenesis of stones.I2 Above all, the rapid onset and rapid disappeargall-bladder sludge, the imperfect methods of detecting it ance of ceftriaxone sludge has mirrored in a compressed, and the lack of a universally accepted differentiation encapsulated form, the natural history of gall-bladder between small gallstones and sludge have contributed to sludge. It has reminded us that, like gallstones, biliary the controversy which surrounds the clinical relevance of sludge is usualiy benign and asymptomatic. However just gall-bladder sludge. Is sludge a pathological culprit which because it is smaller than gallstones does not mean it invariably creates symptoms and eventually leads to cannot cause problems. It can disappear or it can become gallstones? Or is it an irrelevant and innocent curiosity a calcium ceftriaxone gallstone. uncovered by high technology medicine? Most studies

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19. REGER. V., DAWES L. G. & MOORE E. W. Canine common duct and gallbladder bile contain antinucleating factors that inhibit CaCO, precipitation. J. Lab. Clin. Med. 1989; 1. NEU H. C., MEROPOLD N. J. & Fu K. P. Antibacterial 113: 642-50. activity of ceftriaxone (Ro 13-9904) a beta-lactamase stable 20. HEGARDT F. G. & DAMH. The solubility of cholesterol in cephalosporin. Antimicrob. Agents Chemather. 198 1; 19: aqueous solutions of bile salts and lecithin. Z. Ernahrung414-23. swiss 1971; 10: 239-52. 2. MCNAMARA B. T., STOECKELK. & SIEGLERW. H. 21. HOLZBACH R. T., MARCH M., OLSZEWSKI M. & HOLANK. Pharmacokinetics of ceftriaxone following intravenous Cholesterol solubility in bile. Evidence that supersaturated administration of a 3 g dose. Eur. 3. Clin. Pharmacol. bile is frequent in healthy man. 3. Clin. Invest. 1973; 52: 1982; 22: 71-5. 1467-79. 3. RICHARDS D. M. Ceftriaxone, a review of its antibacterial 22. LEES. P., LAMONTT. & CAREY M. C. Role of gallbladder activity, pharmacological properties and therapeutic use. mucus hypersecretion in the evolution of cholesterol Drugs 1984; 20: 469-527. gallstones. Studies in the Prairie Dog. J. Clin. Invest. 4. KELLUM J. M., GARGANO S., GORBACH S. L., TAKEOF C. & 1981; 67: 1712-23. CURTIS L. E. Antibiotic prophylaxis in high-risk biliary 23. GROENA. K., NOORDAM C., DRAPERS J. A. G., ECBERS I’., operations: multicenter trial of single preoperative ceftriaxJANSEN P. L. & TYTGAT G. N. J. Isolation of a potent one versus multidose cefazolin. A m . J. Surg. 1984; 148: cholesterol nucleation-promoting activity from human 15-8. gallbladder bile: role in the pathogenesis of gallstone 5 . BROGARD J. M., BLICKLEJ. F., JEHL F., ARNAUDJ. P., disease. Hepatology 1990; 11: 525-33. PARIS-BOCKEL D. & MONTEIL H. High biliary elimination P. R. c., U P A D H Y A G. A. & STRASBERG s. M. 24. HARVEY of ceftriaxone in man. Int. 3. Clin. Pharmacol. Ther. 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Gall-bladder sludge: lessons from ceftriaxone.

Ceftriaxone-associated sludge has been a fascinating story. The occurrence is novel and unique. It has produced a model of gall-bladder sludge in huma...
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