PATHOGENESIS OF BILIARY STONES MICROBIOLOGY OF BILIARY DISEASE CHOLECYSTITIS IN PREGNANCY As stated earlier, biliary disease, including acute cholccystitis, occurs infrequently during the preg- nant state. In fact, the prevalence of acute chole- cystitis in pregnancy ranges from 1/1,000 to 1/10,000 births. 13,14 Cholclithiasis is obviously the major etiologic factor in the development of acute cholecystitis and it has been established that the pregnant state predisposes women to gallstone for- mation. In light of the key role they play in the etiology of acute cholecystitis, it is only appropriate that a brief description of the pathogenesis of gall- stones be provided in this review. Gallstones are composed of cholesterol, bilirubin, calcium salts, and protein. Each of these ingredi- ents occurs in various percentages. Specifically, there are cholesterol and non-cholesterol stones. Non-cholesterol stones are frequently associated with a chronic hemolytic condition and contain a higher bilirubin concentration. Brown pigment non-cholesterol stones are often associated with in- fection since bacteria are likely to hydrolyze con- jugated bilirubin into calcium salts. This hydrolysis accounts for the brown coloration of many non- cholesterol gallstones. Cholesterol gallstones, 75% of all stones in the Western world, form when cholesterol concentra- tions exceed the ability of bile acids to maintain cholesterol in solution. At higher cholesterol con- centrations, cholesterol micelles coalesce precipi- tating crystals. This coalescence yields gallbladder sludge, which is merely thickened mucoprotein with entrapped cholesterol crystals. Sludge is an important precursor to gallstone formation as the crystals bind to the biliary proteins and ultimately result in cholelithiasis, is The increased risk of developing gallstones dur- ing pregnancy is due to several factors. First, the gallbladder volume is increased during the second and third trimesters. Second, gallbladder motility is decreased in pregnancy, possibly due to elevated progesterone levels. The evidence, however, is only circumstantial as progesterone has been proved only to inhibit gastrointestinal smooth muscle contractility in vitro. 6 The theorized decrease in motility alone cannot completely account for the increased bile volume noted in pregnancy. Analysis of sequential films for gallbladder volume revealed a significant increase 304 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY CASEY AND COX in residual volume after gallbladder emptying. 17 There is also a 50% increase in the bile acid pool associated with a concomitant steroid-induced in- crease in cholesterol secretion during pregnancy. Together with the replacement of deoxycholic and chenodeoxycholic bile acids with cholcic acid, in- creased volume and decreased motility of the gall- bladder enhance the development of biliary stones. When these pregnancy-induced changes occur with a metabolic and/or hereditary predisposition to developing gallstones, the likelihood of biliary disease is predictably high. Identifiable gallstones do not have to be present in order to develop symptomatology. In fact, biliary sludge can precipitate biliary pain, acute cholecys- titis, or even pancreatitis. When sludge develops into gallstones and they obstruct the cystic or com- mon bile ducts, bacterial invasion can occur. How- ever, the primary cause of acute cholecystitis is not bacterial invasion. Instead, it is frequently a chemi- cal inflammation. After obstruction, inflammation, hyperemia, and edema of the gallbladder follow. Subsequent venous and lymphatic obstruction yields ischemia. It is only after this secondary isch- emia that bacterial invasion and infection com- monly occur. 8 The presence of organisms in the bile, per se, does not necessarily imply an active infection. Bactibilia has only been reported in up to 65% of women with acute cholecystitis. In fact, most re- ports state that only 50% of patients with acute cholecystitis will have positive bile cultures. 9 Con- verscly, bactibilia is found in 20-30% of patients with biliary concrements that have minimal or no signs of obstruction. Therefore, the mere presence of biliary calculi seems to support some bacterial growth. 18,9 Ultimately, then, acute cholecystitis can be thought of as a heterogeneous disease. The incidence of bactibilia varies significantly with the stage of disease and the patient’s age. Also, as expected, with infections originating in the gut, the array of organisms in acute cholecystitis is broad. It includes both aerobes and anaerobes with a predominance of enteric gram-negative organ- isms (Table 1). Escherichia coli is the most common organism found in all studies of men and women diagnosed with acute cholecystitis. Klebsiella, Pro- teus, Enterococci, and Streptococci together with