Whither biliary sludge

A mong the growing list of pathogenic events implicated in the formation of human gallstones, gelation of gallbladder mucin with entrapment of “particulate matter” nucleated from bile, also known as biliary sludge, is unquestionably assuming a pivotal role (1,2). The peculiar phrase “biliary sludge” is, of course, jargon. In classic American fashion, the notion is borrowed from sanitary engineering (“sludge thickening tanks”) and, presumably because of its graphic pungency, seems to have become firmly entrenched in both radiologic and surgical nomenclature. Our intent is not to proscribe this appellation, but rather to anoint it. What follows is an attempt to place this common form of biliary tract dysfunction in pathophysiologic context. We will probe the metabolic and physicalchemical origins of biliary sludge, explore how Lee and colleagues, in a recent issue of this journal (3), have furthered our knowledge of its origins and fate, and attempt to provide a unifying hypothesis for further investigation of biliary sludge in the pathogenesis and possible prevention of human gallstones. In our understanding of the evolution of macroscopic cholesterol gallstones, many pieces of the jigsaw puzzle have been fitted into place over the past 20 yr (4). Investigators from diverse disciplines now continue to focus upon the earliest identifiable evolutionary events, such as the metabolic origin (57) and physical-chemical nature (8) of cholesterolsupersaturated bile, gallbladder mucin accumulation and gelation (g-12), biliary nucleation (13,14) and antinucleation factors (l5-l8), nucleation stages, physical chemistry and kinetics (19-21), and gallbladder dysmotility (11,22-29). But the picture is still incomplete; we have broad brush strokes of the secondary colors without a palette that displays the primary colors. Both in gallstone-prone American Indians in the United States and in western populations, gallstones are distinctly rare before the third decade of life (4) yet, during early adolescence, the lipid composition of bile changes from being unsaturated with cholesterol to being supersaturated with cholesterol (30,31). This alteration is most dramatic in women and correlates with enhanced urinary output of endogenous estrogens (3 1). Contrary to previously held beliefs (32) that this resulted generally from hyposecretion of bile salts beginning in adolescence, it is now becoming clear that hypersecretion of biliary cholesterol is the major cause of supersaturated bile in both obese and nonobese humans in the western hemisphere (5,33-35). The pathogenic wisdom of the 1970s was that deficient secretion of bile salts from a contracted bile salt pool was the causative cornerstone in the formation of lithogenic bile (reviewed in Reference 36). This belief now requires reexamination. Hyposecretion of bile salts into the upper small intestine in earlier secretion studies apparently resulted from suboptimal cholecystokinin release during formula perfusion of the duodenum, with diversion of hepatic bile into a partially relaxed gallbladder (37). Furthermore, the presence of gallstones per se in the gallbladder results in an apparent contraction of the bile salt pool when measured by isotope-labeled bile salt dilution kinetics (38). Nevertheless, adult American Indians in the United States may be a genetic and biologically distinct group in this regard. Pima Indians, in addition to being hypersecretors of cholesterol, exhibit true enterohepatic bile salt deficiency before the formation of cholesterol gallstones (39). Hypersecretion of biliary cholesterol is caused by many factors (5). These putatively include the following.