Summary Pathogenesis of cholesterol gallstones is related to the failure of bile to maintain cholesterol in micellar solution. The predominant defect is supersaturation of bile with cholesterol caused mainly by hepatic secretion of free cholesterol. A measure for this defect is the conventional cholesterol supersaturation index (CSI). This parameter seems to over-estimate the ‘effective supersaturation’ in terms of thermodynamic activity of cholesterol monohydrate in bile. The basic information about cholesterol solubilization has been derived from systematic studies of model bile systems at equilibrium. The various cholesterol carriers in bile are summarized in Fig. 8. Mixed micelles and unilamellar vesicles appear to be the major cholesterol carriers. The absolute amount, however, carried by each lipid aggregate cannot be precisely determined by the current methodology. Fusion of cholesterol-rich vesicles and aggregation into large lamellar liquid crystals is correlated with appearance of solid cholesterol crystals. Therefore, it has been postulated that cholesterol crystals nucleate from these liquid crystalline aggregates. Further growth occurs by apposition of cholesterol molecules, presumably derived from unilamellar vesicles. Recently, however, evidence has been provided that the lecithin and cholesterol of liquid crystalline aggregates may derive directly from both micelles and vesicles [87]. In contrast to static model bile systems, native bile is a dynamic open system with changing influxes and effluxes of the various lipids causing a fluctuation of lipid concentration and aggregation over time. Although valuable information has been gained from equilibrium studies, the question remains yet unsolved whether native bile systems are really at equilibration. Also no information exists about the relaxation times for the native system to re-equilibrate to a new configuration, and by which pathways cholesterol is redistributed between the various carriers. This is directly related to the influence of functional defects of the gallbladder. Gallbladder hypomotility, as demonstrated in the gallstone-bearing group, leads to a prolonged reaction time for the multifactorial processes involved in gallstone formation. In addition, the enlarged biliary residual volume is likely to prevent an effective clearing of debris and microcrystals that are involved in biliary sludge formation. A change in secretory function of the gallbladder epithelium, preferentially mucin hypersecretion, seems also to be involved in sludge and finally gallstone formation. Mucus gel may provide the matrix for cholesterol crystal nucleation. Gallbladder mucin itself has been shown to have a nucleation-promoting effect. Considering the high mucin concentration in the mucus gel, this effect may be important, although the specific promoting activity of mucin on cholesterol crystallization is by about 100-fold less potent than the effect reported for other promoting factors. The modulation of metastability under the influence of kinetic factors has been demonstrated for both native and model bile systems. A potent non-mucus promoting glycoprotein could be isolated from abnormal bile. An inhibiting effect of apolipoproteins has been demonstrated. Promoting and inhibiting protein factors are coexistent in both normal and abnormal bile. The isolation of a potent inhibiting glycoprotein has also been reported, the final characterization will soon be available [88,89]. Evidence has been provided that promoting factors exert their effect by direct interaction with vesicle aggregates. In contrast, it is speculated that inhibiting activity targets rapid growth sites at the crystal surface, thus preventing further apposition of cholesterol molecules to preformed crystal germs. In analogy, such a mechanism has been proposed for the effect of antifreeze proteins isolated from sera of polar fish [90]. Of great interest and central to the pathogenesis of cholesterol gallstones is the kinetics of cholesterol crystallization and the modulation by kinetic factors that presumably have a trigger function in the whole system. Initial studies, although using a less than ideal assay, have demonstrated that the antagonistic factors effect cholesterol crystallization on different levels. In addition, these studies suggest that inhibiting activity seems to be saturable and may be exceeded by the promoting activity. As yet, nothing is known about the steps involved after crystallization to form mature gallstones. A balance of the coexisting kinetic factors seems to be important in defining health and, conversely, some form of imbalance seems to be important in cholesterol gallstone pathogenesis. This imbalance could be caused by quantitative changes in kinetic factor concentration or by modification of specific antagonistic factors, as has been described for an inhibitor glycoprotein in calcium oxalate nephrolithiasis [91]. Future investigation on the kinetic factors might teach us how to manipulate their imbalance. This would have an impact not only on treatment of established gallstone disease, but also on preventing of both gallstone recurrence and primary gallstone formation.
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Sep 1, 1994
Marianne A C + 5
Open Access
