Targets for current pharmacologic therapy in cholesterol gallstone disease

Abstract

Gallstone disease is a frequent condition throughout the world and, cholesterol stones are the most frequent form in Western countries. The standard treatment of symptomatic gallstone subjects is laparoscopic cholecystectomy. The selection of patients amenable for nonsurgical, medical therapy is of key importance; a careful analysis should consider the natural history of the disease and the overall costs of therapy. Only patients with mild symptoms and small, uncalcified cholesterol gallstones in a functioning gallbladder with a patent cystic duct are considered for oral litholysis by hydrophilic ursodeoxycholic acid, in the hope of achieving cholesterol desaturation of bile and progressive stone dissolution. Recent studies have raised the possibility that cholesterol-lowering agents that inhibit hepatic cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, may offer, alone or in combination, additional medical therapeutic tools for treating cholesterol gallstones. Recent perspectives on medical treatment of cholesterol gallstone disease are discussed in this article.

Figure 1

Current therapies of gallstone disease, including cholesterol gallstones (adapted from P. Portincasa et al. (1;36;123)). Novel and potentially effective medical therapies are denoted by the symbol (?). See text for details. Results from meta-analyses indicate surgery as the gold standard for the treating symptomatic gallstones (164-166). Laparoscopic cholecystectomy and small incision cholecystectomy (166), are safe and have similar mortality rate (from 0.1% to 0.7%) (122;165). Both approaches are cost-effective, if compared with open cholecystectomy (165). Compared with open cholecystectomy, both convalescence and hospital stay are shorter and total cost is lower for laparoscopic cholecystectomy (122). Complication rates (including bile duct injuries) are similar between laparoscopic and open cholecystectomy (122;165). When looking at surgical options, a “prophylactic” cholecystectomy can be taken into account in a subgroup of asymptomatic patients bearing a high risk of becoming symptomatic: children (who are exposed to long-term physical presence of stones (167)), morbid obese patients undergoing bariatric surgery (who are at high risk to became symptomatic during rapid weight loss (168)), patients at increased risk for gallbladder cancer (169) (i.e. those with large gallstones, greater than 3 cm) (170;171), a “porcelain” gallbladder (172) or gallbladder polyps rapidly growing or larger than 1 cm). Prophylactic cholecystectomy should also be considered in Native Americans with gallstones, who are at increased risk of gallbladder cancer (3 to 5 percent) (173), and asymptomatic gallstone patients with sickle cell anemia, who form calcium bilirubinate gallstones due to chronic hemolysis and may become symptomatic with recurrent episodes of abdominal pain (174). Prophylactic cholecystectomy has also been proposed in patients with small gallstones and gallbladder dysmotility, since the coexistence of these conditions increases the risk of pancreatitis (51). Abbreviations: CT, computerized tomography; ERCP, endoscopic retrograde cholangiopancreatography; EZT, ezetimibe; HIDA, 99mTc-N-(2,6-dimethylacetanilide)-iminodiacetic acid; GB, gallbladder; GS, gallstones; NR, nuclear receptors; NSAIDs, non-steroidal anti-inflammatory drugs; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid; US, abdominal ultrasonography.

Figure 2

Effects of UDCA on bile composition and cholesterol solubility are explained by using the ternary phase diagram (175). A group of the equilibrium phase diagram of cholesterol-lecithin-taurine-conjugated bile saltacid systems (37°C, 0.15 M NaCl, pH 7.0, total lipid concentration 7.5 g/dL) are drawn to display varied positions and configuration of crystallization regions due to decreasing bile salt hydrophobicity. The lipid components are expressed in moles percent. The one-phase micellar zone at bottom is enclosed by a solid curved line. Above it, two solid lines divide the two-phase zones from a central three-phase zone. Based upon the solid and liquid crystallization sequences present in the bile, the left two-phase and the central three-phase regions are divided by dashed lines into regions A to D. The number of phases given represents the equilibrium state. They are cholesterol monohydrate crystals and saturated micelles for crystallization regions A and B. Cholesterol monohydrate crystals, saturated micelles and liquid crystals for regions C and D, and liquid crystals of variable compositions and saturated micelles for region E (175). As the bile acid hydrophobicity decreased, the maximum micellar cholesterol solubility is reduced and crystallization pathways A-E move to the left. This change results in an enlarged region E that extends to the left and overlaps pathophysiological compositions as exemplified in the tauroursodeoxycholate (TUDC)-lecithin-cholesterol system. This event induces a greatly reduced chance for the formation of solid plate-like cholesterol monohydrate crystals in bile. Adapted and reproduced with permission from (175) and (123).

Figure 3

Mechanisms for cholesterol uptake mediated by the NPC1L1 according to the model proposed by Ge et al. (148). Adapted and reproduced with permission, Copyright Bentham Science Publisher, 2009 (123). The NPC1L1 protein recycles between the plasma membrane facing the extracellular space and the endocytic recycling compartment. If extracellular cholesterol concentration is high, cholesterol is incorporated into the plasma membrane and is sensed by cell surface-localized NPC1L1. Both NPC1L1 and cholesterol are then internalized together through clathrin/AP2-mediated endocytosis. The clathrin-coated globular vesicles are transported along microfilaments to the endocytic recycling compartment. The role of myosin in this process is unclear. Large quantities of cholesterol and NPC1L1 are subsequently stored within the endocytic recycling compartment. If the intracellular cholesterol level is low, endocytic recycling compartment-localized NPC1L1 moves back to the plasma membrane along microfilaments and new cholesterol is absorbed. The key role of the NPC1L1 inhibitor ezetimibe (EZT) is shown at the center of the cell. EZT prevents NPC1L1 from entering the AP2-mediated clathrin-coated vesicles. At this stage, the endocytosis of NPC1L1 is inhibited and cholesterol absorption is decreased.

Figure 4

Pathways underlying absorption of cholesterol from the intestinal lumen and its delivery to the liver. High dietary cholesterol through the chylomicron pathway could provide an important source of excess cholesterol molecules for secretion into bile, thereby inducing cholesterol-supersaturated bile and enhancing cholesterol gallstone formation (31;47). Ezetimibe (EZT) significantly suppresses cholesterol absorption from the small intestine via the Niemann-Pick C1-like 1 (NPC1L1) pathway (47). This effect should diminish the cholesterol content of the liver, which in turn decreases bioavailability of cholesterol for biliary secretion. Abbreviations: ABCG5/G8, ATP-binding cassette (transporter); ACAT2, acyl-CoA:cholesterol acyltransferase isoform 2; APO-B48, apolipoprotein B48; MTTP, microsomal triglyceride transfer protein. See text for details.