Gallbladder stones are frequently found in asymptomatic patients during routine abdominal ultrasonography, because in most cases (60%-80%) gallstones do not generate symptoms.43,48,49 Previous observations have shown that the average risk of developing symptomatic gallstones is 2.0% to 2.6% per year.45,50 By contrast, the presence of microstones and sludge in the gallbladder is a major risk factor for the development of biliary pain and complicated gallstone disease, and also plays a main role in the cause of acute otherwise idiopathic pancreatitis.51-53 Nevertheless, the yearly incidence of complications is low (0.3%), and the annual risk for gallbladder cancer is as low as 0.02%.54,55 Treatment of asymptomatic patients with gallstones, therefore, is not routinely recommended, as the overall risk of biliary colic, complications, and gallbladder cancer is low.56-58 Expectant management is considered the appropriate choice in most asymptomatic patients with gallstones (grade A). The decision is different in symptomatic patients with gallstones and should follow the algorithm depicted in Fig. 1, in which surgery (namely laparoscopic cholecystectomy) represents the gold standard for treatment; oral litholysis with hydrophilic bile salts plays a limited role.1,36 Other nonsurgical (nonpharmacologic) therapies include direct contact dissolutions of gallstones using the potent cholesterol solvent methyl tert butyl ether (MTBE),59 and extracorporeal shock wave lithotripsy.60 Both options, however, have lost their popularity because of potential side effects (MTBE) and high postdissolution recurrence rate.1 Available medical treatments for gallstones are discussed in the following paragraphs and include the treatment of biliary colic (all types of stones), oral litholysis by hydrophilic bile acids and novel approaches with statins, EZT, and agonists/antagonists of NR (all for cholesterol gallstones).
MEDICAL TREATMENTS OF GALLSTONE DISEASE Treatment of the Biliary Colic
The presence of a gallstone of any type and size may put the patient at risk of biliary pain. As the intensity of pain is usually high (mean visual analog scale of 9 cm on a 0-to 10-cm scale), patients require immediate medical attention and analgesia. The pain is not exclusively postprandial, and is typically intermittent. The most frequent localization is the right upper quadrant of the abdomen and/or the epigastrium (representative dermatomes T8/9), and the duration is generally longer than 15 to 30 minutes. The pain radiates to the angle of the right scapula and/or shoulder in about 60% of cases. In less than 10% of cases the pain radiates to the retrosternal area. About two-thirds of patients experience an urge to walk,44 and often are nauseated or vomit.41,44,49 In biliary colic, the pain is visceral and is caused by the impaction of the stone in the cystic duct or the sphincter of Oddi. Distension of the gallbladder and/or biliary tract with activation of visceral sensory neurons may follow.41 The pain can last for several hours and be associated with nonspecific symptoms of indigestion. The pain can be relieved if the stone returns into the gallbladder lumen, passes through the sphincter into the duodenum, or migrates back to the common bile duct.40 The
Fig. 1. Current therapies of gallstone disease, including cholesterol gallstones. 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 treating symptomatic gallstones.164-166 Laparoscopic cholecystectomy and small-incision cholecystectomy166 are safe and have similar mortality (from 0.1% to 0.7%).122,165 Both approaches are cost-effective compared with open cholecystectomy.165 Compared with open cholecystectomy, convalescence and hospital stay are shorter and total cost is lower for laparoscopic cholecystectomy.122 Complication rates (including bile duct injuries) are similar for 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 stones167), morbid obese patients undergoing bariatric surgery (who are at high risk of becoming symptomatic during rapid weight loss168), patients at increased risk for gallbladder cancer169 (ie, 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%-5%),173 and asymptomatic patients with gallstones with sickle cell anemia, who form calcium bilirubinate gallstones as a result of 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, because the coexistence of these conditions increases the risk of pancreatitis.51 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, nonsteroidal antiinflammatory drugs; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid; US, abdominal ultrasonography. (Data from Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet 2006;368(9531):230-39. Portincasa P, Moschetta A, Puglisi F, et al. Medical treatment of gallstone disease. In: Borzellino G, Cordiano C, editors. Biliary lithiasis. Basic science, current diagnosis and management. Milano, Italy: Springer Italia S.r.l.; 2008;149-57. Portincasa P, Di Ciaula A, Wang HH, et al. Medicinal treatments of cholesterol gallstones: old, current and new perspectives. Curr Med Chem 2009;16(12):1531-42.)
biliary pain is rapidly responsive to narcotic analgesics (meperidine61) or nonsteroidal anti-inflammatory drugs (NSAIDs) (such as intramuscular or intravenous ketorolac or ibuprofen by mouth), which could also reduce the risk of evolution toward acute cholecystitis.62-65 A second-line therapy includes the use of antispasmodic (anticholinergic) agents like hyoscine (scopolamine) which are known to be less effective than NSAIDs62 (grade A). The patient with biliary colic should remain fasting to avoid release of endogenous cholecystokinin and further gallbladder contraction. If a complicated biliary pain is suspected (association of leukocytosis, nausea, jaundice, vomiting, and fever), the patient should be quickly admitted to hospital and treated accordingly. Typical complications of gallstone disease are acute pancreatitis, acute cholecystitis, biliary obstruction and cholangitis, gallbladder perforation, abscess formation, and mucocele of the gallbladder, which may require additional medical therapy with antibiotics or invasive procedures with or without surgery. In mild and moderate acute cholecystitis, early laparoscopic cholecystectomy is recommended at between 2 and 4 days66 (grade A). The risk of biliary pain in asymptomatic carriers is estimated to be approximately 1% to 2% annually.67,68 Early studies that were not randomized or placebo-controlled found that UDCA, besides its litholytic effect (see later discussion), might also reduce the risk of biliary colic.69,70 In a nonrandomized study, Tomida and colleagues71 treated patients referred for symptomatic or asymptomatic gallstones with 600 mg UDCA per day and used those who refused as a control group. The incidence of biliary pain was apparently reduced by UDCA in asymptomatic patients, although a bias might include a misclassification of symptoms. However, in a large randomized, double-blind, placebo-controlled trial on the effects of UDCA in highly symptomatic patients with gallstones scheduled for cholecystectomy, UDCA did not exert a beneficial effect on biliary colic. The likelihood of remaining colic-free was comparable in patients with strong or weak baseline gallbladder contraction as determined by ultrasonography after a standard mixed meal.72
Dissolution of Cholesterol Gallstones by Oral Bile Acids
About two-thirds of the gallstones in Western countries are composed mainly of cholesterol. However, dissolution therapy by oral administration of the hydrophilic bile acid UDCA, the 7b-epimer of chenodeoxycholate, is suitable only for a small subgroup (about 15%) of symptomatic patients.1,40 Similar results are reached with the taurine-conjugated UDCA (tauroursodeoxycholic acid [TUDCA]). Chances of dissolution are higher if gallstones are small (less than 0.5 cm in size), not calcified (radiolucent on radiograph, including a computed tomography [CT] scan), cholesterol-enriched (ie, more than 80%), and contained within a functioning gallbladder with a patent cystic duct.73 Complete dissolution of gallstones by bile acids was first documented by Rewbridge in 1937,74 although initial reports were published in 1873 and 1876.75,76 The bile acid chenodeoxycholic acid (CDCA) was first used in the 1970s77 but was associated with a dose-dependent increase in serum aminotransfer-ases, serum low-density lipoprotein cholesterol levels, and diarrhea. In 1975 Makino and colleagues78 identified UDCA as a more hydrophilic bile acid that could replace CDCA without side effects. Dissolution of cholesterol gallstones by UDCA following fragmentation by extracorporeal shock wave lithotripsy was introduced first by Sauerbruch and colleagues60 in Munich in 1986. The bile acid UDCA is currently used for oral dissolution at a dosage of 10 to 14 mg/kg body weight per day. Bedtime administration is suggested because it maintains hepatic bile acid secretion rate overnight, thus reducing secretion of supersaturated bile and increasing the dissolution rate79,80 (grade A). Oral UDCA (at least 10 mg/kg/d) results in an increased proportion of biliary UDCA in bile (from less than 8%-10% of biliary bile acid pool to about 40%).
Increasing biliary UDCA, in turn, results in a decreased hepatic secretion of biliary cholesterol and the formation of unsaturated gallbladder bile (ie, containing less cholesterol in solution) with a cholesterol saturation index of less than 1 (Fig. 2).81-83 This step represents a key factor in initiating the process of dissolution of cholesterol crystals and gallstones. During UDCA treatment, cholesterol crystallization can be prevented because more cholesterol can be transported within vesicles that contain mainly phospholipids and cholesterol and little bile acid.84 Also, oral therapy with UDCA is associated with the reduction of intestinal absorption of cholesterol,85-87 as well as with a better contractility of the stimulated gallbladder smooth muscle, as shown by in vitro studies in animals and patients with gallstones.88,89 By decreasing
Fig. 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-leci-thin-taurine-conjugated bile salt 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 as a result of decreasing bile salt hydrophobicity. The lipid components are expressed in moles percent. The 1-phase micellar zone at the bottom is enclosed by a solid curved line. Above it, 2 solid lines divide the 2-phase zones from a central 3-phase zone. Based on the solid and liquid crystallization sequences present in the bile, the left 2-phase and the central 3-phase regions are divided by dashed lines into regions A to D. The number of phases given represents the equilibrium state. There 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 decreases, the maximum micellar cholesterol solubility is reduced and crystallization pathways A to E move to the left. This change results in an enlarged region E that extends to the left and overlaps pathophysiologic compositions as exemplified in the TUDC-lecithin-cholesterol system. This event induces a greatly reduced chance for the formation of solid platelike cholesterol monohydrate crystals in bile. (Data from Wang DQH, Carey MC. Complete mapping of crystallization pathways during cholesterol precipitation from model bile: influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing system. J Lipid Res 1996;37:606-30 and Portincasa P, Di Ciaula A, Wang HH, et al. Medicinal treatments of cholesterol gallstones: old, current and new perspectives. Curr Med Chem 2009;16(12):1531-42.)
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