Therapy of gallstone disease: What it was, what it is, what it will be

Abstract

Cholesterol gallstone disease is a common clinical condition influenced by genetic factors, increasing age, female gender, and metabolic factors. Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones, new perspectives regarding medical therapy of cholelithiasis are currently under discussion, also taking into account the pathogenesis of gallstones, the natural history of the disease and the analysis of the overall costs of therapy. A careful selection of patients may lead to successful non-surgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones. The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations, suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, might be proposed as additional approaches for treating cholesterol gallstones. In this review we discuss old, recent and future perspectives on medical treatment of cholesterol cholelithiasis.

Keywords: Bile; Bile acids; Cholecystectomy; Dissolution therapy; Ezetimibe; Gallbladder; Gallstones; Nuclear receptors; Statins.

Figure 1

Flow-chart depicting the standard therapies of gallstone disease (adapted from Portincasa et al[1,15,23,148]). As a starting point, at the top the gallbladder containing “supersaturated” biliary cholesterol is depicted. Typical solid plate-like monohydrate cholesterol crystals form first and aggregate after, to grow as cholesterol stones. Left: flow-chart reserved to asymptomatic patients with gallstones (i.e., when stones/crystal aggregates are not impacted within the cystic duct). Best choice is expectant management, while few indications for prophylactic cholecystectomy exist and are reported in Table 2; Right: the complex flow-chart reserved to symptomatic gallstone patients is shown. This is the case when stones/crystal aggregates are impacted within the cystic duct. A key step is to identify the “symptomatic” patients with or without complications. In this respect, documenting the presence of biliary colic is of key importance. Meta-analyses indicate that surgery (cholecystectomy) is the gold standard for treating symptomatic gallstones[51-53]. For treatment of uncomplicated and complicated biliary colic, see also Tables 3 and 4. CT: Computed tomography; ERCP: Endoscopic retrograde cholangiopancreatography; HIDA: 99mTc-N-(2,6-dimethylacetanilide)-iminodiacetic acid; HU: Hounsfield Unit; NSAIDs: Non-steroidal anti-inflammatory drugs; NRs: Nuclear receptors; TUDCA: Tauroursodeoxycholic acid; UDCA: Ursodeoxycholic acid; US: Abdominal ultrasonography. The HU is an arbitrary unit of X-ray attenuation used for CT scans. Each voxel is assigned a value on a scale in which air has a value of -1000; water, 0; and compact bone, +1000.

Figure 2

Chemical formula of drugs currently used to induce analgesia in patients with colicky pain. The three categories are: narcotic analgesics, non-steroidal anti-inflammatory drugs, and antispasmodics.

Figure 3

Chemical formula of bile acids used for oral litholysis of small, radiotransparent, cholesterol-enriched gallstones in a functioning gallbladder with a patent cystic duct of patients with symptomatic gallstones. CDCA: Chenodeoxycholic acid; UDCA: Ursodeoxycholic acid; TUDCA: Tauroursodeoxycholic acid.

Figure 4

Chemical formula of different statins used to inhibit hepatic cholesterol synthesis[119-122].

Figure 5

Chemical formula of ezetimibe, the specific inhibitor of the Niemann-Pick C1-like 1 protein.