Recent advances in understanding and managing cholesterol gallstones

Abstract

The high prevalence of cholesterol gallstones, the availability of new information about pathogenesis, and the relevant health costs due to the management of cholelithiasis in both children and adults contribute to a growing interest in this disease. From an epidemiologic point of view, the risk of gallstones has been associated with higher risk of incident ischemic heart disease, total mortality, and disease-specific mortality (including cancer) independently from the presence of traditional risk factors such as body weight, lifestyle, diabetes, and dyslipidemia. This evidence points to the existence of complex pathogenic pathways linking the occurrence of gallstones to altered systemic homeostasis involving multiple organs and dynamics. In fact, the formation of gallstones is secondary to local factors strictly dependent on the gallbladder (that is, impaired smooth muscle function, wall inflammation, and intraluminal mucin accumulation) and bile (that is, supersaturation in cholesterol and precipitation of solid crystals) but also to "extra-gallbladder" features such as gene polymorphism, epigenetic factors, expression and activity of nuclear receptors, hormonal factors (in particular, insulin resistance), multi-level alterations in cholesterol metabolism, altered intestinal motility, and variations in gut microbiota. Of note, the majority of these factors are potentially manageable. Thus, cholelithiasis appears as the expression of systemic unbalances that, besides the classic therapeutic approaches to patients with clinical evidence of symptomatic disease or complications (surgery and, in a small subgroup of subjects, oral litholysis with bile acids), could be managed with tools oriented to primary prevention (changes in diet and lifestyle and pharmacologic prevention in subgroups at high risk), and there could be relevant implications in reducing both prevalence and health costs.

Keywords: bile; cholesterol gallstones; gallbladder; pathogenesis; primary prevention.

Figure 1.. Pathways of cholesterol metabolism in the hepatocyte in humans.

Cholesterol can enter the hepatocytes as low-density lipoprotein (LDL) via the LDL receptor (LDLR), as chylomicron remnants (CMRs) via the prolow-density lipoprotein receptor-related protein 1 (LRP1), and as high-density lipoprotein (HDL) via the scavenger receptor class B member 1 (SRB1). The absorbed cholesterol and the cholesterol synthetized from acetate via the rate-limiting enzyme 3 hydroxy 3 methylglutaryl-coenzyme A reductase (HMGCR) contribute to the intrahepatic cholesterol pool. From here, cholesterol can follow different pathways: esterification (by the acyl-coenzyme A: cholesterol acyltransferase isoform 2, ACAT or SOAT1) and storage in the hepatocyte; incorporation into assembled very-low-density lipoprotein (VLDL) and secretion; catabolic synthesis of bile acids—via the rate-limiting enzymes cholesterol 7α hydroxylase (CYP7A1) and sterol 27 hydroxylase (CYP27A1)—and secretion in bile; and direct secretion into bile. Lipid secretion in bile requires distinct ATP-binding cassette (ABC) transporters at the canalicular membrane of the hepatocytes: the heterodimer ABCG5/G8 for cholesterol, ABCB11 for bile acids, and ABCB4 for phosphatidylcholine. In humans, NPC1L1 is at the canalicular membrane of hepatocytes and is responsible for the reuptake of cholesterol from bile back into the hepatocytes. The nuclear receptors in the hepatocyte (not shown) play a key role at different levels: the farnesoid X receptor (FXR or NR1H1) is controlled via the intestinal fibroblast growth factor 19 (FGF19) and its receptor (FGFR4) in the liver and regulates bile acid synthesis through the small heterodimer partner (SHP) ^, . The liver X receptor (LXR or NR1H3) regulates cholesterol synthesis (via the cytochrome P450 51A1, or CYP51A1), bile acid synthesis (via the UDP glucuronosyltransferase 1–3, or UGT1A3), and biliary cholesterol secretion (via transcriptional activation of ABCG5/G8) ^– . One to three lipids (that is, cholesterol, bile acids, and phospholipids) are secreted into the bile canaliculus, and they aggregate into the typical cholesterol carriers—that is, simple (1–2 nm), mixed micelles (4–8 nm), and small unilamellar (40–100 nm) or large multilamellar (300–500 nm) vesicles .

Figure 2.. Regulation of intestinal cholesterol absorption and role of the Niemann-Pick C1-like 1 protein (NPC1L1) at the enterocyte level in humans.

Bile acids enrich both hepatic and gallbladder bile. Sterols undergo micellar solubilization in the intestinal lumen, and uptake occurs at the enterocyte brush border. The NPC1L1, located at the apical membrane of the enterocytes, governs the active uptake of cholesterol and plant sterols across the brush border membrane of the enterocytes. Ezetimibe specifically inhibits the NPC1L1 pathway. The ATP-binding cassette transporters ABCG5/G8, also located at the enterocyte brush border, promote the active efflux of cholesterol and plant sterols from the enterocytes into the intestinal lumen for fecal excretion. In the enterocyte, new synthesis of cholesterol occurs from acetate (by 3-hydroxy-3-methylglutaryl-CoA reductase, or HMGCR). The esterification of intracellular cholesterol requires the acyl-CoA:cholesterol acyltransferase isoform 2 (ACAT2). Chylomicrons are assembled following triacylglycerol (TG) and phospholipid (PL) synthesis, steps requiring facilitated transport of fatty acids (FAs) and monoacylglycerol (MG) into the enterocytes, which include their FA binding protein 4 (FABP4)-mediated transport into the smooth endoplasmic reticulum. This step is followed by synthesis of diacylglycerol (DG) and TG, whereas PL synthesis is dependent on glucose transport into the smooth endoplasmic reticulum and synthesis of α-glycerophosphate (α-GP) and phosphatidic acid (PA). Apolipoprotein (APO)-B48 and activity of microsomal triglyceride transfer protein (MTTP) are required for assembly of chylomicrons before their secretion into the lymph. Thus, final chylomicron particles contain a core of triglycerides and cholesteryl esters surrounded by a surface enriched with PLs (mainly phosphatidylcholine), unesterified cholesterol, and apolipoproteins, including A-I, A-II, A-IV, B-48, C-I, and C-III. APO C-II and APO-E are acquired when the chylomicrons enter the circulation ^{, ,} . Adapted from .

Figure 3.. Pathogenetic factors involved in the formation of cholesterol gallstones and therapeutic opportunities.

Increased hepatic hypersecretion of cholesterol represents the primary cause of cholesterol gallstone formation developing in the background of genetic predisposition. Gallbladder factors include defective motility due to a form of leiomyopathy developing in response to excess biliary cholesterol, local immune-mediated inflammation, and hypersecretion of mucin in the gallbladder lumen. Bile factors include the accumulation of supersaturated, concentrated gallbladder bile, a predisposing factor to rapid phase transitions of cholesterol to solid crystals, aggregation, and conglomeration within the mucin gel. Intestinal factors increase absorption of cholesterol and reduce absorption of bile acids. Therapeutic interventions include cholecystectomy, which radically cures gallbladder and bile abnormalities (and is effective in the case of pigment gallstones); general lifestyle recommendations; dietary changes; regular physical activity; and cure and prevention of metabolic abnormalities. Ursodeoxycholic acid is reserved to a subgroup of symptomatic uncomplicated gallstone patients with small stones, radiolucent (x-ray) in a functioning gallbladder and patent cystic duct. Also, in the high-risk group of patients undergoing rapid weight loss (that is, bariatric surgery or very-low calorie diet), ursodeoxycholic acid and a daily fat content of 7 to 10 g are recommended to improve gallbladder emptying and to prevent the formation of cholesterol gallstones following rapid weight reduction. All other therapeutic options are currently not supported by strong scientific evidence or require further studies ^{, , , ,} .