The gallbladder serves as a reservoir for bile storage and concentrations, functioning as an accessory organ for the digestive tract. The gross structure of the gallbladder and cystic duct are illustrated in Biliary tree canaliculi.
Gallbladder structure is defined by a fundus, body, and neck that transition into the cystic duct. Structural regions display differences in gallbladder wall thickness and in the complexity and depth of mucosal folds, decreasing in magnitude from the gallbladder neck through the fundus.
Each portion of the gallbladder should be examined microscopically when cholecystectomy is performed, for identification of disease processes that necessitated gallbladder removal.
The largest volume of hepatic bile accumulates in the gallbladder during the interdigestive (between-meal) interval. While bile is continuously modified during transit through the intrahepatic biliary tree, it is largely concentrated and terminally modified in the gallbladder.
The cystic duct merges the gallbladder to the common bile duct, providing the conduit through which bile enters and then discharges from the gallbladder. The common bile duct joins the duodenum at the major duodenal papillae. Here a smooth muscle sphincter (sphincter of Oddi) guards against retrograde contamination of the biliary tree with enteric bacteria or particulate food debris.
The communication between the common bile duct and duodenum is anatomically distinct in the dog and cat.
In a medium-sized dog, the common bile duct is ~5 cm long, ~2.5 mm in diameter, and joins with the duodenum 1.5 to 6.0 cm distal to the pylorus at the major duodenal papilla. At this junction, the common bile duct forms a ~1 to 2-cm intramural junction with duodenal musculature.
This sphincter of Oddi opens near but remains distinct and separate from a nearby slitlike pancreatic duct, the smaller of two pancreatic ducts (the minor pancreatic duct). The minor pancreatic duct enters the duodenum at the major duodenal papilla.
The larger pancreatic duct (accessory pancreatic duct), extending from the dorsal pancreas, opens a few centimeters distally (~3 cm) on the minor duodenal papilla. This duct drains most of the pancreatic secretions in the dog.
The bile duct of the cat is long and sinuous compared with that of the dog, a difference recognizable and sometimes confusing on ultrasonography.
In most cats, the common bile duct unites with the major pancreatic duct in an ampulla (ie, the dilated end of a duct) known as the ampulla of Vater before joining the sphincter of Oddi through a common orifice (major duodenal papilla) positioned ~3 cm caudal to the pylorus.
In some cats the major pancreatic duct opens separately but immediately adjacent to the common bile duct. Approximately 2 cm caudal to the major duodenal papilla, the accessory pancreatic duct enters the duodenum (minor duodenal papilla) in 20% of cats.
While the pancreas in each species is nearly always drained by two ducts, a great deal of variation exists. Nevertheless, because of the close proximity between the pancreas and common bile duct, pancreatitis commonly influences bile flow through the distal portion of the common bile duct, causing flow obstruction and jaundice.
In the cat, inflammatory, neoplastic, or obstructive disorders involving the distal common bile duct usually impact the biliary tree and pancreatic ductal system concurrently because of their joined distal segment.
The ampulla shared by the common bile duct and major pancreatic duct is similar to the anatomy in humans. Thus, it is not surprising that cholelithiasis and other disorders impairing patency of the sphincter of Oddi pose high risk for retrograde bacterial infection and cholelith dissemination into the pancreatic ductal system, as occurs in humans. In cats, this suppurative cholangiohepatitis/cholelithiasis syndrome is commonly mistaken for idiopathic pancreatitis, being clinicopathologically characterized by vacillating liver enzymes and feline-specific pancreatic lipase.
In both the dog and the cat, perfusion to the intrahepatic biliary tree is provided by the peribiliary arterial plexus that occasionally anastomoses with a small branch of the portal vein. Intrahepatic bile ducts are also closely positioned near branches of the portal vein. Consequently, hematogenous dissemination of infectious agents from either the systemic or portal circulations can inoculate the intrahepatic biliary tree leading to bileborne infections. This scenario may initiate development of chronic bileborne bacterial infections with organisms chronically harbored in gallbladder mucosa, which provides a biofilm niche.
Bile is remarkably concentrated and modified during storage in the gallbladder compared to hepatic bile. After 12 hours of food withholding, most of the bile salt pool accumulates in the gallbladder (80%–90%) where it can be concentrated to ~10-fold. Isotonicity (with plasma) is sustained by aggregation of bile salts, Na+, Ca2+, phospholipids, lecithin, and cholesterol into mixed micelles. Gallbladder bile is acidified by absorption of Na+ in exchange for H+, while K+ and Ca2+ are passively equilibrated with plasma.
Most biliary HCO3- is forfeited by reaction with H+, liberating CO2 that diffuses into the systemic circulation. Trivial amounts of conjugated bilirubin are hydrolyzed to unconjugated bilirubin, with small amounts resorbed into the systemic circulation.
Epithelia of larger bile ducts and gallbladder secrete mucins, complex glycoproteins categorized as either membrane-bound or gel-forming. Gel-forming mucins predominate in the canine gallbladder. These form oligopolymers that impart remarkable viscoelastic properties influencing mucin rheology, in this case, to bile.
Hydration status importantly influences gel-forming mucin viscosity, with relative dehydration escalating its tenacity and adhesiveness.
Interdigestive Interval
Between meals, the pressure gradient in the biliary tree favors bile diversion into a relaxed gallbladder (80%–90% delivered into the gallbladder) with the remainder passed on to the duodenum. During gallbladder filling, there is trivial change in the pressure gradient with gallbladder expansion. Relaxation of the gallbladder wall is triggered through fibroblast growth factor 19 (FGF-19), stimulated by bile acid signaling of farnesoid X receptor (FXR) in the ileum.
Myoelectric motor complexes, similar to those associated with intestinal motility, initiate an intermittent bellows-like gallbladder contraction during this time. These contractions propel small bile volumes (or spurts) into the common bile duct and duodenum. Rhythmic or phasic contractions of the sphincter of Oddi and motilin (a hormone released from enteroendocrine cells in the upper small intestines) contribute to this activity.
Erythromycin functions as a motilin agonist and is occasionally administered (0.5 mg/kg, PO, once) to pharmacologically stimulate gallbladder contraction in dogs that have failed an ultrasonographic motility study.
Meal-related Gallbladder Motility
Gallbladder motility is complexly influenced by interplay of neuroendocrine signals coordinating gallbladder contraction with meal ingestion.
Food ingestion (free fatty acids and amino acids) and gastric distention initiate vagal stimulation (parasympathetic) and release of cholecystokinin (CCK) and motilin that stimulate meal-related gallbladder contraction. This initial phase of contraction occurs mainly in response to CCK released from enteroendocrine cells in the upper small intestines. This stimulus synchronizes release of bile and pancreatic enzymes.
Gallbladder contraction is also synchronized with relaxation of the sphincter of Oddi (enhanced by secretin) to facilitate postprandial bile flux into the intestines. Additionally, CCK also stimulates intestinal peristalsis, important for meal digestion and assimilation as well as for propulsion of bile salts to the ileum for enterohepatic recycling.
After meal-provoked gallbladder contraction, subsequent gallbladder filling is modulated by relaxation of its wall in response to somatostatin and neurogenic signaling.
The most important factor signaling gallbladder relaxation is the enterohepatic recycling of bile acids that interact with FXR in enterocytes of the ileum, which induce expression of FGF-19. The FGF-19 ligand is the dominant repressor of postprandial bile acid synthesis and potently relaxes the gallbladder, exploiting its function as a filling reservoir.
Negative feedback signaling from bile acids returning to the liver also inhibits further CCK release. At this point, the sphincter of Oddi tone is reestablished, helping to divert hepatic bile once again into a now relaxed gallbladder. Not all bile transiting the hepatic ducts is diverted into the gallbladder, as this is dependent on the net pressure gradient in the biliary excretory pathway.
In healthy dogs, the maximum interdigestive gallbladder volume (ie, following a period of food withholding) is ~1.2 mL/kg. A gallbladder volume less than this does not warrant motility assessment, unless insufficient filling is suspected (a rare diagnosis). Normal postprandial gallbladder volume in cats ranges from 2.5–5.0 mL, with a maximum interdigestive gallbladder volume of ~1.0–1.2 mL/kg (similar to that in dogs).
Factors influencing bile flow: intrahepatic and extrahepatic biliary tree and gallbladder:
Canalicular biliary ductal pressure modified by secretory contributions from the biliary tree (mainly bicarbonate flux)
Canalicular cholestasis: failed bile transporter expression (endotoxemia), toxin-targeting cholangiocyte function, fulminant hepatic failure, chronic advanced-stage liver disease, acute-on-chronic necroinflammatory hepatobiliary disease
Ductopenia: physical & functional loss of cholangioles (small biliary ductal system)
Obstruction of hepatic ducts or common bile duct causing mechanical cholestasis; major bile duct obstruction: many causes including cholelithiasis, neoplastic mass lesions at sphincter of Oddi, pancreatitis, gallbladder mucocele, others
Variation in physiologic factors modulating gallbladder tone: food ingestion, cholecystokinin (CCK) & motilin elaboration in the upper small intestine, CCK1 receptor expression on gallbladder mucosa, or neurogenic mechanisms; CCK mediation most important
Failed synchronization between sphincter of Oddi tone/contraction & gallbladder contraction
Physically compromised gallbladder wall compliance: congenital gallbladder atresia (ductal plate malformation associated), fibrosing or granulomatous cholecystitis, intramural or extramural mass lesions restricting gallbladder reservoir expansion, ischemic mural gallbladder injury
Failure of gallbladder wall relaxation: failed FXR bile acid binding interrupting fibroblast growth factor 15/19 signaling of gallbladder wall relaxation (malabsorption due to gut disease, infiltrative gut disease, bile duct obstruction, portosystemic shunting?)
gallbladder dysmotility due to numerous potential causes (see gallbladder mucocele section), diseased gallbladder wall, above factors 6,7,8
Digestive Functions of Bile
The most essential digestive function of bile facilitates the solubilization, digestion, and assimilation of dietary fat. Bile acids emulsify ingested fat into mixed micelles that increase the surface area for action of digestive enzymes (eg, lipase that digests lipid). Bile acids also facilitate the digestive activity of lipase, and enteric bile is essential for absorption of fat-soluble vitamins (vitamins A, D, E, and K).
Experimental studies and work in humans confirm that vitamin E and its oxidative metabolites are eliminated in bile, undergoing some degree of enterohepatic recirculation. Vitamin D is partially synthesized in the liver and eliminated in bile, with 25% of the most potent activated form undergoing biliary elimination and enterohepatic circulation.
Biliary excretion and enterohepatic circulation is also associated with riboflavin (vitamin B2) and activated folic acid. Vitamin B12 (cobalamin) is largely stored in the liver and undergoes at least partial biliary elimination and enterohepatic circulation with absorption facilitated by intrinsic factor.
Focused research investigating vitamin metabolism in the liver of dogs and cats is sparse.
A hepato-biliary-enteric bacterial circulation is acknowledged, whereby transmural passage of enteric organisms into the portal vein navigate canaliculi, transcending the biliary tree in bile. Organisms may remain in bile-associated biofilms, undergo multifocal dissemination into hepatic parenchyma, or be completely eliminated in bile. Disorders impairing bile flow within the biliary ductal systems or gallbladder are permissive to survival and replication of bacterial opportunists.
