Bile is a unique alkaline secretion of the body. It is secreted from the hepatocytes and is further altered and refined by the epithelial cells lining the biliary tract. The gallbladder stores this fluid, where it gets concentrated and subsequently released into the digestive tract via the common bile duct.  On receiving stimulation via the hormone cholecystokinin from the intestinal tract due to the presence of food in the intestinal lumen, the gallbladder contracts and secretes the bile into the duodenum.[1] The composition of bile is predominantly water with multiple dissolved substances, including cholesterol, amino acids, enzymes, vitamins, heavy metals, bile salts, bilirubin, phospholipids, and other constituents such as drugs and toxins.[1] The cells lining the intrahepatic and extrahepatic biliary ducts are collectively referred to as cholangiocytes. Their primary role is to alter and refine the contents of the hepatically synthesized bile via a complex mechanism controlled by a multitude of molecules, hormones, and neurotransmitters.[2]

Hepatocytes have specific transporters on their apical as well as basolateral membranes that play a central role in the synthesis of canalicular bile. There are two components of the canalicular bile: bile acids dependent canalicular fraction and bile acids independent canalicular fraction. There is a direct correlation of the quantity of individual bile acids secreted into bile and the amount of water osmotically driven into the bile. Due to the enterohepatic circulation and re-secretion of specific bile acids such as ursodeoxycholic acid, these bile acids have higher choleretic activity and contribute to generating a larger volume of bile.[3]

There are three primary transporters present on the basolateral membrane of the hepatocytes that helps in facilitating sinusoidal uptake of the bile acids. The most important Na+ dependent transporter is the sodium taurocholate co-transporting polypeptide (NTCP). The Na+ independent transporter is the organic anion- transporting polypeptides OATP that brings in the bile acids in exchange for molecules like HCO3-, glutathione, etc. Another sodium-independent bile acid transporter is the OST alpha/ OST beta transporter. This protein helps in bile acid removal from the hepatocytes in case of an excess of bile acid accumulation.[3]

For the secretion of the bile acids, there are specific transporters on the canalicular membrane of the hepatocytes. The ATP dependent bile acid efflux gets carried by BSEP (Bile Salt Export Pump). There are other apical ATP binding cassette (ABC) transporters - multidrug resistance-P glycoprotein 3 (MDR3) for phospholipids, MDR1 for lipophilic cationic drugs, multidrug resistance-associated protein 2 (MRP2) for non-bile acid organic anions, and the protein ABCG5/G8 for the secretion of cholesterol and other sterols.[3]

Various regulatory hormones and substances tightly control the formation and secretion of the bile. There are secretin receptors on the cholangiocytes. These receptors, when stimulated, increase the HCO3 - secretion in the bile. Other hormones such as acetylcholine and VIP increase the biliary HCO3 - secretion, whereas the hormones such as dopamine, somatostatin, and gastrin inhibit the secretin-stimulated efflux of bicarbonate in the bile.[3]

The hepatic tissue begins to evolve as a diverticulum from the ventral foregut endoderm that extends into the septum transversum. There are two parts of the ventral foregut endoderm. The cranial portion gives rise to the intrahepatic bile ducts, whereas the caudal portion leads to the development of the extrahepatic biliary tree.[4][5][6] Around the 8th week of gestation, the intrahepatic bile ducts begin to develop. The development commences at the hilum and extends to the periphery, along the portal venous system.[7][8][9] The formation of a ductal plate occurs when the periportal hepatoblasts, close to the portal mesenchyme near the portal vein tributary, start to get arranged in a uni-layered pattern of small flat epithelial cells. Soon, there occurs regeneration and multiplication of cells in specific portions of the ductal plate, forming the bilayered ductal plate — these plates than enlarge and organize into a tubular shape. These tubules undergo further differentiation and maturation to become individualized intrahepatic bile ducts.[10] The development of the extrahepatic bile ducts occurs earlier than that of the intrahepatic biliary ducts. These two ductal systems connect later at the level of hepatic hilum.[10]

The various organ systems involved in the biliary physiology are the hepatobiliary system, the gastrointestinal system, and the hematologic system. The breakdown of the hemoglobin stored in the red blood cells occurs in the reticuloendothelial system to form the unconjugated bilirubin. The blood transports unconjugated attached to albumin. Once it enters hepatocytes, it gets conjugated by the enzyme UDP glucuronyl transferase and gets secreted in the bile. The bile passes through the intrahepatic and extrahepatic bile ducts to the gallbladder for storage. The bile secretes into the duodenum regulated by various hormones. In the intestines, the conjugated bilirubin converts into urobilinogen, urobilin, and -stercobilin. With the enterohepatic recirculation, the majority of the bile salts get reabsorbed back to the liver.