Bile Secretion and Composition
Bile formed in the hepatic lobules is secreted into a complex network of canaliculi, small bile ductules, and larger bile ducts that run with lymphatics and branches of the portal vein and hepatic artery in portal tracts situated between hepatic lobules. These interlobular bile ducts coalesce to form larger septal bile ducts that join to form the right and left hepatic ducts, which in turn, unite to form the common hepatic duct. The common hepatic duct is joined by the cystic duct of the gallbladder to form the common bile duct (CBD), which enters the duodenum (often after joining the main pancreatic duct) through the ampulla of Vater.
Hepatic bile is an isotonic fluid with an electrolyte composition resembling blood plasma. The electrolyte composition of gallbladder bile differs from that of hepatic bile because most of the inorganic anions, chloride and bicarbonate, have been removed by reabsorption across the gallbladder epithelium. As a result of water reabsorption, total solute concentration of bile increases from 3–4 g/dL in hepatic bile to 10–15 g/dL in gallbladder bile.
Major solute components of bile by moles percent include bile acids (80%), lecithin and traces of other phospholipids (16%), and unesterified cholesterol (4.0%). In the lithogenic state, the cholesterol value can be as high as 8–10%. Other constituents include conjugated bilirubin; proteins (all immunoglobulins, albumin, metabolites of hormones, and other proteins metabolized in the liver); electrolytes; mucus; and, often, drugs and their metabolites.
The total daily basal secretion of hepatic bile is ∼500–600 mL. Many substances taken up or synthesized by the hepatocyte are secreted into the bile canaliculi. The canalicular membrane forms microvilli and is associated with microfilaments of actin, microtubules, and other contractile elements. Prior to their secretion into the bile, many substances are taken up into the hepatocyte, while others, such as phospholipids, a portion of primary bile acids, and some cholesterol are synthesized de novo in the hepatocyte. Three mechanisms are important in regulating bile flow: (1) active transport of bile acids from hepatocytes into the bile canaliculi, (2) active transport of other organic anions, and (3) cholangiocellular secretion. The last is a secretin-mediated and cyclic AMP–dependent mechanism that results in the secretion of a sodium- and bicarbonate-rich fluid into the bile ducts.
Active vectorial secretion of biliary constituents from the portal blood into the bile canaliculi is driven by a set of polarized transport systems at the basolateral (sinusoidal) and the canalicular apical plasma membrane domains of the hepatocyte. Two sinusoidal bile salt uptake systems have been cloned in humans, the Na+/taurocholate cotransporter (NTCP, SLC10A1) and the organic anion–transporting proteins (OATPs), which also transport a large variety of non-bile salt organic anions. Several ATP-dependent canalicular transport systems, “export pumps,” (ATP-binding cassette transport proteins, also known as ABC transporters) have been identified, the most important of which are: the bile salt export pump (BSEP, ABCB11); the anionic conjugate export pump (MRP2, ABCC2), which mediates the canalicular excretion of various amphiphilic conjugates formed by phase II conjugation (e.g., bilirubin mono- and diglucuronides and drugs); the multidrug export pump (MDR1, ABCB1) for hydrophobic cationic compounds; and the phospholipid export pump (MDR3, ABCB4). Two hemitransporters ABCG5/G8, functioning as a couple, constitute the canalicular cholesterol and phytosterol transporter. F1C1 (ATP8B1) is an aminophospholipid transferase (“flippase”) essential for maintaining the lipid asymmetry of the canalicular membrane. The canalicular membrane also contains ATP-independent transport systems such as the Cl/HCO3 anion exchanger isoform 2 (AE2, SLC4A2) for canalicular bicarbonate secretion. For most of these transporters, genetic defects have been identified that are associated with various forms of cholestasis or defects of biliary excretion. F1C1 is defective in progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) and results in ablation of all other ATP-dependent transporter functions. BSEP is defective in PFIC2 and BRIC2. Mutations of MRP2 (ABCC2) cause the Dubin-Johnson syndrome, an inherited form of conjugated hyperbilirubinemia (Chap. 303). A defective MDR3 (ABCB4) results in PFIC3. ABCG5/G8, the canalicular half transporters for cholesterol and other neutral sterols, are defective in sitosterolemia. The cystic fibrosis transmembrane regulator (CFTR, ABCC7) located on bile duct epithelial cells but not on canalicular membranes is defective in cystic fibrosis, which is associated with impaired cholangiocellular pH regulation during ductular bile formation and chronic cholestatic liver disease, occasionally resulting in biliary cirrhosis.
The primary bile acids, cholic acid and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver, conjugated with glycine or taurine, and secreted into the bile. Secondary bile acids, including deoxycholate and lithocholate, are formed in the colon as bacterial metabolites of the primary bile acids. However, lithocholic acid is much less efficiently absorbed from the colon than deoxycholic acid. Another secondary bile acid, found in low concentration, is ursodeoxycholic acid (UDCA), a stereoisomer of CDCA. In healthy subjects, the ratio of glycine to taurine conjugates in bile is ∼3:1.
Bile acids are detergent-like molecules that in aqueous solutions and above a critical concentration of about 2 mM form molecular aggregates called micelles. Cholesterol alone is sparingly soluble in aqueous environments, and its solubility in bile depends on both the total lipid concentration and the relative molar percentages of bile acids and lecithin. Normal ratios of these constituents favor the formation of solubilizing mixed micelles, while abnormal ratios promote the precipitation of cholesterol crystals in bile via an intermediate liquid crystal phase.
In addition to facilitating the biliary excretion of cholesterol, bile acids facilitate the normal intestinal absorption of dietary fats, mainly cholesterol and fat-soluble vitamins, via a micellar transport mechanism (Chap. 294). Bile acids also serve as a major physiologic driving force for hepatic bile flow and aid in water and electrolyte transport in the small bowel and colon.