PHYSIOLOGY OF BILE PRODUCTION AND FLOW
BILE SECRETION AND COMPOSITION
Bile formed in hepatocytes 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%), phospholipids (lecithins, cephalins, and sphingomyelin) (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; heavy metals; 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 bicarbonate-rich fluid into the bile ducts.
Active vectorial trans-hepatocellular movement of bile acids from the portal blood into the bile canaliculi is driven by a set of 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 (OATP1B1/1B3), 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 ...