What is the pathway of bile?

The Pathway of Bile

Bile is produced by hepatocytes and follows a complex pathway from the liver through the biliary system to the small intestine, involving multiple transport mechanisms and modifications along the way. 1

Bile Formation in Hepatocytes

• Bile is formed by hepatocytes and consists of water, electrolytes, bile acids, pigments, proteins, lipids, and various metabolic breakdown products 1
• The primary driving force for bile formation is the uptake and transcellular transport of bile salts by hepatocytes 2
• Energy for bile formation comes from the sodium gradient created by the basolateral Na+/K+-ATPase, to which bile salt transport is coupled 2

Bile Salt Uptake and Transport Within Hepatocytes

• Hydrophilic bile salts are taken up at the basolateral (sinusoidal) membrane via a sodium-dependent, saturable, carrier-mediated process 2
• Hydrophobic bile acids are taken up by a sodium-independent facilitated carrier-mediated mechanism or by passive diffusion 2
• Two major carrier proteins have been identified on the hepatocyte basolateral membrane:
  • A 48-kDa protein involved with Na+-dependent bile salt uptake 2
  • A 54-kDa protein associated with Na+-independent bile salt uptake 2
• Intracellular transport of bile salts may involve cytosolic carrier proteins or vesicular transport mechanisms 2, 3

Canalicular Secretion

• Bile is secreted into the bile canaliculi, which are ~1 μm in diameter channels formed by the apical membranes of adjacent hepatocytes and sealed by tight junctions 1
• Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems 1
• These transport systems consist primarily of ATP-binding cassette (ABC) transport proteins that function as export pumps for bile salts and other organic solutes 1
• Key transporters include:
  • Bile Salt Export Pump (BSEP/ABCB11) for bile salts 3
  • Multidrug Resistance Protein 3 (MDR3/ABCB4) for phospholipids 4
  • Other transporters for various components 3

Bile Flow Through the Biliary System

• Bile canaliculi conduct the flow of bile countercurrent to the direction of portal blood flow 1
• Canaliculi connect with the Canal of Hering and bile ducts which progressively increase in diameter 1
• The bile ducts are lined with cholangiocytes (bile duct epithelial cells) that modify the bile composition 1
• Bile flows through:
  • Bile canaliculi → Canal of Hering → Intrahepatic bile ducts → Extrahepatic bile ducts → Common hepatic duct → Common bile duct → Duodenum 5, 1
• Between meals, bile is diverted to the gallbladder for storage and concentration 6

Gallbladder Storage and Release

• Bile is concentrated in the gallbladder between meals 6
• After eating, gallbladder contractions are provoked by physiologic responses to food 6
• Concentrated bile is expelled into the duodenum via the cystic and common bile ducts 6

Enterohepatic Circulation

• About 90% of bile acids are reabsorbed in the terminal ileum 6, 3
• Reabsorbed bile acids enter the portal vein and return to the liver 6
• In the liver, there is efficient extraction of bile acids from portal blood (first-pass effect) 6
• Reabsorbed bile acids are reconjugated by the liver and secreted again into bile 6
• This enterohepatic circulation occurs 6-10 times per day 3

Common Disorders of Bile Transport

• Genetic defects in bile transporters can lead to various cholestatic disorders 4
• Progressive Familial Intrahepatic Cholestasis (PFIC) includes:
  • PFIC1 (FIC1 deficiency): mutations in ATP8B1 gene 4
  • PFIC2 (BSEP deficiency): mutations in ABCB11 gene 4
  • PFIC3 (MDR3 deficiency): mutations in ABCB4 gene 4
• Bile acid synthesis disorders can result from defects in enzymes involved in bile acid production 4
• Drug-induced cholestasis can occur through inhibition of hepatocellular transporter expression/function or through inflammatory reactions at the bile ductular level 4

Clinical Implications

• Disruptions in bile formation and flow can lead to cholestasis, jaundice, pruritus, and liver damage 4
• Ursodeoxycholic acid (UDCA) is commonly used to treat various cholestatic conditions by changing bile composition from hydrophobic to more hydrophilic 4, 6
• Primary bile acid replacement therapy is effective for bile acid synthesis disorders 4