Enterohepatic Circulation

Definition

• Sleisenger & Fordtran's GI and Liver Disease, p. 1204
• Harrison's Principles of Internal Medicine 22E, p. 2771

The Bile Acid Pool - Key Numbers

• Harrison's 22E, p. 2771; Lippincott Biochemistry 8th Ed., p. 633

Step-by-Step Circuit

1. Hepatic Synthesis & Secretion

• The liver synthesizes primary bile acids: cholic acid and chenodeoxycholic acid from cholesterol (rate-limiting step: CYP7A1, i.e., cholesterol 7-alpha-hydroxylase).
• These are conjugated with glycine or taurine in hepatocytes to form bile salts.
• Bile salts are actively secreted into bile canaliculi via BSEP (Bile Salt Export Pump, ABCB11), an ATP-dependent transporter.

2. Gallbladder Storage (Fasting State)

• Between meals, the sphincter of Oddi contracts. Bile flows into the gallbladder, where it is concentrated ~10-fold by water and electrolyte absorption.
• Almost the entire bile acid pool may be sequestered in the gallbladder overnight for delivery with the first meal.

3. Postprandial Release

• Fat and amino acids in the duodenum trigger release of CCK (cholecystokinin) from intestinal mucosa.
• CCK causes: gallbladder contraction + sphincter of Oddi relaxation → bile empties into duodenum.
• Intraluminal bile acid concentration reaches 5-10 mmol/L (well above the critical micellar concentration of ~1.5 mmol/L).

4. Intestinal Functions

• Bile acids form mixed micelles with phospholipids and cholesterol, which:
  • Activate pancreatic lipase on triglycerides
  • Solubilize long-chain fatty acids, monoglycerides, cholesterol
  • Shuttle hydrophobic lipids across the unstirred water layer to the mucosal surface for absorption
  • Facilitate absorption of fat-soluble vitamins (A, D, E, K)

5. Ileal Reabsorption (Active - Primary Route)

• Conjugated bile acids are actively reabsorbed in the terminal ileum via ASBT (Apical Sodium-dependent Bile Salt Transporter, SLC10A2) - a Na⁺-bile salt co-transporter.
• They exit the ileocyte basolaterally via OST-alpha/OST-beta transporters into the portal blood.
• Unconjugated bile acids may be passively absorbed along the entire small intestine (less efficient).

Why the ileum? Keeping active absorption at the terminal ileum ensures bile acids remain at high concentration throughout the entire small intestine to maximize fat digestion.

6. Portal Return to the Liver

• Bile acids are transported in portal blood bound to albumin.
• Hepatocytes extract them with >90% first-pass efficiency via:
  • NTCP (Na⁺-taurocholate co-transporting polypeptide, SLC10A1) - for conjugated bile acids
  • OATPs (Organic Anion Transporting Polypeptides) - for unconjugated bile acids
• The liver reconjugates, processes, and re-secretes them into bile - completing the circuit.

Secondary Bile Acids & Bacterial Modification

• Bacteria in the colon deconjugate bile salts (remove glycine/taurine) and dehydroxylate at C-7:
  • Cholic acid → Deoxycholic acid
  • Chenodeoxycholic acid → Lithocholic acid (poorly absorbed; mostly excreted)
• A small proportion of these secondary bile acids are absorbed by colonic epithelium and returned to the liver, where they may be re-conjugated and hydroxylated.
• Lippincott Biochemistry 8th Ed., p. 634

Regulation of the Cycle

• Harrison's 22E, p. 2771; Sleisenger & Fordtran

Functions of EHC (Beyond Bile Acid Recycling)

1. Primary mechanism for excreting excess cholesterol - cholesterol is consumed during bile acid synthesis and excreted in micelles in stool
2. Fat digestion - micelle formation is required for dietary lipid absorption
3. Fat-soluble vitamin absorption (A, D, E, K)
4. Lipophilic drug absorption
5. Regulation of water movement - in hepatocytes (into bile) and across small bowel
6. Feedback regulation of cholesterol and bile acid synthesis

• Sabiston Textbook of Surgery, p. 1873

Clinical Significance & Disorders

1. Ileal Resection / Disease (Crohn's disease)

• Loss of terminal ileum disrupts active ASBT-mediated reabsorption
• Large quantities of bile salts lost in stool - hepatic synthesis cannot compensate (max ~5 g/day)
• Depleted bile acid pool → impaired fat absorption → steatorrhea and fat-soluble vitamin deficiency
• Excess bile acids reaching colon → secretory diarrhea (bile acid diarrhea)
• Costanzo Physiology 7th Ed.; Harrison's 22E

2. Cholelithiasis (Gallstones)

• If bile acids decrease relative to cholesterol and phospholipids in bile, cholesterol precipitates → cholesterol gallstones
• Caused by decreased bile acids or increased cholesterol secretion into bile
• Lippincott Biochemistry 8th Ed., p. 634

3. Cholestasis

• Classified as intrahepatic (hepatocyte transport defect) or extrahepatic (biliary obstruction)
• EHC disorders fall into 4 categories:
  1. Defects in bile acid formation (synthesis/conjugation)
  2. Defects in membrane transport (BSEP, NTCP mutations)
  3. Disturbances in bacterial transformation
  4. Disturbances in circulation between organs
• Sleisenger & Fordtran, p. 1455

4. Pharmacological Applications

• Bile acid sequestrants (cholestyramine, colestipol, colesevelam): bind bile acids in gut, prevent reabsorption → liver draws more cholesterol into bile acid synthesis → lowers LDL cholesterol. Used in hypercholesterolemia.
• These resins also affect drugs undergoing EHC (e.g., digoxin, warfarin) by binding them in the gut
• Activated charcoal (multi-dose): interrupts EHC of drugs with long half-lives (e.g., carbamazepine, dapsone, diazepam, amitriptyline) - used in overdose management
• Cholestyramine in thyrotoxicosis: reduces EHC of thyroid hormones, helping lower thyroid hormone levels
• Katzung Pharmacology 16th Ed.; Tintinalli's Emergency Medicine

5. Drugs with Significant EHC

• Diazepam (secondary plasma peak 6-12 h after dose)
• Morphine, chloramphenicol, rifampicin, oral contraceptives, NSAIDs
• This prolongs their half-life and can produce secondary plasma concentration peaks
• Morgan & Mikhail's Clinical Anesthesiology 7e

Summary Diagram (Lippincott)

Quick Summary

Liver (synthesis + conjugation)
   ↓ BSEP
Bile canaliculi → Bile ducts → Gallbladder (concentration, storage)
   ↓ CCK-triggered release
Duodenum/Small Intestine (micelle formation → fat absorption)
   ↓ 95% reabsorbed in terminal ileum via ASBT
Portal vein
   ↓ NTCP / OATPs
Liver (extraction >90%, reconjugation, re-secretion) → cycle repeats 5-10x/day
   ↓ 5% lost
Colon (bacterial modification → secondary bile acids) → Feces (0.5 g/day lost)