Enterohepatic Circulation

Definition

Anatomic Components

• Liver (site of synthesis and re-uptake)
• Biliary tract and gallbladder (storage and delivery)
• Sphincter of Oddi (valve controlling flow)
• Small intestine (site of function + reabsorption)
• Ileocecal valve
• Portal venous circulation (return pathway)
• Colon (minor site of passive absorption + bacterial modification)

Bile Acid Pool and Cycling

The Circuit — Step by Step

1. Hepatic Synthesis & Secretion

• Cholesterol → Primary bile acids (cholic acid [CA] and chenodeoxycholic acid [CDCA]) via the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1)
• Conjugated with glycine or taurine → Primary bile salts (ionized form)
• Secreted into bile canaliculi by the Bile Salt Export Pump (BSEP / ABCB11)
• Transported to duodenum via the bile duct (stored in gallbladder between meals)

2. Intestinal Transit & Function

• In the small intestine, bile salts form mixed micelles with phospholipids and cholesterol, facilitating:
  • Emulsification of dietary fats
  • Activation of pancreatic lipase on triglycerides
  • Solubilization of fat-soluble vitamins (A, D, E, K) for absorption
• Concentration in intestinal lumen: 5–10 mmol/L (threshold for micelle formation: ~1.5 mmol/L)

3. Bacterial Modification (Colon / Distal Gut)

• Gut bacteria deconjugate bile salts (remove glycine/taurine)
• Dehydroxylate at carbon-7 → Secondary bile acids:
  • Cholic acid → Deoxycholic acid (DCA)
  • Chenodeoxycholic acid → Lithocholic acid (LCA)
• A small proportion of secondary bile acids are reabsorbed from the colon and returned to the liver

4. Ileal Reabsorption (Key Step)

• Active, Na⁺-coupled reabsorption in the terminal ileum via ASBT (Apical Sodium-dependent Bile acid Transporter / SLC10A2)
• Exit across the basolateral membrane via OST α/β (Organic Solute Transporter)
• Enter the portal circulation (transported bound to albumin)
• Strategically located in the terminal ileum so bile salts are present at high concentration throughout the entire small bowel for maximal fat absorption

5. Hepatic Re-uptake

• Portal blood delivers bile salts back to hepatocytes
• Taken up by NTCP (Na⁺-taurocholate cotransporting polypeptide / SLC10A1) and OATP1B1/1B3 (organic anion transporters)
• Re-conjugated and re-secreted → cycle repeats

Diagram: Enterohepatic Circulation of Bile Salts

Diagram: Transport Proteins Involved

Regulation: Feedback Control

• Bile salts inhibit CYP7A1 (cholesterol 7α-hydroxylase) → negative feedback on synthesis
• When more bile salts return to the liver → synthesis decreases
• When less returns (e.g., ileal resection, cholestyramine) → synthesis is maximally stimulated but may not compensate → pool depletion
• FGF19 (fibroblast growth factor 19), released from ileal enterocytes in response to bile acid reabsorption, also inhibits CYP7A1 and induces gallbladder relaxation during the interdigestive period
• TGR5 (G-protein coupled receptor) is activated directly by bile acids

Physiological Significance

1. Cholesterol elimination: The enterohepatic circulation is the primary mechanism for eliminating excess cholesterol — it is converted to bile acids and lost in feces
2. Fat digestion: Recycling ensures adequate bile salt concentration for lipid absorption across the full length of the small intestine
3. Choleretic effect: Returning bile salts to the liver stimulates further bile secretion (choleresis)

Clinical Consequences of Disruption

Ileal Resection / Crohn's Disease (Terminal Ileum)

• Loss of active reabsorption → massive fecal bile acid loss
• Synthesis cannot compensate → pool depletion
• Reduced micellar solubilization → steatorrhea, fat-soluble vitamin deficiency
• Bile acids reaching the colon → choleretic diarrhea (bile acid diarrhea)

Disorders of Enterohepatic Circulation (Classification)

1. Defects in bile acid synthesis/conjugation (e.g., CYP7A1 deficiency, Zellweger syndrome)
2. Defects in membrane transport (e.g., BSEP mutations → progressive familial intrahepatic cholestasis)
3. Disturbances in bacterial transformation (e.g., bacterial overgrowth → premature deconjugation → reduced micelle formation)
4. Disturbances in bile acid circulation (e.g., cholestasis, ileal disease)

Cholelithiasis (Gallstones)

• Disruption of the bile salt:cholesterol:phospholipid ratio → cholesterol crystallizes in the gallbladder
• Caused by reduced bile acids or increased cholesterol secretion (e.g., fibrate therapy)

Pharmacological Relevance

Bile Acid Sequestrants (Cholestyramine, Colesevelam)

• Bind bile salts in the gut → prevent reabsorption → increase fecal excretion
• Relieves negative feedback on CYP7A1 → liver diverts more cholesterol into bile acid synthesis → lowers serum LDL cholesterol
• Also used in bile acid diarrhea and cholestatic pruritus

Drugs with Significant Enterohepatic Circulation

• Diazepam (secondary plasma peak at 6–12 hours)
• Morphine, carbamazepine, digoxin, doxepin, phenobarbital, piroxicam, dapsone
• Disruption by antibiotics (killing gut flora) or activated charcoal (interrupts recirculation) can lower drug levels

Multidose Activated Charcoal

• Particularly useful for drugs that undergo enterohepatic circulation and have long half-lives, as it interrupts re-absorption with each cycle

Summary