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106. Physiology of the Biliary System [SKF]

Physiology of the Biliary System

Bile Production

Bile Formation and Composition

  • Functions of Bile Formation:
    • Excretion of organic solutes like bilirubin and cholesterol.
    • Facilitates intestinal absorption of lipids and fat-soluble vitamins.

  • Composition of Bile:

    • Water: Constitutes about 85% of bile volume.

    • Solids:

      • Phospholipids, bile salts, and cholesterol (~90% of solids).
      • Bilirubin, fatty acids, inorganic salts (remaining 10%).

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  • Bilirubin Metabolism:

    • Breakdown product of spent red blood cells.
    • Conjugated with glucuronic acid by glucuronyl transferase in the liver.
    • Excretion: 250–300 mg/day in bile.
      • 75% from red cell breakdown.
      • 25% from hepatic heme and hemoprotein turnover.
  • Bile Salts:
    • Steroid molecules synthesized by hepatocytes.
    • Primary bile salts: Cholic acid and chenodeoxycholic acid (~80%).
    • Conjugation with taurine or glycine.
    • Secondary bile salts: Deoxycholate and lithocholate (formed by intestinal bacteria).
    • Function: Solubilize lipids and facilitate their absorption.
  • Phospholipids and Cholesterol:
    • Phospholipids: Primarily lecithin (>95%).
    • Cholesterol: Produced mainly by the liver; minimal dietary contribution.
    • Role: Integral in forming micelles for cholesterol solubilization.

Bile Secretion and Flow

  • Daily Bile Production: 750–1000 mL by the liver.
  • Factors Contributing to Bile Flow:
    • Hepatic secretion.
    • Gallbladder contraction.
    • Sphincteric resistance.
  • Fasting State:
    • Common bile duct (CBD) pressure: 5–10 cm H₂O.
    • Bile diverted to the gallbladder (stores 50–60 mL).
  • Postprandial State:
    • Gallbladder contraction and sphincter of Oddi relaxation.
    • Stimuli: Vagal input and cholecystokinin (CCK).
    • Gallbladder pressure: Up to 25 cm H₂O.
    • CBD pressure: Up to 20 cm H₂O.
    • Bile flows into the duodenum due to pressure gradient.
  • Bile Concentration:
    • 5–10-fold concentration via absorption of water and electrolytes.
    • Mechanism: Active sodium chloride transport by gallbladder epithelium.
    • Water absorption: Passive, following osmotic gradient.

Bile Salt Secretion

  • Secretion Process:
    • Bile salts are secreted from hepatocytes into canaliculi.
    • Osmotic force of bile salts generates bile flow.
  • Bile Acid Synthesis:
    • Rate: 500–600 mg/day.
    • Pathways:
      • Classic pathway: Produces cholic acid.
      • Alternate pathway: Produces chenodeoxycholic acid.
  • Transport Mechanisms:
    • Plasma Transport: Bile acids bound to albumin or lipoproteins.
    • Hepatocyte Uptake:
      • Sodium-dependent pathway: Mediated by NTCP (sodium-taurocholate cotransporting polypeptide).
        • Accounts for >80% of taurocholate uptake.
      • Sodium-independent pathway: Mediated by OATPs (organic anion–transporting polypeptides).
        • OATP-C is the major transporter in this pathway.
  • Intracellular Transport:
    • Occurs within seconds.
    • Mechanisms:
      • Bile acid–binding proteins.
      • Vesicular transport.
  • Canalicular Secretion:
    • Rate-limiting step in bile salt secretion.
    • Active transport (ATP-dependent) against a 1000-fold concentration gradient.
    • Transporters:
      • BSEP (bile salt export pump): Major transporter for monovalent bile salts.
      • MRP2 (multidrug resistance-associated protein 2): Transports sulfated and glucuronidated bile salts and other organic anions.

Enterohepatic Circulation

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  • Function of Bile Salts:
    • Bind calcium ions in bile.
    • Induce bile flow.
    • Facilitate lipid transport.
  • Cycle of Bile Acids:
    1. Synthesis and Conjugation in the liver.
    2. Secretion into bile.
    3. Storage in the gallbladder.
    4. Release into the duodenum.
    5. Absorption in the small intestine (especially the terminal ileum).
    6. Return to the liver via the portal vein.
  • Efficiency:
    • 95% of bile salts are reabsorbed.
    • Bile salt pool: 2–4 g, recycles 6–10 times daily.
    • Excretion: Only ~600 mg reaches the colon daily.
  • Disruption of Circulation:
    • Ileal resection or ileal diseases (e.g., Crohn's disease) can lead to excessive bile salt loss.
    • Compensation: Increased bile salt synthesis to maintain pool size.
    • Consequences:
      • Bile acid diarrhea due to unabsorbed bile acids reaching the colon.
      • Potential cholesterol gallstone formation due to altered bile composition.

Cholesterol Saturation and Gallstone Formation

Cholesterol Solubilization

  • Insolubility: Cholesterol is nonpolar and insoluble in water.
  • Micelle Formation:
    • Bile salts (amphipathic) form micelles with phospholipids and cholesterol.
    • Hydrophilic portions face outward; hydrophobic cholesterol is sequestered inside.
  • Vesicles:
    • Cholesterol also transported in vesicular form (lipid bilayers).
    • Excess cholesterol can lead to vesicle aggregation and crystal precipitation.

Cholesterol Saturation Index

  • Definition: Numerical value expressing cholesterol saturation in bile.
  • Calculation: Based on relative concentrations of cholesterol, bile salts, and phospholipids.
  • Interpretation:
    • Index >1.0: Bile is supersaturated with cholesterol; risk of gallstone formation.
    • Changes in lipid concentrations can alter micelle capacity and saturation index.

Gallstone Formation

  • Imbalance of Solutes:
    • Altered concentrations of bilirubin, bile salts, phospholipids, and cholesterol.
    • Leads to supersaturation and precipitation.
  • Types of Gallstones:
    • Cholesterol Stones:
      • Most common in Western countries (>85%).
      • Associated with obesity and metabolic factors.
      • Characteristics:
        • Multiple, variable size.
        • Color: Clear yellow to green or black.
        • Radiolucent (less than 10% are radiopaque).
    • Pigment Stones:
      • Black Pigment Stones:
        • Small, black stones.
        • Associated with hemolytic diseases (e.g., hereditary spherocytosis, sickle cell disease).
      • Brown Pigment Stones:
        • Predominant in Asia.
        • Linked to bacterial infections, biliary parasites, and biliary stasis from partial obstruction.
  • Pathophysiology of Gallstones:
    • Cholesterol Supersaturation: Excess cholesterol exceeds the solubilizing capacity of bile.
    • Nucleation: Initiation of cholesterol crystal formation.
    • Gallbladder Motility Disorders:
      • Impaired emptying increases bile residence time.
      • Stasis promotes stone formation.
    • Role of Mucin Glycoproteins:
      • Act as pronucleating agents.
      • Promote cholesterol crystallization.

Bilirubin Metabolism

  • Sources of Bilirubin:
    • 80–85% from degradation of senescent erythrocytes.
    • 15–20% from breakdown of hepatic hemoproteins.
  • Conversion Process:
    1. Heme Oxygenase converts heme to biliverdin.
    2. Biliverdin Reductase reduces biliverdin to unconjugated bilirubin.
    3. Unconjugated bilirubin binds to albumin in plasma.
    4. Hepatic Uptake: Liver extracts bilirubin-albumin complex.
    5. Conjugation:
      • Glucuronyl transferase conjugates bilirubin with glucuronic acid forming bilirubin diglucuronide (conjugated bilirubin).
    6. Secretion: Conjugated bilirubin actively secreted into bile.
  • Intestinal Processing:
    • In the duodenum, conjugated bilirubin is part of mixed micelles.
    • Intestinal bacteria convert bilirubin to urobilinogens.
    • Further oxidation produces urobilins, imparting the brown color to stool.

Gallbladder Function

Absorption

  • High Absorptive Capacity:
    • Gallbladder mucosa absorbs water and electrolytes, concentrating bile fivefold.
    • Active Na-Cl transport drives absorption.
    • Water follows passively due to osmotic gradient.
  • Impact on Bile Composition:
    • Increased concentration affects cholesterol and calcium solubility.
    • Cholesterol Solubility:
      • Micellar solubility increases.
      • Vesicle stability decreases, promoting cholesterol nucleation.
    • Calcium Concentration:
      • Influenced by serum levels and bile concentration.
      • Less efficient absorption compared to sodium and water.
  • Pathological Implications:
    • Unconjugated bile salts (from bacterial deconjugation or inflammation) damage mucosa.
    • Leads to nonselective absorption and potential gallstone formation.

Secretion

  • Secreted Substances:
    • Glycoproteins (Mucins):
      • Secreted primarily from the gallbladder neck and cystic duct.
      • Form a mucus barrier protecting the epithelium from bile salts.
      • Act as pronucleating agents for cholesterol crystals.
      • Prostaglandins stimulate mucin secretion.
    • Hydrogen Ions:
      • Acidify bile, lowering pH to 7.1–7.3.
      • Promote calcium solubility, preventing precipitation.
  • Clinical Significance:
    • Excess Mucin can contribute to gallstone formation.
    • Impaired Acidification may lead to calcium salt precipitation.

Motility

  • Gallbladder Filling and Emptying:
    • Filling:
      • Facilitated by tonic contraction of the sphincter of Oddi.
      • Intermittent emptying during fasting (10–15% volume reductions).
      • Mediated by motilin during the migrating myoelectric complex.
    • Emptying:
      • Triggered by eating; coordinated gallbladder contraction and sphincter relaxation.
      • Gallbladder empties 50–70% within 30–40 minutes post-meal.
      • Refilling occurs over the next 60–90 minutes.
  • Regulation:
    • Involves multiple hormonal and neural pathways.
    • Cholecystokinin (CCK) plays a key role.
  • Pathology:
    • Defects in Motility:
      • Increased bile residence time.
      • Central role in gallstone pathogenesis.

Sphincter of Oddi

  • Structure and Function:
    • Complex sphincter independent of duodenal musculature.
    • Creates a high-pressure zone between the bile duct and duodenum.
    • Regulates flow of bile and pancreatic juice.
    • Prevents regurgitation of duodenal contents.
  • Pressure Dynamics:
    • Bile and pancreatic duct pressures are kept higher than duodenal pressure.
    • High-pressure phasic contractions contribute to sphincter function.
  • Regulation:
    • Neural and Hormonal Factors:
      • Cholecystokinin (CCK) reduces sphincter pressure post-meal.
      • Vagal stimulation influences sphincter activity.
    • Fasting State:
      • High-pressure contractions persist during all phases of the migrating myoelectric complex.
    • Reflexes:
      • Cholecysto–sphincter of Oddi reflex: Sphincter relaxes as gallbladder contracts.
      • Antral Distention: Causes both gallbladder contraction and sphincter relaxation.
  • Clinical Implications:
    • Dysfunction can lead to biliary pain, pancreatitis, or jaundice.
    • Sphincter of Oddi Dysfunction (SOD):
      • Characterized by abnormal sphincter motility.
      • May require diagnostic manometry and therapeutic intervention.

HIGH YIELDING POINTS

Summary: Gallbladder Functions - Motor Activity

  • Gallbladder Filling: Facilitated by the tonic contraction of the sphincter of Oddi, which creates a small pressure gradient between the bile ducts and the gallbladder.
  • Interdigestive Phase (MMC Phase II):
    • The gallbladder repeatedly empties small volumes of bile into the duodenum.
    • This process is partly mediated by the hormone motilin.
  • Response to a Meal:
    • Larger volumes of bile are delivered to the intestine due to a combination of gallbladder contraction and synchronized sphincter of Oddi relaxation.
    • Cholecystokinin (CCK) is the primary stimulus for gallbladder emptying, released from enteroendocrine cells in the duodenum in response to a meal.
    • After eating, the gallbladder empties 50% to 70% of its contents within 30 to 40 minutes, then gradually refills over 60 to 90 minutes as CCK levels decrease.
  • Additional Influences:
    • Minor hormonal and neural pathways also contribute to the coordination between the gallbladder and the sphincter of Oddi.
  • Clinical Relevance:
    • Defects in motor activity that prevent proper gallbladder emptying are implicated in cholesterol nucleation and gallstone formation.

(Source: Schwartz's Principles of Surgery, 11th Edition, Pg. 1397)

MCQ: Neurohormonal Regulation of Gallbladder - True Statements Except

Question: Which of the following is not true regarding the neurohormonal regulation of the gallbladder?

Options: a) Vagus nerve stimulates gallbladder contraction

b) Splanchnic sympathetic nerve inhibits gallbladder contraction

c) Antral distention of stomach causes gallbladder contraction

d) VIP causes gallbladder contraction

Answer: d) VIP causes gallbladder contraction

Explanation:

  • Option A (Vagus nerve stimulates gallbladder contraction): The vagus nerve indeed stimulates gallbladder contraction, promoting bile release.
  • Option B (Splanchnic sympathetic nerve inhibits gallbladder contraction): Splanchnic sympathetic stimulation inhibits the motor activity of the gallbladder, preventing contraction.
  • Option C (Antral distention of stomach causes gallbladder contraction): Antral distention leads to gallbladder contraction and relaxation of the sphincter of Oddi.
  • Option D (VIP causes gallbladder contraction): This statement is not true. Vasoactive intestinal polypeptide (VIP) actually inhibits gallbladder contraction, causing relaxation instead.

Correct Answer: D) VIP causes gallbladder contraction

Summary: Sphincter of Oddi Regulation and Function

  • Length and Pressure
    • The sphincter of Oddi is approximately 4 to 6 mm in length.
    • It has a basal resting pressure of about 13 mmHg above duodenal pressure.
    • On manometry, it shows phasic contractions with a frequency of four per minute and an amplitude ranging from 12 to 140 mmHg.
  • Regulation of Motility
    • The spontaneous motility of the sphincter of Oddi is regulated by interstitial cells of Cajal.
    • This regulation involves intrinsic and extrinsic inputs from hormones and neurons acting on the smooth muscle cells.
  • Relaxation Mechanism
    • Relaxation of the sphincter occurs with a rise in Cholecystokinin (CCK).
    • This results in a diminished amplitude of phasic contractions and reduced basal pressure, allowing for increased flow of bile into the duodenum.

(Source: Schwartz, 10th edition, page 1313)

Summary: Functions and Secretions of the Gallbladder

  • Gallbladder Epithelial Secretions (Option A):
    • The epithelial cells of the gallbladder secrete two key products into the lumen:
      • Glycoproteins
      • Hydrogen ions
  • Mucosal Glands Function (Option B):
    • Mucosal glands located in the infundibulum and neck secrete mucus glycoproteins.
    • These glycoproteins protect the mucosa from the lytic action of bile and facilitate bile passage through the cystic duct.
  • Main Function of the Gallbladder (Option C):
    • The gallbladder's primary function is to concentrate and store hepatic bile and deliver it to the duodenum in response to a meal.
  • Hydrogen Ion Transport and pH Regulation (Option D):
    • The transport of hydrogen ions by the gallbladder epithelium decreases the pH of bile.
    • This acidification promotes calcium solubility, preventing the precipitation of calcium salts.

(Source: Schwartz's Principles of Surgery, 10th ed, Pg 1313)

Summary: Limitations of Oral Cholecystography

Oral cholecystography is not useful in the following conditions:

  • Intestinal malabsorption: The absorption of the oral contrast medium is impaired, leading to inadequate visualization.
  • Vomiting: The inability to retain the oral contrast medium limits the effectiveness of the procedure.
  • Obstructive jaundice: The lack of bile flow into the intestine prevents the concentration of the contrast medium in the gallbladder.
  • Hepatic failure: Reduced liver function impairs the metabolism and excretion of the contrast medium, making the test unreliable.

(Source: Schwartz 10th edition, page 1314)

Summary: Biliary Scintigraphy

  • Primary Use (Option A):
    • Diagnosis of acute cholecystitis: Appears as a nonvisualized gallbladder with prompt filling of the common bile duct and duodenum.
  • Indications of Obstruction (Option B):
    • Delayed or absent filling of the duodenum with visualization of the gallbladder and common bile duct indicates an obstruction at the ampulla.
    • Biliary leaks, often a complication of gallbladder or biliary surgery, can be confirmed and localized using biliary scintigraphy.
  • Noninvasive Evaluation (Option C):
    • Provides a noninvasive assessment of the liver, gallbladder, bile ducts, and duodenum with both anatomic and functional information.
  • Procedure Details (Option D):
    • 99mTechnetium-labeled derivatives of dimethyl iminodiacetic acid (HIDA) are injected intravenously.
    • The tracer is cleared by Kupffer cells in the liver and excreted into the bile.
    • Liver uptake is detected within 10 minutes.
    • The gallbladder, bile ducts, and duodenum are typically visualized within 60 minutes in fasting subjects.

(Source: Schwartz 10th edition, page 1315)