Bile Formation

July 3, 2024

• 750-1000 ml/day.
• 80% water
• Bilirubin, Bile salts, Phospholipids and cholesterol
• Bilirubin - Breakdown of RBC+ Conjugation with glucoronic acid
• BIle salt -
  • Cholic Acid, Chenodeoxycholic Acid (primary)
  • deoxycholate and lithocholate ( secondary)
• Phospholipids - Lecithin

Hepatic Vs GB Bile

• Chloride and Bicarbonate more in Hepatic ( reabsorbed in GB)
• pH Alkaline in Hepatic vs Acidic in GB

• Water absorption
  • Active = Na/H pump
  • passive = aquaporin
• Cl and HCO3 = absorbed by GB epithelium
• Ca and MG = also absorbed but not efficient = hence concentration is higher compared to Hepatic Bile
• Concentration of bilirubin = 10 fold = precipitation of Cal Bilirubinate pigment stones more in GB

Bile Flow

• Primarily driven by Bile salt secretion

• Secretin, CCK, Gastrin : Active secretion of chloride rich fluid by Bile ducts

  

• Enterohepatic circulation of bile salts:

  • Cholesterol is taken up from plasma by the liver.
  • Bile acids are synthesized at a rate of 0.6 g/24 hr and are excreted through the billary system into the small bowel
  • Most of the bile salts are reabsorbed in the terminal ileum and are retumed to the liver to be extracted and re extracted.
  • The total amount of bile acids in the enterohepatic circulation is defined as the circulating bile pool.
  • In this highly efficient system, nearly 95% of bile salts are reabsorbed.
  • Thus, of the total bile salt pool of 2 to 4 g, which recycles through the enterohepatic cycle 6 to 10 times daily, only about 600 mg is actually excreted into the colon.

Classification of Jaundice

Biliary Obstruction

• Biliary system has low pressure ( 5-10cm of H2O)
• Cholangiovenous reflux happens at pressure of 20cm H2O = CHOLANGITIS
  • decreased synthetic function of liver
  • decrease in Kupffer cell clearance, Increase inflammatory cytokines
• Biliary Obstruction pressure ( 30cm H2O)
• Bile contents reflux into sinusoids —> Inflammation —> fibrogenesis —> conversion to type 1 collagen —> Cirrhosis
• EHBD = mucosal atrophy with squamous metaplasia
  • Bile becomes less lithogenic —> decrease cholesterol and phospholipid secretion
  • More lithogenic after decompression d/t increased secretion of cholesterol and phospholipids but the bile acid secretion is not done immediately.
  • this phenomenon may lead to premature occlusion of decompressive biliary stents placed for management of obstructive jaundice.

• In case of Chronic Biliary obstruction:

  • CVS = Decreased PVR + Decreased CO + Decreased LV function
  • Renal = Bile Acid - Diuresis and Natriuresis - AKI
  • Coagulation = Prolongation of PT
  • Endotoxemia = more infective complications
  • Disruption of enterohepatic circulation
  • Delayed Wound healing = Decrease Propyl Hydroxylase

  Therefore in Rx = Good Hydration and Antibiotics and Vit K are given

  

Cholangitis

• MC org = E Coli , Klebsiella
• Increase Intraductal pressure ( 20-30 cm H2O)
• Cholangiovenous/Cholangiolymphatic reflux
• Normal biliary pressure 7-14 cm H2O
• MC cause = Choledocholithiasis
• Mx:
  • Optimal fluids
  • Oral Bile salts
  • enteral feeding
  • Vit K / FFP

Preoperative Biliary Drainage

• Cholangitis
• Liver Resection (Right > Left) = we drain the FLR
• Before NACT = for gemcitabine - bil should be less than 2
• Malnutrition
• Coagulopathy
• Renal Failure
• Intractable Pruritis

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Bilirubin Metabolism ( Doctutorials)

Bile Flow and Gallbladder (GB) Bile

Key Points

1. Normal Bilirubin Metabolism:
   • Steps:
     1. Production
     2. Uptake by the hepatocyte
     3. Conjugation
     4. Excretion into bile ducts
     5. Delivery to the intestine

2. Factors Affecting Bile Flow:

   Increase Bile Flow:

   • Vagal Stimulation
   • Secretin
   • CCK (Cholecystokinin)
   • Gastrin
   • Glucagon
   • Increased bile salt production

   Decrease Bile Flow:

   • Splanchnic Stimulation

   Most Important Factor: Rate of bile salt synthesis by hepatocytes

3. Main Components of Bile:

   • Water: 85%
   • Organic Solutes:
     • Bilirubin
     • Biliary Lipids:
       • Bile Salts: 72% (primary vs secondary)
       • Phospholipids (mainly lecithin): 24%
       • Cholesterol: 4%

4. Gallbladder (GB) Bile:

   Characteristics:

   • During fasting, approximately 90% of bile acid is sequestered in the GB.
   • Concentration of all solutes increases in GB bile except HCO3 and Chloride ions.
   • GB absorbs water both actively and passively via Na+/H+ pumps and aquaporin channels.
   • Solubility of micellar fraction is increased, but the stability of phospholipid cholesterol vesicles is greatly decreased.
   • Concentration of bilirubin can be as high as 10-fold.

   False Statement:

   • GB bile is alkaline compared to hepatic bile.
     • Correction: GB bile is acidic compared to hepatic bile.

Multiple Choice Questions

Answer:

• Correct Answer: F. Splanchnic Stimulation

Answer:

• Correct Answer: B. GB bile is acidic compared to hepatic bile.

Additional Note:

• Bile Flow Regulation: The primary factor influencing bile flow is the rate of bile salt synthesis by hepatocytes. Various hormones and neural stimuli can modulate this process, impacting overall bile secretion and flow.
• Gallbladder Function: The gallbladder concentrates bile during fasting, making it more acidic and altering its composition, which can affect the formation of cholesterol crystals and other components.

Bilirubin Metabolism

Key Points

1. Heme Breakdown:
   • Early Phase:
     • Accounts for 20% of bilirubin.
     • Originates from hemoproteins.
     • Occurs within 3 days of labelling with radioactive heme.
   • Late Phase:
     • Accounts for 80% of bilirubin.
     • Originates from senescent RBCs.
     • Occurs within 110 days.
2. Conversion Process:
   • Heme → Green Biliverdin (BV) via heme oxygenase.
   • Green Biliverdin → Orange Bilirubin (BR) via BV reductase.
3. Circulation:
   • Bilirubin-Alb Complex:
     • Dissociates in the space of Disse.
     • Free bilirubin (BR) enters hepatocytes.
   • Conjugation:
     • In hepatocytes, bilirubin is conjugated via UDP glucuronyltransferase.
     • Conjugated bilirubin is secreted into bile canaliculi (energy-dependent process).
   • Gastrointestinal Tract:
     • Conjugated bilirubin is transported to the GIT.
     • Deconjugation by bacteria in the gut.
   • Urobilinogens:
     • Urobilinogens are formed and undergo oxidation into stercobilin (BS).
     • Some urobilinogens are reabsorbed and enter enterohepatic circulation (EHC) or are excreted in urine.

Summary:

• Early Phase: 20% from hemoproteins within 3 days.
• Late Phase: 80% from senescent RBCs within 110 days.
• Conversion: Heme to biliverdin (BV) via heme oxygenase, then to bilirubin (BR) via BV reductase.
• Circulation: Dissociation of BR-Alb complex in Disse space, free BR into hepatocyte, conjugation via UDP glucuronyltransferase, into bile canaliculi, deconjugation in GIT by bacteria.
• Urobilinogens: Oxidation into stercobilin, reabsorption into enterohepatic circulation or excretion in urine.

Uptake of Bile Salts from Circulation

Key Points

1. Pathways for Bile Salt Uptake:
   • Na-Dependent Pathways:
     • Major pathway for bile salts.
     • Mediates more than 80% of taurocholate and less than 50% of cholate uptake.
     • Transport mediated via NTCP (Na taurocholate cotransporting polypeptide).
     • Has selective substrate affinity.
   • Na-Independent Pathways:
     • Minor pathway for bile salts.
     • Transport mediated via OATPs (Organic Anion Transporting Polypeptides).
     • Has a wider substrate affinity and transports a variety of organic acids other than bile salts.
     • Specific transporters include OATP-C (major uptake system) and OATP-8 (mediates taurocholate uptake).

Summary:

• Na-Dependent Pathway: Major pathway for bile salts, mediated by NTCP.
• Na-Independent Pathway: Minor pathway, mediated by OATPs, transports other solutes as well.

Multiple Choice Question

Answer:

• Correct Answer: D. Major pathway for bile salts, mediated by NTCP.

Additional Note:

• Na-Dependent Pathway: Critical for the majority of bile salt uptake, specifically taurocholate.
• Na-Independent Pathway: Important for the transport of a broader range of organic acids, highlighting the versatility of OATPs in hepatic function.

Bile Salt Transporters and Functions

Key Points

1. Transporters from Hepatocytes into Bile Duct:
   • Active Transport: Energy-dependent process.
     • ABCB11/BSEP: Monovalent bile salts into canaliculus.
     • MRP-2: Sulfated and glucuronidated bile salts into canaliculus.
     • MRP-3: Bilirubin monoglucuronide into bile duct.
2. Bile Acid Function:
   • Mediated via FXR and TGR5 receptors.
   • Regulates gut microbiome, incretin secretion, and production of FGF 15 and 19.
3. Biliary Obstruction:
   • Normal Biliary Pressure: 5-10 cm of water (7-14 cm H2O).
   • High Biliary Pressure: When pressure rises higher than 20 cm H2O, bile secretion decreases and cholangiovenous and cholangiolymphatic reflux occurs.

Multiple Choice Questions

Answer:

• Correct Answer: D. The cycle occurs approximately 6-10 times daily

Answer:

• Correct Answer: C. The patient has associated renal dysfunction.

Explanation:

• A: Unlikely, as complete obstruction alone does not explain such high bilirubin levels.
• B: Duration alone is not typically sufficient to raise bilirubin to 40 mg/dL.
• C: Renal dysfunction can significantly elevate bilirubin levels due to impaired clearance.
• D: Malignancy may cause high levels, but renal dysfunction is a more direct cause.
• E: Gilbert disease usually results in mild hyperbilirubinemia, not as high as 40 mg/dL.