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22 Cards in this Set
- Front
- Back
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Production and physical characteristics of bile
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Produce 0.5 - 1.0 L/day
pH ~ 8.0 Isotonic Water 82.0% Bile acids 12.0% Phospholipid 4.0% Cholesterol 0.7% Other 1.0% |
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Bile salt secretion
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Liver secretes bile continuously
Bile flow into the duodenum is intermittent Bile is diverted to the gall bladder & concentrated during the interdigestive period (~450 ml of bile secreted is concentrated to ~50 ml in GB) |
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Control of bile salt secretion
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Chemical - Bile salts stimulate hepatic bile flow
Neural - Gallbladder contraction is controlled partially by nervous (vagal) stimulation Hormonal - Cholecystokinin (CCK) released by the duodenal mucosa strongly induces gallbladder contraction & Sphincter of Oddi (SOD) relaxation; Fibroblast Growth Factor 19 (FGF19) released by ileum in response to bile acids stimulates gallbladder filling |
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Functions of hepatic bile secretion: overall, major, and minor
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1. Bile is a Digestive Secretion
- Bile Salts (the major constituent of Bile) facilitate intestinal fat digestion and absorption 2. Bile is an Excretory Secretion - Provides a mechanism to excrete natural metabolites, toxins, and drug metabolites - e.g. cholesterol, bilirubin, steroid hormone conjugates, metal cations (iron and copper), drug conjugates Major - Induce bile flow and biliary lipid secretion - Aid in fat solubilization and absorption (Essential for cholesterol and fat-soluble vitamin absorption) - Major route for cholesterol elimination (Regulation of cholesterol metabolism) Minor - Anti-bacterial actions in the gut (Prevention of small bowel bacterial overgrowth) - Prevent formation of Gallstones and kidney oxalate stones - Act as hormones to regulate lipid, glucose, & energy metabolism |
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Function of bile salts: induce bile flow and biliary lipid secretion
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Most bile flow is bile salt-dependent
Bile salts are secreted as free ions and provide the osmotic pull for H20 and electrolytes to move into the canalicular space |
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Function of bile salts: fat solubilization and absorption
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Bile salts are Amphipaths (natural detergents) with both hydrophilic and hydrophobic regions
Above their critical micelle concentration, Bile salts form micelles that “solubilize” and carry fat-soluble substances such as cholesterol, fat-soluble vitamins (A, D, E, K), long chain fatty acids The solubility of cholesterol in bile is 2 million-fold greater than its solubility in water In the liver bile ducts and gallbladder: bile salts help to solubilize cholesterol in bile as simple/mixed micelles and vesicles. In the small intestine -Unstirred water layer (100-500 µm) acts a diffusion barrier for hydrophobic molecules. This reduces their effective concentration at the plasma membrane. --Problem: Fats are not water-soluble --Solution: Bile salts form mixed micelles with cholesterol to increase its aqueous solubility. This increases the rate of cholesterol absorption > 100-fold. |
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Bile fats (biliary lipids)
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Cholesterol - Insoluble in water
Phospholipids - Solubility is enhanced by bile salts. The combination of bile salts and phospholipid is better able to solubilize cholesterol. Bile Salts - Function as natural detergents Bilirubin conjugates – Soluble glucuronide conjugates ( low concentration) |
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Function of bile salts: maintain whole body cholesterol homeostasis
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Bile salts are synthesized from cholesterol in the liver
Bile salts are synthesized first as steroid acids The primary bile salts synthesizedby the liver are: -Cholic acid -- 3 OH groups -- More hydrophilic -Chenodeoxycholic acid --2 OH groups --More hydrophobic Bile salts promote absorption of cholesterol (bad) ~ 40% of total cholesterol removal occurs via its conversion to bile salts.(good) Cholesterol excreted by direct biliary secretion (good) |
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Function of bile salts: gut anti-microbial defense
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Inhibits bacterial overgrowth
Proximal Intestine – Direct bacteriostatic actions of bile salt/fatty acid mixed micelles Distal Intestine – Bile salts act as a hormone to induce expression of anti-microbial factors |
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Function of bile salts: prevent enteric hyperoxaluria and formation of kidney oxalate stones
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Oxalate in food (such as spinach, rhubarb, swiss chard, mixed nuts) usually precipitates as calcium oxalate in the intestinal lumen and is lost in the stool.
Bile salts facilitate the absorption of long chain fatty acids. In the absence of bile salts, long chain fatty acids stay in the lumen of the intestine and compete with oxalate for the available calcium. This blocks calcium oxalate formation and allows more dietary oxalate to be absorbed and ultimately excreted by the kidney. This ‘enteric’ hyperoxaluria can lead to formation of calcium oxalate kidney stones Enteric hyperoxaluria should be considered in patients with: - any form of chronic diarrhea - inflammatory bowel disease (IBD) - pancreatic insufficiency - primary biliary cirrhosis (PBC) - short bowel syndrome - after bariatric surgery |
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Synthesis of bile salts
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Synthesized from cholesterol in liver to form cholic acid or chenodeoxycholic acid.
Then bile salts are conjugated to glycine (2/3) or taurine (1/3) -Reduces pKa so bile salts stay charged at acidic pH -Increases the aqueous solubility of bile salts |
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Metabolism of bile salts
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Bile salts undergo dehydroxylation by the bacterial flora in the intestine.
-Very efficient in colon so that feces has only lithocholic and deoxycholic acid The primary bile salts are converted to Deoxycholic and Lithocholic acid (secondary bile acids) Absorbed and sent back to liver -Intestinal (Ileal) Absorption of bile salts is > 95% Efficient |
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Transport of bile salts
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Efficient system to
-Keep bile salts compartmentalized -Recycle bile salts Enterohepatic circulation 1) Storage chambers gallbladder, small intestine 2) Valves: Sphincter of Oddi, ileocecal valve 3) Mechanical pumps: canaliculi, biliary tract, small intestine 4) Chemical pumps: hepatocyte, ileal enterocyte |
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Bile salt concentrations in different regions
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Bile Salt Concentrations
Gallbladder 50-200 mM Small Intestine 5 - 10 mM Portal Blood ~0.02 mM Peripheral Blood < 0.01 mM |
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Bile salt recycling
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Total bile salt pool 3 - 5 g
Cycles 2-3X per meal 6-10X/day Intestinal reabsorption 20-30 g/day Bile salt loss > 400 mg/day |
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Primary defects in bile salt formation (synthesis and conjugation)
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Rare congenital disorders
Examples – Clinical Presentation (most commonly cholestasis or hepatitis) - 3α-hydroxy-C27-steroid dehydrogenase deficiency – Neonatal Hepatitis - Bile acid conjugation defect – Neonatal cholestasis, fat-soluble vitamin deficiency - Cerebrotendinous xanthomatosis (CTX) – Progressive neurological dysfunction |
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Primary Defects in Membrane Transport (uptake and secretion)
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Rare congenital disorders
Examples - Progressive Familial Intrahepatic Cholestasis Types 1, 2, 3 - Primary Bile Acid Malabsorption |
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Disturbances involving Bacterial Transformation (deconjugation & dehydroxylation)
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Common
Caused by bacterial overgrowth (reduces bile salt solubility) |
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Disturbances in Movement Through or Between Organs (bile salt circulation)
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Most common
Examples: - Biliary obstruction (stones in biliary tract or gallbladder; biliary tract carcinoma) (Gallstones are very common; ~12% of adults have gallstones; 700,000 cholecystectomes/year; costs ~$6 billion) - Biliary Fistula (after biliary trauma) and Gallstone ileus - Cholecystectomy (only small effect on bile salt metabolism) - Cholestasis (Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, drug induced cholestasis, intrahepatic cholestasis of pregnancy, biliary atresia) - Ileal Resection (particularly > 100 cm of small bowel) - Short Bowel Syndrome - Crohn’s disease (Inflammatory Bowel Disease) |
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Cause of gallstones, cholesterol saturation index, prevention of gallstones
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Major cause is too much cholesterol in bile
Cholesterol Saturation Index = ratio of molar % of cholesterol in bile to maximum micellar solubility of cholesterol If CSI > 1.0 - Cholesterol precipitates out of solution and forms crystals Bile salts prevent gallstone formation by: - Solubilizing cholesterol in mixed micelles - Binding Ca++ to prevent formation of calcium bilirubinate, or calcium salts of phosphate, carbonate, or palmitate (insoluble precipitates) (calcium bile salts stay soluble) |
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Cholesterol saturation index phase diagram
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1 phase = unsaturated bile
2 or more phases = supersaturated bile |
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Therapeutic uses of bile salts and sequestrants
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Bile salts:
Ursodeoxycholic acid (UDCA -Cholestatic liver disease Sequestrants: Cholestyramine -Hypercholesterolemia Colesevalam -Type II diabetes, hypercholesterolemia, bile salt malabsorption-associated diarrhea |
