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21 Cards in this Set
- Front
- Back
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Hepatic bile and 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 during the interdigestive period Characteristics of Bile Produce 0.5 - 1.0 L/day pH ~ 8.0 Isotonic with plasma |
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Secretion of bile is under chemical, neural and hormonal control
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Chemical - Bile salts
stimulate hepatic bile flow Neural - Gall bladder contraction is controlled partially by nervous (vagal) stimulation Hormonal - Cholecystokinin (CCK) released by the duodenal mucosa strongly induces gall bladder contraction Fibroblast Growth Factor 19 (FGF19) stimulates gallbladder filling |
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Functions of Hepatic Bile Secretion
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. 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 |
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Bile Composition
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mostly water and then phospholipids and cholesterols
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Function of bile salts
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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) 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 and glucose metabolism |
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Bile is a mixture of 3 secretions
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Hepatocyte Bile salt-dependent
Hepatocyte Bile salt-independent Ductular secretion |
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Bile flow
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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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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. |
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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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Maintenance of 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 synthesized by the liver are: Cholic acid 3 OH groups More hydrophilic Chenodeoxycholic acid 2 OH groups More hydrophobic |
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Gut anti microbial defense with bile salts
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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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prevention of enteric hyperoxaluria and formation of kidney oxalate stones via bile salts
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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 pancreatic insufficiency primary biliary cirrhosis short bowel syndrome after bariatric surgery |
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why and to what are bile salts conjugated
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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 pancreatic insufficiency primary biliary cirrhosis short bowel syndrome after bariatric surgery they are conjugated to lycine or taurine |
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Synthesis and metabolism of bile salts
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Bile salts undergo dehydroxylation by the bacterial flora in the intestine.
The primary bile salts are converted to Deoxycholic and Lithocholic acid. Bile salts are very efficiently deconjugated and dehydroxylated in the large intestine by the bacterial flora |
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Enterohepatic Circultion of Bile salts
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Efficient system to: a) Keep bile salts compartmentalized
b) 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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disorders of bile salt synthesis and cycling
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Primary Defects in Bile Salt Formation (synthesis and conjugation)
2. Primary Defects in Membrane Transport (uptake and secretion) 3. Disturbances involving Bacterial Transformation (deconjugation & dehydroxylation) 4. Disturbances in Movement Through or Between Organs (bile salt circulation) |
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Primary Defects in Bile salt formation
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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
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Rare congenital disorders
Examples: Progressive Familial Intrahepatic Cholestasis Types 1, 2, 3 Caused by mutations in hepatic canalicular transporters for bile salts and phospholipids Primary Bile Acid Malabsorption Caused by mutation in the ileal bile acid transporter |
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Disturbances involving bacterial transformation
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increased deconjugation and dehydroxylation)
Small Intestinal Bacterial Overgrowth Common cause of chronic diarrhea Increases bile salt deconjugation and dehydroxylation Deconjugated secondary bile salts (deoxycholic acid, lithocholic acid) are less soluble than conjugated primary bile salts. These bile acids will precipitate from solution and be excreted in the feces. The soluble bile salt concentration needs to stay above ~ 2 millimolar in order to efficiently absorb fats and fat-soluble vitamins. Small intestinal bacterial overgrowth -> increased bile salt loss & fat malabsorption (steatorrhea). |
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disturbances in movement through or bw organs (bile salt circulaiton)
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Most common
Examples: Biliary obstruction (stones in biliary tract or gallbladder; biliary tract carcinoma) 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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Bile Salts and gall stone disease
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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) |
