resins increase TG and resins and fibrates cause gallstones. what's the mechanism? - USMLE Forums
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Old 02-24-2013
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Default resins increase TG and resins and fibrates cause gallstones. what's the mechanism?

can anyone explain the mechanism?
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Old 02-24-2013
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- Bile acid resins (cholestyramine, colestipol, colesevelam)
--- work by binding bile acids in the gastrointestinal tract, thereby interfering w/ the enterohepatic circulation of bile acids & resultings in the excretion of bile acids.
--- This results in hepatic synthesis of new bile acids, a process that consumes liver cholesterol stores.
--- Hepatic uptake of LDL from the circulation is increased for continued bile acid synthesis.
--- Bile acid production & secretion are increased in 100 fold due to this interruption of the enterohepatic circulation of bile acids.
--- Hepatic cholesterol reduction is an activating factor for HMG-CoA reductase & subsequently results in increased hepatic cholesterol synthesis (i.e. triglycerides)


---------------


- Cholelithiasis is due to precipitation of cholesterol (cholesterol stones) of bilirubin in bile (bilirubin stones) and decrease phospholipids (e.g., lecithin) or bile acids.
--- Recall that both cholesterol & bilirubin are both components of bile
--- Note: bile acids are essential for lipid absorption.
--- They are produced in the liver, released into the duodenum via the gall bladder & common bile duct, absorbed in the ileum & returned to the liver via the portal blood flow (enterohepatic circulation).
--- When we have decreased phospholipids (e.g., lecithin) or bile acids….[recall that bilirubin & bile acids help to sobulize the cholesterol]….we don’t have anything to solubilize/breakdown cholesterol hence increasing the risk that cholesterol will precipitate
--- Fibrates is a lipid lowering agents that increase HMG-CoA reductase activity → increase cholesterol synthesis
--- Fibrates also reduce the conversion of cholesterol to bile acids… if there is no bile acids…cholesterol would be less soluble within thet fluid… if we inhibits the recycling of bile acids by the ileum…therefore, we would have a decreased of bile acids…a decreased of bile acids would increase the risk of cholesterol stones
--- Suppression of cholesterol 7 alpha hydroxylase activity (by medications such as fibrates) reduces the conversion of cholesterol to bile acids, resulting in excess cholesterol secretion in bile.
--- Thus, a decreased of bile acids would increase the risk of cholesterol stones.
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