Shared Flashcard Set


Liver Physiology

Additional Accounting Flashcards




Functional consequences of:
Increased vena caval pressure/hepatic vein obstruction?

Decreased hepatic artery blood flow? and/or Decreased portal vein blood flow?

Effects on the bile duct?
1) You get tremendous congestion!
2) Ischemia but portal vein can inc blood flow so you can actually do well
3) More likely to get ischemia b/c of dependence on hep art
4) Bflow is all off of cystic artery – if tie off hep art => you kill bile duct => strictures bad
A patient has both liver failure and resection of 40cm of the terminal ileum. What is a consequence of this?
The px can't upregulate bile acid production and will have fat malabsorption. Normally after 40cm terminal ileum resection, the bile acids will be upregulated (given the loss into the colon).
Blood supply to the liver
 Tremendous blood flow from portal vein (80%) – carries nutrients, drugs etc.
 Systemic flow from hepatic artery (20%) – carries more oxygen
Decreased blood supply in IVC/hep vein vs. portal vein?
o Increased vena caval pressure/hepatic vein obstruction  congestion
 Normally a low pressure system
 Budd-chiari syndrome: obstruction of hepatic vein(s): clots form in hepatic vein
• Hemorrhage in pericentral-vein area; hepatic vein obscured
• Dilated upstream sinusoids, atrophic/ischemic hepatocytes
o Decreased hepatic artery blood flow/decreased portal vein flow  ischemia! (hepatic artery clamping is not as bad because portal vein still supplies 80% of blood)
o Effects on bile duct?  ischemic necrosis if hepatic artery clamped, no effect if portal vein clamped
 Sole arterial supply is through hepatic artery
 Ischemia or damage to bile duct often leads to injury, fibrosis, STRICTURE (common response to injury)
purpose of fenestrated capillary endothelium
o Fenestrated capillary endothelium – direct access to blood (unique to hepatocytes!)
 Large holes allow access to protein in blood
o Blood flowing on both sides of hepatocytes (basolateral membrane) – big surface area (with microvilli) for exchange
o The apical membrane is between hepatocytes – this is where bile is secreted into bile canaliculi
purpose of sinusoidal endothelial cells
o Sinusoidal endothelial cells: large fenestrations allow direct contact between plasma and hepatocyte surface (protein interaction! – can take protein up and secrete proteins)
 Space of Disse
 Larger chylomicrons too big, but most other things can fit
o Mostly hepatocytes
o Kupffer cells: tissue macrophage
 Filtration device: bacteria, endotoxin, LPS
 Upstream from colon where there are lots of bacteria
 Releases inflammatory mediators that influence hepatocytes positively or negatively
o Ito cell/fat-storing cell
 Rare cell, located in sinusoids (b/w endothelium and hepatocyte)
 Stores lipophilic materials such as Vit A
 Stimulated by chronic inflammation/alcohol converts to myofibroblast  produces collagen and extracellular matrix
 Responsible for much of the excess fibrotic material in cirrhosis
o Defects in glucose metabolism in liver disease - acute vs. chronic?
 Acute liver failure: hypoglycemia  rapid neuronal death
 Chronic liver disease: insulin resistance and diabetes (unknown mechanism)
What does the liver make out of AAs?
o Produces proteins out of AAs that arrive at the hepatocyte
o Produce glucose for storage from AAs
o Produces ketones from AAs – another fuel
o Gets rid of nitrogen group in amino acids  major urea producer
T/F: Liver cantake up chylomicrons (CM) and CM remnants
False: o Liver can’t take up chylomicrons (CM), although can take up CM remnants
VLDL - made of and purpose?
o Fatty acids contribute to VLDL – major contribution to overall cycle of fats in body
 Delivers TGs and some cholesterol to tissues
o Liver also makes phospholipids needed for VLDL synthesis
T/F: The liver requires glucose for its own energy supply.
o Can beta-oxidize (in mitochondria) fatty acids for own energy supply (doesn’t need glucose)
o When fasting, can make ketones
Fed/Fasting state of liver's use of fat
o In fed state, liver uses fat for own purposes (fuel) and sending some as VLDL
o In fasting state, liver sends produces ketones and sends VLDL
Fatty liver mechanism?
o Mechanism: excess fats coming to liver in fed state, insulin deficiency in fasted state or inability to ship TGs out in VLDL (synthesis problems)
o Also can occur from consuming too many carbs (glucose)
proteins/factors that Liver synthesizes and secretes:
lipoproteins, albumin, clotting factors, anti-proteases (alpha-1-anti-trypsin), fibrinogen, complement factors, ceruloplasmin transferring and other binding proteins
Alpha1-anti-trypsin deficiency manifestations, genetic defect, and detection, effects
liver disease manifested in the lungs (protects lungs against inflammation)
• Genetic deficiency: cannot be properly folded in ER, gets stuck and accumulates in ER  little is secreted and often not properly folded
• Can stain for alpha1-anti-trypsin accumulation in hepatocytes (PAS stain)
• Excessive accumulation can also damage hepatocytes (but not main clinical manifestation)
Cells vulnerable to hypoxia?
o Efficient extraction by hepatocytes in series
 Good for clearing substances form blood
 But also means cells at the end are always slightly hypoxic (more vulnerable to ischemia and hypoxic injury)
• Peri-central vein can be clotted off with ischemic damage to hepatocytes
• Injury is reversible since viable cells in the portal area can help regenerate
T/F: Toxic chemicals tend to affect pericentral cells more than periportal cells.
False: o Function of cells not completely identical (some do certain things better than others)
 More secretion in vein cells, more uptake in portal cells
 Periportal necrosis (e.g. from allyl formate toxicity) – periportal cells take it up better, metabolized  cause necrosis
 Pericentral necrosis (e.g. from organic solvents like carbon tetrachloride) – pericentral cells have more of the enzymes needed to metabolize these substances
T/F: cholesterol and bile acid are both planar molecules
F:  Cholesterol  bile acid (no longer a planar molecule, with OH and COOH groups on the hydrophilic side)
 Bile acid is amphipathic (hydrophobic and hydrophilic side – detergent!)
• Cholesterol and TGs are insoluble, so bile acids keep these in solution in bile (essential function)
• Also helps solubilize lipids so they can get to the intesintal epithelium during absorption
how do bile acids get back to liver?
 Organic acid synthesized in liver from cholesterol
 Conjugated to amino acids
 Secreted in bile – essential for fat digestion/absorption
 Reabsorbed in distal ileum and returned to liver via portal vein (recycling system – although liver also synthesizes them)
Pumps across membranes in hepatocytes and intestines for bile acids
Resection of 40cm vs. >100cm (early vs. late)
 About 90% of bile acids are reabsorbed in terminal ileum, 5-10% of bile acids lost daily into the colon  can cause secretion of electrolytes in colon (probably prevent constipation)
• Liver synthesizes 5-10% of total bile acid each day
 Resection of 40cm of terminal ileum is not too problematic  liver can rev up synthesis (bile acid pool and fat absorption remain the same)
 Resection of >100cm of terminal ileum will cause large bile acid loss. Even liver upregulation of synthesis cannot keep up  fat malbsorption
• Early on, bile acid loss in colon  secretory diarrhea
• Eventually, bile acid pool falls and loss through colon is less  no secretory diarrhea but steatorrhea from fat malabsorption
T/F: The total bile acid pool is around 30 grams
 Total bile acid pool is ~3gm
What's the physiologic/clinical effect of too much cholestyramine?
o Cholestyramine: bile acid binding resin that removes excess bile acids from the enterohepatic circulation  depletes bile acid store
 Liver upregulates bile acid synthesis, which uses up cholesterol  cholesterol lowering
 Can make people constipated from binding free bile acid
Process to make bilirubin?
 Bilirubin: RBC breakdown  unconjugated bili  uptake into hepatocyte where it is conjugated  pumped out through ATP pump (MRP-2) into bile canaliculi
Jaundice etiology in newborn? Names of the syndromes?
 Jaundice of the neonate: newborn infants have poorly developed conjugation enzymes so jaundice is common. Premature babies more affected. Unconjugated bilirubin in brain can cuase permanent damage
• Prevent brain damage with phototherapy  blue light will turn unconjugated bilirubin into a water-soluble form (photoisomerase) so it can be excreted in urine
 Can have problems of bilirubin conjugation (UGT1A1) in hepatocytes (Gilbert’s, Crigler-Najjar)  see unconjugated bili in blood
You have a patient that has high levels of conjugated bilirubin in the blood. What is the etiology and name of this syndrome?
problems of bilirubin transport/excretion through ATP pump (Dubin-Johnson, Rotor’s)  see conjugated bili in blood

 Liver disease and bilirubin handling
• Liver conjugation function is mostly maintained in liver disease
• The reason patients develop hyperbilirubinemia in liver disease is because the pump that secretes conjugated bili into canaliculi is affected – rate limiting step is pump
o Thus, hyperbilirubinemia in this case is mostly conjugated bilirubin
excretion of metabolites after biotransformation:
 Larger lipophilic molecules excreted in bile
 Smaller (<400Da) regenerate to blood and excreted by kidneys
2 steps of biotransformation:
 Phase 1: oxidative reactions, CYP (P450) mediated
 Phase 2: conjugation to polar ligands (e.g. conjugate to sugars)
 E.g. cholesterol is hydroxylated by P450-medited pathways, then conjugated to side chain of glycine or taurine
Functional consequences of losing large amount of liver from resection/necrosis
hypoglycemia, poor blood clotting, cholestasis and jaundice, increased blood ammonia (affects cognitive function), decreased drug disposition, abnormal lipid metabolism
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