2 - Hepatic Physiology Flashcards
If the liver is too big
It will shrink
If the liver is too small
It will grow
Bilirubin Produced By
Oxidation of Heme and Reduction of resultant bilverdin
Heme oxygenase converts Heme to Biliverdin
Biliverdin Reductase converts Bilverdin into Bilirubin
After C-Glycine Administration Early Peak
Ineffective Erythropoiesis
Conjugation of Bilirubin
To make it more soluble
Bilirubin
Delivered in sinusoid
Uptaken into hepatocyte
Biotransformed and secreted into biliary flow
Glucuronyl Transferase
Does something I don’t know he did not use enough words
Bilirubins
Unconjugated (UCB)
Mono-Glucuronide (BMG)
Diglucuronide (BDG)
These are progressive steps
Bacterial Breakdown of Bilirubin
In color
Gives stool brown color
Deconjugation
Reduction
Oxidation
No bilirubin in stool
Clay colored stool
Biliary Atresia
Agenesis of common bile duct
Treat with “Cuh-sai” procedure
Sew intestine into intrahepatic bile ducts
Stool color doesn’t matter much actually. Stool swatches were more for parents. What more counts is bilirubin in serum.
Enterohepatic Circulation of Bilirubin - In Hepatocyte dysfunction (hepatocellular)
Increased urobilinogen in urine because it is less efficiently reabsorbed by hepatocytes
Enterohepatic Circulation of Bilirubin - In Biliary Obstruction
Stools appear white
No urobilinogen detected in urine
Measurement of bilirubin in blood
=
Hyperbilirubinemia and Jaundice
Occur when liver fails or when other steps of the metabolism are abnormal.
Bilirubin >35μM can begin to detect jaundice clinically.
Coca Cola urine
Beefy Red Liver
Bile getting stuck in liver
Leads to micronodules too
Cause of Unconjugated Hyperbilirubinemia
Overproduction: Hemolysis or Ineffective Erythropoiesis
Impaired Uptake: Fast, Sepsis, Drugs (eg probenecid)
Impaired Conjugation:
Inherited Mutations in UGT1 - Grigler-Najjar Syndrome (Type I and Type II)
Inherited polymorphisms in UGT1 - Gilbert Syndrome
Cause of Conjugated Hyperbilirubinemia
Hepatocellular Diseases Cause Decreased Secretion:
Cirrhosis
Acute Hepatitis (drugs, viral, alcohol)
Pregnancy
Drugs
Inherited Diseases:
Dubin-Johnson Syndrome (ABCC2 mutation)
Rotor Syndrome (SLCO1B1 and SCLO1B3 mutations)
Biliary Obstruction: Gallstones Tumors Primary Biliary Cirrhosis Sclerosing Cholangitis
“Physiological Neonatal Jaundice”
Results from immaturity of ALL steps in bilirubin metabolism
Increased Production
Decreased Delivery
Decreased Uptake
High bilirubin level
BBB not great yet
Bilirubin in brain leads to kernicterus
Kernicterus
Brain damage due to bilirubin deposition
Treatment of Neonatal Jaundice
Phototherapy
Biliblankets or Bililight
Convert Natural Bilirubin to Photobilirubin (can pee out)
Jaundice
At “50”, you can glow in the dark
Plasma proteins secreted by liver
Albumin Clotting Factors Antithrombin III α-1-antitrypsin Ceruoloplasmin Complement C3 C-reactive protein α-1-fetoprotein fibrinogen Haptoglobin Hemopexin α-lipoprotein β-lipoprotein α-2-macroglobulin Orosomucoid Other clotting factors Prothrombin Transferrin IL-6
Factor VIII Level tells us
High = Liver Failure Low = DIC
Clotting Factor tests
PTT or INR
Responsive to Vitamin K
II, VII, IX, X, Protein C & Protein S
Gotta start heparinizing and coumadinizing them because the tests will hypercoagulabilize them? I don’t understand.
IL-6
Regulates body temperature
Pathway of protein Secretion
Synthesized in ER
Golgi Network
Secretion into bloodstream
Prolonged Prothrombin Time
Bleeding Tendency
Low Serum Albumin
Edema or maybe ascites but that can be portal hypertension as well
Blood Supply of the Liver
Hepatic Artery - Directly from the Heart
Portal Vein - Drains the gut (FIRST PASS METABOLISM)
Drug and Toxin Metabolism
Oxoreductases (Cytochrome P450) - Phase I
Lead to more polar metabolites, generate active groups for transferases
Hydrolases (Phase I)
Lead to more polar metabolites for transferases
Transferases (Phase II)
Addition of groups
Decreased Clearence of Toxins from portal circulation
Buildup of vasodilatory molecules (NO)
Decreased systemic vascular resistance
Increased Cardiac Output
After a liver transplant, you can go into heart failure because your spotter is gone
These mechanisms relate to trying to bypass cirrhosed liver
Ethanol Metabolism
Acetyl Acohol to Acetate
With chronic drinking, P450 catalyzed oxidation more active
Hella hypotheses on how alcohol damages tissues
Carbohydrate Metabolism
Glycogen Storage & Glycolysis
Portal Circulation contains high levels of insulin and glucagon
Glycogen
Polymerized glucose
Stored in liver
Glycogen phosphorylase cleaves glyocgen to make glucose available during fasting
Epinephrine
Stimulates glycogen degradation
Glucagon
Stimulates glycogen degradation
Insulin
Stimulates glygogen synthesis
Gluconeogenesis
You've exhausted your glycogen storage Form new glucose from non-carbohydrate carbon sources Lactate Glycerol Most amino acids
Acute read-out on how well liver is doing
Lactate is the marker
Maybe acid/base metabolism too
Transamination
ALT and AST
Indicators of hepatocyte damage
Urea Cycle
Elimination of Excess Nitrogen (Urea)
Occurs in Liver, Kidney, Striated Muscle
When you don’t clear ammonia and nitrogenous metabolites
Hepatic Encephalopathy
Build-up of neurotoxins (nitrogen-based)
Patients become confused, obtunded, brain swelling, herniation, death
Physical exam - Sign of hepatic encephalopathy
Asterixis!
Fatty Acid Synthesis
Happens in cytosol
Fatty Acid β-Oxidation
Happens in mitochondria
Carnitine palmitoyl transferase 1A (CPT1)
Conjugates fatty acids to carnitine for transfer into inside mitochondria)
LDL Uptake by Hepatocytes
Decreased HMG CoA Reductase (target of Statins)
Increased ACAT
Decreased LDL receptors
LDL Binding > Internalization > Lysosomal Hydrolysis > Regulatory Actions
Familial Hypercholesterolemia
Transplant the kids before soft cheesy plaque lesions become calcified
LDLapheresis
Synthesis of bile salts in liver
Derive from cholesterol
Bile salts reabsorbed
Terminal ileum
Need it out before it hits the colon
Bile Salts
Start with cholesterol, end with bile salts
Enterohepatic Circulation
Important pathway he explained too fast
Primary Bile Acids
Converted to secodnary bile Acids in the intestin, and secondary to tertiary in the liver again
PFIC
Progressive Familial Intrahepatic Cholestasis
Hella itchy
Treat by bypassing terminal ileum through resection or through connecting gall bladder to skin so bile drains out of body. Gotta watch fat soluble vitamins ADEK if you do that though
BSEP
Important in 2 situations:
Dysfunction in sepsis - reason for elevated bilirubins
PFIC Type 2 - Increased bile salts and de
Other important metabolic activities of the liver
Heme biosynthesis (in infancy) Hematopoiesis in utero Iron metabolism Copper metabolism Vitamin A storage Vitamin D metabolism
