What does a portal triad contain?
1) Hepatic arteriole (25% of blood into liver)
2) Portal venule (75% of blood into liver)
3) Bile ductule
(4) Lymphatic vessels)
Blood and bile flow between portal triad and central vein
Blood flows from PT to central vein
Bile flows from central vein to PT
Zone 1, 2, 3 of the liver
Zone 1: around PT; highest O2, gluconeogenesis; viral hepatitis comes in through PT so starts here
Zone 2: combo between 1 and 3
Zone 3: around central vein; lowest O2, glycolysis, lipogenesis; fatty liver starts around central vein
Capillary bed then veins then another capillary bed THEN to the heart
1) Hepatic portal system: capillary bed of gut (splanchnic capillaries) to portal vein into capillary/sinusoids of the liver to hepatic vein to inferior vena cava
2) Pituitary gland
What is the endothelium of the liver?
So albumin can get access to/from hepatocytes
How much of the liver can we cut out?
In humans, cut 1/3 and over 2 to 3 months will grow back
Liver will fill the space its in (either grow or shrink)
What liver diseases occur in the hepatic artery (pre-sinusoidal)?
Portal vein thrombosis (blood clot; imbalance in clotting factors, or cancer)
Schistosomiasis (rare, parasitic infection that feeds off nutrients)
What liver diseases occur in the sinusoids?
Viral hepatitis (B and C are chronic)
Almost all else
What liver diseases occur in the hepatic vein (post-sinusoidal)?
Venoocclusive disease (complication of bone marrow transplant)
Budd Chiari (rare)
Inferior vena cava web (rare)
Heart failure (backflow to liver leads to portal HTN)
What happens when you get cirrhosis?
Shrunken, scarred liver (cirrhosis) --> increased blood pressure in portal vein (portal hypertension) -->
1) Esophageal and gastric varices (50% people die when this happens)
2) Paraumbilical varices (caput medusae)
3) Rectal (NOT hemorrhoids) and paracolic varices
4) Spleen enlarges (splenomegaly), and chews up/traps platelets too much (low platelet count)
What is the apical/canalicular membrane and what goes across this membrane?
2 hepatocytes form a bile canaliculus between them (blood and bile run perpendicularly)
Hepatocytes makes bile salts/acids and secretes them across this membrane
Cl/HCO3 channel to maintain electrical neutrality
Channels for cholesterol, conjugated bile acids, phospholipids (components of BILE!)
Channels for conjugated bilirubin, GSH, drugs/toxins
Flow of bile (Enterohepatic Circulation)
Phospholipids, cholesterol, conj bile acids secreted across apical/canalicular membrane into canaliculus --> thru liver through canals of Hering (liver turns bile acids into bile salts) --> bile salts out of liver into R/L then common hepatic duct, etc. where is modified by absorption/secretion --> gall bladder for concentration (5x)/storage --> through cyctic then common bile duct through sphincter of Oddi --> duodenum --> bile salts partially converted back to bile acids by gut bacteria --> bile salts and bile acids reabsorbed in terminal ileum --> portal vein back to liver
Note: bile acids need to bind to albumin in order to be transported in portal circulation
Portal circulation tied to biliary circulation via Enterohepatic Circulation
Which vitamins are at risk if you have disruption with terminal ileum and enterohepatic circulation?
Fat soluble vitamins: K, A, D, E
Water soluble: B12 (because absorbed at terminal ileum)
How could enterohepatic circulation be interrupted?
Inflammation/edema (infection, IBD (Chron's, Ulcerative Colitis), autoimmune)
What is bile composed of?
67% bile salts
26% phospholipids (lecithin) and cholesterol
Function of bile acids/salts
1) Form micelles
2) Solubilize fatty vitamins A, D, E, K to absorb
3) Absorb heavy metals (Fe2+)
4) Keep intestinal surface clean
5) Promote intestinal motility
6) Mild bacteriostatic effects
7) If too much in colon, induce water secretion and get really bad diarrhea
How do we get rid of cholesterol?
Must secrete it in bile, using bile salts
Difference between bile acid and bile salt
Bile acid is base structure, the salt is the conjugated form with Na+ (which can fall off or on)
How are bile acids made?
Cholesterol to cholic acid by CYP7A1 (7-alpha-hydroxylase) --> primary bile acids cholic acid or chenodeoxycholic acid conjugated to glycine or taurine (by CYP81B) --> bile salts: glycocholic acid, glycochenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid
How does our body know how much cholesterol or bile salts to secrete?
We have endogenous sensors for cholesterol (LXR) and bile acids (FXR) that help control how much cholesterol, conjugated bile acid, and phospholipid is secreted into bile canaliculus
Backup of bile in the liver
Ex: Byler's Disease (common in kids)
What do you have to do to prevent gallstones?
"Zone 1" where you have high bile acid, high phospholipid and LOW cholesterol
Bile with >10% cholesterol forms cholesterol crystals and gallstones
Diseases of conjugation of bilirubin
1) Gilbert's Syndrome: liver doesn't take up unconjugated bilirubin well or MILD decrease in UDP-glucuronyl transferase; high unconjugated bilirubin but usually asymptomatic
2) Crigler-Najjar Syndrome Type 1: ABSENT UDP-glucuronyl transferase activity so fail to conjugate bilirubin; high unconjugated bilirubin; infants get bilirubin deposition in brain called kernicterus and die within a few years (Note: Type 2 is less severe)
3) Dubin-Johnson; Rotor's Syndrome: Cannot transfer/excrete bilirubin into bile canaliculus to get it out of the liver; high conjugated bilirubin because just can't get it out; liver becomes black; benign
What determines which direction bile flows in the biliary tree?
Pressure 1: determined by hydrostatic secretion pressure by liver secretion
Pressure 2: determined by gall bladder secretion induced by CCK
Pressure 3: determined by Sphincter of Oddi open or closed
Consequences of cholestasis (failure to secrete bile)
Dark urine (bilirubin)
Malabsorption (K, A, D, E)
Pain (epigastric, RUQ, right shoulder--referred pain)
Hepatotoxicity (untamed bile acids are highly toxic)
Kernicterus (in neonates)
Get itchy all over body, don't know mechanism!
Extrahepatic causes of cholestasis
Mechanical, plumbing problem, blockage of flow
In biliary tree: gallstones, stricture, cyst, diverticulum, cancer, acalculous cholecystisis
In pancreas: pancreatitis, pseudocyst, cancer
Intrahepatic causes of cholestasis
In biliary tree: ischemic injury, primary biliary cirrhosis, primary sclerosing cholangitis
Drug-induced: oral contraceptives and androgens, phenothiazines, macrolide antibiotics (erythromycin), TPN
Parenchymal diseases: cirrhosis, cancer, hepatitis, infection/sepsis (hyperbilirubinemia of sepsis), infiltrating disease (amyloidosis, TB, sarcoidosis)
How do you measure cholestasis?
Physical exam: Murphy's sign (pain on pressure where liver should be), jaundice, scleral icterus, pruritis, RUQ/epigastric tenderness
Lab: elevations of bilirubin (conjugated), alkaline phosphatase, GGT, 5' nucleotidase
Imaging: ultrasound, abdominal CT, HIDA scanning, ERCP/MRCP
What tests are for hepatocellular disease vs. cholestasis?
AST, ALT: markers of hepatocellular disease
Bilirubin, alkaline phosphatase: markers of cholestasis and biliary dysfunction
How do you treat cholestasis?
Treat underlying condition
Lower cholesterol (get to Zone 1 so you don't develop gallstone)
Give ursodiol: exogenous bile acids
What are true measures of liver function?
Clotting time (PT), platelet count, albumin level
Because liver makes clotting factors, albumin
Diseases that cause increased unconjugated bilirubin
Sickle cell anemia (have hemolysis and would also have high reticulocytes)
Crigler-Najjar Type 1
Diseases that cause increased conjugated bilirubin
Cirrhosis (total, conj and unconj increased)
What two veins feed into the portal vein?
Superior mesenteric vein
(Inferior mesenteric vein feeds into Splenic vein)
What happens when you get portal hypertension?
1) Portocaval anastamoses swell (esophageal varices, caput medusa, rectal varices)
2) Splenomegaly and platelet consumption
Markers elevated in hetapocellular damage
Markers elevated in cholestatic diseases
In portal hypertension, bleeding from which veins would cause varices where?
Azygous vein: esophageal varices
Left gastric--portal: gastric varices
Splenic: splenomegaly (note: not varices)
Superior mesenteric vein--portal: pancreas, duodenum, jejunum, ileum, cecum, appendix, ascending colon, transverse colon
Falciform ligament: caput medusa
Inferior mesenteric vein (specifically superior rectal vein--portal): sigmoid and descending colon