Physiology (Digestive 2) Flashcards
Liver (overall)
Second largest organ in the body (massive)
- 1200-1500 grames
Functions:
1. Biotrasnformation
2. Detoxification
3. Protein Synthesis
4. Metabolsim
5. Storage
6. Immunity
Liver location
Under the right diaphram
- Occupises a large amount of the abdominal cavity
Hepatic Circulation
Dual blood supply:
1. Portal vein (75%)
2. Hepatic artery (25%) - gives O2 blood to the liver
Portal system drains from esophogus to the rectum + spleen + pancreus + gall bladder
Protal system
Protal bring sblood from the esophogus to the erectus
All of the veins from the inetestines coelece to the portal vein –> go to the liver
- Liver gets blood flow from the intetsines (CO2 rich blood) vs.
- Most organs get arteria blood flow vs. Liver gets a lot of non-arterial blood from the veins draining the intetsines
- Hepatic arteru = gives O2 blood to the liver
Nutriernts going to the liver
Absorption of nuterients occurs in the intestines –> nuterints go to protal vein –> blood goes to the liver for trasnormation + detoxification + water solubilization
Hepatic circulation in liver
Blood enters the liver in the Portal vein + hepatic artyer –> PV and HA will branch together in tripartide tripling (Bile duct + Porta + hepatic artery) –> blood goes to the liver in the protal tracts
Blood from the hepatic aretyer and pulinary vein goes to sheet of helatocytes –> blood flows between the hepatocytes –> blood goes to the lower veins –> goe sto the hepatic vein –> goes to the suprior vena cava –> heart
Portal tracts
Defined by the portal vein + biliary duct + hepatic duct
Structure of the liver is defined by portal tracts
Image - blue + green + red in beigh circle = Protal triad (pportal tract)
Liver as a filter
Hepatic circulation is unique because it does have capilaries + has sinusoids
- Sinusoids - liver has holes
- No basement mebrane in hepatic circulation = allows macromolecules to go through
- Liver = has low resistnce
- Liver gets 30% of Cardiac Output
Image - see sinudoidal endothelial cells + fenetrae
Fenestrae
Holes that allow macromolecules to go through
Have decreased hepatic metabolism + increased pressure in the portal vein (portal hyperyension)
Portal Hypertension
Based on Ohm’s law - dP = Flow (blood/min) X resistence
As resustence increases = pressure increases to generate the same amount of flow
- Increases pressure occurs because capilaries of the liver (get fibrousous in the liver = act as basmemt = increase presure)
Consequences of portal hypertension
Blood flow is restricted through liver = tries to get through the heart in other ways:
1. Enlarge vessels in the esophogus
2. enlarges the veins in the rectum (veins that go to the inferior vena cava)
3. Fluid leaks out of the liver and fills the abdominal cavity (Acites)
Acities
Consequence of portal hypertension - fluid goes out of the liver to the abdomen
- Hepatic leaking - get leakage of fluid to the peretenial space = makes the abdomen bulge out
Image - massive Acidies (pushes embulocus outward + drains fluid to give people releif)
Varicies
Consequence of Portal Hypertentions
Varicies - have elargment of vessels in the esophogus and rectum
- Get verecous veins (vericocies)
- Can lead to an internal hemroid
image (small image on right) - see enlarge dvein –> if it bleeds it can be fatal
- Image on left - esophogeal bleed
What are other causes of portal hypertension
Class idea - Blood clot above the liver or below the liver
- Could cause hepatocellular daamge
His List:
1. Posthepatic - Budd chiari syndrome (Veno aclusive disease)
- Included constrictive pericarditus (fibrosis in the heart = heart can’t expand = backflow of pressure in liver = liver is not problem ; if fix heart then liver would improve)
2. Intrahepatic
- Example - Schistosomiasis - fluke infections (eggs of nematode are depsoiited before hepatpcytes in sinusoidal space = get fibrotc response to egg = increase pressure)
3. Prehapatic
Portal Hypertension (Sumary)
Hepatic Paranchyma cells
Hepatocytes (largest amount in liver ; 80% of the liver ; 4 billion in number)
Hepatocytes
Highly transcriptionally active
Hepatocyte Function
Metobolic function:
1. Digestion
- Glucogensis + glycolysis + glycogen sythesis
- Fatty Acid oxidation
- Protein synthesis and breakdown
- Bie acid synethsis/enterohepatic circulation
2. Phase I vs. Phase 2
- Billy Rubin Breakdown
3. Detoxification - RBC breakdown
Hepatocyte Metaoblic Function
Metabolsim and storage of all 4 multi nutrients
Have larger glycogen storage
Hepatocyte Biotransformation
Elements absorbed from the intestine need to be transfered to be detoxified or to solubilize the to be ready to be used by the body
Includes:
1. Metabolize
2. Detoxify
3. Inactive
4. Active
Biotransformation
Function: Usually used for solubilization
Biotransformation - small water soluble mocleues can be directley filtered at the kidney and extreted in the urine
A lot of substances in the blood are too big + bound to plasma proetin + can not be extreted in the urine directley –> such substances are biotrasnformed by the liver into water-soluble molecules that cna be extreted in the bile or the urine
Biotransformation (Process)
- Uptake from the blood across the basolateral/sinusoidal membrane)
- Chemical modification and degredation
- Export into the bile across the apical membrane
- Export into the blood across basolateral membrane
Modification Phase 1 (In biotransformation)
Phase 1 - Involoves redoc reactions in detoxifying elememts and making them useful for cells = uses cytopyso enzymes (uses P-450 cyotochromes)
P-450 Cytochrome
Important in drug development
makes drugs into useful compounds for body to use OR can accelerate the metabolism of drugs
P-450 Cytochrome Function
- Oxidation (redox - keps ROS from targeting tissue)
- Hydroxylation
- Dealkylation (poisonous to body = need to dealkylinate)
- Dehalogenation
- Reduction
P-450 Cytochrome (overall)
Dievrse (more than 150 isoforms)
Found in the ER
Microsomal
Many drugs utolize the same P45- enzyme to be trasnformed (ex. Acetometaphin _ Alchol both use P450 2E1)
Expression of Cyt P450 can be induced or supressed (Ex. Alchohol can indice P450 2E1)
Modification Phase 2(In biotransformation)
Phase 2 = involoved conjugation –> important for solubilizing things + important for decreasing toxicity
Conjugate to:
1. Glucuronate
2. Sulfate
3. Glutathione
Acetometaphine metabolism
Process - P450 2E1 –> makes compoudn with glutathione - when does this it makes a recative itermediate (NAPQI)
- NAPQI = can cause hepatocellualr damage
- If have more glutathione = more NADPQI = glutathionoe is expported out so you get less recative NADPQI???
- If have more glutathione = more NADPQI = glutothionated = exproted
Why can’t you take too much acetometaphine
Because when it is metabolized you get glutthionated BUT have a recative intermediate
We often don’t worry about toxicty of you take a small amouunt BUT could be issue if you mix tylonal with alchol
Alchohol effect on Acetometaphic (Image)
Ahcolole = decrease glutathione + increases P450 E1
Liver structure
Bilirubin metabolism
Macrophages in the spleen –> chew up RBC memebrane in the spleen –> In speen they destroy the heme ring –> Heme ring is broken open by heme oxiynase –> byproduct of breaking open ring is biliverdin –> biliverdn is reduced to make bilirubin
Heme + oxygnated = disscoiated iron –> get biliverdin –> reductase –> make bilirubin (not H20 soluble)
Bilirubin metabolism (depth)
Start - Bilirubin is unconjugated –> needs to be conjugated to be water soluble
Bilirubin is brough to liver form the spleen (in spleen the bilirubin is not H2O soluble) –> bilirubin goes to the liver and is taken up by trasnprters (transported by urila trasnporters) –> Bilurubin goe sto the ER and bevomes bilirubin Mono and Diglucoronide –> becomes Bilurubine glucoronide + urobiligen –> goes to the bile cell –> go to the gall bladder –> gall bladder contracts and puts the bile into the intestines –> in intestines the bilirubine is conjugated and converted to urobilinogen –> converted to stercobilin –> extreted in feces
Conjugated bilirbin = H20 Soluble
- hepatocellular daamge
- Sickle cell + hemoglobulin issues –> increase RBCs turnover
- Liver functions fine to metabilize BUT if have to metabolize too much = back log of unconjugated bilirubin
- Biochemically you can see where issue is by looking at conjugated vs uncojugated bilirubin (see if issue is before ir after liver)
- Metabolsim disease (Ex. UGT enzyme)
Metabolic enzyme zonation
See Porto-central Axes of damage in several metabolic pathways (all metabolsim occurs in gradient)
Image - have gradinet in hormones + oxygen tension (most differet along pathway) + nuterinets
- Infered distction betwen hepatocytes that are aorund protal veins compared tp hepatocytes that reside around central lobular veins
- Have a numver of betablic athways + exposures that are difefrental betwen portal tract vs central lobular vein
- NOT all hepatpcytes are created equal
Image - see what is higher in protal vs. higher in central
Cytochrome P450 2E1 gradinet
CYP2E1 - has central lobular predomincnace of expression ; damage hepatocuytes near lobular vein more than protal vein when drinking alchohol
Other liver diseases = have periprotal damage
Biliary system
Bills cells –> Colongiocyte –> form Canailiculi –> coelece to the bile ductuals –> coelce to large bile duct
- Have left hepatic duct and right hepactic ducts –> form the common hepatic duct – via the systic duct bile accumilates in the gall bladder
Gall bladder constricts due to hormones –> goes to common bile duct –> bile duct goes to the pancreatic duct –> bile goes to duadenum (goes through sphicter to go to duadenum)
- Common bile duct joins wth pancreatic duct at sphicter of Oddi next to duadenum - Bile and pancretic fluid ingress into intestines to assist with digetion
Bile composition
Bile Acid Formation
Image - Progression of bile Acid
Have primary and secondary bile acids - lead to emusifctaion and digestion of fats (required for digestion in intestines)
Liver as Immune Organ
- Liver has envirnmental toxins that it recives from intetinal tract (intestine are place where outside world can enter body)
- Gram negative bacteria with LPS can get in/ endotoxin can get in –> cause inflamtion because TLR4
- Plasma proteins that lver produces that are immunological relevants (suite of complement proteins made by the lievr)
- C reactive protein + Actute phase proteins made by the liver
Liver Immune cells
Liver has cells that function at the adaptive immune level
25% of non-parancymal cells = lymphocytes (most of Alpha/beta T cells)
Composition of Lymphocytes
Liver has many NK and NKT cells
Maybe has more Tregs - don’t wnat to signal too much and cause damage every time we eat a meal
- Liver is an immuno tolerate organ (makes it easier transplant)
Hepatic Immune response
