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
Mixing tylonal with alchol
Alchol increases the synthesis of 2E1 = get more NADPQI
ALSO alchol decreases glutathione = also increases NADPQI
Give people Cetyly ctstein Mucomyst –> ca supplemet people with gluathtione if they take too much tylonal wit alchol
Alchohol effect on Acetometaphic (Image)
Ahcolole = decrease glutathione + increases P450 E1
Liver structure
Billirbin
End product of the breakdown of hemoglobin
Billirubin = potentially toxic catabolic product of heme metabolism
Bilirubin = detoxified and metabolzied in the liver
Hemoglobin
Heme ring (iron in center) + globin molecule
Hemoglobin = toxic BUT when in organic it couples with heaby metals to be able to use them
- Globulin chain = organic
Heme ring = stabilizes iron in core –> has corridincated behavior
- Dexoygenated = hard to oxyginate ; oxygenated = oxygen dissociated well = allows heme to work in lungs (neg O2 in lungs) and in tissues
Heme ring
Heme ring = very toxic –> after RBC life the hemoglobin needs to be recycled
- Have a whole metabolic pathwya devoted to detoxification (occurs in spleen + liver)
Bilirubin is produced when you metabolize hemoglobin
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
Bilirubin Metabolism (Video)
Start - Bilirubin is unconjugated –> needs to be conjugated to be water soluble
- Conjugated with albunin –> complex travels from spleen to liver –> liver i=copex is taken up by trasnprters –> bilirubin is conjugated to glucouronide to produce a water soluble/conjugated bilirubin –> conjugated biirubin is extreted as part of bile –> bile goe sto the bile duct into intestine –> in intestines the conjugated bilibrun is borken dpwn to urobologin then stercobilin –> urobologin is water solble and absorbed into blood and etxreted by the kidney as water soluble urobilin (gives urine yellow color) ; stercolbin in intestines is extred in feces (gievs tool colro)
Bilirubin metabolism (Urine)
Some uroblinogen goes to the kidney and goes to pee (gives urine color)
- 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)
Juandice causes
- Over production - Hemolytic disease
- Conjugation defect
- Example Criger-najjar syndome + Gilbert sydrome) - Transport - affects conjugated bilirubin
- Rotor- Dubin-Johnson
- Obstruction
- ex. Gallstone + Pancreatic cancer
Gilbert syndrome
Affect 3% of peoople
- common with some drugs (Ex. HIV drugs can reveal jaundice – affects transport protein)
Gallstone + Jaundice
Gall bladder when have metabolsim distuptents = get gallblader stones –> wedge into vili duct = get obstruction = juandice because biliruben can’t get to stool or urine
Pancreotic cancer + Jaundice
Way the gallblader is = hooked to intestine but psses through pancreaus –> bile and pancreatic duct.= combine to one duct
- Bulky head of the pancreotic tumor = stop flow of bile = get juandice
Structure of hepatocytes
Hepatocytes = hexoganal structure
Hepatocytes = not one cell type –> have multiple cell types in hepatocytes
- Cell type is revelas by the location in the liver (“Zonation of hepatocyes”
Portal Tract
Image - See portal traids (Traigle shapes) at the corners of hexagonal change + see central lobular veins (blue dots in center) –> leads to a differentraial pattern of blood flow form prtral tracts to central lobular flow –> lead sto graiant of blood flow betwene hapatcytes close to portal tracts compared to hepatocytes that are ditant form protal tracts - decsribed as the portocentral axis of damage
- Because protocentral axis of damage = liver damage can be found in a gradient
Near portal tracts = zone 1 = bathed in nuterinet rich blood
Far from the portakl tracts = zone 3 = less nuetrinets
Porto-central Axes of damage
Porto-central Axes of damage/gradient of blood flow = seen in sevral metabolic pathways:
Cytochrome P45 enzymes and damage from alachol
Metabolism
Microbial translocation
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 gradinet
See Porto-central Axes in Cytochrome P450 amounts
- Mostly preivenous
- many are inducible (inducible by hromaonal + oxygen tension + Transcription factors)
image - P = near Portal vein ; V = near cetral lobular vein
- Example - first B1/2 = Have excess of enzyme in hepatpcytes near the Cnetral lobular vein
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
Hepatic Non-parachymal cells
- biliary endothelium (chologiocytes)
2 Liver sinusoidal endothelium - Hepatic stellate cells
- Kupffer cells
- Dendritic cells
- Lymphocytes (T Cells + B cels + NKT cells)
- NK cells
Hepatocyyes are
Parachymal cells
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
Mix of Bilirubin + cholestural + bile sak
Additional cells that contribute to bile formation
Hepatocytes secrete Bile
Cholanigiocytes contribute to the bile
Gall blader concentrates bile
Bile Function
- By products of hemoglobine detoxification enter bile
- Excretory route for many molecules
- Lipid digestion and absorption
- Bile Salts
Bile Salts
Bile salts = emulsify fats –> bile acids go to intesties – emulfify fats –> bile salts are absorbed along with fats at ilium
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)
Enterohepatic circulation of Bile Acids
Bile Acids –> extreted to the duadenum –> emusify fats from duadenum –> go to the ileu –> reabsorbed at the terminal ileum
- End of the ileum = have absroption
- If have disease of end of the ileum (Ex. Chrones) = issues absorbing of Bile Acids = Loss of Bile Acids in stool ; have issues digesting fats
Bile acids are produced by hepatocytes –> Bile Acid is extreted in the Bile –> enters in the intestines at sphicter of Oddie –> BA progressivley digest fats –> BA is taken out at the terminal ileum (some absorbed to blood stream where they circulate back to body ; some bile acids are extreed in stool)
Primary vs. Secondary bile acids
Primary bile acids (cholic acid + Chenodeoxycholic acid) = converted by bacteria to secondary bile acids (Deoxy chilic acid + lithocolic acid)
- Conversion is required for activity of bile acids + for ability to be recirculated
- Without bile acids = can’t digest fats + without circulation of bile acids we lose the ability to digest fats
Secondary Bile acids – responsible for emulsificatiion (actually do the emulsification)
Is the digestive the outside or inside envirnment?
What we ingest from the outside world –> goes through a tube = the tube is topologically the outside world
- Can have a lot of harmfil things (Ex. Harmful bacteria)
Can have complexes made by bacteria that can be toxic (Ex. Endotoxin + LPS - made in the cell wall of bacteria)
LPS
LPS = made by cell wall in bacteria –> Causes septic shock
LPS = PAMP for TLR4 –> when binds get TNF alpha –> get septic shock
When we eat = we injest LPS peices = triggers sensors = need a way to manage this
Key immune cell in the liver
Kupler cells
Kupffer cells
Liver resident macrophages
Important for innate immunity
Have an enzyme that detoxifies LSP
- Hexacytlated LSP binds ; clearve 2 Acyle groups = won’t bind to LPS
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
Kupffer Cells
Liver macrophages
Function -
1. Phagocytosis
2. Antigen processing and presentation
3. Produce cytokines + prostanoids + NO + reactive oxygen intermediates
4. Detoxify LPS
Hepatic Stellate Cells
Function:
1. Major cell for storage of Vitamen A
2. Transdifferentiate into myofibrolasts under activating conditions
3. Primary producer of extrcellular matrix proteins in fibrosis/cirohsis
- Have fibrosis then cirosis = can be pathogenic
Hepatic lymphocytes
T cell CD4:CD8 Ratio is reversed
- Blood it is 2:1 ; liver it is 1:2
T cell tolerance (liver transplantation)
NK/NKT cells - up to 50% of hepatic lymphocytes
- NKT are larger protant of liver lymphoctyes compared to blood lymphocytes
Plasmacystoid dendritic cells (pDCs) - Produce Type 1 Interferon in response to viral infections
Liver Tolerance
There is somthing unique about the liver that allows it to become tolerant
Could have innate tolerizing force in liver because epxosed to forign antigen - if eveyr time we ate liver sent danger signla it would be bad
- Liver trasnplatation requires less immunosupresstion than other trasnplanations
- Could be why viral hepatitus can be chrinic problem and not acute because the vrial inefcted hepatocytes are tolerate dby liver and not killed
