liver structure Flashcards
what is the conceptual unit of the liver
lobule (fits with heterogenous expression of genes across the lobules
Acini (preferred by pathologist - fits with kind of damage you see in the liver)
what are the cell type in the liver
- Hepatyocytes - full of CYPs
- Kupffer cells = liver macrophages which sits in sinusoids and stay in the liver
- Endothelial cells which are fenstrated (holes which allows passages without transport through cells)
(Space of diss = between endothelial and hepatocytes where Vit A stored by stellate cells) - Billary epithelial = line sbile duct and stores biles
- Oval cells = bi-potential progenitor cells
what is the mechanism of carbohydrate metabolism
- Take glucose and break down to pyruvate (some) and some is converted to Ac-CoA and goes on to make Fatty acids
- Glucose is also converted to its polymonomers (humans version of starch) glycogen
- IN starved function, glycogen is converted to glucose and AA is turn to pyruvate and then to glucose both of these are used to keep brain alive
- Lactate to glucose by gluceogenesis
Amino acid synthesis =
reamination
what serum transport protein are expressed in the liver
Albumin
Transferrin - iron transport
Caeruloplasmin - copper trasnport
what other proteins are expressed in liver
clotting factor, acute phase proteins (1st line defense in inflammatory response), complement protein
what are protein degraded into
Urea
synthesis = removes ammonia (from AA breakdown) from blood because its toxic = causes acute liver failure
Ammonia unable to be excreted so has to be converted to urea
how are lipids metabolised ?
○ Fatty acid synthesis
○ Triglyceride synthesis
○ Cholesterol synthesis
○ Bile acid synthesis (from cholesterol)
○ Lipid oxidation (acetate or ketone bodies) = keeps brain alive during starvation/glycaemia
How are bilirubin metabolised
- Bilirubin is made from breakdown products for red blood cells by spleen (from Heam of RBC)
- Liver glucorindates Bilirubin ad then excreted in the bile
- If liver function is imported then yelloe bilirubin build up in blood, causes yellowish colour in patient
how is xenobiotics metabolised
maybe phase I then phase 2
why is the liver an important immunological defence
Contains the majority of tissue resident macrophage present in the entire body as a whole
- liver macrophages = Kipffer cells which phagocyte particles and bacteria
- defends body from gut bacteria from portal vein
hepatocytes are damage in liver failure and this is localised where
lobular region or zone
What serum ‘liver’ enzymes are present in blood samples of a person with liver failure
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST).
(Enzymes involved in swapping amino groups from AA)
γ-glutamyl transferase (γ-GT) - expressed in bile duct epithelial cells
Alkaline phosphatase (ALP) - periportal damage (cholestatsis) associated
what is alkaline phosphatase a marker for
liver injury (necrosis)
when liver is injured hepatocytes burst and caused enzymes to be release into serum
Y-GT and ALP is indication for
injury to bile duct
evidence of decreased liver function
Bilirubin levels (un-conjugated / conjugated).
Ammonia and urea levels.
Plasma Pro-thrombin - clotting time. - if liver is not producing prothrombin then clot time is slowe
Evaluate the use of biopsy in detection of liver failure
- informative but invoves complication with breathing
Advantages = see liver struture and help diagnosis
Disadvantages = one see a fraction of liver + has risk associated with procedure
what paracetamol dose is a)normal b) risky c) liver damage
a =1g
b = 12g
c = 15g
how is the paracetamol antidote delivered
only effective in a short time window, only effective up to 12-15 hours after ingestion
what are the few symptoms of paracetamol overdose
nasua + vomiting
which liver function test can be carried out on samples as well as blood paracetamol levels
ALT (>1000-10000), rises to much show injury form necrosis
Prothrombin time
Creatine (renal function)
what, pathological, happens during paracetamol overdose
- maximum damage occurs 3-4 days after overdose
Jaundice - impaired liver function (UDP-glucose!) (Yellow first in eyes then skin)
Hypoglycaemia (low glycogen / gluconeogenesis function)
Coagulopathy (reduced clotting factor expression, internal bleeding)
Encephalopathy (raised blood ammonia – brain ammonia = Confusion = coma = death)
More clinical liver disease is exposure to continous or repeated _ can casue sub lethal acute damage
Hep B and C
Alcohol
Obesity
Autoimmune disease
Inherited disease - dysfunctional copper transported causes build up of copper in bod
What does a fatty liver cause
steatosis
how does steatosis occur
Fat accumulates -> cell death occurs in liver tissue. Fibrosis (scarring) occurs while liver recovers. During liver scarring stallate change to myofibroblast
what does steatosis lead to
results to cirrhosis which is irreversible scarring of liver. the extracellualr matric inhibits regeneration of liver therefore unable to recover
Primary liver cancer is _ but likely _ to steatosis
rare
endpoint
what is NASH and when does it occur
Non-alcohol hepatosis
inflammation is recurrent causes NASH, the steatosis which bypass the necrosis of liver tissue to cause fibrosis
Fully describe end-stage liver disease
yellowing of skin = fuild up of fluid in the abdomen where portal blood cant flow due to scarring so fluid builds up in gap between guts and skin = swelling
Bleeding (Varices) = blood is diverted to stomach causes bursting of verices veins and blood of stomach = throwing up blood and death
What can be done to correct pressure in end-stage
Perform TIPS procedure or shunt blood to hepatic vein to reduce pressure
what is necrosis
Accidental cell damage. organelle swelling and disruption. ATP levels fall. Loss of plasma membrane integrity releases of intracellular contents. Digestion by lysomal enzymes. Local inflammation causes phagocytes to migrate to the site
what is apoptosis
Programmed cell death, hijacking elements of PCD pathway. Its normally signal dependent. Organelle remains intact for much of the time though cells often shrink. ATP levels are high while the plasma membrane remains intact therefore no release of cell count. Digestion occurs by caspase enzymes and there is no inflammation as neighbouring cells ingest apoptosis bodies.
what directly causes undesirable effects and what indirectly causes it
- heat, oxygen deprivation, chemical (formaldehyde)
- protoxin (requires activation), often cell specific, typical of drug induced toxicity
why is the liver often subjected to the toxic action of many xenobiotics
- directly toxic xenobiotics are not often ingested
- the liver is the first organ to see xenobiotics after gut absorption
- the liver expresses high levels of enzymes to metabolise xenobiotics (pro-toxin) are metabolsied to toxic products
give 4 examples of pro-toxins and what toxin are they activated to. Where does necrosis take place
paracetamol -(P450)-> NAPQI (Centrilobular)
CCL4 -(P450)-> CCI3OO- (Centrilobular)
bromobenzene -(P450)-> epoxide (Centrilobular)
Allyl alcohol -(AlcDH)-> acrolein (periportal)
what does 60% of paracetamol metabolise to, then other 40%, and the minor product
60% = sulphate
40% = glucuronide
minor = NAPQI
how does NAPQI occur
paracetamol is metabolsied by CYP2E, 1A2,3A4
how is NAPQI detoxified
glutathione-s-transferase
what can occur when GSH and NAPQI are around each other
thiol group of NAPQI is susceptible to electrophilic attach from SH group of GSH
what are the function of GSH
protect cellular thiols either as a
- scavenger of sulfhydryl reactive agents
- reduce oxidised thiols
what is glutathione and while it is present in all cells it is high in what
Tripeptide (cysteine/glutamine amide bond through glutamine R group)
hepatocytes
Where are the three units of GSH synthesised from
Glycine and glutatmine = from mtabolic intermediates (non-essential amino aicds)
Cysteine = from methionine
how does paracetmol turn into MAPQI and why
Paracetamol is metabolised by sulphation/glucuronidation however these pathways can be overwhelmed as the dose increase.
Paracetamol may be N hydroxylated by CYP450 to an unstable intermediate. The intermediate re-arranges to from NAPQI
When is toxicity to paracetamol established
Occurs when GSH is depleted by more than 80%
what is the antidotes to paracetamol intoxication
Antidotes work in part through bolstering GSH levels through the supply of cysteine
-Methionine (needed urgently)
-N acetyl cysteine which works at later times after OD because cystathionase synthase & cystathionase is SH dependent and deacetylase is SH independent
why is methionine not added routinely to paracetamol (to prevent OD)
methionine affects folic acid levels (implicated in pregnancy). There is long term effect on the heart
how does GSH protect against active oxygen species/ lipid hydroperoxides
H2O2 is converted to 2H20 using 2GSH (GSH peroxidase) which converts to GSSG
GSSG is reduced to 2GSH (GSH reductase) by NADP/H+ converting to NADP+
What is normally considered to be a good model of paracetamol toxicity for man and why
Mouse NOT the rat
Rats posses a greater basal and adaptive capacity for hepatic stress responses than mice and humans
how has it been proved that rats are more similar to rats
Microarray screening
showed that compared to mice, rats had higher protein levels for protection against ROS, ER stress and autophagy
what is hepatocyet injurgy and death associated with -
mitochondrial dysduction
NAPQI binds to mitocondria (key events)
leads to covalent binding
mitochondrial covalent binding associates with
mitocondrial oxidative stress
Using the Two hit model - explain how does NAPQI derived from paracetamol cause necrosis
- NAPQI binds to the mitocondria - decrease electron transport (first hit)
- this produces ROS/RNS
- this activates JNK which translocate to the mitocondria where it leads to (Mitochondrial permeability transition) MPT and necrosis
How is CCl4 hypothesised to be activated
Carbon tetrachloride is reduced by CYP450 to produce a free radical
CCL4 + e- —–> CCL3- + Cl-
why are new born rats normally relativly insensitive
low hepatic CYP450
why is CCL4 necrosis located to and what is it dependent on
Centrilobular region
CYP450
what is the time course for the effects of CCL4 in rats
- lipid peroxidation (0-12h)
- steatosis (4-24h)
- necrosis (12-36h)
- regeneration (24-48+h)
what are the biochemical effects of CCL4 intoxication
- ER degranulation and swelling within 2 hours
- ER enzyme inactivation eg CYP450, glucose 6-phosphatase.
- Thiol oxidation – no GSH depletion (initially) – this contrasts with chloroform intoxication
is CCL4 a mutagen or carcinogen
- not mutagenic (tested in the AMES test)
- its a weak carcinogens
what is chloroform intoxication
CHCl3 -> COCL2 ——-> GS-C-SG + 2HCL
what occurs in the mitocondria during CCL4 intoxication
intact for several hours
but at 10-12 hours: swollen
uncontrolled respiration
depleted ATP
inactivated enzymes
what occurs to the plasma membrane during CCL4 intoxication
liver enzyme leakage by 6 hours
what occurs when CCL3- reacts with O2
CCL3O2-
both the carbon and chloride radical isoform bind to proteins and lipids at a 1:3 ratio
In vivo there is covalent binding and these conjugate dienes are detected
what are conjugated dienes a product of
lipid peroxidation (key cytotoxic event in CCL4 toxicity)
- requires oxygen, damges membrane functionality
- LOOH breaks dow to aldehydes/ketone/alkanes some of which are toxic
what prevents lipid peroxidation
Vitamin E which accepts the radical electron instead of an carbob/Chloride ect
what are allyl alcohols
Pesticides - organic syntheisis
H2C=CH-CH2-OH
How do alcohols convert to acid
Alcohol is converted to aldehyde (reactive)
by alcohol dehydrogenase
Aldehyde is then converted to acid by acetaldehyde dehydrogenase
infusion of allyl alcohol for 20 mins caused
-depleted hepatic glutathione content by 95% in both regions of the liver lobule
though thiol depletion alone cant explain local toxicity to peroportal regions
bar GSH/thiols what else does allyl alcohol effect
protien lysines (biogenic amine)
what is flushing reaction
the inability to convert acetaldehyde to acetic acid after consuming alcohol
- Replicated by disulfuram
