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Toxicology > liver structure > Flashcards

liver structure Flashcards

1
Q

what is the conceptual unit of the liver

A

lobule (fits with heterogenous expression of genes across the lobules
Acini (preferred by pathologist - fits with kind of damage you see in the liver)

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2
Q

what are the cell type in the liver

A
  • 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
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3
Q

what is the mechanism of carbohydrate metabolism

A
  • 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
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4
Q

Amino acid synthesis =

A

reamination

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5
Q

what serum transport protein are expressed in the liver

A

Albumin
Transferrin - iron transport
Caeruloplasmin - copper trasnport

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6
Q

what other proteins are expressed in liver

A

clotting factor, acute phase proteins (1st line defense in inflammatory response), complement protein

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7
Q

what are protein degraded into

A

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

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8
Q

how are lipids metabolised ?

A

○ Fatty acid synthesis
○ Triglyceride synthesis
○ Cholesterol synthesis
○ Bile acid synthesis (from cholesterol)
○ Lipid oxidation (acetate or ketone bodies) = keeps brain alive during starvation/glycaemia

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8
Q

How are bilirubin metabolised

A
  • 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
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8
Q

how is xenobiotics metabolised

A

maybe phase I then phase 2

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9
Q

why is the liver an important immunological defence

A

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

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10
Q

hepatocytes are damage in liver failure and this is localised where

A

lobular region or zone

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11
Q

What serum ‘liver’ enzymes are present in blood samples of a person with liver failure

A

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

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12
Q

what is alkaline phosphatase a marker for

A

liver injury (necrosis)
when liver is injured hepatocytes burst and caused enzymes to be release into serum

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13
Q

Y-GT and ALP is indication for

A

injury to bile duct

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14
Q

evidence of decreased liver function

A

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

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15
Q

Evaluate the use of biopsy in detection of liver failure

A
  • 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
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16
Q

what paracetamol dose is a)normal b) risky c) liver damage

A

a =1g
b = 12g
c = 15g

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17
Q

how is the paracetamol antidote delivered

A

only effective in a short time window, only effective up to 12-15 hours after ingestion

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18
Q

what are the few symptoms of paracetamol overdose

A

nasua + vomiting

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19
Q

which liver function test can be carried out on samples as well as blood paracetamol levels

A

ALT (>1000-10000), rises to much show injury form necrosis
Prothrombin time
Creatine (renal function)

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20
Q

what, pathological, happens during paracetamol overdose

A
  • 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)
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21
Q

More clinical liver disease is exposure to continous or repeated _ can casue sub lethal acute damage

A

Hep B and C
Alcohol
Obesity
Autoimmune disease
Inherited disease - dysfunctional copper transported causes build up of copper in bod

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21
Q

What does a fatty liver cause

A

steatosis

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22
Q

how does steatosis occur

A

Fat accumulates -> cell death occurs in liver tissue. Fibrosis (scarring) occurs while liver recovers. During liver scarring stallate change to myofibroblast

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23
Q

what does steatosis lead to

A

results to cirrhosis which is irreversible scarring of liver. the extracellualr matric inhibits regeneration of liver therefore unable to recover

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24
Q

Primary liver cancer is _ but likely _ to steatosis

A

rare
endpoint

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25
Q

what is NASH and when does it occur

A

Non-alcohol hepatosis
inflammation is recurrent causes NASH, the steatosis which bypass the necrosis of liver tissue to cause fibrosis

26
Q

Fully describe end-stage liver disease

A

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

27
Q

What can be done to correct pressure in end-stage

A

Perform TIPS procedure or shunt blood to hepatic vein to reduce pressure

28
Q

what is necrosis

A

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

29
Q

what is apoptosis

A

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.

30
Q

what directly causes undesirable effects and what indirectly causes it

A
  • heat, oxygen deprivation, chemical (formaldehyde)
  • protoxin (requires activation), often cell specific, typical of drug induced toxicity
31
Q

why is the liver often subjected to the toxic action of many xenobiotics

A
  • 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
32
Q

give 4 examples of pro-toxins and what toxin are they activated to. Where does necrosis take place

A

paracetamol -(P450)-> NAPQI (Centrilobular)
CCL4 -(P450)-> CCI3OO- (Centrilobular)
bromobenzene -(P450)-> epoxide (Centrilobular)
Allyl alcohol -(AlcDH)-> acrolein (periportal)

33
Q

what does 60% of paracetamol metabolise to, then other 40%, and the minor product

A

60% = sulphate
40% = glucuronide
minor = NAPQI

34
Q

how does NAPQI occur

A

paracetamol is metabolsied by CYP2E, 1A2,3A4

35
Q

how is NAPQI detoxified

A

glutathione-s-transferase

36
Q

what can occur when GSH and NAPQI are around each other

A

thiol group of NAPQI is susceptible to electrophilic attach from SH group of GSH

37
Q

what are the function of GSH

A

protect cellular thiols either as a
- scavenger of sulfhydryl reactive agents
- reduce oxidised thiols

38
Q

what is glutathione and while it is present in all cells it is high in what

A

Tripeptide (cysteine/glutamine amide bond through glutamine R group)
hepatocytes

39
Q

Where are the three units of GSH synthesised from

A

Glycine and glutatmine = from mtabolic intermediates (non-essential amino aicds)
Cysteine = from methionine

40
Q

how does paracetmol turn into MAPQI and why

A

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

41
Q

When is toxicity to paracetamol established

A

Occurs when GSH is depleted by more than 80%

42
Q

what is the antidotes to paracetamol intoxication

A

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

43
Q

why is methionine not added routinely to paracetamol (to prevent OD)

A

methionine affects folic acid levels (implicated in pregnancy). There is long term effect on the heart

44
Q

how does GSH protect against active oxygen species/ lipid hydroperoxides

A

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+

45
Q

What is normally considered to be a good model of paracetamol toxicity for man and why

A

Mouse NOT the rat
Rats posses a greater basal and adaptive capacity for hepatic stress responses than mice and humans

46
Q

how has it been proved that rats are more similar to rats

A

Microarray screening
showed that compared to mice, rats had higher protein levels for protection against ROS, ER stress and autophagy

47
Q

what is hepatocyet injurgy and death associated with -

A

mitochondrial dysduction
NAPQI binds to mitocondria (key events)
leads to covalent binding

48
Q

mitochondrial covalent binding associates with

A

mitocondrial oxidative stress

49
Q

Using the Two hit model - explain how does NAPQI derived from paracetamol cause necrosis

A
  • 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
50
Q

How is CCl4 hypothesised to be activated

A

Carbon tetrachloride is reduced by CYP450 to produce a free radical
CCL4 + e- —–> CCL3- + Cl-

51
Q

why are new born rats normally relativly insensitive

A

low hepatic CYP450

52
Q

why is CCL4 necrosis located to and what is it dependent on

A

Centrilobular region
CYP450

53
Q

what is the time course for the effects of CCL4 in rats

A
  • lipid peroxidation (0-12h)
  • steatosis (4-24h)
  • necrosis (12-36h)
  • regeneration (24-48+h)
54
Q

what are the biochemical effects of CCL4 intoxication

A
  • 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
55
Q

is CCL4 a mutagen or carcinogen

A
  • not mutagenic (tested in the AMES test)
  • its a weak carcinogens
56
Q

what is chloroform intoxication

A

CHCl3 -> COCL2 ——-> GS-C-SG + 2HCL

57
Q

what occurs in the mitocondria during CCL4 intoxication

A

intact for several hours
but at 10-12 hours: swollen
uncontrolled respiration
depleted ATP
inactivated enzymes

58
Q

what occurs to the plasma membrane during CCL4 intoxication

A

liver enzyme leakage by 6 hours

59
Q

what occurs when CCL3- reacts with O2

A

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

60
Q

what are conjugated dienes a product of

A

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

61
Q

what prevents lipid peroxidation

A

Vitamin E which accepts the radical electron instead of an carbob/Chloride ect

62
Q

what are allyl alcohols

A

Pesticides - organic syntheisis
H2C=CH-CH2-OH

63
Q

How do alcohols convert to acid

A

Alcohol is converted to aldehyde (reactive)
by alcohol dehydrogenase
Aldehyde is then converted to acid by acetaldehyde dehydrogenase

64
Q

infusion of allyl alcohol for 20 mins caused

A

-depleted hepatic glutathione content by 95% in both regions of the liver lobule
though thiol depletion alone cant explain local toxicity to peroportal regions

65
Q

bar GSH/thiols what else does allyl alcohol effect

A

protien lysines (biogenic amine)

66
Q

what is flushing reaction

A

the inability to convert acetaldehyde to acetic acid after consuming alcohol
- Replicated by disulfuram

Toxicology (11 decks)

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