Hepatotoxicity

Question 1

What is the liver?

Answer 1

The largest organ in the body which receives dual blood supply – nutrient rich but poorly Oxygenated blood via the hepatic portal vein and well oxygenated blood through the hepatic arteriole

Question 2

How is the liver divided functionally?

Answer 2

It is divided into functional lobules centred around a central vein and outlined by portal triads

Question 3

How is the liver lobule divided up into zones?

Answer 3

There is zone 1 which is periportal, zone 3 which is centrilobular -around the central vein- as well as zone 2 which covers the region between zone 1 and 2
These zones reflect both an oxygen gradient (high in zone 1) and a metabolic gradient- formed by differential enzyme expression-

Question 4

What are the functional cells of the liver?

Answer 4

The hepatocytes which lie in plates which are 1 cell thick separated by vascular spaces- sinusoids- which combined with the high permeability of the blood vessels- due to endothelial fenestrations- allows the hepatocytes to be bathed by nutrients and O2 in the space of disse (in between the hepatocytes and endothelial cells)
The hepatocytes form the bile duct through making tight junctions with one another

Question 5

What physiological functions does the liver perform?

Answer 5

Carbohydrate metabolism (postprandial glucose consumption and glycogen storage), Lipid metabolism (triglyceride synthesis and uptake, LDL/HDL cholesterol synthesis), Protein metabolism (synthesis and deanimation of amino acids and conversion of ammonia to urea) Nutrient uptake and storage, synthesis and release of hormones, binding proteins
Protective clearance functions through detoxification of xenobiotics

Question 6

What is unique about the regenerative functions of the liver?

Answer 6

The liver can fully restore itself after significant tissue loss, as even if 70% of the liver is re3moved it will be fully restored in 5-7 days and theoretically a single hepatocyte could produce 50 livers

Question 7

How does the liver biotransform xenobiotics?

Answer 7

Non-polar xenobiotics are treated as toxins as they will be unable to be excreted in the urine and could accumulate to toxic levels
To account for this the liver converts them to polar products to increase their excretion in the bile and urine
This can unfortunately result in the production of toxic products like free radicals in the cell

Question 8

What are examples of xenobiotics which are toxic to the liver?

Answer 8

Industrial chemicals such as halogenated aromatic compounds, nitroaromatic compounds, aliphatic hydrocarbons and inorganic compounds such as copper and iron

Question 9

What results from damage to the bile duct epithelium?

Answer 9

This can impede bile excretion leading to choleostasis

Question 10

What results from damage to the function of hepatocytes?

Answer 10

This can result in a lack of bile transport as well as altered function leading to accumulation of fat associated with steatosis

Question 11

What pattern of enzyme changes can indicate damage to the bile duct epithelium/choleostasis?

Answer 11

High Alkaline Phosphatase as it is expressed at high levels in the cannicular membrane of the hepatocyte, and high levels of gamma glutamyl transferase ass this is constitutively expressed in the bilaiary epithelium but not in hepatocytes

Question 12

Why are alanine aminotransferase and aspartate amino transferase used for routine monitoring of hepatocyte injury?

Answer 12

They are easy to measure

Question 13

What are the sensitive enzyme markers for hepatocyte injury?

Answer 13

The mitochondrial enzyme ornithine carbamoyltransferase and lactate dehydrogenase

Question 14

What results from damage to the endothelial cells in the liver?

Answer 14

Venocclusion

Question 15

What results from damage to the sinusoidal cells?

Answer 15

This can result in fibrosis and altered uptake of nutrients due to altered bloodflow

Question 16

What is associated with chronic hepatocellular death?

Answer 16

Abberant tissue repair which combined with fibrosis can lead to cirrhosis

Question 17

What can result in cholestasis?

Answer 17

Damage to the bile ductules or hepatocellular cannicular membrane

Question 18

What are the symptoms of cholestasis?

Answer 18

Pruitis, Jaundice and malabsorption of lipids and vitameins

Question 19

Why is cholesterol an important biological molecule?

Answer 19

It is used in the synthesis of steroid horomones and bile acids (via the CYP7A1 enzyme)

Question 20

What is the link between loss of bile acids and malabsorption of vitamins?

Answer 20

Major bile acids are chenodeoxycholic acid and cholic acid which are conjugated to taurine or glycine forming taurocholic or glycocholic acid which are secreted into the bile duct and stored in the gall bladder where they will be released into the intestine to emulsify fats and fat soluble vitamins to allow them to be absorbed

Question 21

What is steatorrhea?

Answer 21

If there is malabsorption of dietry fat then there is also excessive excretion of faecal fat which leads to floating, foul smelling faeces

Question 22

What is bilirubin?

Answer 22

A water insoluble compound contained in bile which is formed from the breakdown of haemoglobin (found in erythrocytes) by kupfer cells
Hepatocytes can conjugate this with glucorinde to form water soluble bilirubin glucuronide for excretion

Question 23

How can damaged biliary excretion cause cholestatic damage to the liver?

Answer 23

There is an accumulation of bile which can be due to extra or intra-hepatic obstruction
Intrahepatic accumulation can lead to hepato-cellular toxic damage
This is usually first observed in zone 1 -as this is where the bile is usually excreted- as yellow-greenish accumulations of bile salts

Question 24

What can lead to intra-hepatic obstruction of the bile duct?

Answer 24

Selective damage of the canaliculi membrane transporters, direct damage to hepatocytes or latered uptake of bile salts across the basolateral membrane

Question 25

What is bland cholestasis?

Answer 25

There is arrested bile flow but no obvious hepatocellular damage (potentially suggesting damage to cannicular transporters)

Question 26

What is hepatocanalicular cholestasis?

Answer 26

This is when there is apparent hepatocellular damage along with a failure to appropriately excrete bile

Question 27

What are some of the suggested mechanisms through which toxins may cause cholestasis?

Answer 27

Physicochemical changes to the bile at high drug concentrations such as an increased viscosity of bile or precipitation of drug solids
Some toxin may damage the bile efflux pumps

Question 28

What are the clinical features of choleostasis?

Answer 28

The defective bilirubin excretion leads to its accumulation in the skin and sclera leading to jaundice
The defective biliary excretion of cholesterol bile salt leads to accumulation in the skin and pruritis (itching)
Defective production/delivery of bile leads to fat malabsorption, vitamin deficiency and steatorrhea

Question 29

What causes venocclusive damage to the liver resulting in nutmeg liver?

Answer 29

Damage to endothelial cells especially the efferent hepatic vein which can lead to centrilobular necrosis casuing hepatic congestion, this can be caused by oncotherapeutic agnets such as thioguanine and X-Rays

Question 30

What can cause steatosis?

Answer 30

There may be mitochondrial damage leading to an impairment of its function of fat oxidation, causing an accumulation of fat
This mitochondrial damage may also result in decreased energy production, open of permeability pores with Ca2+ influx, cell odema and lysis

Question 31

What occurs when fatty acids undergoes beta-oxidation?

Answer 31

This transfomrs them into acetyl-coA subunits undergo further degradation via the krebs cycle to fomr CO2 and generate NADH and FADH2 which are reoxidised by the respiratory chain to generate ATP
If this process is impaired then the fatty acids will build up leading to steatosis

Question 32

What is steatosis?

Answer 32

An imbalance between storage of fat and its removal where lipoprotein transport is disrupted an/or fatty acids accumulate

Question 33

What is the result of steatosis on the liver?

Answer 33

It will be slightly enlarged and have a pale yellow appearance

Question 34

What reasons, other than impaired beta-oxidation which can cause fat to accumulate in hepatocytes?

Answer 34

Increased rate of delivery (excessive dietary input) increased synthesis or decreased export from the liver
In children with Reyes syndrome it can be a toxic effect of aspirin

Question 35

How can aspirin cause steatosis?

Answer 35

Reyes syndrome occurs when there is a combination of viral illness and aspirin intake which can cause encephalopathy with microvascular hepatic steatosis
Aspirin is hydrolysed into salicylic acid at the outer surface of the mitochondrion salicylic acid is converted to salicylic acid-coA which can sequester acetyl coA disrupting the TCA cycle and therefore beta oxidation and cellular energy levels

Question 36

What can cause necrotic damage to hepatocytes?

Answer 36

Damage to the mitochondria/cell membranes leading to ion flux and then cell lysis

Question 37

What does the area of necrosis potentially say about the cause of necrosis?

Answer 37

Where the toxin enters or forms in the liver often resulting in zonal necrosis, with zonal 1 showing periportal damage and zone 3 showing centrilobular damage
There may also be nonzonal necrosis which may be diffuse, focal or massive and may include apoptotic cell damage as a rare idiosyncratic response to a drug

Question 38

How can iron Fe2+ cause damage?

Answer 38

This is a direct acting toxin as high levels of these irons react with membrane lipid hydroperoxides to produce free radicals as well as catalysing the formation of OH free radicals from hydrogen peroxide

Question 39

What region of the liver does iron cause damage?

Answer 39

Zone 1 hepatocellular necrosis as this is the area with the highest level of O2 and where iron will enter the liver through the hepatic portal vein

Question 40

How does CCL4 cause damage?

Answer 40

This is an indirect toxin requiring metabolic activation by CYP2E1 to generate the trichloromethyl free radical which can then cause peroxidation of membrane lipids

Question 41

Where does CCL4 cause liver damage?

Answer 41

Zone 3 hepatocellular necrosis as this is where most of the CYP enzymes are located which can activate this indirect toxin
It is also dependent on oxygen gradient as high O2 will inactive the enzyme which leads to bioactivation of CCL4

Question 42

How can paracetamol cause liver damage?

Answer 42

This is and indirect acting toxin which causes zone 3 necrosis due to the high levels of CYP enzymes

Question 43

What are the three phases of clinical features of chemical hepatic injury (which may occur in an overdose of paracetamol etc)?

Answer 43

Phase 1: Nausea, vomiting and collapse (1-12 hours)
Phase 2: Few or no symptoms (12-48 hours)
Phase 3: Hepatic failure which may also include renal failure (2-10 days)