Into To Liver Flashcards

1
Q

Describe the anatomy of the liver

A

The liver has a vascular system, the biliary tree (a system of ducts
that transport bile out of the liver into the small intestine) and an arrangement of liver cells within
these two systems. The liver has a left and right lobe anteriorly with each lobe supplied with its own
blood supply. The two lobes are separated by the falciform ligament. At the bottom of the liver is the
gall bladder (not all species have one).

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2
Q

Describe the quantities of blood supply in the liver

A

The blood supply of the liver is unique in that around 75% of it is venous blood via the portal vein
coming from the GI tract. This is related to the liver’s function of removing harmful toxins and waste
products before they reach other parts of the body. The remaining 25% of blood supplying the liver
comes from the hepatic artery.

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3
Q

Where does blood from the central veins drain into

A

Blood from the central veins in the liver lobules drains into the
hepatic vein that then drains into the vena cava.

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4
Q

What are the two types of liver cell

A

There are two primary cell types of the liver and these are hepatocytes
and Kupffer cells.

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5
Q

What do hepatocytes and kupffer cells do

A

Hepatocytes account for around 60% of the cells in the
liver and they perform most of the liver’s metabolic functions whilst
Kupffer cells account for around 30% of cells in the liver. Kupffer cells are a
type of tissue macrophage and remove damaged RBCs, bacteria and
viruses.

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6
Q

What are other liver cell types that are present

A

Other liver cell types include liver endothelial and stellate cells.

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7
Q

Describe the functional unit of the liver

A

Afunctional unit in the liver is known as the hepatic lobule. It is composed
of hexagonal plates of hepatocytes around a central hepatic vein. At each
6 corners of a lobule is a triad of branches of the portal vein, hepatic
artery and bile duct. Blood from the hepatic arteries and the portal veins
drains into sinusoids that are lined with hepatocytes. These hepatocytes
are then able to access the different nutrients found in the blood passing
through the sinusoids as well as oxygen for respiration. Blood from the sinusoids then drains into
venules that collect in larger veins and then eventually the hepatic vein.

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8
Q

How is bile able to secreted by hepatocytes

A

The bile duct carries bile and
is lined by hepatocytes that secret bile through a series of channels between cells known as
canaliculi that drain into ducts increasing in size that join up to become the common bile duct. The
flow of bile is in the opposite direction to the flow of blood.

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9
Q

What is the function of Lobule and microstructure structure

A

The lobules give the liver a very dense
structure. The liver’s microstructure give it a massive surface area for exchange of molecules as well
as a sophisticated way of separating blood from bile. It also allows for specific positioning of different
pumps to achieve specific localisation of materials at the cellular level.

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10
Q

How does the liver act as a protective barrier to the body

A

The liver acts as a protective barrier to the body mainly mediated through its Kupffer cells. As blood
flows through intestinal capillaries, it picks up many bacteria from the intestine that are almost
always able to colonise. This blood is then filtered at the liver through sinusoids that have Kupffer
cells lining them. These Kupffer cells efficiently remove any bacteria from the blood they come into
contact with (only 0.01s contact time). Less than 1% of bacteria entering portal blood succeeds in
passing through the liver into systemic circulation.

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11
Q

Describe bile and it’s contents

A

Bile is a complex greenish-yellow liquid consisting of water, electrolytes and organic molecules that
include bile acids, cholesterol, bilirubin and phospholipids. Around 400-800 ml of bile is produced
everyday with hepatocytes initially secreting this bile into canaliculi.

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12
Q

Describe bile before and after modification

This bile that flows into bile

A

ducts contains large amounts of bile salts, cholesterol and other organic compounds. Its components
are then modified by epithelial ductal cells that secrete bicarbonate-rich secretions as well as water.
Bile is essential for fat digestion, specifically in fat emulsification.

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13
Q

What is the functions of bile

A

Bile in conjunction with pancreatic
juice, also neutralises gastric juice as it enters the small intestine to provide an environment for
digestive enzymes in the small intestine to work at their optimum.
Bile is also involved in the
elimination of waste products from blood, in particular, bilirubin and cholesterol (approximately 500
mg of cholesterol converted to bile acids daily).

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14
Q

How can bile collected from hepatic ducts be collected

A

Bile from hepatic ducts can be collected into the
common bile duct where it then enters the duodenum via the sphincter of Odii, or it can be diverted
into the gall bladder via the cystic duct where it is concentrated 5-fold (by removing water and
electrolytes in a process that can lead to gall stones) and stored for future use (30-50 ml).

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15
Q

What compound is excreted into bile

A

The liver metabolises and excretes many compounds into bile with an important compound being
bilirubin. This is a yellow compound formed from the breakdown of haemoglobin.

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16
Q

Why must bilirubin be excteretd

A

It is useless and
toxic, however is made in large quantities (around 6 g/day caused by the high turnover of RBCs that
releases haemoglobin) and must be eliminated.

17
Q

Describe how bilirubin is formed

A

Dead and damaged RBCs are digested by
macrophages throughout the body. The iron from haemoglobin is recycled and the protein chains are
catabolised. Haem (porphyrin) cannot be recycled and must therefore be eliminated. Haem is first
converted to bilirubin in a series of steps. This process involves the conversion of haem to biliverdin
that is then converted to bilirubin. Bilirubin is then released into the plasma where it circulates
bound to albumin. The albumin-bilirubin complex is broken down at hepatocytes that then absorb
the bilirubin. Bilirubin is then conjugated through the addition of glucuronic acid with the conjugated
bilirubin now secreted into bile. Conjugated bilirubin then enters the intestines along with bile where
it is metabolised by bacteria in the intestinal lumen and eliminated in faeces or urine.

18
Q

What is the major metabolite excreted through feaces

A

The major
metabolite excreted through faeces is stercobilin that has a brown colour whilst in urine, the major
metabolites are the yellow coloured urobilin and urobilinogen.

19
Q

What is jaundice

A

Jaundice is when excessive free or conjugated bilirubin builds up in the body to cause yellow
discolouration of the skin, sclera (white part of the eye) and mucous membranes. Normal plasma
bilirubin concentrations are under 17 micromoles/L whilst concentrations in the plasma of patients
suffering from jaundice are around 34-51 micromoles/L (no apparent discolouration below this
threshold).

20
Q

What is green jaundice

A

In green jaundice, a mutation in the biliverdin reductase gene means biliverdin is not
converted to bilirubin and instead built up in plasma giving it a green colour.
The type of jaundice can be related to its pathophysiology.

21
Q

What are the three pathological causes of jaundice

A

Jaundice can in fact be pre-hepatic

(haemolytic), hepatic or post-hepatic jaundice.

22
Q

What is pre hepatic jaundice - who’s it common in , therapy

A

Pre-hepatic jaundice is when excessive breakdown of
RBCs occurs that causes levels of unconjugated bilirubin to rise above the capacity the liver has to
process and conjugate it. Unconjugated bilirubin cannot be excreted and therefore remains in
circulation. Pre-hepatic jaundice is especially common in new-borns. Neonates have increased red
cell mass in utero for survival. At birth and the consequent first few days of life, increased RBC
destruction occurs as foetal haemoglobin is replaced with adult haemoglobin resulting in normal
physiological jaundice. This is further compiled by the fact there is a delay in the processing of
bilirubin due to the immaturity of the liver. Light therapy is used to treat neonatal jaundice where
free bilirubin is isomerised to water-soluble compounds that are excreted via urine and stools (in
low-resource countries, natural filtered light (filtered of YVA, UVB, UVC, IR, etc rays to decrease risk
of over-heating) is used as treatment). All new-borns have raised levels of unconjugated bilirubin
with 50-60% of them having high enough levels to cause jaundice.

23
Q

What is the cause of hepatic jaundice

A

In hepatic jaundice, jaundice is caused by problems to hepatocytes (e.g. damage to hepatocytes and
biliary tree caused by cirrhosis, drugs and viral infections (hepatitis A, B, C, E and EBV) that results in
an increase in amounts of unconjugated and conjugated bilirubin. An example of hepatic jaundice is
Gilbert’s syndrome where patients have decreased levels of the enzyme that conjugates bilirubin
with glucuronic acid. Hepatic jaundice however only occurs if more than 80% functionality of
hepatocytes are affected. In post-hepatic jaundice, passage of conjugated bilirubin into the
duodenum is blocked and the bilirubin instead leaks into circulation and urine (making it very dark).
This can be caused by gall stones and carcinoma of the pancreas and bile ducts and causes symptoms
like itching and pruritis (severe itching of the skin).

24
Q

What substances does the liver excrete

A

The liver is vital to metabolism and excretion of various substances that can be toxic to the body. As
already mentioned, bilirubin is one of these. Other substances include ammonia (urea cycle),
hormones (e.g. all steroid hormones that are inactivated by conjugation and are then excreted
mainly as glucuronide and sulphide conjugates) as well as drugs and exogenous toxins (e.g.
paracetamol, aspirin and ethanol).

25
Q

What are the consequences of liver impairment

A

Impairment of liver function has consequences like overactivity oF
the hormonal system (e.g. gonadal dysfunction (for men) and spider angioma (for women) in steroid
hormone metabolism dysfunction).

26
Q

How does the liver metabolise drugs

A

The liver metabolises drugs and hormones in two phases. Phase 1 primarily involves oxidation and
reduction reactions that occur in the smooth ER of hepatocytes and are catalysed by cytochrome
P450 enzymes that serve to make the compound more polar (sometimes can be more toxic and
active). Phase 2 reactions involves conjugation to make the compound water-soluble (e.g. glucuronyl
(most importantly), acetyl, methyl, glycyl, sulphate and glutamate). Not all drugs use both phases of
reactions however, most follow the sequence of phase 1 followed by phase 2 reactions.

27
Q

What happens to conjugated compounds

A

The
conjugated compounds are then eliminated into the blood or bile via ATP pumps in what is
sometimes referred to as phase 3.

28
Q

How is paracetamol metabolised

A

Paracetamol can be metabolised via 3 pathways; glucuronidation (45-55%),
sulfation (20-30%) and N-hydroxylation and dehydration. Both glucuronidation and sulfation are
phase 2 reactions that occur without phase 1 reactions under normal circumstances (no overdose).
The third mechanism utilises phase 1 and phase 2 reactions. The phase 1 reaction involves N-
hydroxylation and rearrangement to produce the toxic NAPQI intermediate. This is then detoxified by
glutathione detoxification in the phase 2 reaction.

29
Q

What happens in paracetamol overdose

A

In paracetamol overdose, the liver enzymes
involved in these reactions are quickly saturated and glutathione stores are depleted. This leads to a
build-up of the toxic NAPQI that leads to toxic reaction with proteins and nucleic acids that causes
liver necrosis and kidney damage. The damage however is not immediate meaning treatment via
infusion of the precursor to glutathione, N-acetyl cysteine, can be effective at preventing the
negative consequences of overdose.

30
Q

How is ethanol metabolized

A

Another example of a drug that is metabolised is ethanol. Ethanol cannot be stored and can only be
metabolised in the liver where it is oxidised (only liver enzymes able to oxidise ethanol). Alcohol
dehydrogenase catalyses the conversion of ethanol to acetaldehyde in the presence of NAD+ that is
itself reduced to NADH.

31
Q

What pathways is NADH used in

A

The NADH can then be used in other metabolic processes. The conversion of
pyruvic acid to lactic acid is one of these reactions with the build-up of lactic acid leading to acidosis.
This pyruvic acid is intended for conversion into glucose by gluconeogenesis so the lack of it can
result in hypoglycaemia. NADH is also a reducing agent in two pathways involved in lipogenesis (one
in the synthesis of glycerol and the other in the synthesis of fatty acids) meaning drinking ethanol can
lead to one becoming overweight. The NADH may also be used directly in the ETC to synthesise ATP
and this has the effect of reducing fatty acid oxidation. This results in fat accumulation, as well as
acetyl coA accumulation that are then converted to ketone bodies that build up.

32
Q

How can the accumulation of fats in the liver be alleviated

A

The accumulation of
fats in the liver can be alleviated by release into circulation, however, this has the effect of causing
circulatory problems including increasing the risk of heart attack.

33
Q

Why is acetyladehyde a problem and how is it converted

A

Excess acetaldehyde itself is also
toxic to the liver leading to hepatitis and cirrhosis. Acetaldehyde is converted to acetate by
acetaldehyde dehydrogenase in a phase 1 reaction with acetate then released harmlessly into
circulation. 50% of Asians however have a deficiency in acetaldehyde dehydrogenase meaning they
experience alcohol flush at much lower levels than Caucasians. The flush itself is caused by the
accumulation of acetaldehyde.

34
Q

What is the overall consequences of alcoholism

A

Alcoholic liver disease occurs after prolonged heavy drinking (typically over 10 years). Alcohol causes
fatty liver, alcoholic hepatitis (inflammation of the liver) and alcoholic cirrhosis where liver cells are
damaged and replaced by scar tissue. The initial consequences of alcohol consumption are the
formation of a fatty liver. This is where fat deposits cause an enlarged liver with strict abstinence
leading to full recovery. Sustained exposure to alcohol can cause the liver to become fibrotic where
recovery is possible however scar tissue will remain.

35
Q

What happens in cirrhosis

A

In cirrhosis, growth of connective tissue occurs

that destroys liver cells and this damage is irreversible and transplant is needed.

36
Q

What is the liver also responsible for the synthesis of f……

A

The liver is also responsible for coagulation factor synthesis. Blood clotting factors include fibrinogen,
prothrombin as well as nearly all the other factors (e.g. V, VI, IX, X, XII) are affected. In severe liver
disease, excessive bleeding may occur due to a lack of these factors. Hepatocytes are also important
sites of storage with stellate cells important depots for fat-soluble vitamins D, K, E and A. Liver
dysfunction can lead to malabsorption of fat which leads to vitamin deficiency. There are enough
vitamin B12 stores in the liver to last 2-3 years however, deficiency of vitamin B12 is associated with
pernicious anaemia. The liver also stores folate that is required in early pregnancy as well as iron as
ferritin to be released when needed. Deficiency of both these substances occurs during liver
dysfunction.