Where does bilirubin come from?
- every haem molecule produces one molecule of bilirubin
- haem molecules are found in haemoglobin and myoglobin
- cytochrome enzymes also produce one molecule of bilirubin
Where does production of bilirubin mostly take place?
What is the name of the cells that perform this function?
- production of bilirubin from haem mostly occurs in the spleen (by macrophages) and in the liver (by Kupfer cells)
- it also occurs by macrophages all over the body and in renal tubular cells
- the cells that perform this job are collectively known as the reticuloendothelial system
What is the purpose of the reticuloendothelial system?
What are the 2 main cellular components?
it is made up of Kuppfer cells in the liver and reticular cells in the bone marrow
the system defends the body against hazardous substances by phagocytosis
What happens once bilirubin-forming molecules are taken up by reticuloendothelial cells?
- bilirubin-forming molecules (i.e. haem) are taken up by reticuloendothelial cells
- inside these cells, haem oxygenase enzymes break down the haem
- iron (which is recycled) and carbon monoxide are removed
- this produces biliverdin
What is the main difference in properties of bilirubin and biliverdin?
biliverdin is very water soluble, whilst bilirubin is not
What test can determine how much haem is being turned into biliverdin?
the detection of carbon monoxide in breath
this can be used to determine how much haem is being turned into biliverdin
What happens to biliverdin whilst within the reticuloendothelial cells?
whilst still in the reticuloendothelial cell, biliverdin is converted to bilirubin
this is performed by biliverdin reductase
What is a benefit of not directly secreting biliverdin, but converting it to bilirubin first?
bilirubin is not just a waste product
it takes up free radicals and acts as an antioxidant
What happens to bilirubin after it is released from reticuloendothelial cells?
What happens if there are very high concentrations of bilirubin?
- it travels in the blood bound to albumin
- this ensures that no bilirubin is excreted in the urine
- at very high concentrations, bilirubin can slowly diffuse into the peripheral tissues where it is toxic
How is bilirubin removed from circulation?
Is this passive or active?
- bilirubin is removed from the circulation in the sinusoids by hepatocytes
- this is a passive process that occurs down a concentration gradient
- the fact that hepatocytes are in direct contact with the sinusoidal fluid helps this process
What happens to bilirubin as soon as it enters the hepatocyte?
- it becomes bound to glucuronyl transferase which conjugates bilirubin ready for excretion
- bilirubin is joined with glucuronic acid in the conjugation process
- very small amounts of bilirubin evade this process and end up in bile as unconjugated bilirubin
What is the benefit of conjugating bilirubin when it is secreted?
it requires energy to secrete conjugated bilirubin into the canniculi
the process of conjugation makes the bilirubin water soluble and easier to excrete
What happens in situations where the liver cannot excrete conjugated bilirubin?
- in situations where the liver cannot excrete conjugated bilirubin, the kidneys take over this job
- once plasma concentrations are high enough (above 600 umol/L) then the kidneys cannot conjugate bilirubin and can only excrete it after this process has occurred
What happens to bilirubin that is deconjugated by bacteria in the gut?
What makes this process more likely to occur?
- bilirubin that is deconjugated by bacteria in the gut will be reabsorbed in the colon
- this process is more likely in the presence of increased bile acids (i.e. bile acid malabsorption)
When does bile acid malabsorption occur?
What compensatory mechanism is in place in these patients and what is the associated increased risk?
bile acid malabsorption occurs in cases of intestinal disease and resection
in these patients, as a compensatory mechanism, the body excretes higher concentrations of bile salts
this increases the risk of gallstones
How does fasting affect the amount of bilirubin that is reabsorbed?
more bilirubin is reabsorbed during fasting
this also increases the risk of gallstones
What is bilirubin in the colon turned into?
much of the bilirubin in the colon is turned into stercobilogens and urobilogens
urobilogens are colourless
stercobilogens give faeces its colour
What happens to urobilogens that enter the circulation?
- some urobilogens are absorbed and enter the circulation, where they are removed mainly by the liver, but also by the kidney
- in liver disease and excessive haemolysis, the liver may not be able to remove all excess urobilogens and so more are removed by the kidney
Why is bile green in colour?
bilirubin oxidises back to biliverdin after excretion
this leads to the green colour of bile
What are the 4 stages of bilirubin metabolism and the enzymes involved?
converted to biliverdin by haem oxygenase
converted to bilirubin by biliverdin reductase
converted to conjugated bilirubin by glucoronyl transferase
What is jaundice?
What is normal bilirubin level?
a condition where there is yellowing of the skin, sclera and mucous membranes as a result of increased bilirubin concentration in bodily fluids
normal bilirubin level is 1 - 20 umol / L
What type of disease does jaundice indicate?
What level does bilirubin have to reach before jaundice is visible?
jaundice is the clinical sign of hyperbilirubinaemia that indicates the presence of disease of the liver or biliary tree
it is usually detectable when bilirubin concentrations reach 50 umol/L
Where is jaundice usually first visible?
What becomes darker and what is not affected?
jaundice is first visible in the sclera, and more subtly in the skin
urine is also likely to be dark
sputum and saliva are not affected
What can occasionally mimic jaundice and how can these be told apart?
carotenemia may mimic jaundice
this is usually caused by eating too many carrots or vitamin A
the yellowness is more visible in the palms than the sclera if this is the case
What is another name for haemolytic jaundice?
What causes it?
this results from excessive RBC (or their precursors in the bone marrow) breakdown
Why does it take a long time for pre-hepatic (haemolytic) jaundice to show up?
Why do babies often appear jaundiced shortly after birth?
- the liver is able to secrete 6x the normal amount of bilirubin before it becomes overwhelmed
- a very large amount of bilirubin is needed before jaundice will develop
- newborn babies have a reduced ability to remove bilirubin, so often appear jaundiced shortly after birth