Production of Bilirubin
- Bilirubin-forming molecules (i.e. haem) are taken up by reticuloendothelial cells.
- Inside these cells, Haem oxygenase enzymes break down the haem, removing iron (which is recycled) and carbon monoxide, leaving biliverdin. The detection of carbon monoxide in breath can be used to determine how much haem is being turned into biliverdin. Biliverdin is very water soluble, whilst bilirubin is not.
- Biliverdin is then converted to bilirubin, whilst still in the reticuloendothelial cell. This is done by the enzyme biliverdin reductase.
- Bilirubin is not just a waste product. It takes up free radicals, and thus is an antioxidant. This is perhaps the benefit of not directly secreting biliverdin, but converting it to bilirubin first.
- After bilirubin is released from reticuloendothelial cells, it travels in the blood, bound to albumin. This ensures no bilirubin is excreted in the urine. At very high concentrations, bilirubin can slowly diffuse into the peripheral tissues where it is toxic.
- Bilirubin is then removed from circulation in the sinusoids by hepatocytes. This is a passive process, which occurs down a concentration gradient. The fact that hepatocytes are in direct contact with the sinusoidal fluid helps this process.
- As soon as bilirubin enters the hepatocyte, it will become bound to glucuronyl transferase which conjugates the bilirubin ready for excretion. Bilirubin is joined with glucuronic acid in the conjugation process. Very small amounts of bilirubin will somehow evade this process and end up in bile as unconjugated bilirubin.
- It requires energy to secrete conjugated bilirubin into the canniculi.
- The process of conjugation makes the bilirubin water soluble, and thus easier to excrete.
Haemolytic Jaundice (pre-hepatic jaundice)
- This results from excessive RBC (or their precursors in bone marrow) breakdown. The liver is able to secrete 6x the normal amount of bilirubin before it becomes overwhelmed, and thus you have to have a serious amount of bilirubin before it will show up in this situation. However – newborn babies have a reduced ability to remove bilirubin, thus they often appear jaundiced shortly after birth.
- Stools are dark (although probably not noticeably different from normal)
- Urine will be dark if left to stand, due to increased urobillogens as a result of an increased amount of bilirubin. The urine will initially be ‘normal’ colour, but as the urobilinogen oxidise to urobilin, it becomes darker coloured.
- Pallor due to anaemia is usually present
- There is often splenomegaly as a result of increased reticuloendothelial activity.
- LFT’s are normal, plasma bilirubin is usually about 100 µmol/L
- There is no bilirubinuria because the excess bilirubin is mainly unconjugated.
- A full blood count may show evidence of haemolytic anaemia.
- The most common causes are sickle-cell anaemia and thalassemia. Some drugs are also known to cause this, such as sulfasalazine and methyldopa.
- The condition has an excellent prognosis, and normally requires no treatment. It is only really important because it can be mistaken for serious liver disease.
- This results from an inability of the liver to excrete and/or conjugate bilirubin, as a result of liver tissue damage. Bilirubin transport is impaired somewhere between the stages of unconjugated bilirubin uptake and conjugated bilirubin secretion into the calliculi.
- In addition to this, the swelling of the cells and oedema caused by the disease may exaggerate the effect.
- Levels of both conjugated and unconjugated bilirubin increase.
- Main causes are cirrhosis and hepatitis, and drug induced liver injury. Paracetamol and halothane are two main causes of drug induced hepatitis.
- This results from an obstruction in the bile duct. The liver is able to conjugate the bilirubin but not able to excrete it
- It will result in lots of conjugated bilirubin – causing very dark urine and pale stools.
- This condition has many causes, including:
- Basically, you should do an ultrasound, which would then tell you if there was an obstruction in the biliary tree (usually you would just see dilated biliary tree). Then, you would do ERCP to get a better image, and hopefully carry out therapy. If ERCP is unsuccessful, then you would consider surgery.
- If the cause isn’t in the biliary tree (i.e. you can’t see anything on ultrasound) then you should test for hep A, B and C, and also check for copper levels of the patient is under 40 – they may have Wilson’s disease.
- Intrahepatic masses on ultrasound will warrant a test for fetoprotein and other tumour markers.
- This can result from mutations to genes coding for UDP-glucuronyl transferase. There will be varying degrees of unconjugated bilirubin depending on the gene variant. It is thought that this may be related to Gilbert’s syndrome.
- There are also some drugs that seem to cause jaundice in some people, and it is thought that this again depends of genes variants.
- Crigler-Najjar syndrome – is a condition caused by a genetic inherited defect. It is very rare, and affects the metabolism of bilirubin. It is a cause of brain damage in infants. There is a lot of circulating unconjugated bilirubin. Type I is an autosomal dominant condition, where the infant will become progressively more jaundiced and brain damage (‘kernicterus’ – the term for this specific type of brain damage) may occur if it is not treated. Type II is recessive and will tend to cause persistent mild jaundice in young adults. It is not serious and will not cause brain damage – the effects are purely cosmetic. It is thought that type II Crigler-Najjar, and Gilbert’s are possibly the same disease – just that Crigler-Najjar is a more serious version.
- Type I – is treated either with liver transplantation, or with blue light therapy for 16 hours daily. The light oxidises bilirubin to water-soluble non-toxic products which are then excreted by the kidney and liver.
- This occurs to some extent in all newborns. The effect is worse in premature infants. It is thought to be due to a combination of two factors:
- Immaturity of glucuronyl transferase
- Rapid breakdown of foetal RBC’s that are no longer needed – foetal RBC’s need to have greater ability to attract oxygen as they have to dissociate the oxygen from the mothers blood into their own. Once a baby breathes real air, then they don’t need such strong ability to hold onto oxygen.