Bilirubin Metabolism & Types of Jaundice

Question 1

Where does bilirubin come from?

Answer 1

• every haem molecule produces one molecule of bilirubin
• haem molecules are found in haemoglobin and myoglobin
• cytochrome enzymes also produce one molecule of bilirubin

Question 2

Where does production of bilirubin mostly take place?

What is the name of the cells that perform this function?

Answer 2

• 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

Question 3

What is the purpose of the reticuloendothelial system?

What are the 2 main cellular components?

Answer 3

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

Question 5

What happens once bilirubin-forming molecules are taken up by reticuloendothelial cells?

Answer 5

• 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

Question 6

What is the main difference in properties of bilirubin and biliverdin?

Answer 6

biliverdin is very water soluble, whilst bilirubin is not

Question 7

What test can determine how much haem is being turned into biliverdin?

Answer 7

the detection of carbon monoxide in breath

this can be used to determine how much haem is being turned into biliverdin

Question 8

What happens to biliverdin whilst within the reticuloendothelial cells?

Answer 8

whilst still in the reticuloendothelial cell, biliverdin is converted to bilirubin

this is performed by biliverdin reductase

Question 9

What is a benefit of not directly secreting biliverdin, but converting it to bilirubin first?

Answer 9

bilirubin is not just a waste product

it takes up free radicals and acts as an antioxidant

Question 10

What happens to bilirubin after it is released from reticuloendothelial cells?

What happens if there are very high concentrations of bilirubin?

Answer 10

• 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

Question 11

How is bilirubin removed from circulation?

Is this passive or active?

Answer 11

• 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

Question 12

What happens to bilirubin as soon as it enters the hepatocyte?

Answer 12

• 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

Question 13

What is the benefit of conjugating bilirubin when it is secreted?

Answer 13

it requires energy to secrete conjugated bilirubin into the canniculi

the process of conjugation makes the bilirubin water soluble and easier to excrete

Question 14

What happens in situations where the liver cannot excrete conjugated bilirubin?

Answer 14

• 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

Question 17

What happens to bilirubin that is deconjugated by bacteria in the gut?

What makes this process more likely to occur?

Answer 17

• 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)

Question 18

When does bile acid malabsorption occur?

What compensatory mechanism is in place in these patients and what is the associated increased risk?

Answer 18

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

Question 19

How does fasting affect the amount of bilirubin that is reabsorbed?

Answer 19

more bilirubin is reabsorbed during fasting

this also increases the risk of gallstones

Question 20

What is bilirubin in the colon turned into?

Answer 20

much of the bilirubin in the colon is turned into stercobilogens and urobilogens

urobilogens are colourless

stercobilogens give faeces its colour

Question 21

What happens to urobilogens that enter the circulation?

Answer 21

• 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

Question 22

Why is bile green in colour?

Answer 22

bilirubin oxidises back to biliverdin after excretion

this leads to the green colour of bile

Question 23

What are the 4 stages of bilirubin metabolism and the enzymes involved?

Answer 23

haem

converted to biliverdin by haem oxygenase

converted to bilirubin by biliverdin reductase

converted to conjugated bilirubin by glucoronyl transferase

Question 24

What is jaundice? What is normal bilirubin level?

Answer 24

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**

Question 25

What type of disease does jaundice indicate? What level does bilirubin have to reach before jaundice is visible?

Answer 25

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**

Question 26

Where is jaundice usually first visible? What becomes darker and what is not affected?

Answer 26

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_**

Question 27

What can occasionally mimic jaundice and how can these be told apart?

Answer 27

**_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

Question 28

What is another name for haemolytic jaundice? What causes it?

Answer 28

**_pre-hepatic jaundice_** this results from **_excessive RBC_** (or their precursors in the bone marrow) **_breakdown_**

Question 29

Why does it take a long time for pre-hepatic (haemolytic) jaundice to show up? Why do babies often appear jaundiced shortly after birth?

Answer 29

* 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

Question 30

How are stools and urine affected in haemolytic jaundice?

Answer 30

* stools are **dark** (although probably not noticeably different from normal) * urine will be **dark if left to stand** this is due to **increased urobilinogens** as a result of increased amounts of bilirubin urine is initially a normal colour, but as the **urobilinogen oxidises to urobilin**, it becomes darker in colour

Question 31

What other symptoms may accompany haemolytic jaundice?

Answer 31

* **pallor** due to anaemia * **splenomegaly** as a result of increased reticuloendothelial activity

Question 32

What do blood tests and LFTs show in haemolytic jaundice? What is plasma bilirubin?

Answer 32

* LFTs are **normal** * FBC may show evidence of **haemolytic anaemia** * plasma bilirubin is usually about **100 umol/L**

Question 33

Is there bilirubinuria in haemolytic anaemia? Why?

Answer 33

there is no bilirubinuria are the excess bilirubin is mainly unconjugated

Question 34

What are the most common causes of haemolytic anaemia?

Answer 34

the most common causes are **_sickle cell anaemia_** and **_thalassaemia_** some drugs can also cause this - **sulfasalazine** and **methyldopa**

Question 35

What is the prognosis like in haemolytic anaemia?

Answer 35

it has **excellent prognosis** and normally requires **no treatment** it is only important as it can be mistaken for serious liver disease

Question 36

What causes hepatocellular jaundice?

Answer 36

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

Question 37

What can exaggerate the effect of hepatocellular jaundice?

Answer 37

the **swelling of the cells** and **oedema** caused by the disease may exaggerate the effect

Question 38

How do levels of bilirubin change in hepatocellular jaundice?

Answer 38

levels of both **_conjugated_** and **_unconjugated_** bilirubin increase

Question 39

What are the main causes of hepatocellular jaundice?

Answer 39

the main causes are **_cirrhosis_** and **_hepatitis_** it can also be caused by **drug-induced liver injury** **_paracetamol_** and **_halothane_** are the 2 main causes of drug-induced hepatitis

Question 40

What is meant by cholestatic jaundice?

Answer 40

jaundice resulting from an **_obstruction in the bile duct_** the liver is able to **conjugate** the bilirubin but **_not able to excrete it_**

Question 41

What are the causes of cholestatic jaundice?

Answer 41

* primary biliary cirrhosis * primary sclerosing cholangitis * alcohol and drugs * viral hepatitis / autoimmune hepatitis * cystic fibrosis * severe bacterial infections * post-operative complications * hodgkin lymphoma * pregnancy

Question 42

What are the different investigations and their order involved in cholestatic jaundice?

Answer 42

* an **_ultrasound_** is done to identify whether there is an **obstruction in the biliary tree** * a dilated biliary tree may be seen * **_ERCP_** would then be done to get a better image and carry out therapy * if ERCP is unsuccessful, **_surgery_** is considered

Question 43

What should be done in cholestatic jaundice if the cause is not in the biliary tree (cannot see anything on ultrasound)?

Answer 43

if the cause isn't in the biliary tree, then a test should be done for **_hep A, B and C_** **copper levels** should be checked if the patient is under 40 as they could have **_Wilson's disease_**

Question 44

What should be done if a patient has cholestatic jaundice and intrahepatic masses are seen on ultrasound?

Answer 44

this warrants a test for **_fetoprotein_** and **other tumour markers**

Question 45

What does familial hyperbilirubinaemia result from? What syndrome is it thought to be related to?

Answer 45

it results from mutations to genes coding for **_UDP-glucuronyl transferase_** there are **varying degrees of unconjugated bilirubin** depending on the gene variant it is thought that this may be related to **_Gilbert's syndrome_**