Week 7/8 - A - Heme metabolism, Pre/Intra/Post hepatic Jaundice (signs/L.F.Ts), Gilbert's/Crigler-Najjar/Dubin-Johnson/Rotor

Question 1

What is the life span of a red blood cell? Where is it broken down?

Answer 1

When red blood cells complete their life span of approximately 120 days, or if they are damaged, they are broken down in the spleen One of these breakdown products is bilrubin

Question 2

How does red blood cell breakdown in the spleen end up forming bilirubin?

Answer 2

Red blood cells rupture as they enter the reticuloendothelial system allowing haemoglobin and other contents to enter circulation Macrophages breakdown haemoglobin into heme and globin The heme group is broken down by haemoxygenase to a prophyrin ring which is brokwn down to biliverdin Biliverdin is broken down by biliverdin reductase to form unconjugated BILIRUBIN

Question 3

The unconjugated bilirubin is not water soluble * What does it bind to in order to be transported to the liver? * What happens to it in the liver? * Where does the bilirubin go after the liver?

Answer 3

Unconjugated bilirubin binds to albumin to be transported to the liver Once unconjugated bilirubin arrives in the liver, a liver enzyme UDP-glucuronyl transferase conjugates bilirubin (adds glucoronic acid) Conjugated bilirubin is water-soluble and excreted into the gallbladder as bile

Question 4

After entering the gallbladder, the bile (containing bilirubin) is secreted into the 2nd part of the dudodenum to breakdown foods What happens to the bilirubin once entering the intestines? * What colour does the breakdown of bilirubin give stool? * What colour does the breakdown of bilirubin give urine?

Answer 4

* In the GI tract, bilirubin is converted into urobilinogen by intestinal bacteria. Most urobilinogen is converted into stercobilinogen and further oxidized into stercobilin. Stercobilin is excreted via feces, giving stool its characteristic brown colour. * A small portion of urobilinogen is reabsorbed back into the GI cells. Most reabsorbed urobilinogen undergoes hepatobiliary recirculation. * A smaller portion is filtrated into the kidneys. In the urine, urobilinogen is converted to urobilin, which gives urine its characteristic yellow color

Question 5

Disorders affecting bilirubin/heme metabolism can be classified as pre-hepatic, intra-hepatic or post-hepatic What is pre-hepatic jaundice? What type of bilirubin builds up in the blood stream?

Answer 5

* Pre-hepatic jaundice is where there is an excess production of bilirubin in the bloodstream (due to excess breakdown of heme) This causes a build up in the levels of unconjugated bilirubin as the UDP-glucoronyl transferase enzyme becomes saturated

Question 6

What is intra-hepatic jaundice? What type of bilirubin builds up in the boodstream?

Answer 6

In intrahepatic jaundice, there is dysfunction of the hepatic cells to take up, conjugate or excrete bilirubin * Hepatocyte defects, such as a compromised hepatocyte uptake of unconjugated bilirubin and/or defective conjugation may occur in liver disease, or deficiency of UDP-glucuronyl transferase. This leads to both unconjugated and conjugated bilirubin in the blood, termed a ‘mixed picture’.

Question 7

What is post-hepatic jaundice? What type of bilirubin builds up here?

Answer 7

Post-hepatic jaundice refers to obstruction of biliary drainage. The bilirubin that is not excreted will have been conjugated by the liver, hence the result is a conjugated hyperbilirubinaemia.

Question 8

A good estimation of which type of jaundice is present (prior to any further investigation) can be made from observing the colour of the urine. Conjugated bilirubin can be excreted via the urine (as it is water soluble), whereas unconjugated cannot. Therefore which type of jaundice would be seen if the * Urine was dark? * Urine was normal?

Answer 8

Dark urine - would imply that there is a conjugated hyperbilirubinaemia - intra hepatic or post hepatic jaundice Urine was normal - seen in unconjugated hyperbilirubinaemia (pre-hepatic jaundice)

Question 9

Why is it that in normal cases, conjugated bilirubin will enter the intestines, * be converted by intestinal bacteria into urinobilinogen * Some will be reasborbed and excreted by the kidneys * and give the urine a yellow colour However in conjugated hyperbilirubinaemia, when there is an obstruction preventing conjugated bilirubin entering the intestines, the urine will become even darker?

Answer 9

Most of the bilirubin in the plasma becomes the conjugated type rather than the unconjugated type * Excess conjugated bilirubin is filtrated into the urine without urobilinogen in obstructive jaundice. * Conjugated bilirubin in urine (bilirubinuria) gives urine an abnormally dark brown color

Question 10

What type of jaundice would be seen if the * Stool was pale * Stool was normal

Answer 10

Conjugated bilirubin gives the stool its normal brownish colour If the stool was pale, this would imply there no blirubin entering the intestine due to a blockage - conjugated hyperbilirubinaemia -> intrahepatic or obstructive jaundice If the stool was normal - bilirubin is normally entering the intestines -> unconjugated hyperbilirubinaemia -> pre-hepatic jaundice

Question 11

Most people presenting with jaundice will have various predictable patterns of liver panel abnormalities, State how the following tests would look for pre-hepatic jaundice * Total serum bilirubin * Conjugated bilurbin (direct) * Unconjugated bilirubin (indirect) * Urobilinogen * Urine colour * Stool colour * ALP * ALT/AST * Bilirubinruia (conjugated bilirubin in urine)

Answer 11

Pre-hepatic jaundice * Total serum bilirubin - normal/raised * Conjugated bilurbin (direct) - normal * Unconjugated bilirubin (indirect) - raised * Urobilinogen - normal/ increased (UDP-GT saturated) * Urine colour - normal * Stool colour - normal brown * ALP - normal * ALT/AST - normal * Bilirubinruia (conjugated bilirubin in urine) - none

Question 12

State how the following tests would look for intra-hepatic jaundice * Total serum bilirubin * Conjugated bilurbin (direct) * Unconjugated bilirubin (indirect) * Urobilinogen * Urine colour * Stool colour * ALP * ALT/AST * Bilirubinruia (conjugated bilirubin in urine)

Answer 12

* Total serum bilirubin - raised * Conjugated bilurbin (direct) - raised * Unconjugated bilirubin (indirect) - raised * Urobilinogen - decreased * Urine colour - dark * Stool colour - pale * ALP - may be slightly raised * ALT/AST - very raised * Bilirubinruia (conjugated bilirubin in urine) - raised

Question 13

State how the following tests would look for post-hepatic jaundice * Total serum bilirubin * Conjugated bilurbin (direct) * Unconjugated bilirubin (indirect) * Urobilinogen * Urine colour * Stool colour * ALP * ALT/AST * Bilirubinruia (conjugated bilirubin in urine)

Answer 13

* Total serum bilirubin - raised * Conjugated bilurbin (direct) - raised * Unconjugated bilirubin (indirect) - normal * Urobilinogen - decreased * Urine colour - dark * Stool colour - pale * ALP - very raised * ALT/AST - may be slightly raised * Bilirubinruia (conjugated bilirubin in urine) - raised

Question 14

CAUSES OF JAUNDICE What are the different causes of pre-hepatic jaundice?

Answer 14

Pre-hepatic jaundice is most commonly caused by a pathological increased rate of red blood cell (erythrocyte) hemolysis eg sickle cell anemia spherocytosis thalassemia pyruvate kinase deficiency glucose-6-phosphate dehydrogenase deficiency microangiopathic hemolytic anemia hemolytic-uremic syndrome severe malaria

Question 15

What are the different causes of intra-hepatic jaundice? - try to name 4 inherited conditions * 2 cause impaired conjugation of bilirubin * 2 cause failure to excrete conjugated bilirubin

Answer 15

* acute hepatitis, chronic hepatitis, hepatotoxicity * cirrhosis, drug-induced hepatitis, alcoholic liver disease Impaired conjugation of bilirubin * Gilbert’s syndrome * Crigler-Najjar syndrome Failure to excrete conjugated bilirubin * Dubin Johnson syndrome * Rotor syndrome

Question 16

What are the different causes of post hepatic jaundice?

Answer 16

Post-hepatic jaundice is caused by a blockage of bile ducts which transport bile containing conjugated bilirubin out of the liver for excretion. Examples of causes * Choledocholithiasis (common bile duct gallstones) * Pancreatic cancer of the pancreatic head * Biliary tract strictures * Biliary atresia * Primary biliary cholangitis * Cholestasis of pregnancy * Acute Pancreatitis and Chronic Pancreatitis * Pancreatic pseudocysts

Question 17

Why can it be dangerous to not treat increased levels of (unconjugated) bilirubin?

Answer 17

Unconjugated bilirubin can is able to cross the BBB When unconjugated bilirubin increases in the blood, this can cause damage to the brain resulting in a condition known as Kernceturs - bilirubin induced brain damage * This can cause hypoxia, lethargy, poor feeding, yellow staining of the brain * Long term - deafness, decreased IQ, cerebral palsy

Question 18

Let’s discuss the inherited disorders that can cause intrahepatic jaundice Impaired conjugation (unconjugated hyperbilirubinaemia) * Gilbert’s syndrome * Crigler-Najjar syndrome (Type 1 and 2) Failure to excrete conjugated bilirubin (conjugated hyperbilirubinaemia) * Dubin Johnson syndrome * Rotor syndrome What is the inheritance of all four (five if Crigler-Najarr counts as two) of these conditions?

Answer 18

Gilbert’s syndrome Crigler Najjar syndrome (type 1 and 2) Dubin Johnson syndrome Rotor syndrome These 5 conditions make up the five known hereditary defects in bilirubin metabolism and are all autosomal recessive in inheritance

Question 19

GILBERT’S SYNDROME What causes Gilbert’s syndrome?

Answer 19

Gilbert’s syndrome is due to a mutation in the UGT 1 (UDP-gluconryl transferase 1) enzyme acitivty causing a mild deficiency of this enzyme and therefore decreasing conjugation of bilirubin

Question 20

How does Gilbert’s syndrome present?

Answer 20

It can present with intermittent jaundice during illness, exercise or fasting but can go unnoticed for many years

Question 21

What is the usual treatment? What can be given if there is severely raised levels of jaundice?

Answer 21

No treatment required usually Phenobarbital can increase conjugation of bilirubin and excretion of bilirubin in severe unconjugated hyperbilirubinaemia cases

Question 22

Crigler-Najarr syndrome ( very rare in comparison to Gilbert’s syndrome) What is the difference in the two types of Crigler-Najjar syndrome?

Answer 22

Crigler-Najarr type 1 * Gene mutation in UDP-glucoronyl transferase causes an absolute deficiency of UDP - absent ability to conjugate and therefore excrete bilirubin Crigler-Najarr type 2 * Gene mutation in UDP-glcoronyl transferase impaires UDp - mild deficiency in ability to conjugate and excrete bilirubin * Less severe

Question 23

Crigler-Najarr type 1 typically has a terrible prognosis and causes severe neonatal jaundice What is the treatment? What is the treatment of Crigler-Najarr type 2?

Answer 23

Crigler Najarr-type1 treatment * Phototherapy and plasmapheresis to control jaundice * Liver transplant before irreversible kernicterus develops Crigler Najarr type 2 treattment * Usually no treatment needed * If severely raised bilirbin - can give phenobarbital

Question 24

Why can’t phenobarbital be given in Crigler-Najarr type 1?

Answer 24

In type 1, there is no UDP glucuronosyltransferase 1 expression that can be detected in the liver tissue. Hence, there is no response to treatment with phenobarbital,which inmproves conjugation of bilirubin by causing CYP450 enzyme induction.

Question 25

Dubin Johnson Syndrome and Rotor syndrome Which type of bilirubinaemia do these conditions cause and how? Which type causes a non-itching jaundice?

Answer 25

These conditions cause defective hepatocyte excretion of conjugated biirubin causing a conjugated hyperbilirubinaemia * Dubin Johnson affects the ability of the hepatocytes to excrete conjugated bilirubin * Rotor syndrome affects the ability of hepatocytes to store conjugated bilirbin that then leaks into plasma causing hyperbilirubinemia Rotor syndrome causes a non-itching jaundice whereas Dubin-Johnson syndrome is associated with itching

Question 26

Dubin Johnson syndrome and Rotor syndrome are very similar How can you differentiate between the two?

Answer 26

Both typically present in childhood/teens with mild jaundice Rotor syndrome causes non-itching jaundice On liver biopsy, dubin Johnson has a diagnostic pigmented liver (black) Rotor syndrome has normal liver appearance on histology Also can test for different gene mutations in the two

Question 27

What is the treatment of Dubin Johnson syndrome and Rotor syndrome?

Answer 27

Treatment is generally not needed Phenobarbital may be used if severe jaundice