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Phase 2 - Week 2 - GI > Bilirubin Metabolism > Flashcards

Bilirubin Metabolism Flashcards

1
Q

How is the onsent of bilirubin production commenced?

A
  • Based on the breakdown of red blood cells
  • Red blood cells have a lifespan of 120 days - as part of his
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2
Q

State the components of bile as refresher

A
  • Bile salts
  • Bile pigments (main one is bilirubin)
  • Cholesterol
  • Phospholipids
  • Water
  • Bicarbonate
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3
Q

Bile pige pigments are broken down from hemoglobin-derived haem in the ???????? of the ????????? in the ?????????????/?????/??????

A
  • Bile pigments are broken down from the hemoglobin derived heme in the macrophages of the reticulo-endothelial system in the spleen/bone marrow liver

The reticuloendothelial system consists of the various cells of the body that primarily function to remove dead or abnormal cells, tissues, and foreign substances.

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4
Q

Outline the metabolism of bilirubin to the point where it is ready to leave the liver.

A
  • RBCs breakdown - release their hemoglobin
  • Macrophages from the reticuloendothelial sytstem phagocystose the hemoglobin throughout the body
    • The Hemoglobin is split into globin and heme, and the heme ring is converted to Biliverdin*** by the enzyme ***Haem Oxygenase
    • This Biliverdin is rapidly reduced to form Unconjugated bilirubinwhich isgradually relesed form macrophages into the plasma
    • This unconjugated bilirubin rapidly combines with Albumin to make it soluble to allow transport it around the blood
    • This albunin-unconjugated blilirubin is absorbed into the liver, where it is released from plamsa albumin
    • Here, the liver is conjugated to form Bilirubin glucuronide and bilirubin sulfate - it is then excreted by the liver hepatocytes into the bile canaliculi and then into the intestines
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5
Q

What happens to the haem component from hemoglobin?

A

Broken down into amino acids

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6
Q

What enzyme convets biliverdin to uncojugated bilirubin?

A

Biliverdin reductase

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7
Q

What transport allows albumin-bound unconjugated bilirubin to enter hepatcytes from the blood (i.e. from the sinusoids)

A

Sinusodial Bilirubin transporters

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8
Q

What enzyme catalyzes the conversion of uncojugated bilirubin to conjugated bilirubin? What are the two forms of this particular conjugated bilirubin?

A
  • Conjugated with glucuronic acid by the enzyme UDP Glucuronyltransferase making it once again soluble
  • Bilirubin mono-glucorinide or Bilirubin diglucorinide
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9
Q

Conjugated bilirubin undergoes further metabolism. Outline this

A
  • Conjugated bilirbun in the small intestine is converted back to unconjugated bilirubin by Beta-Glucoronidase
    • ​Unconjugated bilirbun is then modified by the intestinal bacteria to form one of the 3 urobilinogen isomers by hydrlysis - UROBILINOGENS SEEMS TO BE THE TERM USED rather than fannying about with one of the 3 isomer namesMesobilinogen (less important) and Stercobilinogen
    • Urobilinogens then have one of two fates; it can be converted to stercobilin and excreted as poo (approximatelty 90% of urobilinogens)
      • Some amount of Urobilinogen (the other 10%) is NOT converted but is instead reabsorbed and returned to the liver and recycled for bile (5%), whilst the rest is returned to the liver before being transported to the kidneys (5%) and when it is passed into the urine it is oxidised to form Urobillin.

Note that urobilinogen, stercobilinogen and mesobilinogens seem to have lots of cross play but for the basic understanding it’s best to just refer to them collectively as urobilinogens. :)

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10
Q

This has been covered in another card, but remember that conjugated bilirubin will converted by the small intestinal bacteria to urobilinogen, stercobilinogen and mesobilinogen. What are the possible fates of urobilinogen?

A
  1. Excreted in fecaes
  2. Reabsorbed into the blood and then filtered by kidneys into urine
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11
Q

BIle salts have both hydrophobic and hydrophillic regions. Bile salts aggregate together to form micelles The micelles are organised so that what layer is orientated in what specific way?

What process in the gut do micelles play a role in?

A
  • Hydrophillic regions are facing the aqeuous medium while the hydrphobic groups face each other to form a lipid core

Emulsification

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12
Q

State two of the main bile salts (bile acids)

A

Glychloic Acid

Taurochloic Acid

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13
Q

Explai the role of bile salts in fat digestion

A
  • Process occurs by coating large lipid droplets with bile salts

- This is able to break up the large lipid into droplets, thereby increasing the surface available for lipases to break down lipids

- The small lipid droplets are broken down by lipases

  • The bile salts then have another role in which they form micelles, which aid in the transportation of lipdds across the inestinal membrane
  • from here the intestinal cells synthesize new triglycerides from the monoglycerides and fatty acids - these triglycerides along with absorbed steroids, and fat-soluble vitamins are coated with proteins resulting complexes called chylomicrons

- Chylomicrons are then excreted into the interstitial fluid by exocityosis, where they then diffuse into the intestinal lacteals.

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14
Q

Summarise the neural and hormonal control of bile secretion.

A
  • Vagus nerve secreting Ach has a role in stimulating gall bladder contraction
  • CCK is the main stimulus, is produced when food bolus (in particular fat) is detected in the duodenum - CCK triggers gall bladder contraction as well as relaxation of the sphincter of Oddi
  • Secretin also has a much lesser role, which is produced by the duodenum in response to chyme - increases bile secretion as well as reducing gastric motility
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15
Q

Bile salts are not produced in high enough quantites for a single meal, so will have to be recycled. This achieved by the “enterhepatic circulation”. Explain how this works

A
  • vast majority of bile salts (95%) of are re-absorbed in the terminal ileum, rest are excreted
  • Travel thourgh hepatic portal vein and go back to the liver where they are taken up into hepaocytes , where they are re-packaged
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16
Q

Hyperbilirubinaemia means what?

A

Too much bilirubin in the blood

17
Q

Normal levels of total and conjugated bilirubin

A

Total = <21umol/L

Conjugated = <7mol/L

18
Q

Total biliruin <30umol/L: jaundice may be visible in the sclera

Total bilirubin > 100umol/L : jaundice may be visible in the skin

A
19
Q

Pre-hepatic jaundice is when there is an upstream pathology that is affecting the liver’s ability to regulate bilirubin metabolism. One condition that pre-hepatic jaundice is a complication of is ???????. The liver is unable to cope with the high levels of ???????????. What diseases/drugs might be responsible for pre-hepatic jaundice?

A
  • Elevated haemolysis - more RBC breakdown, more haemoglobin and thus more bilirubin produced - presumably uptake is impaired
  • unconjugated bilirubin - going to be much higher as a result - you would probably expected conjugated bilirubin to be higher too
  • Yellow Fever, Malaria, side effect of qunine based anti-malarial drugs
20
Q

Another type of pre-hepatic jaundice is Physiological jaundice of the newborn. - This is a physiological jaundice and not pathology. Explain why this occurs.

A
  • After birth, new-borns must destroy fetal haemoglobin and replace with adult haemoglobin,
  • At this stage Liver is not capable of producing significant amounts of UDP glucuronyltransferase, and is not able to cope with the elevated haemolysis
    • Furthermore, if the baby is being breast feed, there are inhibitors of bilirubin conjugation, which can further contribute to build up of unconjugated bilirubin,
  • Bilirubin peaks at 3-5 days and lasts for less than 14 days
    • ​Phototherapy can be used to treat, blue light changes unconjugated bilirubin to a water-soluble form that can be excreted.
21
Q

Another cause of neonatal jaundice is Haemolytic disease of the newborn. Outline this

A
  • In addition to blood groups, you have Rhesus D (Rh), which as antigen that can be present on the surface of red blood cells.
  • triggered by Rhesus negative mother being sensitized to the rhesus antigen by a previous pregnancy that was Rhesus positive
    • As such, maternal antibodies can attack the babies red blood cells, causing mass hemolysis - this causes very high levels of bilirubin in newborn
    • Also puts the baby at risk of Kernicterus - which is when bilirubin crosses the immature blood brain barrier, which can result in deposition of bilirubin in the basal ganglia and brainsteam nuclei and can result in brain damage.
    • Treatment is photheray and blood transfusion
22
Q

Hepatic jaundice is jaundice caused by problems with liver itself. State causes of hepatic jaundice

A
  • impaired uptake of conjugated bilirubin
  • impaired conjugation of bilirubin - GIlberts disease, which is where the is rduced UDP glucuronyltransferase activity)
  • Impaired transport of CB into bile canaliculi - can happen in primary biliary cholangitis - autoimmune destruction of small bile ducts
  • Can also be in many conditions that cause liver damage and result in cholestasis due to sweling and oedema
    • Cirrhosis
    • viral hepatitis
    • Hepatotoxic drugs
23
Q

How would you expect bilirubin levels to be in Hepatic jaundice?

A
  • Depends on the clinical presentation
  • Conjugated and unconjugated both up generally,
    • More UCB if conjugation is impaired
    • Increased CB if not not being excreted effeciently (inflammation, impaired transport to canaliculi)
      • You would also potentially find conjugated bilirunin in urine for the same reasons
24
Q

Post-hepatic jaundice is a jaundice caused by obstruction of the hepatic, cystic or common bile duct. Bile release is impaired. Give examples of conditions that cause this

A
  • NB that bile is not being released into the small intestine = Cholestasis
  • Gallstones - small pebbles made of cholesterol that can end up in the ducts
  • Pancreatitis - acute or chronic inflammation of the pancreas following infection or damage - swelling blocks bile flow
  • Pancreatic tumours - tumour growth can block bile flow - particulary tumours in the head of the pancreas.
25
Q

Gallstones can cause post-hepatic jaundice in a variety of ways. Summarise some of the main places blockages and accompanying symptoms.

A
  • Cystic bile duct - strong pain
  • COmmon Bile duct
    • No bile secretion to the gut
    • Steaorrhea
    • Grey faceas (as no bile pigments, stercobillin)
    • Post-hepatic jaundice)
  • Duodenal papilla
    • No bile or pancreatic secretion
    • Malnutrition
    • Acute pancreatitis
26
Q

What levels of bilirubin would you expect in pre-hepatic jaundice?

A
  • conjugated up a lot, since it is spilling intot the blodo
    • SOme of this will also end up in the urine via the kidneys, causing dark urine
    • Since Conjugated bilirubin is not entering the GI tract, you would not expect to see urobilinogen
    • You would also not expect to strecobilinogen
27
Q

What vitamins require bile salts for efficient digestion and absorption?

A
  • A,D,E and K
28
Q

Vitamin K required for efficient coagulation. What enzyme is it a cofactor for? What coagulation factors is it required for?

A
  • gamma glutamyl carboxylase
  • 2,7,9 and 10
29
Q

Explain the mechanism by which conjugated bilirubin ends up in the blood

A

A rise in intrabiliary pressures as a result of intra-/extrahepatic obstruction to bile flow will eventually overcome the resistance of tight junctions between the apical ends of hepatocytes, which is the only barrier that normally prevents bile from mixing with blood. If this happens, conjugated bilirubin will appear in the bloodstream. Furthermore, the conjugated hyper- bilirubinemiaofobstructivejaundiceisaccompaniedbyraised blood levels of alkaline phosphatase (2), an enzyme from bile duct epithelial cells, indicating that the above explanation is correct.

30
Q

Summary of pre-hepatic jaundice

Points of note:

  • unconjugated bilirubin up quite a bit, also conjugated but not as much
  • You will see more urobilinogen in intestine, more stercobillin in faeces
  • Urobillin will be slightly up
  • You wont see any conjugated bilirubin in urine because it is not water soluble
A
31
Q

Summary of hepatic jaundice

Points of note

Both conjugated and unconjugated up - but what proportion depends on the abnormality

Cnjugated bilirubin in urine, increased urobilin

A
32
Q

Summary of post-hepatic jaundice

Notes:

  • lots of conjuated bilirubin
  • Urobilinogen and sterobilin both down since bile pigments not getting down to the intestine
  • urobillin down as well, conjugated bilirubin
A
33
Q

SUmmary of key changes in jaundice

A
  • note that you would require other tests for strong diagnosis, liver function tests and blood tests
34
Q

There are tests that allow measurement of bile pigments of serum. One reagent is Diazo reagent.

Outline the process for measuring Conjugated Bilirubin.

Outline the process for Total bilirubin.

A
  • add diazo reagent to serum
  • conjugated bilirubin converted to blue/purple diazo derivatve of bilirubin Azobilirubin
  • Measurement of absorbance @530-545nm and number produced is proportional to conjugated bilirubin
  • Compare to known standards to caclulate concentration
  • Add diazo with caffeine to serum
  • Caffeine displaces unconjugated bilirubin from albumin - allowing the unconjugated albumin to act with Diazo reagent, forming Azobilirubin
  • Measure as before to get conjugated and unconjugated
  • Comapre to standards as before
35
Q

You can measure bile pigments in urine - ideally measure using a photomertic reader.

A
36
Q

How does a urine strip work for bilirubin

A
  • Test area impregnated with diazide that forms a tan colour in presence of excess conjugated bilirubn
    • This will not test for unconjugated as that is not water soluble
    • Conjugated will be in very low amounts in healthy patient
    • hyperbilirubinuria is always pathological as it means conjugated bilirubin has leaked back into the blood stream
37
Q

How does a urine strip work urobilinogen

A
  • test area impgrenated with p-dimethylaminobenaldehyde - forms a pink dye in the presence of urobilinogen
  • normall present in low cocentrations, low concentrations can indidate increase hemolysis or liver disease (pre-hepatic or hepatic jaundice)
  • Absence of raised urobilinogen in a jaundiced patient can indictate biliary obstruction
38
Q

Blood gas analysers can also be used to check bilirubin levels and can provide results in 2 hours - can have results in 2 hours

A
39
Q

Trancutaneous measurements can also be made

A

Phase 2 - Week 2 - GI (8 decks)

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