GB 18. Bile and Jaundice Flashcards by Jennita Ariaratnam

Where is bile synthesized and stored?

bile is synthesized in the liver
bile is stored in the gall bladder
bile can be released from both liver and gall bladder

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What is the function of Cholescytokinin (CCK)?

It stimulates the gall bladder to contract and release the stored bile into the intestine

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What are the primary functions of bile? [2]

[1] Excretory

[2] Digestive

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What is bile synthesized in the liver and gall bladder primarily made up of?

mainly made of water

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What is the excretory function of bile? What are the principal excretory products?

Goal: it provides an excretory route for many substances

Principal Excretory Products include….

bile pigments (degradation of haem)
cholesterol
bile acids/salt
drugs + their metabolites
particulate matter (removed from blood stream by Kupffer Cells of Liver)

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What is the digestive function of bile? What mechanisms does this work by?

Goal: digests biomolecules (particularly fats)

Mechanisms:
- Alkaline Secretion
( rich in bicarbonate pH 8.0 )
( neutralizes acidity of gastric content )

Bile Salts + Phospholipids emulsify fats into small droplets
Bile Salts activate pancreatic hydrolase precursors

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How do you create a bile acid?

cholesterol is conjugated with glycine and taurine

- there are primary and secondary bile acids

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Where is a primary bile acid created? What are some examples?

created in liver

cholic acid
chenodeoxycholic acid

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Where is a secondary bile acid created? What are some examples?

created in gut (through bacterial alpha-hydroxylase)

deoxycholic acid
lithocholic acid

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How is a bile salt created?

conjugated bile acid + (Na+) + (K+)

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What is bilirubin? Where can bilirubin be created (2 categories)?

a natural degradation product of haem in erythrocytes

75% of bilirubin in the body is derived from RBCs
process requires phagocytosis and/or lysis of senescent RBCs

bilirubin can be created..

intravascular
extravascular

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Hemolysis can either be…

[1] Intravascular

[2] Extravascular

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Explain the process of extravascular hemolysis and formation of bilirubin.

haemoglobin of RBCs split into (a) globin and (b) haem
haem is then split into (a) Fe2+ and (b) bilirubin
the bilirubin is then excreted

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What is the difference between intravascular and extravascular hemolysis?

Intravascular Hemolysis: RBCs that are lysed in the blood stream and release haem into the blood circulation

Extravascular Hemolysis: RBCs are lysed in the spleen (or by spherocytes)

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What are the main mechanisms behind the handling of free (intra-vascular) haemoglobin? (the 3 complexes)

[1] Haptoglobin

haptoglobin binds to free haemoglobin
haemoglobin-haptoglobin complex metabolized in liver + spleen
forms iron-globin complex and bilirubin
PREVENTS LOSS OF IRON IN URINE

[2] Haemopexin

binds free haem
haem-hemopexin complex taken up by liver
iron stored bound to ferritin

[3] Methaemalbumin
- complex of oxidized haem and albumin

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What is the main function of the haptoglobin-haemoglobin complex?

it prevents loss of iron in urine

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What are the main goals of andling free intra-vascular haemoglobin? [3]

[1] scavenge iron
[2] prevents major iron losses
[3] complex free haem (very toxic)

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List the steps involved in haem degradation and processing. (starting from haem)

[1] Haem
[2] Bilirubin Formation
[3] Albumin transports Unconjugated Bilirubin in the Bloodstream
[4] Taken up by Liver
[5] Bilurubin Conjugated with Glucoronic Acid (for water solubility)
[6] Excreted into Bile
[7] Urobilinogens Formed in Intestinal Tract
(a) re-absorbed: excreted from kidney as urinary urobilin
(b) excreted as faecal stercobilin

What are the 2 fates that urobilinogens may undergo?

[1] re-absorbed: excreted from kidney as urinary urobilin

[2] excreted as faecal stercobilin

What is Urobilinogen? How is it created?

is a colorless by-product of bilirubin reduction

- formed in the intestines by bacterial action on bilirubin

What are the steps (+ enzymes) involved with the degradation of haem to bilirubin?

[1] Haem
[2] Heme Oxygenase Enzyme converts Haem to BILIVERDIN
[3] Biliverdin - intermediate
[4] Biliverdin Reductase Enzyme converts Biliverdin to UNCONJUGATED BILIRUBIN

Explain the steps involved in the metabolism of bilirubin. (slides 16 + 17)

[1] liver takes up bilirubin by carrier-mediated facilitated diffusion (high binding capacity)

[2] binds to cytoplasmic proteins (ligand - glutathione S-transferases + protein Y)
- prevents efflux back into the blood

[3] bilirubin conjugated with glucoronic acid

catalysed by UDP-glucoronyl transferase
UDP-glucoronoosyltransferase
makes bilirubin water-soluble

[4] conjugated bilirubin secreted into biliary tree

active transport via Multidrug Resistant-Like Protein MRP-3)
RATE LIMITING STEP

[5] bile excreted from liver into gut
- glucoronidases in intestinal flora de-conjugate bilirubin

[6] some fat-soluble bilirubin is absorbed

[7] most bilirubin oxidized to urobilinogens

(a) colourless urobilinogen metabolised to brown stercobilin + excreted in faeces
(b) some re-absorbed urobilinogen oxidised to yellow urobilin + excreted by kidney

What is the rate-limiting step in the metabolism of bilirubin?

the conjugated bilirubin being secreted into the biliary tree
active transport via Multidrug Resistant-like Protein MRP-3

What is Icterus?

Jaundice

Why does Jaundice arise? What is normally the upper limit? When number value does jaundice arise at?

Hyperbilirubinemia - normal upper limit for plasma [bilirubin] = 17umol/L - arises when patient has plasma [bilirubin] of approx. 35 umol/L

What are the external signs of icterus?

- yellow discolouration of skin and sclera

What are the 3 classifications of jaundice? Give a brief overview of each.

[1] Pre-Hepatic Jaundice - bilirubin production exceeds uptake capacity of liver [2] Intra-Hepatic Jaundice - bilirubin cannot be taken up, conjugated and/or excreted because hepatocytes somehow damaged - e.g. liver damage (cirrhosis) [3] Post-Hepatic Jaundice - obstruction to biliary flow - conjugated bilirubin "regurgitated" back into systemic circulation - e.g cancer of head of pancreas

What are some other names for pre-hepatic jaundice?

- haemolytic jaundice | - hematogenous jaundice

What are some causes of pre-hepatic jaundice?

- excess RBC lysis due to autoimmune disease (e.g. haemolytic disease of newborn, structural abnormal RBCs [sickle cell anaemia]...) - excess production of bilirubin following haemolysis

What are some other names for intra-hepatic jaundice?

- hepatic jaundice | - hepatocellular jaundice

What are some causes of intra-hepatic jaundice?

- impaired uptake, conjugation or secretion of bilirubin - reflects generalized liver cell (hepatocyte) dysfunction - hyperbilirubinaemia usually accompanied by other abnormal biochemical markers of liver function - -- ELEVATED AST OR ALT

What are some other names for post-hepatic jaundice?

- obstructive jaundice | - choleostatic jaundice

What are some of the causes of post-hepatic jaundice?

- obstruction to biliary tract - plasma bilirubin conjugated - -- other biliary metabolites (such as bile acids) accumulate in the plasma

What is post-hepatic jaundice characterized by?

- pale stools (absence of faecal bilirubin or stercobilin) | - dark urine (increased conjugated bilirubin)

In complete obstruction of the biliary tract, what happens (in the case of post-hepatic jaundice)?

urobilin absent from urine

What causes Newborn Jaundice? List some of the causes as well

- unconjugated hyperbilirubinaemia - due to immaturity of enzymes involved in bilirubin conjugation Causes: - immature/impaired hepatic uptake/conjugation of bilirubin - RBC destruction

What is a *major* complication that may arise in Newborn Jaundice?

- the free (unbound) unconjugated bilirubin may be deposited in the brain - can cause Kernicterus (rare form of brain damage)

What is Kernicterus?

- rare form of brain damage | - can arise when free (unbound) unconjugated bilirubin may be deposited in the brain

What are some aggravating factors of Newborn Jaundice?

- haemolysis - sulphonamides (displaces bilirubin from albumin) - Novobiocin - inhibits glucoronyltransferase

What are some treatments for Newborn Jaundice?

- Phototheraphy (UV Light) converts bilirubin to water-soluble, non-toxic form - exchange blood transfusion to remove excess bilirubin - Maternal Phenobarbitone prior to induction of labour of premature infant - -- crosses placenta and induces synthesis of UDP-glucoronyl transferase [UDP-glucoronosyltransferase]

What is Gilbert's Syndrome? What is a possible treatment?

- characterized by mild, fluctuating UNCONJUGATED HYPERBILIRUBINEMIA (often correlated with fasting or illness) - 50% of cases are inherited (mainly males than females) - caused by.... - -- reduced activity of UDP-glucoronyl transferase (UDP-glucoronosyltransferase) - -- defect in bilirubin uptake Treatment: - treated with small doses of Phenobarbitone to stimulate UDP-glucoronyl transferase (UDP-glucoronosyltransferase) activity

What is Crigler-Najjar Syndrome? What are the treatments for it?

- autosomal recessive disorder presenting with UNCONJUGATED HYPERBILIRUBINEMIA - caused by mutation in gene coding for UDP-glucoronyl transferase - -- type I: complete absence - -- type II: marked reduction in enzyme activity - affected individuals at high risk for kernicterus Treatment: - Type I by Liver Transplant (by 5 years of age) - Type II with Phenobarbitone or Phototherapy (10-12 hours/day)

What is Dubin-Johnson and Rotor's Syndrome?

- benign autosomal recessive disorder presenting with CONJUGATED HYPERBILIRUBINEMIA - characterized by impaired biliary secretion of conjugated bilirubin (!) - mutation in gene coding for MRP-2 (Dubin-Johnson Syndrome)