WEEK 11 (Heme degradation) Flashcards
What happens to RBCs after 120 days in the circulation?
RBC are taken up and degraded by the MONONUCLEAR PHAGOCYTE SYSTEM (MPS), particularly in the liver and spleen
Where do the heme destined for degradation come from?
- Senescent RBC
- Degradation of hemeproteins other than Hb
Describe the process of Heme Degradation
1) Heme is converted into BILIVERDIN catalysed by HEME OXYGENASE in MACROPHAGES [Three successive oxygenations result in opening of the PORPHYRIN RING producing CO and releasing Fe2+]
2) BILIVERDIN (green) is converted to BILIRUBIN (red-orange) via BILIVERDIN REDUCTASE.
[Bilirubin has poor solubility in water -> carried by ALBUMIN to liver]
3) In the Liver, BILIRUBIN is converted to BILIRUBIN DIGLUCURONIDE (CONJUGATED BILIRUBIN) by BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE
[bilirubin solubility is increased by sequential addition of two molecules of glucuronic acid in a process called CONJUGATION]
4) CONJUGATED BILIRUBIN is actively transported into the BILE CANALICULI and then excreted in bile into the GUT
5) In the gut, CONJUGATED BILIRUBIN is hydrolysed to form UROBILINOGEN (colourless) which is then excreted in faeces (STERCOBILIN), excreted in urine (UROBILIN) or enters the ENTEROHEPATIC CIRCULATION
What can happen to Urobilinogen in the gut?
- Further oxidised by bacteria to STERCOBILIN (gives faeces the brown colour)
- Reabsorbed from gut and enters portal blood -> enters ENTEROHEPATIC UROBILINOGEN CYCLE in which its taken up by the liver and resecreted into the bile
- Transported to kidney -> converted to yellow UROBILIN -> gives urine its colour
What is Jaundice?
Jaundice is a condition in which the skin, whites of the eyes and mucous membranes turn yellow because of a high level of bilirubin (a yellow-orange bile pigment)
Earliest sign: SCLERAL ICTERUS & UNDER THE TONGUE
NORMAL: < 1mg/dl
JAUNDICE: >3mg/dl
Accompanied by dark urine (seen with elevated conjugated bilirubin)
What are the different Jaundice classifications?
- PREHEPATIC = overproduction + impaired uptake by the liver
- HEPATIC = decreased conjugation
- POSTHEPATIC = decreased excretion
What is the importance of Bilirubin?
- Functions at low levels as an antioxidant
- Oxidised to Biliverdin which is reduced by BILIVERDIN REDUCTASE, regenerating bilirubin
What does the excess capacity of the liver to conjugate and excrete Bilirubin allow for?
Allows for the liver to respond to increased heme degradation with a corresponding increase in CONJUGATION and secretion of CONJUGATED BILIRUBIN
What does extensive hemolysis do?
It produces Bilirubin faster than it can be conjugated -> UCB levels in the blood become elevated causing jaundice
What are the causes of Pre-hepatic jaundice?
- Hemolysis
- Ineffective erythropoiesis
- Increased bilirubin production
- Medication side effect
- Transfusion reactions
- Sickle cell anemia
- Thalassemia
- Autoimmune disease
What happens in Hepatocellular Jaundice?
- Damage to liver cells -> Unconjugated hyperbilirubinemia as a result of decreased conjugation
- UROBILINOGEN increased in urine because hepatic damage decreases the ENTEROHEPATIC CIRCULATION of compound -> allows more to enter blood which is filtered into urine
- Urine darkens & stool is pale
- Plasma levels of ALANINE and ASPARTATE TRANSAMINASES are elevated
What happens if Conjugated Bilirubin is made but not efficiently secreted from the liver into bile?
It can leak into the blood causing a conjugated hyperbilirubinemia
What are the causes of Interhepatic Jaundice?
- Impaired bilirubin conjugation
- Hepatocellular injury
- Impaired hepatic excretion of bilirubin
- Intrahepatic cholestasis
- Hepatitis
- Cancer
- Cirrhosis
- Drugs
What happens in Posthepatic Jaundice?
Jaundice is not caused by overproduction of bilirubin or decreased conjugation but instead from obstruction of the common bile duct
[Presence of tumour/bile stones may block duct preventing passage of CONJUGATED BILIRUBIN into intestine -> GI pain, nausea and pale, clay colour stools -> CB regurgitates into blood and is eventually excreted in the urine]
What are the causes of Posthepatic Jaundice?
- Gallbladder and gallstone disease
- Inflammatory processes
- Infection
- Tumours
