haematology 3 Flashcards
what is the function of iron in haemoglobin
- Fe2+ and Fe3+
- participates in redox reactions by switching reversibly between states
- Fe2+ can bind to molecular oxygen haem group
- excess Fe is toxic as it forms free radicals so is stored and transported in ferric Fe3+ state
how is iron transported
1) Fe3+ in diet
2) ferric reductase converts it into Fe2+
3) transported into cell via haem transporter, endosomes or divalent metal transporter 1
4) Fe2+ can be converted back to Fe3+ and bound to transferrin within the intestinal cell or can be transported into the blood by ferroportin (FP) and hephaestin (HP).
5) in the blood Fe2+ is oxidised by HP to form Fe3+ which is used to form plasma transferrin made in the bone marrow
what causes a reduction in ferric iron
- high pH
- lack of gastric acid - impairs absorption
- inorganic anions - form insoluble complex with iron
- ascorbic acid (vitamin c) enhances absorption
what is hepcidin
- regulator of iron absorption, produced by the liver upon availability of iron from transferrin
what occurs in ribosomes when iron stores are low
- ribosomes produce more DMT1
- DMT1 mRNA has iron response element in 3’ untranslated region
- low iron causes iron regulatory proteins to bind to these iron response elements and protect mRNA from nuclease attack
when is hypoxia-inducible factor 2a activated and what does it do
- decreased O2 supply activates it
- transcription factor that binds to promotor region of DMT1 and FP stimulating transcription
- mechanism which chronic anaemia increases iron absorption
what are the causes, symptoms and treatment of iron deficiency
- chronic blood loss, growth spurts, late stage of pregnancy, lactation, acute massive haemorrhage
- pallor, weakness, fatigue
- ferrous sulphate combined with ascorbic acid
what is the haem structure
- a porphyrin containing iron and 4 pyrrole rings connected by methylene bridges
where does haem synthesis occur
- 85% in the bone marrow
where is porphobillinogen (PBG) present and what does it do
- mitochondrial membrane
- removes 2 H20 from the 2 x gamma-ALA to form 1 x PBG released into the cytosol
what is linear tetapyrrole made of and what does it form
4 PBG molecules
- looses 4 x CO2 and re entreres mitochondria as protoporphyrinogen IX
what does ferrochelatase do
- adds Fe2+ to protoporhyrin IX to form haem
what regulates game-ALA synthase
- haem
- degades after 1-3 hours
what inhibits PBG synthase and ferrochelatase
- heavy metals eg. Pb
what is haem production required for in the liver and erythroid cells
- liver - formation of haemoproteins for detoxification
- erythroid cells - synthesis of Hb
what role does macrophages play in degradation
- engulf senescent erythrocytes
- oxide haem to ferric (3+) state to produce hemin
- haem oxygenate catalyses hemin to billiverdin
what do splenic macrophages do in haem degradation
- catalyse the production of bilirubin from biliverdin by biliverdin reductase
how is bilirubin transported and converted
- from the spleen to the liver by tight, non-covalent forces to serum albumin
- in hepatocyte ER it is conjugated with glucuronic acid to form bilirubin diglucuronide by uridine diphosphate
- intestinal bacteria de-conjugate to form uncoloured urobilinogen
what is the pathway of urobilinogen
1) some absorbed by ileum
- reduced to stercobilin by intestinal bacteria - brown
- small amount excreted by kidneys which is oxidised to urobilin
2) most is cleared by the liver and re-secreted in bile
what is the causes of jaundice
- hyperbilirubinemia by conjugated and unconjugated bilirubin
what is conjugated bilirubin
- water soluble
- causes yellow-brown colouration of urine
- causes of choleric jaundice
what is unconjugated bilirubin
- tightly bound to albumin
- lipid soluble
- can enter brain causing bilirubin encephalopathy/ kerniecterus infants
what happens in pre-hepatic jaundice
- increased production or impaired hepatic uptake of bilirubin
- haemolysis increases total plasma due to excess unconjugated fraction
- increase in urine bilirubin because unconjugated bilirubin is insoluble
what happens in intra hepatic jaundice
- caused by parenchymal liver disease
- causes bilirubin conjugation and impairments of energy dependent secretion of conjugated bilirubin into bile
what is post hepatic jaundice
- obstruction or reduction of bile flow
- impacted gallstone, pancreatic cancer, liver diseases that prevent bile formation
- cannot reach intestine so overflows into blood
what is Gilbert syndrome
- compensatory haemolysis
- impaired uptake and conjugation of bilirubin
what is rotors syndrome
- conjugated hyperbilirubinameia
- caused by intermittent jaundice
what is cringer nejjar syndrome
- servere unconjugated hyper-bilirubinaemia
- deficiency in enzyme needed for bilirubin conjugation
what is Dublin-johnson syndrome
- retention of conjugated bilirubin
- turns the liver black with intermittent jaundice
what are the treatments for jaundice
- phototherapy - adds oxygen to bilirubin to increase solubility
- phenobarbital - induction of enzyme synthesis
- breastfed babies - higher risk of jaundice
