5-14 GOUELI Heme Metabolism Flashcards
What is the rate limiting step in the synthesis of heme?
Glycine + Succinyl-CoA –> δ-ALA (aminolevulinic acid)
How is δ-ALA synthase activity regulated?
Negative feedback from Heme
What is the significance of vitamin B6 in heme synthesis?
It’s a cofactor for δ-ALA synthase
What can a vitamin B6 deficiency cause?
↓B6 –>↓Hb synthesis –> microcytic, hypochromic (low color) anemia
What is one concern with Isoniazid?
Isoniazid, which is Tx for TB, can –> B6 deficiency
What’s the site of lead toxicity in the heme synthesis pathway?
δ-ALA dehydratase, and ferrochelatase
What can lead toxicity lead to?
Microcytic anemia
What does heme positively increase production of?
Globin, to make hemoglobin
What happens to heme after RBCs die?
It is degraded to bilirubin
Where does the breakdown of heme to bilirubin occur?
In the RES (Reticuloendothelial system, ie spleen, macrophages, etc)
What happens to bilirubin in the liver?
It is conjugated
What do we mean when we say bilirubin is conjugated?
You’re adding UDP-glucouronate to make it more water soluble
What is the difference btwn direct and indirect bilirubin?
Direct is conjugated. Indirect is unconjugated.
What is the significance of direct vs indirect bilirubin?
If patient has jaundice (which is due to build-up of bilirubin), type of bilirubin (direct vs indirect) can help us figure out where damage is occurring
If patient has intravascular hemolysis (like seen in G6PD deficiency), what form will the bilirubin in her system be in?
Unconjugated (indirect) form b/c it hasn’t passed through liver yet
If patient has obstruction of biliary system, what form will the bilirubin in his system be in?
Conjugated bilirubin (direct) b/c it HAS passed through liver
Define porphyria
A genetic deficiency in one of the enzymatic steps of the heme synthesis pathway –> disease b/c toxic accumulation of enzyme precursor
How can you detect a porphyria in a patient?
Urine measurements of enzyme intermediates, particularly ALA and PBG
What is the inheritance pattern of the porphyrias?
Autosomal dominant (except ALA dehydratase deficiency which is AR)
What symptoms would you see in an acute intermittent porphyria patient?
Polyneuropaty
Painful abdomen
Port-colored urine (darkens b/c light oxidizes enzyme precursors)
Precipitated by drugs
What is there long-term increased risk of in AIP patient?
Hepatocellular carcinoma
How do you treat AIP?
Glucose and heme (IV) to inhibit heme synthesis pathway!
What is the #1 porphyria?
Porphyria cutanea tarda (PCT)
Is Porphyria cutanea tarda life-threatening?
No
If you have a patient with PCT (Porphyria Cutanea Tarda), what do you need to test for?
Hepatitis C b/c >50% of patients are positive
What are symptoms of PCT?
Photosensitivity
Hyperpigmentation
Hypertrichosis (hair growth)
Bullous dermatosis (blistering skin lesions)
What is the pathogenesis of PCT?
For some reason, too much iron
↑iron –> symptoms
What is Tx for PCT?
Reduce iron! Use phlebotomy or chelation
Discuss the malleability of RBCs
RBCs must be very malleable to fit through tiny capillaries and handle changes in tonicity
Must also have high SA for gas exchange
Membrane composed of complex cytoskeletal system
What are the important proteins involved in the RBC membrane cytoskeleton?
Ankryin
Spectrin
Actin
What can genetic defects of the RBC membrane cytoskeletal proteins lead to?
Inherited hemolytic anemias
What is hereditary spherocytosis?
Genetic defect in Spectrin protein -> less malleable RBCs
Less malleability –> premature RBC destruction in spleen
Morphology of RBC in Hereditary Spherocytosis?
Spherocyte: RBC is more of a sphere and less concave disk
Sx of Hereditary Spherocytosis?
Hemolysis & anemia
Jaundice
Splenomegaly
Tx of Hereditary Spherocytosis?
Splenectomy
How are damaged RBCs that are no longer deformable eliminated?
They are trapped in spleen and destroyed by macrophages
