Heme Metabolism Flashcards
Heme is the most common ____ ring in the body.
porphyrin
Besides hemoglobin, what are some examples of molecules heme is complexed in?
myoglobin and cytochromes
What is the rate limiting step in heme synthesis?
the condensation of succinyl CoA and glycine to form d-ALA (via d-ALA synthase)
What cofactor is necessary for the rate limiting step in heme synthesis?
vitamin B6 - pyridozal phosphate (that’s why a deficiency causes anemia)
What TB drug is associated with vitamin B6 defiency and the related microcytic, hypochromic anemia?
isoniazid - that’s why you have to give it with B6 supplementation
How many molecules of glycine and succinyl CoA are necessary for one molecule of heme?
8 of each
How does heme regulate it’s own production in a negative feedback loop?
It inhibits the synthesis of d-ALA synthase and by directly inhibiting the enzyme itself
What two enzymes in the heme synthesis pathway are affected by lead poisoning?
d-ALA dehydratase (the 2nd step) and ferrochelatase (the last step)
What will accumulate in lead poisoning then?
d-ALA and protoporphyrin IX - the production of heme is greatly decreased
If heme synthesis is reduced, what type of anemia will occur in lead poisoning?
a microcytic anemia
For the degradation of heme, what is bilirubin conjugated with in the liver? Why?
glucuronic acid (from UDP-glucaronate)- it’s so it can be excreted in the bile
What happens to the conjugated bilirubin in the small intestine?
It’s deconjugated and converted to urobilinogens (then excreted in urine and feces)
What’s the difference between direct and indirect bilirubinemia?
In indirect, there’s something wrong with with the RBCs such that they lyse prematurely. This means there is so much free heme/bilirubin that the body cannot conjugate it fast enough and you get an increase in UNCONJUGATED bilirubin.
In direct, there’s usually a biliary blockage so the bilirubin can be conjugated, but it can’t be excreted, so you get an increase in CONJUGATED bilirubin
In general what is porphyria?
It’s an inherited disorder resulting from a deficiency of enzymes in the pathway for heme synthesis - the intermediates accumulate and have toxic effects
What are the two classes of porphyrias?
acute and non-acute/cutaneous
What is the most common acute porphyria?
acute intermittent porphyria
What enzyme is lacking in acute intermittent porphyria? How is it inherited?
it’s an autosomal dominant deficiency of PBG deaminase
What are the symptoms of acute intermittent porphyria?
GI symptoms (pain, vomiting, constipation), hyponatremia, neuropathy (sensory, motor, psychiatric), hypertension, tachycardia
note that photosensitivity is NOT present in this one
What is the treatment for an acute porphyria?
- hospitalize
- provide nutrition and supportive treatment (like IV fluids to correct electrolyte imbalance)
- carbohydrates to decrease porphyrin synthesis
- IV hematin to try to shut down the whole process by skipping the endogenous heme synthesis
- suppress ovulation since that’s usually a trigger
What is the most common non-acute porphyria?
porphyria cutanea tarda
In general, what happens in the cutaneous porpyrias?
the porphyrins get deposited in the upper layers of the skin in response to cutaneous photosensitivity
What is the enzyme defiency in porphyria cutanea tarda?
hepatic uroporphyrinogen decarboxylase (URO-D) (usually autosomal dominant but not always - there is also an acquired form)
What viral infection is often associated with porphyria cutanea tarda (in over 50% of cases!)?
hepatitis C - this is where the acquired form often comes into play
What are the symptoms of porphyria cutanea tarda?
you get bullous detmatosis of the skin in response to sunlight, scarring, hyperpigmentation and hypertrichosis
Besides hepatitis C, what should you screen for if you suspect porphyria cutanea tarda?
a hemachromatosis (and other forms of iron overload)
What is the treatment for porphyria cutanea tarda?
avoid the trigger (like alcohol) and phlebotomy until remission to remove iron from the body
If phlebotomy isn’t possible, what else can you do to prevent the body’s absorption of iron?
give meds to chelate the iron
Can you detect a porphyria on labs during an asymptomatic period?
not necessarily
During a symptomatic period, there will always be an increase in heme precursors (absence would indicate it’s not a porphyria)
During an asymptomatic period individuals may have normal precursor levels
