Heme Metabolism

Question 1

Heme is the most common ____ ring in the body.

Answer 1

porphyrin

Question 2

Besides hemoglobin, what are some examples of molecules heme is complexed in?

Answer 2

myoglobin and cytochromes

Question 3

What is the rate limiting step in heme synthesis?

Answer 3

the condensation of succinyl CoA and glycine to form d-ALA (via d-ALA synthase)

Question 4

What cofactor is necessary for the rate limiting step in heme synthesis?

Answer 4

vitamin B6 - pyridozal phosphate (that’s why a deficiency causes anemia)

Question 5

What TB drug is associated with vitamin B6 defiency and the related microcytic, hypochromic anemia?

Answer 5

isoniazid - that’s why you have to give it with B6 supplementation

Question 6

How many molecules of glycine and succinyl CoA are necessary for one molecule of heme?

Answer 6

8 of each

Question 7

How does heme regulate it’s own production in a negative feedback loop?

Answer 7

It inhibits the synthesis of d-ALA synthase and by directly inhibiting the enzyme itself

Question 8

What two enzymes in the heme synthesis pathway are affected by lead poisoning?

Answer 8

d-ALA dehydratase (the 2nd step) and ferrochelatase (the last step)

Question 9

What will accumulate in lead poisoning then?

Answer 9

d-ALA and protoporphyrin IX - the production of heme is greatly decreased

Question 10

If heme synthesis is reduced, what type of anemia will occur in lead poisoning?

Answer 10

a microcytic anemia

Question 11

For the degradation of heme, what is bilirubin conjugated with in the liver? Why?

Answer 11

glucuronic acid (from UDP-glucaronate)- it’s so it can be excreted in the bile

Question 12

What happens to the conjugated bilirubin in the small intestine?

Answer 12

It’s deconjugated and converted to urobilinogens (then excreted in urine and feces)

Question 13

What’s the difference between direct and indirect bilirubinemia?

Answer 13

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

Question 14

In general what is porphyria?

Answer 14

It’s an inherited disorder resulting from a deficiency of enzymes in the pathway for heme synthesis - the intermediates accumulate and have toxic effects

Question 15

What are the two classes of porphyrias?

Answer 15

acute and non-acute/cutaneous

Question 16

What is the most common acute porphyria?

Answer 16

acute intermittent porphyria

Question 17

What enzyme is lacking in acute intermittent porphyria? How is it inherited?

Answer 17

it’s an autosomal dominant deficiency of PBG deaminase

Question 18

What are the symptoms of acute intermittent porphyria?

Answer 18

GI symptoms (pain, vomiting, constipation), hyponatremia, neuropathy (sensory, motor, psychiatric), hypertension, tachycardia

note that photosensitivity is NOT present in this one

Question 19

What is the treatment for an acute porphyria?

Answer 19

1. hospitalize
2. provide nutrition and supportive treatment (like IV fluids to correct electrolyte imbalance)
3. carbohydrates to decrease porphyrin synthesis
4. IV hematin to try to shut down the whole process by skipping the endogenous heme synthesis
5. suppress ovulation since that’s usually a trigger

Question 20

What is the most common non-acute porphyria?

Answer 20

porphyria cutanea tarda

Question 21

In general, what happens in the cutaneous porpyrias?

Answer 21

the porphyrins get deposited in the upper layers of the skin in response to cutaneous photosensitivity

Question 22

What is the enzyme defiency in porphyria cutanea tarda?

Answer 22

hepatic uroporphyrinogen decarboxylase (URO-D) (usually autosomal dominant but not always - there is also an acquired form)

Question 23

What viral infection is often associated with porphyria cutanea tarda (in over 50% of cases!)?

Answer 23

hepatitis C - this is where the acquired form often comes into play

Question 24

What are the symptoms of porphyria cutanea tarda?

Answer 24

you get bullous detmatosis of the skin in response to sunlight, scarring, hyperpigmentation and hypertrichosis

Question 25

Besides hepatitis C, what should you screen for if you suspect porphyria cutanea tarda?

Answer 25

a hemachromatosis (and other forms of iron overload)

Question 26

What is the treatment for porphyria cutanea tarda?

Answer 26

avoid the trigger (like alcohol) and phlebotomy until remission to remove iron from the body

Question 27

If phlebotomy isn’t possible, what else can you do to prevent the body’s absorption of iron?

Answer 27

give meds to chelate the iron

Question 28

Can you detect a porphyria on labs during an asymptomatic period?

Answer 28

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