Heme Biochemistry

Question 1

What are the key features of porphyrin rings in heme?

Answer 1

Have four 5-membered rings containing N connected by single C bridges
Iron present in ferrous state
Oxidation to ferric states inactivates Hb (methemoglobin)

Question 2

Where does biosynthesis of heme primarily occur?

Answer 2

In the liver and erythroid cells of bone marrow

Question 3

What are the three phases of heme biosynthesis?

Answer 3

Phase I - in the mitochondria
Phase II - in the cytosol
Phase III -in the mitochondria

Question 4

What happens in phase I of heme biosynthesis?

Answer 4

Gly + succinyl CoA —> ALA via ALA synthase and vitamin B6 (PLP)
Inhibited by heme and hemin

Question 5

What happens in phase II of heme biosynthesis?

Answer 5

ALA —> porphobilinogen via ALA dehydratase
Prophobilinogen —> hydroxymethylbilane via porphobilinogen deaminase
End result is production of coproporphyrinogen II which has a porphyrin ring

Question 6

What happens in phase III of heme synthesis?

Answer 6

Generation of protoporphyrin and introduction of iron to form heme via ferrochelatase

Question 7

What inhibits both ALA dehydratase and ferrochelatase?

Answer 7

Pb (lead)

Question 8

Describe lead poisoning

Answer 8

Lead inactivates ALA dehydratase and ferrochelatase causing accumulation of ALA and protoporphyrin IX
ALA is neurotoxic and heme production is lowered
Causes anemia (microcytic and hypochromic)
Also impacts ATP synthesis and energy metabolism

Question 9

What are porphyrias?

Answer 9

Inherited metabolic disorders caused by defects in heme synthesis
Different types including acute hepatic (neurological sx) and erythropoietic (affects skin and causes photosensitivity)

Question 10

Describe congenital erythropoietic porphyria

Answer 10

Erythropoietic
Deficiency in uroporphyrinogen III synthase in RBCs
Results in buildup of uroporphyrinogen I and its oxidation production uroporphyrin I (not a substrate for the next enzyme)

Question 11

What are the sx associated with congenital erythropoietic porphyria?

Answer 11

Produces a red color in urine, red fluorescence in teeth, destruction of RBCs and skin photosensitivity

Question 12

Describe variegate porphyria

Answer 12

Defective protoporphyrinogen IX oxidase 
Hepatic form 
Autosomal dominant 
Photosensitivity and neurologic sx and developmental delay in children
“Celebrity porphyrias”

Question 13

Describe porphyria cutanea tarda (PCT)

Answer 13

Defective uroporphyrinogen decarboxylase
Hepatoerythropoietic form
Leads to accumulation of uroporphyrinogen III which converts to uroporphyrinogen I
MC porphyria in the US
Photosensitivity resulting in vesicles and bullseye on skin of exposed area, wine red colored urine

Question 14

Describe acute intermittent porphyria

Answer 14

Hepatic form
Defective PBG deaminase in liver
Deficiency leads to excessive production of ALA and PBG
Periodic attacks of abdominal pain and neurologic dysfunction

Question 15

Describe heme degradation

Answer 15

Handled by the reticuloendothelial system which degrades hemoglobin into globin and heme
Globin broken down into amino acids and heme processed for degradation

Question 16

What is the process for heme degradation?

Answer 16

Heme broken down into biliverdin via heme oxygenase which requires O2
-release CO and iron is oxidized from ferrous to ferric state
Biliverdin converted into bilirubin via biliverdin reductase which requires NADPH

Question 17

What is jaundice?

Answer 17

Elevated levels of bilirubin in the bloodstream (hyperbilirubinemia)
Imbalance between production and excretion of bilirubin
Can be pre, intra or post hepatic

Question 18

Describe pre-hepatic jaundice

Answer 18

Increased production of unconjugated bilirubin
Excess hemolysis (hemolytic anemias), Internal hemorrhage, problems with incompatibility of maternal-fetal blood groups (in neonates)
Capacity of liver to uptake exceeded

Question 19

Describe intra hepatic jaundice

Answer 19

Impaired hepatic uptake, conjugation or secretion of conjugated bilirubin
Caused by generalized hepatic dysfunction
Ex. Liver cirrhosis, viral hepatitis, Criggler-Najjar syndrome, Gilbert syndrome

Question 20

Describe post hepatic jaundice

Answer 20

Aka cholestatic jaundice or cholestasis (decreased bile flow)
Problems with bilirubin excretion
Caused by obstruction to biliary drainage, cholangiocarcinoma, gall stones, infiltrative liver disease, lesions, drugs

Question 21

What findings occur in post hepatic jaundice?

Answer 21

Elevated blood levels of conjugated bilirubin
Conjugated bilirubin is present in urine (will be dark)
Elevated ALP and no stercobilin in feces (pale stool)
Small increase in unconjugated form

Question 22

Describe type I Criggler-Najjar syndrome

Answer 22

Results from deficiency of UDP-GT
Complete absence of the gene
Severe hyperbilirubinemia
BR accumulates in the brain of babies and causes encephalopathy (kernictus) and brain damage

Question 23

What forms of therapy are used in type I Criggler-Najjar syndrome?

Answer 23

Blood transfusions, phototherapy, heme oxygenase inhibitors, oral Ca phosphate and carbonate, liver transplantation

Question 24

Describe type II Criggler-Najjar syndrome

Answer 24

Benign form
Results from mutation in the UDP-GT gene
Enzyme has less activity

Question 25

Describe Gilbert syndrome

Answer 25

Relatively common benign disorder
Results from reduced activity of UDP-GT
Serum BR <6mg/dL but may increase with fasting, stress, or alcohol consumption

Question 26

What is hepatitis?

Answer 26

Inflammation of the liver
Leads to liver dysfunction
Causes include viral hepatitis (Hep A, B and C), alcoholic cirrhosis, liver cancer
Increased levels of unconjugated and conjugated BR in blood
BR accumulates in skin and sclera of the eyes causing yellow discoloration
Dark, tea colored urine

Question 27

Describe the color change that occurs in bruises

Answer 27

Red - heme
Green - biliverdin
Orange - bilirubin
Reddish brown - hemosiderin (iron)

Question 28

What is neonatal jaundice?

Answer 28

Physiological jaundice 
Elevation of unconjugated bilirubin 
Immature hepatic metabolic pathways 
Deficiency of UDP-GT enzyme 
Breakdown of fetal Hb as it is replaced with adult Hb

Question 29

Describe phototherapy used to treat jaundiced newborns

Answer 29

When exposed to blue fluorescent light BR undergoes photo conversion to form more soluble isomers

Question 30

What is another line of Tx for neonatal jaundice?

Answer 30

Intramuscular injection of tin mesoporphyrin (strong inhibitor of heme oxygenase) to prevent heme breakdown to form bilirubin