L53: Diseases of Heme Synthesis and Degradation

Question 1

What does vitamin B6 deficiency lead to?

Answer 1

Decreased activity of ALAS [1] activity and microcytic hypochromic anemia

Question 2

What does lead toxicity lead to?

Answer 2

ALA dehydratase [2] and ferrochelatase [8] are affected. delta-aminolevulinic acid (ALA) and Zn protoporphyrin IX accumulate

Question 3

What is cause of porphyrias?

Answer 3

Defect in enzyme of heme biosynthesis

Question 4

Describe classification of porphyrias based on site of heme precursor accumulation

Answer 4

Hepatic type - liver; rapid onset of neuropsychiatric symptoms
Erythropoietic type - bone marrow, RBCs, cutaneous photosensitivity

Question 5

Describe porphyria cutanea tarda

Answer 5

Uroporphyrinogen decarboxylase [5] defects
Hepatic type
Most common type; usually caused by liver damage
Skin symptoms (due to reactive oxygen species generated by photoactivated porphyrinogens)
Uroporphyrins accumulate in liver, plasma, urine, stool

Question 6

Describe acute intermittent porphyria

Answer 6

Porphobilinogen deaminase [3] mutations
Hepatic type
Neurological symptoms, can be severe
Lacks skin disease (porphyrinogens not made)
ALA and porphobilinogen in plasma, urine (darkens on standing)

Question 7

Describe erythropoietic protoporphyria

Answer 7

Ferrochetelase mutation
Most common erythropoietic type
Mainly skin symptoms
Protoporphyrin accumulates in bone marrow, RBCs, plasma, liver and bile rather than in urine (it is insoluble)

Question 8

What enzyme converts heme to biliverdin?

Answer 8

Heme oxygenase uses NADP to create biliverdin, releasing iron and CO in the process

Question 9

Where are bile pigments created?

Answer 9

RES cells: spleen, liver, marrow

Question 10

What are the differences b/w the heme oxygenases?

Answer 10

HMOX 2 is constitutively expressed. HMOX 1 is rate-limiting and induced by heme, heavy metals, and stress (hypoxia)

Question 11

What enzyme converts biliverdin to bilirubin?

Answer 11

Biliverdin reductase

Question 12

What are the 3 forms of bilirubin?

Answer 12

Free - insoluble
Bound - soluble
Conjugate - very soluble

Question 13

What does bilirubin bind with and where?

Answer 13

With albumin in circulation (in blood)

Question 14

What is bilirubin conjugated w/ and where?

Answer 14

Conjugated w/ 2 glucose molecules to form bilirubin diglucuronide. Occurs in the liver

Question 15

What causes dark color in feces?

Answer 15

Stercobilin

Question 16

What causes yellow color of urine?

Answer 16

Urobilin

Question 17

What is portal circulation?

Answer 17

Circulation back from intestine to liver

Question 18

What is taken up by portal circulation?

Answer 18

Urobilinogen

Question 19

What are the 3 general causes of jaundice?

Answer 19

Pre-hepatic: excessive RBC lysis
Hepatic: impaired or inadequate liver function
Post-hepatic: bile duct obstruction (inadequacy of draining from liver to intestine)

Question 20

What products increase in pre-hepatic jaundice?

Answer 20

Everything increases since there is increased amount of heme products. Urine is more yellow than normal since higher urobilin content. Stool is darker than normal since higher stercobilin content.

Question 21

What is hepatic jaundice caused by?

Answer 21

Impaired bilirubin conjugation: neonatal jaundice, Crigler-Najjar and Gilbert sydromes
Impaired deficient transport of conjugated bilirubin: Dubin-Johnson and Rotor syndromes
Both: wide-scale liver damage; liver cirrhosis, viral hepatitis

Question 22

What is neonatal jaundice caused by?

Answer 22

Developmental impaired bilirubin conjugation

Question 23

What are Crigler-Najjar and Gilbert syndromes caused by?

Answer 23

Genetic deficiencies of bilirubin UDP-glucuronyl transferase and thus impaired bilirubin conjugation

Question 24

How are degradation products redistributed in hepatic jaundice?

Answer 24

Since bilirubin diglucuronide can escape into circulation from the liver, feces is paler since less stercobilin is produced. Urine is dark because bilirubin diglucuronide makes its way into the kidneys from circulation and bilirubin diglucuronide itself makes its way into the urine. Urobilin is also higher (why tho?).

Question 25

What causes post-hepatic jaundice?

Answer 25

Obstructive jaundice (gall stones, pancreatic cancer, parasitic infection, primary billiary cirrhosis)

Question 26

How are degradation products redistributed in post-hepatic jaundice?

Answer 26

Bilirubin diglucuronide can’t move into the intestine from the liver, so there is less stercobilin produced and feces is light. Bilirubin diglucuronide content is up in urine since from the blood it is taken up by the kidney. Urine is dark even though urobilin levels are down.

Question 27

What is the van den Bergh reaction?

Answer 27

Clinical assay for bilirubin in the plasma or serum

Question 28

What is the reactant? What is the product?

Answer 28

Reactant is diazonium salts. Product is azo dye (red-purple color)

Question 29

What solution is the direct test conducted in? What results?

Answer 29

It’s conducted in water. So, only the conjugated (soluble) bilirubin is measured.

Question 30

What solution is the total test conducted in? What results?

Answer 30

Conducted in alcoholic solution. Both the conjugated (soluble) and unconjugated (insoluble) react and are measured.

Question 31

How is the amount of unconjugated bilirubin in the serum calculated?

Answer 31

Total - direct = indirect (unconjugated bilirubin)

Question 32

What is the difference between ALAS 1 and ALAS 2?

Answer 32

ALAS 1 is a housekeeping gene in all cells. It is feedback-inhibited by heme.
ALAS 2 is in erythroid cells and is feedback-inhibited by iron. X-linked gene.