Heme, Iron , Bilirubin

Question 1

where does hemoglobin synthesis occur

Answer 1

red blood cells in the bone marrow

**normal synthesis depends on adequate supply of Fe, normal heme, and normal globin

Question 2

what form of Fe can hemoglobin bind

Answer 2

Fe2+

Question 3

methemoglobin reductase

Answer 3

converts methemoglobin (Fe3+) back to hemoglobin

Question 4

once inside the cell, what happens to heme

Answer 4

heme oxgenase oxidizes the fe2+ in heme and then releases Fe3+ which is then reduced to Fe2+

Question 5

where does Fe2+ that is inside a duodenal epithelial cell go

Answer 5

binds to mobilferrin for transit across the cell to the basolateral membrane

Fe2+ then leaves the cell via ferroportin (FP1) and after hephaestin oxidizes it to Fe3+ the iron binds to transferrin in plasma

Question 6

where is heme iron from ?

Answer 6

from breakdown of myoglobin and hemoglobin in meats

Question 7

where is nonheme primarily from

Answer 7

vegetables

may be either ferrous or ferric form

Question 8

what happens to dietary Fe3+ from nonheme iron prior to entering duodenum

Answer 8

reduced to Fe2+ by ferric reductase

Question 9

DMT1

Answer 9

cotransports Fe2+ and H into cells

Question 10

apoferritin

Answer 10

binds to iron to form ferritin the storage form of iron

decreased apoferritin synthesis (usually due to liver disease) results in elevated serum iron levels

Question 11

hepcidin

Answer 11

negative regulator of iron absorption

secreted by hepatocytes

binds to ferroportin at the cell surface to initiate ferroportin internalization and degradation

Question 12

loss of hepcidin protein

Answer 12

results in severe iron overload- hemochromatosis

Question 13

increased hepatic hepcidin production (associated with inflammatory conditions)

Answer 13

may lead to anemia of chronic disease by blocking iron absorption

Question 14

what is bilirubin

Answer 14

breakdown product of hemoglobin molecule liberated from dead erythrocytes by the reticuloendothelial system

Question 15

what are the major steps in bilirubin metabolism

Answer 15

o Hemoglobin from RBCs is degraded into heme-iron (Fe) complex + a globin chain by macrophages
o Heme moiety is converted to biliverdin + Fe
o Fe is reabsorbed and recycled to be used in formation of new RBCs
o Biliverdin is converted to UNCONJUGATED OR WATER-INSOLUBLE bilirubin (≈ 250-350 mg/day)
o Unconjugated bilirubin can be converted from the “trans” to the “cis” form by light. The cis form is more easily excreted in urine.

o Unconjugated bilirubin enters portal circulation where it is combined with albumin
o It then enters the hepatocytes through the sinusoids via two mechanisms:
• Passive diffusion
• Receptor-mediated endocytosis
o The unconjugated bilirubin travels to the smooth endoplasmic reticulum (SER) of the hepatocyte
o At the SER, the unconjugated bilirubin undergoes a conversion to CONJUGATED OR WATER-SOLUBLE bilirubin catalyzed by the enzyme uridine 5’-diphosphate glucuronyl transferase (UDPGT).

Question 16

UDPGT

Answer 16

adds glucuronide to the bilirubin molecule (primarily two glucuronide molecules) to form bilirubin diglucuronide which is the conjugated or water-soluble form of bililrubin

Question 17

what happens to conjugated bilirubin once it has now been made water soluble

Answer 17

o The conjugated bilirubin is then delivered to the opposite side of the hepatocyte and enters the bile canaliculi for active secretion into…
o The intestinal tract where intestinal bacteria degrade it to urobilinogen and urobilin
o A small part of the urobilinogen remaining in the gut is metabolized to stercobilin, which is the compound giving stool its pigment
o However, the majority of the urobilinogen is reabsorbed by the gut and re-excreted by the liver with a small amount being excreted in the urine

Question 18

when is urinary urobilinogen elevated

Answer 18

hyperbilirubinemia

Question 19

increased urinary bilirubin occurs when ….

Answer 19

there is an increase in serum conjugated bilirubin

Question 20

what is the normal range of total serum bili

Answer 20

0.2-1.0

of this total usually less than 0.2 is conjugated

the remainder is unconjugated

Question 21

when does jaundice appear

Answer 21

when bili exceeds 2-3 mg/dL

Question 22

what levels of bili cause kernicterus

Answer 22

bili exceeding 15-20 mg/dL

Question 23

what are the causes of prehepatic jaundice

Answer 23

hemolytic process

the liver is usually functioning normal

excessive bilirubin presented to the liver for metabolism

Question 24

what are the lab findings in prehepatic jaundice

Answer 24

increased serum unconjugated bili (total bili usually doesn’t exceed 5 mg)

negative urine bilirubin

urinary urobilinogen increased

Question 25

what are some causes of hepatic jaundice

Answer 25

Gilbert's- Crigler-Najjar Dubin Johnson Hepatitis

Question 26

Gilbert's

Answer 26

enzyme mutation/impaired hepatocellular uptake serum total bili <3.0 = primarily composed of unconjugated bili increased urinary urobilinogen

Question 27

Crigler-Najjar type I

Answer 27

enzyme mutation/defective conjugation serum unconjugated bili >5.0 increased urinary urobilinogen

Question 28

Dubin-Johnson

Answer 28

defective secretion by hepatocyte increased serum conjugated bili

Question 29

hepatitis with lower conjugation or excretion

Answer 29

increased serum direct and indirect bili with total levels of 5-10 mg/dL

Question 30

what are the causes of posthepatic jaundice

Answer 30

impaired excretion of bilirubin mechanical obstruction of the flow of bile into the intestine due to gallstones or tumors

Question 31

what are the lab findings of posthepatic jaundice

Answer 31

increased serum AND urine conjugated bilirubin decreased level of urobilin/stercobilin in stool (Clay colored stools***) negative urinary urobilinogen

Question 32

when does HbF disappear from the RBC's of normal infants

Answer 32

by age of 6 months

Question 33

what is Hb gower

Answer 33

embryonic form of Hb

Question 34

how is heme formed

Answer 34

1) condensation of succinyl-CoA and glycine for form ALA (aminolevulinic acid) by ALA synthase (comitted step, rate-limiting) 2) PBG synthase (AKA ALA dehydratase) (porphobilinogen synthase) catalyzes the condensation of two molecules of ALA to form PBG (porphobilinogen) in the cytosol 3) Condensation of 4 molecules of PBG to form protoporphyrin ring - 4) iron is inserted into protoporphyrin by ferrochelatase to form heme

Question 35

ALA synthase

Answer 35

in the mitochondria succinyl CoA + glycine to form ALA mutations in this cause sideroblastic anemia

Question 36

PBG synthase

Answer 36

(Aka ALA dehydratase) catalyzes the condensation of two molecules of ALA to form PBG (happens in the cytosol) mutations in this enzyme would result in porphyria Pb poisoning ?

Question 37

ferrochelatase

Answer 37

incorporation of ferrous iron into protoporphyrin (in the mitochondria) Pb poisoning Mutation= protoporphyria

Question 38

where does globin synthesis occur

Answer 38

cytoplasm of normoblasts and reticulocytes (immature erythrocytes) - synthesized in the cytoplasmic ribosomes increased availability of heme promotes globin synthesis

Question 39

alpha globin chains made on what chromosome

Answer 39

16

Question 40

beta globin chains are made on what chromosome

Answer 40

11

Question 41

HbF, Hb Portland

Answer 41

most abundant Hb in fetal development

Question 42

adult Hb

Answer 42

HbA

Question 43

is there any HbF in adults?

Answer 43

yes a very small amount

Question 44

what takes over function of break down of red cells if the pt has no spleen

Answer 44

liver

Question 45

what are the 2 inefficient pathways in red cells that are the energy sources

Answer 45

Glycolysis pentose phosphate cycle (PPC) --> supplies NADPH to maintain reduced state of glutathione and sulfhydryl groups

Question 46

after removal of senescent red cells from the circulation Hb is degraded within macrophages of the RES into its 3 components:

Answer 46

Fe: goes into storage for reutilization (recycling) Protoporphyrin: split and converted to bilirubin, excreted from body Globin: degraded and returned to amino acid pool for possible reutilization

Question 47

how is the porphyrin ring broken down

Answer 47

heme oxygenase yields CO (which forms carboxyhemoglobin) and biliverdin Biliverdin is reduced to bilirubin in the macrophage and transported to the liver attached to plasma albumin. It is removed from the circulation by the hepatocytes and conjugated for excretion in bile

Question 48

deoxyhemoglobin

Answer 48

reduced hemoglobin

Question 49

oxyhemoglobin

Answer 49

hemoglobin carring oxygen

Question 50

methemoglobin

Answer 50

(usually <3% of total hgb) hemoglobin carrying oxidized (ferric) iron… loses its ability to carry oxygen & becomes non-functional

Question 51

methemoglobin reductase

Answer 51

converts methemoglobin back to hemoglobin If Fe2+ is oxidized to Fe3+, (can be due to oxidizing drugs such as nitrites or sulfonamides), methemoglobin is formed and is incapable of binding oxygen.

Question 52

Sulfhemoglobin

Answer 52

(Usually not present) oxidized, partially denatured hemoglobin which may result in RBC destruction & hemolysis. Usually due to sulfur-containing drugs (sulfonamides) or aromatic amine drugs (phenacetin, etc.) Cannot carry O2 Phenacetin- pain relieving and fever-reducing drug, widely used from its introduction in 1887 until banned in the US by the FDA in 1983

Question 53

Carboxyhemoglobin

Answer 53

(Usually <3% of total hemoglobin) hemoglobin carrying CO produced during heme degradation to bilirubin. CO is eliminated via respiration Can also be formed due to CO poisoning

Question 54

HbF

Answer 54

2α & 2γ globin chains

Question 55

HbA

Answer 55

2α & 2β globin chains

Question 56

HbA2

Answer 56

2α & 2δ globin chains

Question 57

when does the gower Hb go away

Answer 57

around 3 months

Question 58

when does beta chain of Hb start to form

Answer 58

3 months

Question 59

when does fetal hemoglobin start to form

Answer 59

3 months

Question 60

what occurs in Sickle cell disease (S/S)

Answer 60

Missense mutation of β globin chain: amino acid substitution at position 6- valine for glutamic acid HbA --> HbS develops around 6 months HbS replaces HbF