Heme, Iron, Bilirubin Metabolism

Question 1

hepcidin

Answer 1

• negative regulator of iron absorption that acts by inhibiting ferroportin release of iron –> thus reducing dietary iron intake
• it is a circulating peptide that is secreted by hepatocytes, that binds to ferroportin at the cell surface to initiate ferroportin internalization and degredation
• it is upregulated in inflammatory times, and thus during sickness you see less iron in the circulation

Decreased hepcidin expression (HAMP gene mutation) leads to dysregulation, iron overload and hemochromatosis

Increased expression (inflammatory conditions) can lead to blocked iron absorption and anemia of chronic disease

Question 2

ferroportin

Answer 2

negatively regulated by hepcidin - this releases dietary iron from the luminal cells into the blood circulation

Question 3

apoferritin

Answer 3

“iron buffer system”: it can take up xs circulating iron for storage and release iron when circulating levels are too low

• decreased apoferritin synthesis - due to liver disease, results in elevated serum iron levels

Question 4

transferrin

Answer 4

carries iron to a site to be stored

Question 5

ferritin

Answer 5

the storage form of iron

Question 6

heme oxygenase

Answer 6

splits heme and iron inside of cells into Fe3+

also used to release the porphyrin ring from iron in order to make porphyrin ring into biliverdin

Question 7

methemoglobin reductase

Answer 7

a protective enzyme contained in erythrocyte, which converts methemoglobin back to hemoglobin.

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

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 8

where are heme and globin synthesized?

Answer 8

heme = in mitochondria
globin = in cytoplasm

of immature RBCs and bone marrow

Question 9

how is heme iron absorbed?

Answer 9

• from metas *
• absorbed by duodenal epithelial cells
• once inside cells heme oxygenase splits the heme iron and releases Free Fe3+, CO, and biliverdin (which is converted to bilirubin)
• enterocytes convert Fe3+ to Fe2+
• Fe2+ leaves via ferroportin and after it exits is converted back to Fe3+ to be carried by transferrin

Question 10

how is nonheme iron absorbed?

Answer 10

• vegetables *

either Ferric or Ferrous form.

• Ferrous is absorbed more readily so Dcytb reduces nonheme Fe3+–> Fe2+
• Fe2+ is cotransported via DMT1 into the cell
• Fe2+ leaves the cell via ferroportin(mobilferrin) at basolateral membrane
• After Fe2+ exits the cell its converted back to Fe3+ and binds to transferrin for transport throughout body tissues
• circulating Fe is primarily deposited in liver and

Question 11

hemochromatosis

Answer 11

loss of hepcidin protein (decreased expression) - resulting in severe iron overload

Question 12

anemia of chronic disease

Answer 12

increased hepatic hepcidin production (associated with inflammatory conditions) may lead to the blockage of iron absorption

Question 13

major steps in bilirubin metaoblism?

Answer 13

Hgb from RBCs is degraded into heme-iron complex and globin chain

heme is converted to biliverdin and Fe

Fe is reabsorbed and recycled

Biliverdin is converted to unconjugated/water-insoluble bilirubin, which is carried in blood stream to liver by albumin

unconjugated bilirubin enters portal circulation where its combined with albumin

it then enters hepatocytes and at the SER it undergoes conversion into conjugated or water-soluble bilirubin catalyzed by ** 5’-diphosphate glucuronyl transferase (UDP/UDPGT) **

conjugated bili is then delivered to bile canaliculi for active secretion into the intestinal tract (where intestinal bacteria degrade it to urobilinogen and urobilin) (small part of urobilinogen remains in gut and is metabolized to stercobilin which gives the stool its pigment)

the majority of urobilinogen is converted to urobilin and excreted in the feces, some is reabosrbed by the gut and re-excreted by the liver as bile, and a small percent is excreted in the urine as urobilinogen.

Question 14

bili light

Answer 14

given to children with high unconjugated bilirubin

converts the trans to the cis form so that it can be excreted in the urine

Question 15

normal total serum bili

Answer 15

0.2 - 1 mg/dL

usually <.2 is conjugated (water soluble) - the remainer is unconjugated

Question 16

when does jaundice appear?

Answer 16

when bilirubin exceeds 2-3 mg/dL

kernicterus is seen in infants with bilirubin more than 15-20

Question 17

prehaptic jaundice

Answer 17

excesive bilirubin presented to liver for metabolism, overcomes the ability of the liver to clear

• in most cases the liver function is normal

causes = HEMOLYTIC PROCESS!

lab findings:

• increased serum unconjugated bilirubin (total bili not usually exceeding 5 mg/dL)
• negative urine bili
• increased urobilinogen

Question 18

Gilbert’s syndrome

Answer 18

mild reduction in UDP= hepatic cause of jaundice

• serum total bili < 3.0 mg/dL (primarily composed of unconjugated bili, and increased urinary urobilinogen)

Question 19

Crigler-Najjar type I

Answer 19

enzyme mutation/absence in UDPGT = (hepatic cause of jaundice)

findings:
- serum unconj. bili > 5.0 mg/dL, increased urinary urobilinogen

Question 20

Dubin-Johnson syndrome/Rotors

Answer 20

defective secretion by hepatocyte, hepatic jaundice

findings = increased serum conjugated bilirubin, black liver (only in Dubin Johson)

Question 21

hepatitis

Answer 21

see lowered conjucation and excretion resulting in increased direct and indirect bili with total levels being 5-10mg/dL

Question 22

posthepatic jaundice

Answer 22

due to mechanical obstruction of flow of bile, into intestines due to gallstones or tumors

see increased serum AND urine conjugated bilirubin

see decreased level of urobilin/stercobilin in the stool (clay colored stools)

negative urinary urobilinogen

Question 23

haptoglobin

Answer 23

binds up free hemoglobin that is released into the circulation - when the binding capacity is exceeded the hgb is converted into methemoglobin (carrying Fe3+)

low plasma haptoglobin is an early indicator of xs Hgb breakdwon

Question 24

heme synthesis?

Answer 24

formation of porphobilinogen from SuccCoA and glycine

formation of heme from protoporphyrin ring and Fe

Iron is inserted into protoporphyrin by ferrocheltase to form heme

Question 25

mutation in delta ALA synthetase?

Answer 25

leads to sideroblastic anemia (in mito)

a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells

Question 26

mutation in prophobilinogen sythase (ALA dehydrogenase)/PGB deaminase?

Answer 26

porphyria: (in cytosol) mutations result in deposits in the skin that cause itching and photosensitivity - historically people are unable to avoid the light

lead poisoning can also lead to this

Question 27

mutations in ferrochelatase?

Answer 27

protophorphyria (in mito)

lead poisoning can also lead to this

Question 28

where are alpha and beta chains?

Answer 28

alpha = chromosome 16
beta = chromosome 11

disruption of the chain balances is called thalassemia

fetal Hgb see gamma globulins along with alpha

Question 29

where does hemoglobin synth occur?

Answer 29

immature RBCs and in bone marrow - supplied iron via transferrin

Normal adult hemoglobin (HbA) consists of four heme groups and four globin chains (two α and two β) twisted together so the heme groups are exposed on the outside of the molecule

Normal synthesis depends on:
an adequate supply of Fe (transferred to the marrow in plasma via transferrin from sites of absorption/storage)
normal heme (synthesized in mitochondria) and….
normal globin synthesis (synthesized in the cytoplasmic ribosomes)

Question 30

how do RBCs get energy?

Answer 30

glycolysis, 90%

pentose phosphate cycle, 10%

Question 31

hemoglobinemia

Answer 31

free hgb in plasma - this is nephrotoxic

hemoglobinuria = free hgb in the urine

Question 32

sickle cell

Answer 32

missence, point mutation of Val –> glut

Missense mutation during globin chain production causes hemoglobin to be susceptible to polymerization at low oxygen concentrations or with dehydration
Reduces flexibility of RBC membrane
“sickling” of the RBCs results with hemolytic episodes &
possible jaundice due to the hemolysis

Result: Hypoxic tissue injury from micro-vascular occlusions-”crises”
Painful muscle aches and pains – tissue damage

*** These patients will have high levels of bilirubin/jaundiced