Heme, Iron and Billirubin DSA 8/21

Question 1

Hemoglobin synthesis

Answer 1

• occurs in immature RBCs in bone marrow.
• Synthesis depends on supply of Fe (transferred to marrow in plasma via transferrin), normal heme (sythesized in mitochondria) and normal globin synthesis (synthesized in the cytoplasmic ribosomes).
• Heme leaves the mitochondria and is joined to the globin chains in the cytoplasm

Question 2

Hemoglobin binding Fe

Answer 2

Hemeoglobin can only bind Fe2+, if it is oxidized to Fe3+ (because of drugs like nitrites or sulfonamides) - Methemoglobin is formed which is incapable of binding O2. Erythrocytes conver methemoglobin to hemoglobin via methemoglobin reductase.

Question 3

Heme Iron

Answer 3

There are two types of dietary Fe (heme and nonheme)- both which are absorbed differently by the duodenum

• Heme Iron is from breakdown of myoglobin and hemoglobin.
• absorbed by duodenal epithelial cells via binding or endocytosis
• inside cells, heme oxygenase splits heme iron, releases Free Fe3+, CO and biliverdin –> bilirubin
• enterocytes convert Fe+3 to Fe+2

Question 4

Nonheme Iron: Transport into cells, movement to liver….

Answer 4

• this is dietary iron: may be either ferric of ferrous form (ferrous is absorbed more readily by GI Mucosa)
• dietary Fe3+ reduced to Fe2+ by ferric reductase (Dcytb) prior to absorption
• DMT1: cotransports Fe2+ and H+ into cells
• Fe2+ moves into cell and binds to mobilferrin at basolateral membrane.
• Fe2+ exits cells via FP1 and it is converted back to Fe3+ and binds to transferrin for transport to other tissues!
• circulating Fe is primarily deposited in the liver and RES by binding to the protein apoferritin to form ferritin (storage form of iron)

Question 5

“Iron Buffer System”

Answer 5

Fe binds to the protein apoferritin to form ferritin for storage in the liver.
- Apoferritin is called the “iron buffer system” b/c it can take up excess circulating iron for storage or release iron when circulating levels are too low –> maintains a constant serum iron level.

Question 6

Hepcidin

Answer 6

Regulation of Iron Absorption:

• Hepcidin (encoded by HAMP gene) is primary negative regulator and is a circulating peptide secreted by hepatocytes
• It binds to ferroportin at cell surface to initiate ferroportin internalization (through DMT1) and degredation by lysosomes
• hepcidin-dependent regulation of ferroportin reduces dietary iron absorption
• loss of the hepcidin protein results in SEVERE IRON OVERLOAD.

Question 7

Bilirubin

Answer 7

• breakdown product of the hemoglobin molecule liberated from dead erythrocytes by the reticuloendothelial system (RES)
• transported by the hepatobiliary system into the hepatocytes for conjugation and secretion

Question 8

Bilirubin Metabolism (Part I): from hemoglobin –> hepatocytes

Answer 8

• Hemoglobin from RBC’s is degraded into heme-iron complex and a globin chain by macrophages
• Heme moiety is converted to BILIVERDIN and Fe
• Fe is reabsorbed and recylced to be used in formation of new RBCs
  Bilverdin is converted to UNCONJUGATED OR WATER-INSOLUBLE BILIRUBIN.
• Unconjugated bilirubin enters circulation is is combined with albumin. It then enters the hepatocytes through passive diffusion or receptor-mediated endocytosis where it goes to SER of hepatocytes.

Question 9

Bilirubin Metabolism (Part II): from hepatocytes

Answer 9

• At the SER of hepatocytes uncongugated bilirubin is converted to CONJUGATED OR WATER-SOLUBLE BILIRUBIN via UDPGT.
• UDPGT adds glucuronide to bilirubin molecule to form bilirubin diglucoruronide
• the conjugated bilirubin enters the bile canaaliculai for active secretion into the intestinal tract (where its degraded into urobilnogen and urobilin) or a small part of urobilinogen remaining in the gut is betabolized to stercobilin (gives stool its pigment color)

Question 10

Hyperbilirubenemia

Answer 10

• this occurs when there is too much urobilinogen in the urine
• ->the majority of urobilinogen is reabsorbed by the gut and re-excreted by the liver with a small amount excreted in the urine

Question 11

Jaundice

Answer 11

Accumulation of bilirbuin in the serum

• ->usually conjugation allows the bilirubin to be excreted from the liver, but in hepatocellular diseases or biliary obstructive disease the bilirubin is not excreted.
• -> increased urinary bilirubin is the result of an increase in serum bilirubin

Question 12

Physical Jaundice of the Newborn

Answer 12

Unconjugated bilirubin can be converted to the “cis” form via light which is more easily excreted in the urine. Newborns with elevated unconjugated bilirubin are placed under a “bili lght” and the light allows for the conversion to cis unconjugated bilirubin for easier elimination.