Heme Degradation And Iron Metabolism

Question 1

What are our sources of Heme?

Answer 1

Haemoglobin and cytochrome

Question 2

What are the substances involved in heme degradation

Answer 2

Heme. Biliverdin. Bilirubin. Urobilinogen. Urobilin. Stercobilin

Question 3

Where does bilirubin production occur and how?

Answer 3

It happens in the reticuloendothelial system (RES). Which are in monocytes ( in spleen and lymphocytes) and macrophages (kuppfer cells). Hemes’ tetrapyrrol rings’ methyl bridge between the A and B subunits is broken by heme oxidase, and the C is released as CO, the O atoms are oxidized and become ketones. This forms biliverdin. Now biliverdin reductase forms bilirubin by reduction of the central methyl bridge and turning NADPH into NADP

Question 4

Explain bilirubin processing

Answer 4

Bilirubin in the large intestine is called urobilinogen.

It is converted to urobilin (yellow colour for urine in the kidneys) and stercobilin (brown colour for feces)

Question 5

Where does lysis of RBC occur

Answer 5

Normally extravascularly - in monocytes and macrophages

Can be intravascularly- in the blood stream (spontaneous lysis)

Question 6

Explain the extravascular pathway for RBC degradation

Answer 6

RBC are phagocytised and Hb is acted upon. The globus chains are turned into amino acids. The heme is turned into Fe2+ by heme oxidase and into bilirubin

Question 7

What occurs during intravascular degradation?

Answer 7

Haptoglobin: binds free hemoglobin and delivers it to liver and spleen, where it is metabolized to iron-globin complexes and bilirubin. This mechanism prevents loss of iron in the urine.
•Hemopexin: binds free heme. The heme-hemopexin complex is taken up by the liver and the iron is stored bound to ferritin.
•Methemalbumin: complex of oxidized heme and albumin.

Question 8

Refer to slide 6, and 13, 20, 26,29,30, 31, 39

Answer 8

For amount of bilirubin in humans

Question 9

Explain the hepatocellular bilirubin transport

Answer 9

Albumin-bound bilirubin in sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte surface, entering the cell by both facilitated and simple diffusional processes. Within the cell it is bound to glutathione-S-transferases and conjugated by bilirubin-UDP-glucuronosyltransferase (UGT1A1) to mono and diglucuronides, which are actively transported across the canalicular membrane into the bile.
MRP2 : multidrug resistance associated protein

Question 10

What is the conjugation of bilirubin

Answer 10

It is the conversion of hydrophobic bilirubin into hydrophilic bilirubin diglucoronide (or mono). Done by adding UDP- glucoronic acid (oxidized form of UDP- glucose)

Question 11

How is bilirubin present in circulation . What are the opposing effects of CO and bilirubin

Answer 11

It is bound with albumin forming serum albumin.
CO has a vasodilator effect
Bilirubin has an antioxidant effect

Question 12

What is HYPERBILIRUBINEMIA

Answer 12

It is an increased plasma concentration of bilirubin ( >1.2mg/dL). This is diagnosed as jaundice. It has 3 divisions : prehepatic, intrahepatic, posthepatic jaundice.

Question 13

Explain prehepatic jaundice (hemolytic)

Answer 13

Is uncommon, is caused by hemolysis, and is in autoimmune or abnormal HB.
Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis.
• Excess RBC lysis is commonly the result of autoimmune diseases, hemolytic disease of the newborn (Rh- or ABO- incompatibility), structurally abnormal RBCs (Sickle cell disease), or breakdown of extravasated blood.
• High plasma concentrations of unconjugated bilirubin (normal concentration ~0.5 mg/dL)

Question 14

Explain intrahepatic jaundice

Answer 14

Impaired liver uptake, conjugation, or secretion of bilirubin.
• Reflects a generalized liver (hepatocyte) dysfunction.
• In this hyperbilirubinemia case, is usually accompanied by other abnormalities in biochemical markers of liver function.

Question 15

Explain posthepatic jaundice

Answer 15

Caused by an obstruction of the biliary tree
. • Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma.
• Characterized by pale colored stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin).
• In a complete obstruction, urobilin is absent from the urine.

Question 16

Explain neo natal jaundice

Answer 16

Common, particularly in premature infants
• Transient (resolves in the first 10 days)
• Due to immaturity of the enzymes involved in bilirubin conjugation
• High levels of unconjugated bilirubin are toxic to the newborn – due to its hydrophobicity it can cross the blood-brain barrier and cause a type of mental retardation known as kernicterus • If bilirubin levels are judged to be too high (> 12-14 mg/dl), then phototherapy with UV light is used to convert it to a water soluble, non-toxic form
• If necessary, exchange blood transfusion is used to remove excess bilirubin
• Phenobarbital is sometimes administered to moms prior to an induced labor of a premature infant – crosses the placenta and induces the synthesis of UDP glucuronyl transferase
• Jaundice within the first 24 hrs of life or which takes longer then 10 days to resolve is usually pathological and needs to be further investigated

Question 17

What is Gilberts syndrome

Answer 17

Benign liver disorder
•½ of the affected individuals inherited it
•Characterized by mild, fluctuating increases in unconjugated bilirubin caused by decreased ability of the liver to conjugate bilirubin – often correlated with fasting or illness
•Males more frequently affected then females
•Onset of symptoms in teens, early 20’s or 30’s
•Can be treated with small doses of phenobarbital to stimulate UDP glucuronyl transferase activity

Question 18

What is crigler najar syndrome

Answer 18

Autosomal recessive
•Extremely rare (< 200 cases worldwide; gene frequency is < 1:1000)
•High incidence in the “plain people of Pennsylvania” (Amish and Mennonites)
•Characterized by a complete absence or marked reduction in bilirubin conjugation
•Present with a severe unconjugated hyperbilirubinemia that usually presents at birth
•Afflicted individuals are at a high risk for kernicterus
•Condition is fatal when the enzyme is completely absent
•Treated by phototherapy (10-12 hrs/day) and liver transplant by age 5

Question 19

What are dubins Johnson and rottars syndrome , how are they different

Answer 19

Characterized by impaired biliary secretion of conjugated bilirubin • Present with a conjugated hyperbilirubinemia that is usually mild .
Dubins has a MRP2 transporter defect, and there is an accumulation of dark pigments

Question 20

What is the function of feroxidase

Answer 20

The oxidation of iron to the 3+ state as it leaves the enterocytes

Question 21

What is hemosiderin

Answer 21

It is a glycogen like form of ferritin

Question 22

Discuss iron absorbtion

Answer 22

Low but regulated (10-15% of Fe2+ from the diet)
• Ferric to ferrous iron conversion is needed (Fe3+ → Fe2+)
• Reducing agents aid uptake (vitamin C)
• Heme iron by separate pathway (unknown
• Factors in breast milk facilitate uptake (lactoferrin)

Question 23

What are the promoters of non- heme iron

Answer 23

Ascorbic  acid 
Meat 
Citric Acid 
Some  spices
 Beta-carotene
 Alcohol

Question 24

What are inhibitors of non- heme iron

Answer 24

Phytic acid
Polyphenols
Tannins
Calcium

Question 25

Explain ferritin, serum ferritin, and hemosiderin

Answer 25

Ferritin (most common in liver but also found in the spleen).
• Serum ferritin (concentration of ferritin-bound Fe is low compared to that of transferrin-bound Fe)
• Hemosiderin (only made when iron concentration is very high)

Question 26

Iron mobilisation is dependant on

Answer 26

Copper ferroxidases

Question 27

Iron imbalance can be due to

Answer 27

Excretion
Deficiency
Toxicity ( hemochromatosis, enviromental , genetic)

Question 28

What are the consequences of iron deficiency

Answer 28

Poor pregnancy outcomes
• Increased perinatal morbidity
• Defective psychomotor development
• Impaired educational performance • Impaired work capacity

Question 29

What is hepcidin

Answer 29

Liver-produced antimicrobial peptide
• Lowers iron absorption by binding to ferroportin, resulting in internalization, and degradation
• Expression is complex and related to liver iron mediated by TfR2 (high iron levels in the blood plasma induce HAMP synthesis)
• Expression increased by IL6