13714687 Catabolism of Heme

8/14/2019 13714687 Catabolism of Heme

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2009دط عومك – الحويالءدولبخصحضرات ايهب/دواسالالدةإعاد-

CATABOLISM OF HEME

A. Introduction:

1. The average life of the red blood cells is 120 days.2. At the end of that time, they are removed from circulation by the cells

of reticuloendothelial (RE) system present in liver, spleen and bone

marrow. They are hemolysed and hemoglobin comes out, giving globin and heme

molecules.

a) Globin molecule hydrolyzes into free amino acids.

b) Heme gives iron and bilirubin




B. Formation of bilirubin:

1. The heme ring is catabolized by the microsomal heme oxygenase

enzymes of the RE cells.

2. In this reaction (which needs, heme oxygenase enzyme, O2 andNADPH), iron (Fe++) is removed for re-use. The remaining of heme

ring is cleaved between pyrrole rings number I and II to form biliverdin

(green pigment) and carbon monoxide (CO)

3. Biliverdin is then reduced into bilirubin (golden yellow) in a reactionrequires biliverdin reductase enzyme.







C. Transport of bilirubin in the plasma:

1. Bilirubin is nonpolar, and is insoluble in plasma. Therefore it bindsby noncovalent bonds to plasma albumin. This form is called:unconjugated or indirect bilirubin.

D. Uptake of bilirubin by the liver:

1. Bilirubin dissociates from the carrier albumin molecule and enters

hepatocytes.

2. Bilirubin is conjugated with one or two molecules of glucuronic

acid (the acid form of glucose) to form bilirubin monoglucuronide and

bilirubin diglucuronide. This reaction needsUDP-glucuronyl transferase enzyme:

E. Secretion of bilirubin into bile:

Bilirubin diglucuronide is actively transported against concentration

gradient into the bile canalciuli and then into the bile.




F. Formation of urobilin in the intestine:

1. Intestinal bacteria acts on bilirubin diglucuronide leading to:

a) Removal of glucuronides (by -glucuronidases enzymes).

b) Reduction of bilirubin to colorless compounds called:

urobilinogens2. A small fraction of urobilinogens are reabsorbed from intestine to the

liver again and re-excreted in the bile, forming the enterohepatic

urobilinogens cycle.




G. Excretion of urobilinogens in stool and urine:

1. Most of the colorless urobilinogens are oxidized to the colored

urobilin .which excreted in the stool giving its brown color.

2. Part of urobilinogens are reabsorbed to the liver, then to the blood to be

excreted by the kidney in urine and converted into urobilin.3.Urobilin -together with urochrome-give the characteristic yellow color

of urine.

Van den Bergh reaction

1-This is a reaction between bilirubin and Ehrlich diazo reagent givinga reddish purple compound.

2- Conjugated bilirubin reacts directly with the reagent. Thus it is

called: direct bilirubin

3- Unconjugated bilirubin does not react with the reagent directly

except after addition of methyl alcohol. Thus it may be called: indirectbilirubin

Differences between unconjugated bilirubin and conjugated bilirubin

Unconjugated bilirubin Conjugated bilirubin

1 Present normally in plasma 1 Present normally in bile.

2 Attached non-covalently to

albumin.2 Conjugated to glucuronic acid.

3 Has high molecular weight and

cannot be filtered through thekidney.

3 Has small molecular weight

and if present in plasma can befiltered through the kidney.

4 Nonpolar, insoluble in plasma

and can cross brain barrier in

neonates causing brain damage.

4 Polar, soluble In plasma and

can not cross brain barrier.

5 Gives indirect Van den Bergh

reaction.5 Gives direct Van den Bergh

Heme catabolism is classified into several stages:

Stage 1: Formation of bilirubin in reticuloendothelial system. Inreticuloendothelial system (RES), hemoglobin is degraded into heme

and globin. Globin is either degraded to amino acids or reused for

synthesis of hemoglohin. Heme is converted into biliverdin (green)

then to bilirubin (yellow).

One gram of hemoglobin yields 35 mg of bilirubin. The daily bilirubin

formation in adult human is about 250 mg. Bilirubin is transported to the

liver in conjunction with plasma albumin (termed indirect or




unconjugated bilirubin). Each molecule of albumin has one high

affinity site and one low affinity site for bilirubin.

Stage II: This stage occurs in the liver and can be divided into three

processes:

1-Uptake of bilirubin by liver parenchymal cells.

This is followed by removal of albumin and release of free bilirubin.

2-Synthesis of bilirubin-diglucuronide.

This is catalyzed by bilirubin-glucuronyl-transterase to form bilirubin

diglucuronide. UDP-glucuronate (UDP-GlcUA) acts as donor or the

glucuronate group to form bilirubin-monoglucuronide then bilirubin-diglucuronide (termed cholebilirubin. direct or conjugated bilirubin)

and it is water soluble.

3-Bilirubin-diglucuronide is actively secreted into bile.

Stage III: This is produced by the action of intestinal bacteria.

Bilirubin is deconjugated from glucuronate, and then reduced tourobilinogens (colorless). Most of urobilinogens are excreted in feces

and oxidized to the colored pigments urobilins by oxygen. This explains

darkening of feces upon standing in air. Normally small amounts of

urobilinogens are reabsorbed by portal blood and excreted by liver cells

into bile (enterohepatic circulation) and traces escape and excreted in

urine.

Plasma Bilirubin or Bile Pigments

The nonnal level of bilirubin in plasma (or serum) is less than 1.2 mg/dL

and it is present in two forms, indirect and direct.

1-Indirect reacting (bilirubin-albumin complex or unconjugated bilirubin).

It requires the addition of methanol to react with the diazo reagent of Van den Bergh (used for its estimation). It is the main fonn present

nonnally in plasma and it ranges from 0.3 to 0.8 mg/dL. It increases in allcases of hemolytic anemia and when liver fails to take up or conjugate

bilirubin.




2-Direct reacting (bilirubin-diglucuronide or conjugated bilirubin).

It is water-soluble and reacts directly with the diazo reagent of van den

Bergh. It represents the bilirubin-diglucuronide which escapes from

liver to systemic blood. It increases when liver fails to excrete bilirubin

after conjugation or when there is obstruction in the biliary system thatprevents its passage to the intestine. Normally its level in plasma is less

than 0.3 mg/ldL.

HYPERBILIRUBINEMIA

Hyperbilirubinemia exists when bilirubin levels exceeds 1.2 mg/dL.Jaundice (yellow discoloration of skin and sclera of eyes) becomes

manifest usually at levels above 2 mg/dL.

Depending on the type of bilirubin present in plasma,

hyperbilirubinemias include two main types, unconjugated andconjugated hyperbilirubinemias.

A-Unconjugated Hyperbilirubinemia

It is due to overproduction of bilirubin by reticuloendothelial system

over the capacity of the liver to remove and clear from blood. It is

characterized by high level of indirect or unconjugated bilirubin. This

type of bilirubin can cross the blood-brain barrier into the central

nervous system and cause kernicterus (encephalopathy).

Unconjugated bilirubin is water insoluble and not excreted in urine

(acholuric jaundice).

Unconjugated hyperbilirubinemia occurs in the following conditions:

I-Neonatal or Physiologic Jaundice: This is the most common cause of

jaundice in neonatal age. It results from accelerated hemolysis and

immature hepatic system for uptake, conjugation and secretion of

bilirubin. It is characterized by high plasma level of unconjugated

bilirubin, if it exceeds 20-25 mg/dL

These cases are treated by:

a-Phenobarbital which acts as inducer for UDP-glucuronyl transferase

enzyme.

b-Phototherapy (exposure to visible light) helps hepatic excretion of

bilirubin by converting bilirubin to other derivatives that are more soluble

and easily excreted in bile.




II-Hemolytic jaundice (Anemia) Hemolytic anemia is caused by one of the following causes:

1-The presence of abnormal hemoglobins e.g. sickle cell anemia and

thalathemia.

2-Erythroblastosis fetalis: when Rh negative mother has Rh positivefetus (due to Rh positive father).

3-Congenital spherocytosis where the red cells are abnormally fragile.

4-Favism, due to deficiency of G 6 PD.

5-Deficiency of Pyruvate kinase or other glycolytic enzymes

6-Incompatibl blood transfusion.

7-Some diseases e.g. malaria and black water fever

III-Congenital Syndromes related to uptake and conjugation of

bilirubin as follow :

1. Crigler-Najjar Syndrome

Type 1: Due to severe decrease in the activity of UDP-glucuronyltransferase.

Type II: Due to decreased activity of UDP-glucuronyl transferase

that adds the second glucuronide group.

2. Gilbert Disease It is mainly due to hepatic defect in the uptake of bilirubin by

liver cells.

IV-Toxic HyperbilirubinemiaThis is due to toxin-induced liver dysfunctions e.g. chloroform, carbon

tetrachloride and mushroom poisoning.

B-Conjugated Hyperbilirubinemia

Conjugated hyperbilirubinemia is due to reflux of direct or conjugated

bilirubin into blood due to biliary obstruction, conjugated bilirubin is

water soluble, so it is excreted in urine and darken its colour (Choluric

jaundice).

It occurs in the following conditions:

1-Obstructive Jaundice (Cholestatic Jaundice) Conjugated hyperbilirubinemia results from blockage of hepatic or

common bile duct (stones and tumors), bilirubin diglucuronide is not

excreted and returns to hepatic veins and lymphatics and appears in bloodand urine.

It may be produced by micro-obstruction of intrahepatic biliary ductules

by swollen damaged hepatocytes e.g. viral hepatitis and liver cirrhosis.

Both cases are associated with marked increase of conjugated bilirubin



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13714687 Catabolism of Heme