BLOOD PHYSIOLOGY Hb Synthesis, degradation, jaundice and Iron metabolism

By Dr. Mudassar Ali Roomi (MBBS, M. Phil)

Assistant Professor Physiology

Formation of hemoglobin

 Synthesis of Hb begins in the proerythroblasts and continues even into the reticulocyte stage of the RBCs. MCQ Steps of hemoglobin synthesis: 1. succinyl-CoA binds with glycine to form a pyrrole molecule (Mitochondria) MCQ 2. four pyrroles combine to form protoporphyrinI X, which then combines with iron to form the heme molecule. 3. Finally, each heme molecule combines with a globin chain forming a subunit of Hb called a Hb chain 4. Each chain has a molecular weight of about 16,000; four of these in turn bind together loosely to form the whole Hb molecule. 5. Hb has a molecular weight of about 64,000.

Formation of hemoglobin

Figure 326 Basic structure of Hb molecule, showing one of the four heme chains that bind together to form the Hb molecule.

Oxygen does not combine with the two positive bonds of the iron in the hemoglobin molecule. Instead, it binds loosely with one of the socalled coordination bonds of the iron atom. MCQ

four molecules of oxygen (or eight oxygen atoms) can be transported by each Hb molecule. MCQ

Normal Types of Hb in humans

= alpha, = beta, = gamma, = delta, = epsilon, =zeta In the embryo: In the fetus:
Gower 1 (22) Gower 2 (22)

In postnatal people:

Hemoglobin F (22) MCQ

Hemoglobin A (22) The most common with a normal amount over 95%. MCQ Hemoglobin A2 (22) chain synthesis begins late in the third trimester and, in adults, it has a normal range of 1.53.5%. MCQ

Variant forms of Hb that cause disease:

Hemoglobin S (2S2) A beta chain variant form of Hb found in people withsickle cell disease. Hb C (2C2) Another variant due to a variation in the -chain gene.

FATE OF RED BLOOD CELLS

Life span in blood stream is 120 days. MCQ old and fragile RBCs are phagocytosed and are lysed. Normally, lysis occurs extravascularly in the reticuloendothelial system subsequent to RBC phagocytosis. Lysis can also occur intravascularly (in blood stream) .

PATHWAY FOR RBC DESTRUCTION

Lysis in: Liver, Bone marrow, & Spleen
Phagocytosis & Lysis

Hemoglobin

Globin

Heme

Bilirubin

Amino acids

Fe2+

Amino acid pool

Recycled

Excreted

DEGRADATION OF HEME TO BILIRUBIN

85% bilirubin is derived from heme as a result of RBC degradation. In normal adults this results in a daily load of 250-300 mg of bilirubin but liver has the ability to conjugate 3000mg /day of bilirubin.
P450 cytochrome

Normal plasma concentration of bilirubin is < 1 mg/dl and jaundice occurs usually at conc. Is > 2mg/dl. MCQ bilirubin is Hydrophobic or water insoluble and is transported by albumin to the liver for further metabolism prior to its excretion.

unconjugated bilirubin

Heme Degradation
NADPH Fe+3 NADPH NADP+

Heme Catabolism

HEME

O2 NADP+

(opens the porphyrin ring)

BILIVERDIN

BILIRUBIN

BILIRUBIN diglucuronide

BILE

JAUNDICE
Due to Hyperbilirubinemia (greater than 2mg/dl):

Two forms of bilirubin:

Direct bilirubin: Conjugated with glucoronic acid and is soluble in water.
Indirect bilirubin: unconjugated, insoluble in water.

DIFFERENCES BETWEEN
UNCONJUGATED BILIRUBIN Insoluble in water. Cannot be excreted in urine. Can deposit in brain(kernicterus). CONJUGATED BILIRUBIN Soluble in water. Can be excreted in urine. Cannot be deposited in brain.

Plasma level increases in pre-hepatic jaundice.

Plasma level increases in hepatic and post-hepatic jaundice.

Hemolytic jaundice

Hepatocellular jaundice

Obstructive jaundice

excess hemolysis

unconjugated bilirubin (in blood) conjugated bilirubin (released to bile duct)

unconjugated bilirubin (in blood) conjugated bilirubin (in blood)

unconjugated bilirubin (in blood) conjugated bilirubin (in blood)

PREHEPATIC (HEMOLYTIC) JAUNDICE

Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis. Excess RBC lysis is commonly the result of hemolytic diseases, structurally abnormal RBCs (Sickle cell disease). High plasma concentrations of unconjugated bilirubin (normal concentration ~0.5 mg/dL)

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

POSTHEPATIC JAUNDICE
Caused by an obstruction of the biliary tree.

Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma which causes itching. Characterized by paleor clay coloured stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin)
In a complete obstruction, urobilin is absent from the urine

DIAGNOSES OF JAUNDICE

NEONATAL JAUNDICE
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. MCQ

If bilirubin levels are judged to be too high, then phototherapy with UV light is used to convert it to a water soluble, non-toxic form

IRON METABOLISM

 iron is important for the formation of: hemoglobin, myoglobin, cytochromes, cytochrome oxidase, peroxidase and catalase. MCQ The total iron in the body 4 to 5 grams:
65 %in the form of Hb 4 %in the form of myoglobin, 1 % in cytochromes, 0.1 % is combined with the protein transferrin in the blood plasma 15 to 30 per cent is stored for later use, mainly in the reticuloendothelial system and liver parenchymal cells, principally in the form of ferritin.

Transport and Storage of Iron

TRANSPORT FORM OF IRON= MCQ STORAGE FORM OF IRON=
soluble form of iron. MCQ insoluble form of iron. MCQ

Daily Loss of Iron:

A man excretes about 0.6 mg Fe/day, mainly into the feces.

In a woman Fe loss is about 1.3 mg/day.