1. Heme synthesis occurs in mitochondria and involves two starting molecules, succinyl CoA and glycine. The reaction produces aminolevulonic acid and needs the enzyme ALA synthase. 2. There are several types of hemoglobin in humans including HbA, HbA2, fetal Hb, and HbA1c. HbA1c levels are used to monitor diabetes by indicating average blood glucose levels over several weeks. 3. Abnormal hemoglobins include methemoglobin, carboxyhemoglobin, sulfhemoglobin, and hematin. Porphyrias are diseases caused by deficiencies in heme synthesis enzymes that can cause anemia, pain, and photosensitivity.

1. Heme metabolism
Dr. Mohamed Badr

7. Heme synthesis: A.Location: a. Intracellular location: Mitochondria,cytosol and
then mitochondria again. b. Organ location: Liver and bone marrow. B. Steps:
1) The two starting molecules are succinyl CoA (derived from citric acid cycle)
and Glycine. The reaction occur in mitochondria and needs aminolevulonic
acid (ALA) synthase enzyme and pyridoxal phosphate as activator for glycine

9. Ferrochelatase

13. B. Types of hemoglobin:
Several different types of haemoglobin are normally found in human. They
vary in
the primary structure of the peptide chains of globin.
1- Hemoglobin A:
It is the major Hemoglobin in adults (97%).
Its globin comprises 4 polypeptide chains: 2 alpha and 2 Beta chains.
2- Hemoglobin A2:
It is minor in adults (2%).
Its globin comprises 4 polypeptide chains: 2 alpha and 2 Delta chains.
3- Fetal hemoglobin (HbF):
It is present in fetus during intrauterine fetal life.
It is 1 % of adult human hemoglobin.
Its globin comprises 4 polypeptide chains: 2 Alpha and 2 gamma chains.
4- Hemoglobin A1c (Glycated hemoglobin):
Hemoglobin A reacts non-enzymatically with glucose to form glycated
hemoglobin (HbA1c). It is normal Value: 5 – 6.5 %.
In diabetes mellitus the concentration of HbA1c may reach 12 % or more
The HbA1c level is proportional to average blood glucose concentration
over the previous four weeks to three months.
The HbA1c is used in monitoring Diabetes Mellitus.

14. Abnormal derivatives of haemoglobin
1- Methemoglobin (Met-Hb):
It is oxidized hemoglobin (Fe++ oxidized to Fe+++).
Oxidation may occur by some drugs, hydrogen peroxides, and free radicals.
Met-Hb binds oxygen irreversibly thus cannot act as oxygen carrier.
2- Carboxyhemoglobin (COHb):
It is hemoglobin combined with carbon monoxide.
Carbon monoxide has 200 time greater affinity to Hb than oxygen.
Increase in COHb more than 40% results in unconsciousness and may be
fatal.
3- Sulfhemoglobin (S-Hb):
It is hemoglobin combined with sulfur.
It is caused by exposure of hemoglobin to toxic effect of certain drugs as
sulfonamides.
S-Hb produce anoxia & cyanosis because it cannot act as oxygen carrier.
4- Hematin:
It is hemoglobin without iron (i.e. protoporphyrin combined with globin).
It may be formed following intravascular hemolysis

15. Porphyrias: A.These are a group of diseases resulting
from a deficiency of one of the enzymes needed for
heme synthesis. Effect of porphyraris: porphyrias lead to
disturbance in heme synthesis and causes:
1) Anemia: due to decrease production of heme.
2) Abdominal pain and neuropsychiatric symptoms due
to toxic effect of accumulated porphyrin
intermediates.
3) Photosensitivity: Some porphyrin derivatives when
exposed to light react with molecular oxygen to
form oxygen radicals which cause skin damage. B.
Porphyrias are either hereditary or acquired.

18. Hemoglobin Catabolism
The average life span of red blood cells is 120 days.
At the end of that time, they are removed from the
circulation by the cells of reticuloendothelial system mostly
present in liver, spleen and bone marrow, where they are
hemolysed and hemoglobin comes out giving globin and
heme molecules.
Globin molecule is hydrolyzed into amino acids.
Heme gives iron and bilirubin.

23. Types of Hyperbilirubinemia
A. Neonatal (Physiological) 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.
If bilirubin levels are judged to be too high, then phototherapy with
UV light as bilirubin is broken down in light.
Jaundice within the first 24 hrs. of life or which takes longer than 10
days to resolve is usually pathological and needs to be further
investigated.

30. Pathological Hyperbilirubinemia
1. Prehepatic (haemolytic) Jaundice
Results from excess production of bilirubin (beyond the livers ability
to conjugate it) following hemolysis.
Excess RBC lysis is commonly the results of autoimmune diseases;
hemolytic disease of the newborn; structurally abnormal RBC’s (sickle
cell disease).
High plasma concentrations of unconjugated bilirubin (normal
concentration 0.5 mg/dl)

31. Types Causes Characters
Pre-hepatic jaundice
(Hemolytic jaundice)
Excessive destruction
of RBCs.
 ↑ in unconjugated or indirect bilirubin
(serum bilirubin exceeds 5 mg/dl)
 Bilirubin not appears in the urine
(why)
 unconjugated bilirubin if increased, can
cross BBB and cause brain damage.
Hepatic jaundice
(Hepatocellular)
liver cell damage by
cirrhosis, infective
hepatitis, or toxins
 ↑ Both direct & indirect bilirubin due to
impaired cellular uptake of bilirubin by
liver cells or from abnormal secretion
of bilirubinby the livercells
Types Causes Characters
Post-hepatic jaundice
(Obstructive)
mechanical obstruction
oftheflow ofbile
into the
intestine either by
stoneortumorofhead of
pancreas
 ↑inconjugated bilirubin
 Thestoolbecomesclaycolored.
 Conjugatedbilirubinappearsinurine
 Bilirubin & bile salts are return to
blood, increased bile salts in blood
leads to Itching (because bile salts are
irritant to sensory nerve) &
Bradycardia

32. Post hepatic 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.
Characterized by pale colored stool (absence of fecal bilirubin or urobilin),
and dark urine (increased conjugated bilirubin).
In a complete obstruction, urobilin is absent from the urine.

34. Type Cause Age Characters
Gilbert's disease Mild deficiency of
UDP-glucuronyl
transferase enzyme
At any age Male
more
than female
Bilirubin concentration less
than 3 mg/dl
Crigler-Najjar
syndrome
Marked reduction of
UDP-glucuronyl
transferase enzyme
Neonates
leading to
kernicterus →
early death
bilirubin concentration
exceeds 20 mg/dl
Dubin-Johnson
syndrome (conjugated
non
cholestatic)
defect in hepatic
secretion of
conjugated bilirubin into
bile
adult life ↑ conjugated bilirubin
 Normal bile acid level
(exclude cholestasis)
 Bilirubin present
in urine
 Prognosis is excellent
 No treatment needed.
Congenital hyperbilirubinemia:

35. Gilbert's syndrome Crigler-Najjar syndrome
 Due to defect in uptake of
bilirubin by liver &low
activity of UDPG
transferase.
 Due to deficiency of UDPG
transferase
 Attacks bet.10 -20 years old  Presents at birth
 plasma level of IB =1.2-2.5
mg/dl
 plasma level of IB exceeds the
protein binding capacity
 No kernicterus  kernicterus present
 Harmless condition  Serious condition
 Confusion with hepatitis &
hemolysis