abnormal hemoglobin metabolism

1. ABNORMAL HEMOGLOBIN METABOLISM
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HEMOGLOBINOPATHIES

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OBJECTIVES
To review some of the variant Hemoglobins.
To briefly review some types of
Hemoglobinopathies.
To diagnose and treat Hemoglobinopathies.

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HEMOGLOBIN STRUCTURE
Is a Tetramer composed of 2 pairs of globin
(polypeptide) chains.
Alpha-beta dimers (insoluble) , aggregate to form
(soluble) Tetramers.
Heme Complex of (ferrous iron and protoporphyrin)
Covalently linked to each Globin monomer Reversibly
binds one oxygen molecule

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Hemoglobin Structure
Primary Structure
Alpha chain – 141 amino acids
Beta chain – 146 amino acids
HbA: α2β2
HbA2: α2δ2
HbF: α2γ2

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Definition:
•Are genetic diseases due to Hb molecule abnormality in
which an individual inherited the allele for an abnormal
hemoglobin from one or both parents causing:
1- Qualitative Mutational defects of globin chains
leading to:
1- Amino Acid Substitutions, Deletions, or Elongation
of the globin chain.
2- Quantitative defects: abnormal alpha/beta ratio.
ABNORMAL HEMOGLOBIN METABOLISM

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Functional defects (low solubility & instability) :
Causes hemolysis.
Alters oxygen affinity.
Decrease ability to protect Heme iron from oxidation.
The erythrocytes of these patiants are few and
abnormal, In addition to large numbers of immature
cells.
The most common types are:
SICKLE CELL anemia and THALASSEMIA.

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TERMINOLOGY of abnormal HEMOGLOBIN
A.Thalassemias:
Are characterized by decreased production of the
affected globin chains.
primarily grouped into α or β thalassemias.
The Globin chains that are produced are STRUCTURALLY
NORMAL, however there is an imbalance in the α to β
globin chain ratio which is the cause of the
manifestations seen.

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B. HEMOGLOBINOPATHIES:
These are a group of disorders in which there is a
structural abnormality of either the α, β or δ chains.
The majority of these are due to a single amino acid
substitution caused by a point mutation in the globin
chain DNA.
C. Hereditary persistence of fetal hemoglobin and β
thalassemia:
These are a group of disorders which are
characterized by persistent elevation of fetal
hemoglobin (HB F) into adulthood.

10. The altered properties of hemoglobin result
from a single amino acid SUBSTITUTION, a
Valine instead of a Glutamine at position 6 in
Beta chains.
This hemoglobin is then called hemoglobin-s.
These cause deoxyhemoglobin-S to be
insoluble and forms long, insoluble fibers
characteristic of sickle shape of RBCs.
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Sickle Cell Anemia

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There are two types of sickle cell anemia:
the sickle-cell disease:
Individuals who receive the sickle-cell allele from
booth parents and are the homozygous for the
gene encoding hemoglobin.
sickle-cell trait:
Individuals who receive the sickle-cell allele from
only one parent. (heterozygous).
Sickle-cell anemia

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Thus heterozygous experience a milder
condition.
only about 1% of their erythrocytes
become sickled on deoxygenation.
These individuals may live completely
normal if they avoid vigorous exercise or
other stresses on the circulatory system.
Sickle-cell anemia

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Because sickled cells are very fragile and
rupture easily; this results in anemia.
A more serious consequence is that:
capillaries become blocked by the long,
abnormally shaped cells, causing severe pain
and interfering with normal organ function
a major factor in the early death of many
patiants.

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Sickle-cell anemia is a life-threatening and painful
disease.
People with sickle-cell anemia suffer from repeated
crises brought on by physical exertion, infection,
respiratory dis.
They become weak, dizzy, and short breath, with an
increased pulse rate.
The hemoglobin content of their blood is only about
half the normal value .

15. The genetic defects known as thalassemia
result from:
the partial or total absence of one or
more α or β chains of hemoglobin.
Either the α chain (Alpha thalassemia) or
β chain (Beta thalassemia) can be
affected.
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Thalassemias

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There are two types of thalassemia:
Thalassemia major : in patients homozygous to the
defect.
Thalassemia minor : in patients heterozygous to the
defect.
Thalassemia major is a more sever form of anemia,
with splenomegaly and abnormal bone marrow
function.
Thalassemia minor is usually a symptom-free disease.
Treatment:
Apart from marrow transplantation, treatment is
symptomatic.

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BARTS HYDROPS FETALIS
If a 2 alpha chain deletion is inherited from each
parent, then no Hb A can be produced.
This condition is incompatible with life.
On electrophoretic methods, there is no HbA or HbF
present, only Hb Barts (γ4) and a small amount of Hb
Portland.
There are two types of Hb Portland seen, Hb Portland I
(ζ2 γ2), Portland II (ζ2 β2).
Hb Portland II is only seen in this pathologic
condition.

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1- family history and clinical examination.
2- signs and symptoms:
Sever anemia, hemolytic crisis , splenomegaly,
jaundice…
3- laboratory findings:
Low Hb, raised serum bilirubin, increased bilirubin
execration in urine.
4- Abnormal blood and bone marrow films and Hb
electrophoresis.
Diagnosis of hemoglobinopathies

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Hb electrophoresis
Hemoglobinopathies usually detected and characterized
on basis of:
-Abnormalities in electrophoretic mobility of hemoglobin
molecule.
-Heat or isopropanol stability of hemoglobin molecule .
-Oxygen affinity of hemoglobin molecule .
-Spectrometry of hemoglobin molecule.
-DNA sequence analysis of hemoglobin molecule.

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