Transcript الشريحة 1

GLUCOSE-6-PHOSPHATE
DEHYDROGENASE
DEFECEINCY
(G6PD)
Introduction
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This anemia is classified as a hereditary hemolytic
anemia due to an intrinsic defect (i.e., in the same
major group of the spherocytosis).
It is similar to HS because: 1- it is hereditary, 2- the
defect is intrinsic, and 3- of a hemolytic nature.
It differs from HS in the pattern of inheritance where
G6PD deficiency is X-linked (HS is autosomal
dominant), and, that the cell membrane is
compromised by other mechanism (discussed in
detail, below).
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G6PD deficiency along with other anemias
such as Pyruvate Kinase deficiency, and
Glutathione Reductase deficiency are
classified in a group of anemia referred to as
“hereditary erythrocyte enzymopathies”
(only G6PD is discussed in detail in this
course).
G6PD deficiency is the most common
erythrocyte enzymopathy leading to hemolytic
anemia. Anemia results from the inheritance
of one of many variant forms of the defective
enzyme.
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The disease is X-linked and therefore all men
affected with the disease show its symptoms,
where as women can be either affected
(homozygotes) or carriers (heterozygotes).
G6PD deficiency is very common in West
Africa, the Mediterranean, the Middle East,
and South East Asia
Pathophysiology
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Glucose-6-phosphate dehydrogenase is one of the
most important enzymes in the Pentose Phosphate
Pathway (PPP), where it is required for the
conversion of Glucose-6-Phosphate (G6P) to 6PhosphoGluconate (6-PG), and for the subsequent
production of NADPH and reduced Glutathione
(GSH).
GSH protects proteins and Hgb from oxidative
radicals such as Hydrogen Peroxide, by detoxification
and neutralization.
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RBC’s deficient in G6PD enzyme cannot detoxify
hydrogen peroxide (due to low GSH), and
subsequently the Hgb gets oxidized to methemoglobin
(Hgb with iron in the Fe3+ form).
This leads to the release of haem from hemoglobin
molecule and the denaturation of the globin molecule
forming little inclusions known as the “Heinz bodies”.
Heinz bodies attach to the membrane increasing its
rigidity, and therefore the cells get trapped and
phagocytozed in the splenic microcirculation.
Clinical presentation
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Haemolysis occure in 1-2 days, and it is self
limiting.
Anaemia takes 7-10 days.
Jaundice.
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The symptoms of G6PD deficiency vary from a
patient to another according to the race of the
patient, the variation in the enzyme deficiency, and
the degree of the oxidative stress.
However, most patients experience hemolytic
episodes after an exposure to a strong oxidative
event, e.g., after taking oxidative drugs, severe
infections, diabetic acidosis, etc.
For instance, under normal situations patients with
the G6PD- variant are not anemic and do not show
hemolysis until there is a major stress of oxidative
nature, which affects the older RBC’s, mostly.
Lab findings
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CBC (Complete Blood Count)
Usually, Hgb is within normal range but falls
by 3-5 g/dL suddenly after an oxidative
stress.
The anemia that develops is usually
normocytic normochromic, which gets
followed by an increased reticulocytes count
3-5 days after the onset of the hemolytic
episode.
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During the hemolytic episode, peripheral blood
smears show non-specific changes including
polychromatophilia , increased retic count,
poikilocytosis, some spherocytes, and some
fragmentation effect (known as the “Bite”
cells).
Bite cells are the result of the splenic removal
of Heinz bodies, and therefore, they are not
considered as specific to G6PD deficiency as
they can occur in hemoglobinopathies, GSH
deficiency, and normal individuals after
massive oxidative event.
Acute hemolysis in glucose-6-phosphate dehydrogenase (G6PD)
deficiency (arrow indicates a “bite” cell, or keratocyte).
Chemical assays
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A number of tests can be useful in aiding the
diagnosis of G6PD deficiency. All of which
aid to diagnose Qualitative and Quantitative
G6PD defects.
Acute hemolysis in G6PD deficiency (arrows indicate “blister
or bite cells,” and arrowheads irregularly contracted cells).
Heinz bodies by supravital stain
SICKLE CELL ANAEMIA
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Sickle cell disease is a group of
haemoglobin disorders, in which the there
is inherence globin abnormality, caused
by substitution of valine for glutamic acid
in position 6 in the B chain, that affect the
shape and function of the red blood cell
Pathology:
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Hb S is insoluble and forms crystals when
exposed to low oxygen tension. Deoxygenated
Hb polymerizes into long fibers and the Red
Blood Cells (RBCs) form crescent or sickle
shape and slow or may block different areas of
the microcirculation or large vessels causing
infarcts of various organs.
Types of sickle cell disease:
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AS, SS, SC, S/ Thalassemia.
When it of the SS type, it called sickle cell
anaemia (homozygous condition).
Sickle cell anaemia (homozygous
condition).
Clinical features:
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Chronic haemolysis, leads to jaundice and
anaemia.
Vaso-occlusion of blood vessels leads to pain.
Infarction and infections.
Complications:
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Begin at 6 months of age
Pain in fingers and toes
Folate deficiency.
Chronic hemolytic anemia
jaundiceInfective crises, Bacterial infections
(children)
Aplastic crises. bone marrow stops making RBCs
A vascular necrosis of the head of the femur.
Kidney damage, Stone in the gall bladder.
Ulcer in the median side of the leg.
Laboratory findings:
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Low Hb.
Stained peripheral blood film shows, sickle cells and
target cells. Normocytic Normo anemia, Sickle cells,
Target Cells, Nucleated RBC/ Polychromasia
Features of splenic atrophy (Howell-Jolly body and
Pappenheimer), also appears.
Reticulocytosis
Screening tests for sickiling are positive.
Haemoglobin electrophoresis detected the presence of
Hb S while no Hb A is detected Hgb F = 1-20%, Hgb A2
= 2-5%.
Increased bilirubin
Sickle cell trait:
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This is a benign condition, where there is no anaemia
and normal appearance of RBC on the PBF.
Haematouria is the most common symptom. Care
must be taken with anesthesia, pregnancy and at high
altitude.
The diagnosis of sickle cell trait is established by an
electrophoresis that shows about 55% hemoglobin A
and 45% hemoglobin S. Hemoglobin, reticulocyte
count and all laboratory tests are normal with sickle
cell trait.
THALASSAEMIAS
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Thalassaemias are a heterogeneous group of
genetic disorders, which results from a reduced
rate of œ (alpha) and ß (beta) chain syntheses,
this can result in moderate to severe anemia
Basic defect is reduced production of selected
globin chains:
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In alpha thalassaemia, there is no or little alphachain syntheses.
In beta thalassaemia, there is no or little beta-chain
syntheses.
Demographics:
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Found most frequently in the
Mediterranean, Africa, Western and
Southeast Asia, India and Burma
1-  (alpha)- Thalassaemia
syndromes:
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Greek letter used to designate globin chain:
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/ : Indicates division between genes inherited from both
parents: /
- Indicates a gene deletion: -/
Classification & Terminology
Alpha Thalassemia
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Normal
Silent carrier
Minor
Hb H disease
Barts hydrops fetalis
/
- /
-/- or --/
--/-
--/--
1- Major alpha- thalassaemia or
Hydrops fetalis:
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four genes deletion, leads to complete
suppression in the syntheses of alphachain.
Alpha chain is important in formation of
hemoglobin F in neonate, so in this case
the formation of this haemoglobin which
is important for fetal life will fail, leading
to death in uterus.
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2- Three genes deletion:
leads to moderate to sever microcytic
hypochromic anaemia, with splenomegaly.
This is known as Hb H disease.
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3- One or two genes deletion:
alpha-thalassaemia trait, usually not associated
with anaemia.
ß- Thalassaemia syndromes:
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Greek letter used to designate globin chain: 
+ : Indicates diminished, but some production
of globin chain by gene: +
0 : Indicates no production of globin chain by
gene: 0
ß- Thalassaemia syndromes:
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Classification & Terminology of Beta
Thalassemia
Normal
/
Minor
/0 or /+
Intermedia
0/+
Major, very sever.
0/0 or +/+
1- ß- Thalassaemia major:
 Sever anaemia (Hb 3-6 g/dl).
 Enlargement of liver ad spleen.
 Expansion of bones, leads to Bone deformities.
Laboratory findings:
 Sever microcytic hypochromic anaemia
(anisocytosis)
 Poikilocytosis, normoblast, target and Howell-Jolly
bodies.
 Reticulocytosis.
 Haemoglobin electrophoresis shows absence of Hb
A, Hb A2 is normal.
2- ß- Thalassaemia intermedia:
 Of moderate severity (Hb 7-10 g/dl). The
patient may show bone deformity, enlarged
liver and spleen.
3- ß- Thalassaemia trait (minor):
 This is usually symptom less, and mild
anaemia.