Objectives Introduction Definition Factors cause G6PD
deficiency Factors cause G6PD deficiency Pathophysiology
(mechanism) Symptoms Lab findings
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Introduction FUNCTION OF G6PD Regenerates NADPH, allowing
regeneration of glutathione Protects against oxidative stress Lack
of G6PD leads to hemolysis during oxidative stress- infection,
medication, fava beans Oxidative stress leads to Heinz body
formation, extravascular hemolysis
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History & Definition It was discovered in 1950s after it
was observed that some black soldiers receiving antimalarial drug
primaquine developed hemolytic anemia. It is the most common red
cell enzymopathy associated with hemolysis. Large no. of abnormal
genes code for the G6PD The inheritance of either of them results
in this disorder.
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Definition X-linked disease, sesult in G6PD Deficiency (RBCs
enzym deficiency ) asymptomatic unless Oxidative stress causes the
RBCs to break apart. Inherited , Recessive
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Genetics The G6PD gene is located on the X chromosome Thus the
deficiency state is a sex-linked trait Affected males inherit the
abnormal gene from their mothers who are usually carriers
(heterozygotes)
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G6PD Deficiency
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Individuals who have inherited one of the many G6PD mutations
do not show clinical manifestation. Some of patients with G6PD
develop hemolytic anemia if they are exposed or ingest any of the
followings oxidizing agents: 1-Oxidant drugs 1-Oxidant drugs:
Remember AAA? Antibiotics Antibiotics : e.g. sulfamethoxazole
Antimalarias Antimalarias : e.g. primaquine Antipyretics
Antipyretics : e.g. acetanilid 2- Favism: The hemolytic effect of
ingesting of fava beans is not observed in all individuals with
G6PD deficiency but all patients with favism have G6PD deficiency
factors cause G6PD deficiency: factors cause G6PD deficiency:
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G6PD Deficiency Biochemistry summary G6PD Reduces NADP + to
NADPH Which is responsible for Glutathione Which fights Free
radicals Which damage blood cells
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Pathophysiology Oxidative denaturation of hemoglobin is the
major cause of H. A in G6PD deficiency It is important in the
conversion of glucose-6- P to phosphogluconate For subsequent
production of NADPH & reduced glutathione (GSH) GSH protects
enzymes & hemoglobin against oxidation by reducing H2O2 &
free radicals
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Pathophysiology H2O2 is generated normally in small amounts
during normal red cell metabolism Larger amounts produced when an
oxidant drug interacts with oxyhemoglobin Normal red cells have
sufficient G6PD activity to maintain adequate GSH levels When
deficient, red cells fail to produces sufficient G6PD to detoxify
peroxide
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Pathophysiology Hb is then oxidized to Hi, heme is liberated
from globin & globin denatures producing Heinz bodies Heinz
bodies attach to membrane sulfhydryl groups inducing cell rigidity
At this point red cells can no longer traverse the splenic
microcirculation Hence lysis occurs
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Symptoms Persons with this condition do not display any signs
of the disease until their red blood cells are exposed to certain
chemicals in food or medicine, or to stress. Symptoms are more
common in men and may include: Dark urine Enlarged spleen Fatigue
Pallor Rapid heart rate Shortness of breath Yellow skin color
(jaundice)
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G6PD Deficiency Malaria Treatment cchloroquine
aatovaquone-proguanil (Malarone) aartemether-lumefantrine (Coartem)
mmefloquine (Lariam) qquinine qquinidine ddoxycycline (used in
combination with quinine) cclindamycin (used in combination with
quinine) pprimaquine
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Diagnosis of G6PD Deficiency Hemolytic Anemia 1-CBC Bite cells,
blister cells, irregular small cells, Heinz bodies, polychromasia
G-6-PD level Bite cells Spleen removes portion of RBC that had
Heinz body, preventing intravascular hemolysis 2-Screening:
Qualitative assessment of G6PD enzymatic activity (UV-based test)
3-Confirmatory test: Quantitative measurement of G6PD enzymatic
activity 4-Molecular test: Detection of G6PD gene mutation
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Special test Methemoglobin reduction test Methemoglobin
reduction
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Methemoglobin Reduction Test Sodium nitrite converts Hb
(hemoglobin) to Hi (methemoglobin) Adding methylene blue should
stimulate the pentose phosphate pathway, reducing methemoglobin In
G6PD Deficiency, methemoglobin persists
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Methemoglobin Reduction Test Normal blood clear red color
Deficient blood brown color Deficient blood Normal blood
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Clinical Manifestations The patient may experience an acute
hemolytic crisis within hours of exposure to the oxidant stress
Hemolytic crisis is self-limited even if the exposure continues
& Only older cell population is rapidly destroyed A minority of
patients are sensitive to exposure to fava beans (favism
phenomenon)
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What is PNH? Paroxysmal sudden onset Nocturnal occuring at
night (or early in morning upon awakeneing) Hemoglobinuria Despite
the name, most patients do not present this way.
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What is PNH? A rare and unusual acquired hematologic disorder
characterized by Intravascular hemolysis Bone marrow failure
(cytopenias) Thrombosis.
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What is PNH? A rare and unusual acquired hematologic disorder
characterized by Intravascular hemolysis Bone marrow failure
(cytopenias) Thrombosis
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What causes PNH? PNH is due to a change (mutation) in a single
gene in a bone marrow stem cell. PNH is due to a condition that
allows this mutated cell to become the dominant cell in the bone
marrow.
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Paroxysmal nocturnal hemoglobinuria 1. Pathogenesis - an
acquired clonal disease, arising from a somatic mutation in a
single abnormal stem cell - glycosyl-phosphatidyl- inositol (GPI)
anchor abnormality - deficiency of the GPI anchored membrane
proteins (decay-accelerating factor =CD55 and a membrane inhibitor
of reactive lysis =CD59) - red cells are more sensitive to the
lytic effect of complement - intravascular hemolysis 2. Symptoms -
passage of dark brown urine in the morning.
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3. PNH laboratory features: - pancytopenia - chronic urinary
iron loss - serum iron concentration decreased - hemoglobinuria -
hemosiderinuria - positive Hams test (acid hemolysis test) -
positive sugar-water test - specific immunophenotype of erytrocytes
(CD59, CD55)