G6PD deficiency is caused by mutations in the G6PD gene resulting in reduced activity of the G6PD enzyme. This enzyme is critical for generating NADPH which protects red blood cells from oxidative damage. Lack of G6PD activity leads to hemolysis of red blood cells during times of oxidative stress from infections, drugs, or foods. The condition is diagnosed through screening tests detecting NADPH production or dye reduction, and confirmed by quantitative enzyme assays. Management focuses on preventing hemolysis through treating infections promptly and avoiding oxidative triggers. G6PD deficiency provides some protection against malaria in endemic areas.
G6PDD is an inherited genetic disorder in the red blood cell enzyme known as G6PD. The effects of this disease are preventable by avoiding the triggers.
G6PDD is an inherited genetic disorder in the red blood cell enzyme known as G6PD. The effects of this disease are preventable by avoiding the triggers.
Discussion regarding Glucose 6 phosphate dehydrogenase deficiency and the genetics involved in inheritance of disease. The possible treatment options and mutations identified so far has also been discussed.
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challenges in interpreting abnormal hemoglobin study- the key is to correlate with patient age, ethnicity,RBC indices & morphology findings. Two tier approach for correct characterization of abnormal hemoglobins of HPLC &/or capillary electrophoresis.
Discussion regarding Glucose 6 phosphate dehydrogenase deficiency and the genetics involved in inheritance of disease. The possible treatment options and mutations identified so far has also been discussed.
UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.
challenges in interpreting abnormal hemoglobin study- the key is to correlate with patient age, ethnicity,RBC indices & morphology findings. Two tier approach for correct characterization of abnormal hemoglobins of HPLC &/or capillary electrophoresis.
Haemolysis indicates that there is shortening of the normal red cell lifespan of 120 days. There are many causes.
To compensate, the bone marrow may increase its output of red cells six- to eightfold by increasing the proportion of red cells produced, expanding the volume of active marrow, and releasing reticulocytes prematurely. Anaemia occurs only if the rate of destruction exceeds this increased production rate.
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3. About G6PD Enzyme
It is the first enzyme of HMP Pathway which is the
only source of NADPH in RBC.
Critical for protecting red cells against oxidant injury.
Active form of G6PD enzyme is a dimer.
Monomer – 515 amino acids
Molecular weight – 59 kd.
5. Glucose-6-phosphate Dehydrogenase Deficiency
is the most common enzyme deficiency affecting
about 400 million people worldwide.
Characterised by reduced activity of G6PD in RBCs
and occurrence of hemolysis usually after exposure to
oxidative stress.
6. G6PD located on X chromosome.
X linked recessive inheritence.
7. Etiology
G6PD deficiency , X-linked hereditary disorder caused by
mutations in the G6PD gene at q28 locus.
The q28 locus of the X-
chromosome…
8. Phenotype
• As an X-linked disorder, G6PD deficiency mainly affect males.
• Females are heterozygous, and mostly asymptomatic.
• Expression of G6PD deficiency in females is variable, due to
random inactivation of one X chromosome (lyonization) during
embryogenesis and depends on relative proportion of normal and
abnormal chromosome that are inactivated.
• Homozygous females showing clinical features have also been
reported.
9. Classification of genetic Variants of
G6PD
The World Health Organization classifies G6PD genetic
variants into five classes on the basis of magnitude of enzyme
deficiency and also on severity of hemolysis.
The first three of which are deficiency states.
Class I- Very Severe deficiency (<10% activity) with chronic
(nonspherocytic) hemolytic anemia
Class II -Severe deficiency (<10% activity), with intermittent
hemolysis
Class III – Mild to Moderate deficiency (10-60% activity),
hemolysis with stressors only
Class IV - Non-deficient variant, no clinical sequelae
Class V - Increased enzyme activity, no clinical sequelae
10. Oxidative stress
Bulidup of cellular oxidants
Cross linking of – SH group of globin chain
l/t denaturation
Formation of membrane bound
precipitates (Heinz bodies)
Severely damage the
membrane l/t IVH
Less severe membrane damage l/t reduced deformability
Heinz body containg RBCs passes through splenic cords
,macrophages pluck these bodies.
Bite cells,
Phagocytosed by splenic macrophages EVH
11. G6PD Variants
Variants Activity Hemolysis WHO
class
Race
G6PD B Normal No Class IV Caucasians ,
Asians &
Blacks
G6PD A+ Normal No Class IV African
Blacks
G6PD A- Reduced Mild to Mod. Class III Blacks
G6PD
Mediterranean
Markedly
Reduced
Severe Class II Caucasians
G6PD Canton Markedly
Reduced
Severe Asians
12. G6PD variants
There are over 400 variants of the G6PD enzyme.
G6PD A-: Most common type
Half life of enzyme – 13 days
Older RBCs are deficient in enzyme so on exposure to
oxidative stress older RBCs are rapidly destroying.
Whereas younger RBCs having enzymatic activity thus
hemolytic episode is self limiting.
Confers protection against Malaria.
G6PD B: Enzyme normal
Half life of enzyme- 62 days
No hemolysis takes place.
13. G6PD variants
G6PD Mediterranean :
Half life – 1 day
Severe hemolysis
Enzyme is deficient in both young & old red blood cells.
More severe than G6PD A.
14. Common Variants in India
G6PD Mediterranean
G6PD Kerala-kalyan
G6PD orissa
G6PD deficiency commonly seen in Parsees and Vataliya
Prajapatis
15. • G6PD is the first enzyme in the hexose
monophosphate shunt, a pathway critical for
generating nicotinamide adenine dinucleotide
phosphate (NADPH).
• NADPH is required for the regeneration of reduced
glutathione.
• Reduced glutathione is used for the detoxification of
oxidants produced by the interaction of hemoglobin
and oxygen and by exogenous factors such as
drugs, infection, and metabolic acidosis.
Pathophysiology
16. Pathogenesis
Normally when RBCs are exposed to drugs & toxins
which generated free radicals , glucose metabolism via
HMP shunt increased.
Larger amount of reduced glutathione is generated
which inactivate oxygen radicals.
18. Oxidative stress
Bulidup of cellular oxidants
Cross linking of – SH group of globin chain
l/t denaturation
Formation of membrane bound
precipitates (Heinz bodies)
Severely damage the
membrane l/t IVH
Less severe membrane damage l/t reduced deformability
Heinz body containg RBCs passes through splenic cords
,macrophages pluck these bodies.
Bite cells,
Phagocytosed by splenic macrophages EVH
21. Acute hemolytic anemia
Acute hemolysis usually occur after-
infection,
exposure to an oxidative drug.
Self limited- class III variant
affecting older erythrocytes first, younger erythrocytes and reticulocytes
that typically have higher levels of enzyme activity are able to sustain the
oxidative damage without hemolysis.
In class II variant, hemolysis is marked affecting all stages of RBC hence
not self limited.
Hemolysis typically occurs- 24 to 72 hours after ingestion.
There is sudden development pallor,
dark coloured urine,
back or abdominal pain
Yellowish discolouration of skin and sclera.
22. Favism
The disorder favism results from hemolysis secondary to the
ingestion of fava bean.
Commonly associated with G6PD Mediterranean.
Most commonly seen in Italy, Greece and middle east.
Fava beans contain naturally occurring oxidants
Pyrimidine aglycone, devicine and isouramil.
Affects children 1-5 yrs of age.
Peak seasonal incidence April and May.
Characterized by acute intravascular hemolysis
Headache, nausea, back pain , fever with chills and rigors.
Followed by hemoglobinuria anemia and jaundice.
23. Chronic nonspherocytic hemolytic
anemia.
Patients with chronic nonspherocytic hemolytic anemia
generally have a profound deficiency of G6PD that causes
chronic anemia and an increased susceptibility to
infection.
The susceptibility to infection arises because the NADPH
supply within granulocytes is inadequate to sustain the
oxidative burst necessary for killing of phagocytosed
bacteria.
24. Investigations
Complete blood count and reticulocyte count;
Peripheral smear for Heinz bodies
Liver enzymes (to exclude other causes of jaundice);
LDH (Lactate dehydrogenase) (elevated in hemolysis
and a marker of hemolytic severity)
Haptoglobin (decreased in hemolysis);
A "direct antiglobulin test" (Coombs' test) – this
should be negative, as hemolysis in G6PD is not
immune-mediated;
25. Lab findings
Fall in Hb to 6-10g/dl
Increased Reticulocyte count by 20-30 %
Inreased unconjugated bilirubin
Increased Urobilinogen
Increased LDH
Decreased Haptoglobin
Hemoglobinemia
Hemoglobinuria
Peripheral Smear shows-
Heinz Bodies
Fragmented red cells
Anisopoikilocytosis with polychromatic RBCs
Bite cells
27. Screening Test
Beutler fluorescent spot test
Methhemoglobin reduction test
Dye decolorisation test
28. Fluoroscent Spot Test
Detecting the generation of NADPH from NADP. As NADPH
fluoresce under UV light while NADP fails to do so. The test is
positive if the blood spot fails to fluoresce under ultraviolet light.
Procedure
Reagent mixture + Whole Blood
A Drop of This Mixture
Applied to filter paper
Examined under UV light
Glucose 6 phosphate
NADP
Saponin & Oxidised
glutathione
29. Methhemoglobin Reduction Test
Sodium nitrite oxidises oxyhemoglobin to
methhemoglobin
Methylene blue is a redox dye that reduces
methhemoglobin to hemoglobin in G6PD normal red cell
but not in deficient RBC.
Methhemoglobin imparts brownish color which indicate
G6PD deficiency.
31. Dye Decolourization Test
Hemolysate incubated with buffered solution of
dichlorophenol Indophenol, glucose 6 phosphate, and
NADP.
If G6PD exist in Hemolysate NADPH is generated which
reduces the dye to colorless compound.
In G6PD deficiency time taken for dye decolourization is
longer.
32. Diagnosis
Quantitative G6PD assay
In patients with acute hemolysis, testing for G6PD deficiency
may be falsely negative because older erythrocytes with a
higher enzyme deficiency have been hemolyzed. Young
erythrocytes and reticulocytes have normal or near-normal
enzyme activity.
So enzyme assay should be performed 2-3 months after acute
hemolysis.
Quantitative spectrophotometric analysis
Tests based on Polymerase chain reaction
detect specific mutations and are used for population
screening, family studies, or prenatal diagnosis.
33. G6PD deficiency should be suspected in patients of
African, Mediterranean, or Asian ancestry who present
with either an acute hemolytic episode or neonatal
jaundice.
The key to management of G6PD deficiency is
prevention of hemolysis by prompt:
1- treatment of infections
2- avoidance of oxidant drugs (e.g., sulfonamides,
sulfones, nitrofurans) and toxins (e.g., naphthalene).
Although most patients with a hemolytic episode
will not require medical intervention, those with severe
anemia and hemolysis may require resuscitation and
Treatment
34. Correlation with Malaria
• In areas in which malaria is endemic, G6PD deficiency has a
prevalence of 5% to 25%; in nonendemic areas, it has a prevalence
of less than 0.5% .
• G6PD deficient RBC does not allow parasite to grow since the ribose
metabolite required for nucleic acid synthesis in malaria parasite are
not available.
• This protection is largely limited to heterozygous females.
Editor's Notes
As an X-linked disorder, G6PD deficiency predominantly and most severely affects males. Rare symptomatic females have a skewing of X chromosome inactivation such that the X chromosome carrying the G6PD disease allele is the active X chromosome in erythrocyte precursors.
Sodium nitrte
MB activate HMP which produces NADPH. This NADPH converts methHb (brown colored) into oxyHb (red color). In G6PD def. person NADPH not generated so methHb not converted into oxyHb and the color of sample remained brown .
