Glucose 6 Phosphate Dehydrogenase Deficiency

Slide 1 · Glucose-6-phosphate

dehydrogenase deficiency

Oxidative injury, red-cell morphology, and episodic hemolysis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain how G6PD generates NADPH for antioxidant defense.

Relate X-linked inheritance and enzyme stability to red-cell vulnerability.

Trace oxidative damage to Heinz bodies, bite cells, and hemolysis.

Interpret major triggers, timing, and the recovery pattern.

Slide 3 · G6PD deficiency is an inherited enzymatic hemolytic disorder

Reduced G6PD activity compromises red-cell protection against oxidant stress.

The defect is in the hexose monophosphate shunt.

Hemolysis is commonly intermittent, following oxidant exposure.

The affected circulating cell is the erythrocyte.

Slide 4 · Where it sits among the hemolytic anemias

Underlying defect

Inherited red-cell enzyme deficiency

Impaired antioxidant capacity

Intrinsic vulnerability of erythrocytes

Result

Premature red-cell destruction

Intravascular and extravascular pathways

Compensatory erythropoiesis after injury

Slide 5 · Hemolysis reduces the circulating red-cell life span

Red-cell injury

Premature destruction

Anemia

Increased erythropoiesis

The general response to hemolysis explains why reticulocytosis appears during recovery.

Slide 6 · Two locations of red-cell destruction

Intravascular

Erythrocytes rupture in the circulation.

Hemoglobin enters plasma.

Hemoglobinuria may follow.

Extravascular

Abnormal erythrocytes lose deformability.

Splenic macrophages remove affected cells.

Jaundice may reflect heme breakdown.

Slide 7 · Why erythrocytes need oxidative defense

Oxidants can injure hemoglobin and membrane proteins.

Hydrogen peroxide is an important example of an oxidant.

Reduced glutathione helps detoxify peroxide.

NADPH is required to regenerate reduced glutathione.

Slide 8 · G6PD initiates the protective NADPH supply

Glucose-6-phosphate

G6PD-mediated oxidation

NADP⁺ → NADPH

Reducing power

Glucose-6-phosphate oxidation is coupled to reduction of NADP⁺.

Slide 9 · The hexose monophosphate shunt supports red-cell survival

The pathway is a source of the reducing equivalents required for glutathione recycling.

G6PD occupies the first depicted step.

The clinically consequential output is NADPH.

Reduced NADPH availability lowers oxidant tolerance.

Slide 10 · NADP⁺ and NADPH are distinct redox states

NADP⁺

Oxidized electron acceptor

Reduced during the G6PD-linked reaction

Precursor to NADPH

NADPH

Reduced electron donor

Supplies reducing equivalents

Enables reduced-glutathione regeneration

Slide 11 · Glutathione cycles between reduced and oxidized forms

GSH: Reduced glutathione

Peroxide detoxification

GSSG: Oxidized glutathione

NADPH-dependent reduction

NADPH allows GSSG to return to the protective GSH pool.

Slide 12 · Glutathione peroxidase consumes reduced glutathione

H₂O₂ (oxidant)

Glutathione peroxidase + GSH

H₂O (water)

GSSG forms

The peroxidase reaction neutralizes peroxide while oxidizing GSH.

Slide 13 · Glutathione reductase restores the GSH pool

GSSG

Glutathione reductase

NADPH → NADP⁺

Regenerated GSH

This regeneration is impaired when the NADPH supply is inadequate.

Slide 14 · G6PD, reductase, and peroxidase form a defensive system

Glucose-6-phosphate

6-phosphogluconate

G6PD

NADP⁺

NADPH

Reducing equivalents

GSSG

2 GSH

Glutathione

Reductase + NADPH

H₂O₂

H₂O

Glutathione

Peroxidase + GSH

Conceptual coupling of NADPH generation to glutathione-dependent oxidant detoxification

Slide 15 · G6PD deficiency weakens the entire defensive chain

Lower G6PD activity

Reduced NADPH supply

Less GSH regeneration

Oxidant injury

The upstream enzyme deficiency compromises a downstream detoxification pathway.

Slide 16 · Mature red cells cannot replace unstable enzyme

Circulating mature erythrocytes cannot synthesize new proteins.

Some clinically important G6PD variants undergo rapid degradation.

The enzyme reserve therefore decreases as red cells age.

Older cells become especially sensitive to oxidative stress.

Slide 17 · G6PD deficiency follows X-linked inheritance

Gene transmission

Recessive X-linked trait

Males have a single X chromosome

One deficient allele can confer susceptibility

Clinical consequence

Symptomatic deficiency is more common in males

Inheritance informs family-history interpretation

Not all variant carriers have equal hemolytic severity

Slide 18 · Variant diversity does not imply equal clinical severity

Several hundred G6PD genetic variants.

Two historically important hemolysis-associated examples are A− and Mediterranean.

The major mechanism discussed is decreased protein stability.

Variant-dependent enzyme half-life influences red-cell vulnerability.

Slide 19 · G6PD B is the textbook comparator

G6PD B is used as the common normal reference variant.

Other variants are compared by residual enzyme persistence.

Shorter protein half-life causes activity to decline with red-cell aging.

Do not infer a patient-specific severity from a name alone.

Slide 20 · G6PD A− shows moderately reduced enzyme persistence

Biochemical behavior

Protein is less stable than G6PD B.

Activity decreases during red-cell aging.

Functional result

Old red cells are especially susceptible.

Younger cells retain more protective enzyme activity.

Slide 21 · G6PD Mediterranean has more marked instability

Biochemical behavior

Enzyme half-life is markedly decreased.

Aging rapidly reduces activity.

Functional result

Older erythrocytes become poorly protected.

Certain oxidant exposures may produce more severe hemolysis.

Slide 22 · Variant stability predicts age-dependent susceptibility

Variant

Relative enzyme persistence

Physiologic implication

G6PD B

Normal comparator

Antioxidant capacity maintained

G6PD A−

Moderately reduced half-life

Greater injury in older cells

G6PD Mediterranean

Markedly reduced half-life

Marked age-related vulnerability

Slide 23 · The age of the erythrocyte matters

Relative protection

Young red cells

Older red cells

Insufficient defense during oxidant challenge

Qualitative schematic — no quantitative G6PD activity data are represented

Slide 24 · Hemolysis requires a disturbance in oxidant balance

Everyday state

Oxidant burden can remain manageable.

Residual protection may be sufficient.

A person may appear clinically well.

Trigger exposure

Free-radical burden rises.

Reduced NADPH becomes limiting.

Red-cell injury crosses a functional threshold.

Slide 25 · Infections commonly precipitate hemolytic episodes

Activated leukocytes generate oxygen-derived free radicals.

This increases the oxidative challenge to vulnerable red cells.

Viral hepatitis, pneumonia, and typhoid fever as examples.

The infectious illness acts as a precipitant, not the inherited defect.

Slide 26 · An infection links immunity to erythrocyte injury

Infectious illness

Leukocyte activation

Reactive oxygen species

Hemolysis in susceptible RBCs

Host inflammatory oxidants can act on red cells with limited antioxidant reserve.

Slide 27 · Certain medicines can create oxidant stress

Primaquine and chloroquine among historical examples.

It also mentions sulfonamides and nitrofurantoins.

Risk varies with the drug, exposure, and G6PD variant.

A textbook example is not a comprehensive current prescribing restriction list.

Slide 28 · Drug susceptibility is not uniform across variants

Exposure

Oxidant-generating medicinal agent

Potential increase in reactive intermediates

Dose and agent influence the burden

Host susceptibility

Residual enzyme activity matters

Variant stability differs

Older erythrocytes may be preferentially lost

Slide 29 · Fava beans are a classic dietary precipitant

Fava-bean metabolism produces oxidant substances.

Susceptible erythrocytes cannot fully neutralize the resulting stress.

The clinical syndrome after exposure is termed favism.

Mediterranean, Middle Eastern, and African settings.

Slide 30 · Favism illustrates gene–environment interaction

Inherited G6PD deficiency

Fava-bean exposure

Oxidant load exceeds defense

Acute hemolytic episode

The inherited susceptibility may remain silent until an environmental trigger occurs.

Slide 31 · Distinct triggers converge on the same redox problem

Infection

Oxidant medicine

Fava beans

Increased oxidant burden

Hemoglobin and membrane injury

Slide 32 · Oxidants cross-link reactive globin sulfhydryl groups

Excess oxidants

Sulfhydryl oxidation

Globin denaturation

Hemoglobin precipitates

Denaturation and precipitation are the structural basis of Heinz-body formation.

Slide 33 · Heinz bodies are precipitated denatured hemoglobin

Heinz bodies are membrane-associated precipitates of oxidatively damaged globin.

They arise after strong oxidant stress.

They are distinct from normal hemoglobin distribution.

They can themselves compromise membrane integrity.

Slide 34 · Heinz bodies require an appropriate staining method

Crystal violet preparation

Dark inclusions.

The inclusions represent denatured globin.

This is a special stain finding.

Routine morphology

Bite cells are a downstream clue.

Inclusion removal changes cell contour.

Do not label a routine smear as a Heinz-body stain.

Slide 35 · Oxidative globin damage affects the red-cell membrane

Globin precipitation

Membrane attachment

Decreased deformability

Mechanical vulnerability

Membrane-associated inclusions can impair red-cell survival.

Slide 36 · Severe and less severe injury lead to different fates

Severe membrane injury

Major loss of integrity

Cell may rupture in circulation

Intravascular hemolysis

Less severe membrane injury

Cell remains intact but rigid

Splenic macrophages remove inclusions

Extravascular hemolysis

Slide 37 · Direct lysis produces intravascular hemolysis

Severe oxidative injury

Membrane failure

Red-cell rupture

Plasma free hemoglobin

Circulating free hemoglobin provides the basis for hemoglobinemia and hemoglobinuria.

Slide 38 · Hemoglobinemia reflects release of red-cell contents

Intravascular destruction releases hemoglobin directly into plasma.

Haptoglobin normally binds free hemoglobin.

Hemoglobinemia appears when the burden of circulating hemoglobin rises.

This pathway distinguishes intravascular from solely splenic destruction.

Slide 39 · Hemoglobinuria follows extensive intravascular lysis

Plasma free hemoglobin

Haptoglobin consumption

Renal filtration of hemoglobin

Hemoglobinuria

The parent hemolytic-anemia section describes red-brown urine from filtered hemoglobin.

Slide 40 · The spleen removes Heinz-body inclusions

Heinz-body–bearing cell

Passage through splenic cords

Macrophage “pitting”

Residual cell returns altered

The process removes both the inclusion and a portion of membrane.

Slide 41 · Pitting explains the characteristic bite cell

Heinz-body–bearing cell

Bite cell

Splenic macrophage removes inclusion + membrane

The macrophage removes Heinz-body material and adjacent membrane, leaving a crescent-like indentation.

Schematic morphology — editable teaching shapes, not a microscopic specimen

Slide 42 · Membrane loss can also produce a spherocyte

Biconcave red cell

Spherocyte

Loss of membrane surface area

A smaller membrane surface area alters red-cell shape; Spherocytes are not specific to G6PD deficiency.

Schematic morphology — editable teaching shapes, not a microscopic specimen

Slide 43 · Both bite cells and spherocytes can be cleared

Membrane loss

Reduced deformability

Trapping in splenic cords

Macrophage phagocytosis

These are extravascular components of an oxidant-mediated hemolytic process.

Slide 44 · Three red-cell appearances reflect successive events

Before injury

Heinz body

Bite cell

Simplified native-vector morphology; Not a clinical photomicrograph.

Slide 45 · A bite cell is a consequence—not the initial lesion

Upstream event

Insufficient antioxidant reserve

Denatured hemoglobin precipitates

Heinz-body formation

Downstream appearance

Splenic macrophage removes inclusion

Membrane contour becomes indented

Bite cells may circulate temporarily

Slide 46 · Acute hemolysis usually follows exposure by days

Oxidant exposure

~2–3 days

Hemolysis becomes apparent

Reticulocytic recovery

Typical onset 2–3 days after environmental triggers.

Timing is characteristic but does not replace individual clinical assessment.

Slide 47 · Older cells are depleted first

Relative protection

Young red cells

Older red cells

Insufficient defense during oxidant challenge

Qualitative schematic — no quantitative G6PD activity data are represented

Slide 48 · The hemolytic episode often terminates spontaneously

Older susceptible cells lyse

Younger cells remain

Residual G6PD is higher

Hemolysis subsides

A self-limited episode can occur even while the exposure persists; This does not make continued exposure safe.

Slide 49 · Reticulocytosis marks hematologic recovery

The marrow responds to anemia by increasing red-cell production.

Reticulocytes are newly released erythroid cells.

Their appearance helps identify recovery after a hemolytic episode.

Reticulocytosis is a response to hemolysis, not its initiating cause.

Slide 50 · The episodic course limits chronic hemolytic sequelae

Typical episodic G6PD deficiency

Attacks occur intermittently

Periods of relative normality

Chronic splenomegaly and gallstones usually absent

Persistent hemolysis generally

Repeated hemoglobin breakdown

Pigment-gallstone risk over time

Splenic enlargement when clearance is sustained

Slide 51 · Neonatal jaundice is an uncommon presentation

Robbins recognizes neonatal jaundice as a less frequent presentation.

Its existence shows that an obvious drug or food trigger is not obligatory.

Neonatal jaundice warrants clinical evaluation for multiple causes.

Do not assume all jaundice in a G6PD-deficient infant has one mechanism.

Slide 52 · Chronic low-grade hemolysis occurs in some variants

A minority of patients can have hemolysis without a recognized exposure.

Chronic low-grade anemia differs from the usual episodic course.

Severity reflects the functional behavior of the enzyme variant.

The absence of a trigger does not exclude G6PD-related hemolysis.

Slide 53 · G6PD deficiency and hereditary spherocytosis differ

Finding

G6PD deficiency

Hereditary spherocytosis

Primary defect

Oxidant defense enzyme

Membrane skeleton

Typical pattern

Trigger-associated episodic

Often chronic hemolysis

Bite cells

Can follow splenic pitting

Not characteristic

Spherocytes

May develop secondarily

Characteristic morphology

Splenomegaly

Usually absent in episodic disease

Common in clinically evident disease

Slide 54 · Interpreting a hemolytic episode

Clinical clues

Recent illness, medicine, or fava beans

Onset over the following days

Anemia, jaundice, or dark urine

Mechanistic clues

Heinz bodies with special stain

Bite cells or spherocytes

Later reticulocytosis

Slide 55 · Case 1: Hemolysis after a respiratory infection

Teaching vignette: A boy with inherited G6PD deficiency develops jaundice and dark urine after pneumonia.

What links the infection to red-cell destruction?

Activated leukocytes generate oxidants that overwhelm the limited NADPH–glutathione defense.

Hypothetical teaching vignette; Not a patient record

Slide 56 · Case 2: An oxidant medicine precedes anemia

Teaching vignette: A patient with a susceptible G6PD variant becomes anemic several days after an oxidant-generating medicine.

Why is the delay compatible with the mechanism?

Oxidative injury accumulates in vulnerable older red cells; Onset commonly after 2–3 days.

Hypothetical teaching vignette; Not a patient record

Slide 57 · Case 3: Why can an attack subside?

Teaching vignette: A brief hemolytic episode is followed by rising reticulocytes and cessation of red-cell destruction.

Which circulating cells now predominate?

Younger erythrocytes with higher residual enzyme activity, which tolerate the same oxidant burden better.

Hypothetical teaching vignette; Not a patient record

Slide 58 · Case 4: Identifying the morphological sequence

Teaching vignette: An inclusion is visible with crystal violet; Later, a notched erythrocyte is seen on a smear.

Which splenic event connects the two findings?

Macrophage removal of the Heinz body and adjacent membrane (“pitting”) produces a bite cell.

Hypothetical teaching vignette; Not a patient record

Slide 59 · An integrated mechanism: Gene to clinical episode

Unstable G6PD variant

NADPH–GSH defense declines

Trigger causes globin injury

Hemolysis and reticulocytosis

Gene, environment, membrane morphology, and clinical recovery are linked parts of one mechanism.

Slide 60 · Core points to retain

G6PD supplies NADPH to recycle glutathione and neutralize oxidants.

Unstable enzyme variants leave aging red cells especially vulnerable.

Infections, certain medicines, and fava beans can initiate attacks.

Heinz bodies, bite cells, and both hemolytic routes follow oxidative damage.

Typical attacks begin after exposure and recover with reticulocytosis.

Slide 61 · Primary references

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026). Chapter 14, pp. 579–582.

Source topic: “Glucose-6-Phosphate Dehydrogenase Deficiency,” pp. 581–582.

Context: “Hemolytic Anemias,” pp. 579–580.

Original teaching diagrams and case vignettes are interpretive educational reconstructions.