G6PD Deficiency

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"G6PD deficiency"[MeSH Terms] AND management

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I now have comprehensive data from Harrison's, Robbins, Goldman-Cecil, Lippincott Biochemistry, and Tietz Lab Medicine. Let me compile the complete answer.

G6PD Deficiency (Glucose-6-Phosphate Dehydrogenase Deficiency)

Overview

G6PD deficiency is the most common enzymopathy in humans, affecting an estimated 400+ million people worldwide. It is an X-linked disorder that leaves red blood cells (RBCs) unable to defend against oxidant stress, triggering episodic or chronic hemolytic anemia.

Lippincott Illustrated Reviews: Biochemistry, 8th ed, p. 445
Tietz Textbook of Laboratory Medicine, 7th ed, p. 3054

Biochemical Mechanism

The enzyme G6PD catalyzes the first and rate-limiting step of the pentose phosphate pathway (PPP): conversion of glucose-6-phosphate to 6-phosphogluconolactone, generating NADPH. In RBCs, the PPP is the only source of NADPH.

NADPH is required to:

Reduce oxidized glutathione (G-S-S-G) back to reduced glutathione (G-SH) via glutathione reductase
G-SH then detoxifies H₂O₂ via glutathione peroxidase

When G6PD is deficient → less NADPH → depleted G-SH → H₂O₂ accumulates → oxidizes hemoglobin → Heinz bodies form → RBC membrane rigidity and hemolysis.

Pathways of glucose-6-phosphate metabolism in the erythrocyte, showing how G6PD deficiency impairs NADPH production and leads to oxidative hemolysis

Lippincott Illustrated Reviews: Biochemistry, Fig. 13.10

Key point: Other tissues can generate NADPH via the malic enzyme pathway, but RBCs cannot - making them uniquely vulnerable. Additionally, mature RBCs have no nucleus or ribosomes and cannot synthesize new G6PD enzyme, leaving them entirely dependent on the activity of the enzyme already present.

Epidemiology & Genetics

Feature	Details
Inheritance	X-linked recessive
Prevalence	~400-500 million affected worldwide
Sex	Primarily males (hemizygous); females usually carriers but can be affected with unfavorable lyonization
Gene locus	Xq28, 18 kb, 13 exons
Variants	>400 described; >200 different mutations (mostly missense point mutations)

High-prevalence regions overlap with malaria-endemic zones (sub-Saharan Africa, Mediterranean, Middle East, South and Southeast Asia). This is not coincidental - G6PD-deficient RBCs lysed by oxidant stress induced by Plasmodium falciparum actually protect the host from severe malaria, providing a selective evolutionary advantage.

Goldman-Cecil Medicine, International Edition
Tietz Textbook of Laboratory Medicine, 7th ed

WHO Classification of Variants

Class	Enzyme Activity	Example Variant	Distribution	Clinical Features
Class I	<10% (severe)	G6PD Guadalajara	Sporadic	Chronic nonspherocytic hemolytic anemia (CNSHA) + NNJ + acute exacerbations
Class II	<10% (severe)	G6PD Mediterranean (Ser188Phe)	Middle East, South/Central Asia	Acute hemolysis; favism common
Class III	10-60% (moderate)	G6PD A- (Val68Met + Asn126Asp)	Africa (10% of African-Americans)	Acute hemolysis after oxidant stress; self-limited
Class IV	60-150% (normal)	G6PD A, G6PD B	Worldwide	No clinical manifestations
Class V	Increased activity	G6PD Hektoen	Rare	None

Tietz Textbook of Laboratory Medicine, 7th ed, Table 78.2

G6PD A- (African variant): Half-life only 13 days vs. ~60 days for normal enzyme. Only older RBCs are G6PD-deficient; younger cells generated during the hemolytic episode have near-normal activity. This self-limiting nature means hemolysis abates even if the offending drug is continued.

G6PD Mediterranean: Much lower residual activity (<5%). Young and old RBCs are deficient; hemolysis is therefore more severe and prolonged. Associated with favism.

Precipitating Factors ("Triggers")

1. Oxidant Drugs

Commonly remembered as categories starting with "A":

Antibiotics: Sulfonamides (sulfamethoxazole), dapsone, nitrofurantoin, nalidixic acid
Antimalarials: Primaquine, chloroquine (high doses), pamaquine
Analgesics: Aspirin (high doses), phenacetin
Antipyretics: (various)
Other: Methylene blue, rasburicase, vitamin K derivatives

2. Favism

Fava beans (broad beans) contain oxidant compounds (vicine, convicine). Particularly associated with the G6PD Mediterranean variant. All patients with favism have G6PD deficiency, but not all G6PD-deficient individuals develop favism.

3. Infection

The most common precipitant in practice. The inflammatory response generates free radicals in macrophages (as part of the host defense), which diffuse into RBCs and cause oxidative damage.

Lippincott Illustrated Reviews: Biochemistry, 8th ed, p. 447-448
Robbins & Kumar Basic Pathology, p. 389

Pathological Features

Heinz Bodies

Oxidized hemoglobin denatures and precipitates, forming intracellular inclusions called Heinz bodies, attached to the RBC membrane. These are visible on supravital staining (crystal violet or brilliant cresyl blue), not on routine Giemsa stain.

Bite Cells (Degmacytes)

Splenic macrophages attempt to "pluck out" Heinz bodies from RBCs. This creates characteristic bite cells (notched cells) visible on peripheral blood smear. These cells have reduced deformability and are subsequently trapped and destroyed in the spleen.

Peripheral blood smear in G6PD deficiency showing bite cells; inset shows Heinz bodies on supravital stain

Robbins & Kumar Basic Pathology, Fig. 10.6

Clinical Manifestations

G6PD deficiency presents in 5 clinical syndromes:

Syndrome	Features
Acute Hemolytic Anemia (AHA)	Onset 2-3 days after oxidant exposure; pallor, jaundice, dark urine (hemoglobinuria), fatigue
Favism	Severe hemolytic crisis after fava bean ingestion; more severe than drug-induced
Neonatal Jaundice (NNJ)	Appears 1-4 days after birth; unconjugated hyperbilirubinemia; can be severe; not always accompanied by significant anemia
Chronic Nonspherocytic Hemolytic Anemia (CNSHA)	Class I variants; ongoing hemolysis without clear precipitant; lifelong
Infection-induced hemolysis	Most common trigger in clinical practice

Harrison's Principles of Internal Medicine, 22E, p. (block 11)
Tietz Textbook of Laboratory Medicine, 7th ed

Diagnosis

Peripheral blood smear: Bite cells, blister cells, Heinz bodies (on supravital stain)
G6PD enzyme assay (fluorescent spot test or spectrophotometric): Quantitative measurement of enzyme activity. Important caveat: Test should ideally be done 2-3 months after a hemolytic episode - during acute hemolysis, older deficient cells have been destroyed and the remaining younger cells have near-normal activity, giving a false-normal result (especially with G6PD A-)
DNA mutation analysis: For definitive variant identification
Reticulocytosis, elevated unconjugated bilirubin, elevated LDH, decreased haptoglobin: Markers of hemolysis

Management

Acute Hemolytic Anemia

Identify and remove the trigger (stop offending drug, treat infection)
Mild-moderate cases: Supportive care only; hemolysis is self-limiting (especially G6PD A-)
Severe anemia: Blood transfusion (especially in children - can be a medical emergency)
Acute renal failure (hemoglobinuria): Hemodialysis may be needed, but recovery is the rule without pre-existing kidney disease
Ensure adequate hydration

Neonatal Jaundice

Managed as for any neonatal jaundice: phototherapy or exchange transfusion depending on bilirubin levels

Chronic Nonspherocytic Hemolytic Anemia (Class I)

Regular folic acid supplementation
Regular hematologic surveillance
Transfusions during exacerbations
In severe cases with significant transfusion requirement: Splenectomy (evidence is limited but beneficial in practice, unlike hereditary spherocytosis where it is well-established)
Iron chelation if regular transfusions required

Prevention

Screen before prescribing oxidant drugs (primaquine, dapsone, rasburicase)
Patient education: avoid fava beans, inform all healthcare providers
Neonatal screening programs in high-prevalence populations
Harrison's Principles of Internal Medicine, 22E
Miller's Anesthesia, 10e

Key Points Summary

Feature	Value
Inheritance	X-linked recessive (Xq28)
Mechanism	↓ NADPH → ↓ GSH → oxidative damage → Heinz bodies → bite cells → hemolysis
Most common worldwide variant	G6PD A- (Africa), G6PD Mediterranean (Middle East/Mediterranean)
Key triggers	Infections > drugs (sulfonamides, primaquine, dapsone) > fava beans
Blood smear	Bite cells + Heinz bodies (supravital stain)
Enzyme testing pitfall	False normal during/after acute episode (destroyed older cells)
Evolutionary advantage	Protection against P. falciparum malaria
Self-limiting feature	G6PD A- hemolysis stops as young cells with normal activity replace old ones

Sources: Harrison's Principles of Internal Medicine 22E (2025) | Robbins & Kumar Basic Pathology | Goldman-Cecil Medicine | Lippincott Illustrated Reviews: Biochemistry, 8th ed | Tietz Textbook of Laboratory Medicine, 7th ed | Miller's Anesthesia, 10e

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