G6PD Deficiency and Malaria: Mechanisms and Clinical Patterns

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common enzyme deficiencies worldwide, affecting millions. This genetic condition weakens red blood cells, making them more vulnerable to oxidative stress, which can lead to hemolysis. While often linked to drug-induced or infection-related complications, G6PD deficiency also influences susceptibility and resistance to malaria.

Understanding how this deficiency interacts with malaria provides insight into disease patterns in endemic regions. Researchers have explored its protective effects against severe malaria while also noting increased risks for hemolytic episodes.

Hereditary Enzyme Variants In RBCs

G6PD deficiency results from mutations in the G6PD gene on the X chromosome, leading to varying enzyme activity levels across populations. Over 200 enzyme variants exist, each with different degrees of functional impairment. These mutations reduce G6PD stability or efficiency, affecting red blood cells’ ability to maintain redox balance by generating nicotinamide adenine dinucleotide phosphate (NADPH). Without sufficient NADPH, RBCs become susceptible to oxidative damage triggered by medications, infections, or dietary factors.

The distribution of G6PD variants aligns with regions historically affected by malaria. The most common variants, such as the African (G6PD A-) and Mediterranean types, differ in severity. The African variant retains partial function, leading to moderate deficiency, whereas the Mediterranean variant causes more severe enzymatic impairment and a higher risk of hemolysis. Other variants, like the Mahidol type in Southeast Asia and the Canton variant in China, further illustrate this genetic diversity. These regional differences suggest evolutionary selection likely driven by malaria.

The World Health Organization (WHO) classifies G6PD deficiency into five categories, from Class I (severe deficiency with chronic hemolysis) to Class V (increased enzyme activity). Most clinically significant cases fall into Class II or III, where enzyme activity is significantly reduced but not absent. The degree of deficiency influences hemolytic risk, with Class II variants posing a greater threat than Class III. Since the G6PD gene is X-linked, males are more frequently affected, while heterozygous females exhibit a mosaic pattern of enzyme activity due to random X-chromosome inactivation. This variability complicates diagnosis and management, as some female carriers may experience hemolysis despite having intermediate enzyme levels.

Mechanisms Affecting Malarial Infection

The relationship between G6PD deficiency and malaria is shaped by the altered red blood cell environment. Plasmodium parasites, particularly P. falciparum and P. vivax, rely on host RBCs for replication. However, G6PD-deficient erythrocytes are more susceptible to oxidative stress, which can impair the parasite’s life cycle. Reduced NADPH production leads to an accumulation of reactive oxygen species (ROS), damaging both host cells and the invading pathogen.

Parasitized RBCs with deficient G6PD activity often undergo premature destruction, either through increased phagocytosis by macrophages or direct hemolysis. This limits parasite replication, reducing overall parasite burden. Research in The New England Journal of Medicine indicates that individuals with moderate G6PD deficiency exhibit lower parasitemia levels than those with normal enzyme activity, supporting the idea that this trait provides a survival advantage in malaria-endemic regions. The protective effect is particularly pronounced in heterozygous females, where a mixed population of RBCs disrupts optimal parasite propagation.

Despite these advantages, G6PD deficiency does not confer absolute immunity. While parasite densities may be lower, individuals remain susceptible to infection and clinical symptoms. Additionally, the oxidative vulnerability of deficient RBCs increases the risk of hemolytic episodes during malaria. Plasmodium-induced oxidative stress exacerbates erythrocyte fragility, contributing to severe anemia. A study in The Lancet Global Health found that G6PD-deficient individuals infected with P. vivax were more likely to develop hemolytic anemia after treatment with primaquine, a drug used for radical cure. This highlights the complex interplay between genetic resistance and treatment risks.

Clinical Patterns In Endemic Regions

In malaria-endemic regions such as sub-Saharan Africa, Southeast Asia, and the Mediterranean, the prevalence of G6PD deficiency influences disease patterns. The coexistence of these conditions affects susceptibility to infection and the severity of hemolytic complications.

G6PD deficiency often goes undiagnosed until hemolytic episodes occur, triggered by infections, certain foods like fava beans, or medications such as antimalarials. The severity of these episodes varies, from mild anemia to severe acute hemolysis requiring hospitalization. The Mediterranean variant poses a higher risk of severe hemolysis, leading to complications like hyperbilirubinemia and neonatal jaundice. In newborns, early-life oxidative stress can result in kernicterus, a potentially fatal neurological condition. This burden is particularly pronounced in regions with limited access to early screening and phototherapy.

Antimalarial treatments further complicate clinical outcomes. Primaquine and tafenoquine, used to eliminate P. vivax and P. ovale hypnozoites, can induce hemolysis in G6PD-deficient individuals. In some countries, mandatory G6PD screening precedes primaquine administration, while others rely on adjusted dosing to minimize adverse effects. However, routine screening remains unavailable in many low-resource settings, increasing the risk of severe drug-induced hemolysis.

Biochemical Pathways Leading To Hemolysis

Red blood cell breakdown in G6PD deficiency stems from an impaired ability to counteract oxidative stress. G6PD is the first enzyme in the pentose phosphate pathway, a metabolic route generating NADPH, which maintains glutathione in its reduced form. Reduced glutathione (GSH) neutralizes reactive oxygen species (ROS) that accumulate from normal metabolism and external stressors like infections or medications. In G6PD-deficient RBCs, inadequate NADPH production depletes GSH, leaving cells vulnerable to oxidative damage.

When oxidative stress overwhelms protective mechanisms, hemoglobin denatures, forming Heinz bodies—aggregates of oxidized hemoglobin that attach to the RBC membrane. These damaged cells lose flexibility, making them prone to destruction in the spleen. Macrophages recognize and remove these compromised erythrocytes, leading to extravascular hemolysis. In severe cases, RBC membranes become unstable, causing intravascular hemolysis, where cells rupture directly in the bloodstream, releasing free hemoglobin and leading to hemoglobinuria, a hallmark of acute hemolytic episodes.

Diagnostic Approaches

Diagnosing G6PD deficiency is essential in malaria-endemic regions, where both the condition and its interaction with antimalarial treatments pose risks. Diagnosis relies on detecting reduced enzyme activity in RBCs, with several laboratory methods available based on clinical context and resource availability.

Quantitative spectrophotometric assays are the gold standard, measuring NADPH generation to assess enzyme function. These tests provide precise enzyme levels but require specialized equipment and trained personnel, limiting accessibility in remote settings. Qualitative point-of-care tests (POCTs), such as the fluorescent spot test (FST) and rapid diagnostic tests (RDTs), offer practical alternatives. The FST detects NADPH fluorescence under ultraviolet light, distinguishing deficient individuals from those with normal or intermediate activity. RDTs use colorimetric or lateral flow techniques, making them suitable for field settings with limited laboratory infrastructure.

Molecular testing further refines diagnosis by identifying specific G6PD gene mutations. Polymerase chain reaction (PCR)-based assays detect known variants, offering insights into genotype-phenotype correlations. However, these tests are costly and not widely used outside research settings. Diagnosing heterozygous females presents a challenge, as X-chromosome inactivation results in a mixed population of deficient and normal RBCs. Standard tests may underestimate their risk of hemolysis. Flow cytometry-based methods, which assess single-cell enzyme activity, show promise but remain largely unavailable. Expanding access to reliable diagnostics is a priority, particularly in malaria-endemic regions where hemolysis-inducing treatments necessitate informed clinical decisions.