Oxidative stress unleashed: A case report of haemolytic crisis following respiratory illness in glucose-6-phosphate dehydrogenase deficiency

INTRODUCTION

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most prevalent enzymatic disorder worldwide, affecting over 400 million individuals.^[1] It is an X-linked hereditary condition that is particularly common among males of African, Asian, Mediterranean and Middle Eastern descent. G6PD plays a crucial role in the pentose phosphate pathway by catalysing the conversion of nicotinamide adenine dinucleotide phosphate (NADP⁺) to its reduced form, nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is essential not only for biosynthetic processes such as the synthesis of fatty acids, cholesterol and deoxyribonucleotides but also for maintaining cellular defence against oxidative stress. In erythrocytes, where the pentose phosphate pathway is the sole source of NADPH, G6PD activity is critical. NADPH helps regenerate reduced glutathione (GSH), which, in turn, neutralises hydrogen peroxide (H₂O₂) and hydroxyl free radicals. A deficiency in G6PD compromises this defense mechanism, making red blood cells particularly vulnerable to oxidative damage, which results in haemolysis. In addition, oxidative stress can convert haemoglobin into methemoglobin, which impairs its oxygen-carrying capacity, further exacerbating clinical symptoms.^[2,3]

CASE REPORT

A 3-year-old male presented to the paediatric emergency department with complaints of dark-coloured urine of acute onset, associated with fever and cough for 2 days. There was no history of drug intake, recent travel or exposure to known oxidative agents. The child had a significant neonatal history of hyperbilirubinaemia requiring exchange transfusion on day 6 of life.

On physical examination, the child was markedly pale and icteric. Vital signs were stable, and systemic examination was unremarkable.

Laboratory investigations revealed severe anaemia with a haemoglobin of 3.9 g/dL, elevated lactate dehydrogenase (LDH) and indirect hyperbilirubinaemia. The direct coombs test (DCT) was negative. The peripheral smear showed anisopoikilocytosis, spherocytes and the presence of hemighost (bite) cells, suggestive of oxidative haemolysis.^[4]

A quantitative G6PD enzyme assay confirmed G6PD deficiency, as shown in Table 1 and Figure 1. The child was managed with two units of packed red blood cell transfusions, intravenous fluids, folic acid supplementation and empirical intravenous antibiotics for the concurrent respiratory infection. Clinical improvement was noted within 48 h, and the child was discharged with a haemoglobin level of 11.6 g/dL.

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Figure 1:

Peripheral smear findings.

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Family members were screened for G6PD deficiency, and caregivers were counselled regarding avoidance of known triggers.

DISCUSSION

G6PD plays a crucial role in the first step of the pentose phosphate pathway, an alternative metabolic route to the Krebs cycle. This enzyme catalyses the conversion of glucose-6-phosphate to 6-phosphogluconolactone, which is subsequently hydrolysed to form 6-phosphogluconate. During this process, NADP⁺ is reduced to NADPH⁺ H⁺. G6PD deficiency, leading to haemolytic anaemia, is the most common erythrocyte enzymopathy globally.^[5,6]

Based on the enzymatic activity (both physicochemical and chromatographic) of G6PD and considering various clinical features, the World Health Organization has classified G6PD variants into five categories. In most instances, the deficiency is linked to mutations that affect the enzyme’s stability, primarily through amino acid substitutions. These mutations result in a significantly reduced half-life of the enzyme, especially in the severe Mediterranean variant, where the half-life may be shortened by up to 8 days. This reduced stability is considered a major factor contributing to clinical symptoms.^[7]

Under normal conditions, oxidative stress leads to an accumulation of H₂O₂, which can be toxic to cells. The body neutralises H2O2 through reduced GSH, which itself is oxidised to form oxidised GSH. This process is linked with the NADPH/NADP⁺ redox cycle, where G6PD is normally active at low levels (around 2%). However, during oxidative stress, G6PD activity increases as NADPH levels drop, helping the cell adapt to stress. In individuals with G6PD deficiency, oxidative stress leads to a build-up of H₂O₂, which damages red blood cell membranes, causing haemoglobin to precipitate into Heinz bodies and triggering cell rupture. Various factors, including fava beans, certain medications (like chloroquine) and infections (e.g. Escherichia coli, beta-haemolytic streptococcus and rickettsial infections), can exacerbate oxidative stress due to their redox properties.^[8,9]

The G6PD gene is located on the X chromosome, making the condition X-linked and hereditary. Males with a mutated gene will always present with some form of deficiency, with varying clinical manifestations. In females, the clinical expression depends on whether they are homozygous or heterozygous for the mutation. Lyonisation (the inactivation of one X chromosome in each cell) results in two distinct cell populations – those expressing the normal G6PD gene and those with the deficient variant – leading to phenotypic variability.

G6PD deficiency predisposes red blood cells to oxidative stress and subsequent intravascular haemolysis. Infections are common triggers, especially in children. Neonatal hyperbilirubinaemia is often the first clinical sign, as seen in the patient described. This case highlights the importance of considering G6PD deficiency in paediatric patients with acute haemolysis, particularly when the DCT is negative and peripheral blood smears show characteristic features such as bite cells. Prompt diagnosis and appropriate supportive care are essential in managing acute haemolytic episodes and preventing complications like acute kidney injury.

CONCLUSION

This case highlights the critical importance of considering G6PD deficiency in paediatric patients presenting with acute haemolysis, particularly in the absence of known oxidative triggers and with a history of neonatal hyperbilirubinaemia. The presence of hemighost (bite) cells on peripheral smear, a negative DCT and markedly elevated LDH and indirect bilirubin levels were key diagnostic clues pointing toward oxidative haemolysis. Timely recognition and supportive management, including red blood cell transfusions and treatment of underlying infections, led to a favourable clinical outcome. This case underscores the need for heightened awareness of G6PD deficiency in endemic regions, early diagnostic evaluation and caregiver education to prevent future haemolytic crises.

This case illustrates a classic presentation of G6PD deficiency precipitated by a respiratory infection. Prompt diagnosis and supportive treatment resulted in favourable clinical outcomes. Family screening and education on trigger avoidance are key components of long-term management.