Glucose 6 phosphate dehydrogenase deficiency is not associated with cerebrovascular disease in children with sickle cell anemia

To the editor:

Cerebrovascular disease is an important complication in children with sickle cell anemia (SCA).¹  Hemolysis is increasingly implicated in the pathogenesis.^2,3  Recently, Bernaudin et al found that glucose 6 phosphate dehydrogenase (G6PD) deficiency was associated with high transcranial Doppler (TCD) velocities.⁴  We have retrospectively analyzed data from children with SCA who have been seen at our hospital over the last 6 years, to assess the proposed link between G6PD deficiency and cerebrovascular disease.

TCD imaging was performed using standard protocols. A 2-stage assay was used to quantitate G6PD activity, and deficiency was defined as activity less than 5.2 IU/g hemoglobin. No attempt was made to identify female heterozygotes. Data were collected as part of an audit. Statistical analysis was performed using SPSS Statistics 17.0 (SPSS).

Of 329 children with SCA, 218 had G6PD results available. Twenty-four (11.0%) had G6PD deficiency. Five of 97 females and 19 of 121 males (χ² = 6.1, P = .013) had the deficiency, the excess of males reflecting X-linked inheritance. Twenty-seven children with known G6PD status had cerebrovascular disease (10 with averaged mean of the maximum velocity [TAMMX] > 200 cm/sec, 13 with TAMMX > 169 cm/sec but < 200 cm/sec, and 4 with strokes and stenosed vessels on magnetic resonance (MR) angiography but inadequate TCDs). TCD imaging tends to give lower readings than TCD, although the exact equivalence is not defined, and we have classified a TAMMX greater than 169 cm/sec as abnormal, requiring further investigation or action. There was no significant difference between the mean TAMMX in females versus males (130 vs 126 cm/sec, P = .297, t test).

The data were analyzed in several ways, and none showed a statistical relationship between TAMMX and G6PD deficiency. Four of 27 children with cerebrovascular disease were G6PD-deficient compared with 18/128 with no cerebrovascular disease (χ² = 0.08, P = .930). Similar analysis involving only those with TCDs more than 199 cm/sec showed a similar lack of effect of G6PD deficiency (χ² = 2.38, P = .123).

Logistic regression confirmed the relationship between cerebrovascular disease and hemoglobin, hemolysis (lactate dehydrogenase [LDH], aspartate transaminase [AST], reticulocyte count), and HbF levels, which has been described previously (Table 1).^3-5  Many of our patients had not been genotyped for deletional α thalassemia, but we analyzed mean cellular hemoglobin (MCH) as a surrogate; this showed a significant protective effect of a lower MCH against cerebrovascular disease.⁶  The significant factors were analyzed together by multivariate logistic regression (with LDH representing hemolysis), against cerebrovascular disease, and only LDH and MCH maintained their significance. G6PD deficiency was not associated with any differences in laboratory parameters.

G6PD deficiency was not linked to abnormal TCD velocities in our study. We confirmed the link between hemoglobin, LDH, and α thalassemia (MCH) and TCD velocities. It is difficult to know why the results of this study differ from that of Bernaudin et al. A priori, the link between G6PD and cerebrovascular disease seems unlikely, in that it is X-linked and the effects of deficiency would be more common in males. To date, no studies have shown such an effect of sex.⁷  We have provided further evidence that increased rates of hemolysis are linked to the development of cerebrovascular disease, but the importance of G6PD deficiency in this context is unconfirmed.