Hemoglobin E and Pyrimidine 5′ Nucleotidase Deficiency

To the Editor:

We read with interest the report of Rees et al.1 Increased intraerythrocytic levels of reduced glutatione (GsH) caused by pyrimidine 5′ nucleotidase deficiency along with increased Fe⁺⁺⁺ have been proposed as the possible cause of destabilization of mildly unstable hemoglobin E (HbE) in a Bangladeshi patient converting hemoglobin E disease into an unstable hemoglobinopathy-like disease.

Pyrimidine 5′ nucleotidase deficiency has been shown to interfere with hexose monophosphate shunt.2 This had prompted the investigators to wonder whether the combination of HbE and G6PD deficiency produce more severe clinical phenotype. Several investigators have studied the co-occurence of HbE3-6 or HbE thalassemia3,6 with glucose 6 phosphate dehydrogenase (G6PD) deficiency without any apparent change in clinical phenotype. Furthermore it has also been pointed out earlier6 that the plasma hemoglobin level is increased in cases of HbE thalassemia, indicating some kind of intravascular hemolysis in these cases but not in HbE disease or in HbE traits.

G6PD deficiency normally tends to decrease the level of the reduced glutathione in the red blood cells contrary to pyrimidine 5′ nucleotidase deficiency, which tends to increase this level. Hence, if we accept the idea that the increased levels of reduced glutathione and Fe⁺⁺⁺ together are causing the problem in the present case, co-occurence of G6PD deficiency and HbE disease is unlikely to behave in that way.

To prove conclusively the correct hemolytic status, the Cr⁵¹ survival studied in the propositus would have been ideal. Furthermore, the demonstration of increased numbers of Heinz bodies in the peripheral blood smear after splenectomy would have provided morphologic evidence of unstable hemoglobin-like disease in the propositus described.

Moreover, pyrimidine 5′ nucleotidase deficiency interferes with many of the metabolic activities of red blood cells, reducing the pH of the milieu interior of red blood cells and precipitating ribonucleotides interfering with proper red blood cell function.

In some studies,3 6 G6PD deficiency has been shown to be more often associated with HbE than with the normal population (20% v 3.4%). Hence, it appears that G6PD deficiency has no added part to play in making HbE trait clinically worse.

One wonders about the discrepancy in the globin chain biosynthetic ratio in the parents of the propositus despite the fact that both are carriers of HbE and pyrimidine 5′ nucleotidase deficiency. Coinheritance of nondeletional α thalassemia could be one explanation. Some other unexplored factors might have been coinherited and could be responsible for producing the instability of HbE in the present case.