Enzyme Deficiency Appears to Worsen Sickle Cell Symptoms

G6PD deficiency in Congo was linked to more blood transfusions, hospitalizations

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The prevalence of a genetic disorder affecting red blood cells, called glucose-6-phosphate dehydrogenase (G6PD) deficiency, was equally high among people with sickle cell disease (SCD) and healthy blood donors in the Democratic Republic of Congo (DRC), a study has found.

In addition, among SCD patients, the presence of G6PD deficiency was associated with worse symptoms, and more blood transfusions and hospitalizations.

These findings add to previous conflicting results on the frequency and effects of G6PD deficiency in the SCD patient population.

More studies are needed to clarify the impact not only of this condition, but also of receiving blood from G6PD-deficient, but apparently healthy, blood donors in the clinical course of SCD, the researchers noted.

The study, “Does glucose-6-phosphate dehydrogenase deficiency worsen the clinical features of sickle cell disease? A multi-hospital-based cross-sectional study,” was published in Hematology. 

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What is G6PD deficiency?

SCD and G6PD deficiency “are the most common genetic and hemolytic red blood cell diseases worldwide, particularly in sub-Saharan Africa,” the researchers wrote.

Hemolysis refers to the destruction of red blood cells, resulting in anemia, which happens when not enough healthy red blood cells are available to carry oxygen through the body.

SCD is caused by mutations in both copies of the HBB gene, leading to the production of a faulty hemoglobin, the protein red blood cells use to shuttle oxygen through the bloodstream. Hemoglobin’s abnormalities result in misshapen red blood cells prone to breaking apart and dying off.

G6PD deficiency occurs when the body lacks enough of the G6PD enzyme that helps protect red blood cells from a type of cellular damage called oxidative stress. This can lead to the destruction of these cells, particularly as a result of infections and the use of certain medications, such as antibiotics and malaria treatments.

While both diseases are largely prevalent in the same geographic regions, they are genetically independent, meaning they are not systematically inherited together.

Since the 1960s, when G6PD deficiency was suggested to be more common in people with SCD, conflicting results on a potential link between the two diseases have been reported.

Understanding this potential link “is of great importance in the management of SCD patients since it has been postulated that G-6-PD deficiency could worsen the clinical features of SCD mainly through exacerbation of hemolysis,” the researchers wrote.

Now, a team at the University of Kisangani, in the DRC, along with colleagues in Belgium, sought to determine the frequency and clinical impact of G6PD deficiency in SCD patients treated at five health facilities in Kisangani from September 2019 to March 2021.

Kisangani lies in a region with a relatively high prevalence of SCD and G6PD, in addition to malaria, meaning there’s also a high use of anti-malarial medications that may exacerbate G6PD deficiency.

Included in the analysis were 122 SCD patients (64.8% male), with a mean age of 13.8 years, and 211 healthy blood donor volunteers (96.2% male), with a mean age of 26.1 years — who served as a control group.

Among the controls, 17.5% had sickle cell trait, meaning they carried only one faulty copy of the HBB gene. Since two faulty HBB copies are needed for SCD to manifest, individuals with sickle cell trait usually do not show symptoms.

G6PD deficiency was determined by testing the blood of participants for G6PD enzyme activity — yielding an overall prevalence of 34.2%. But rates of the enzyme deficiency did not significantly differ between patients and controls, occurring in 35.2% of those with SCD and 33.6% of healthy controls.

The disorder was significantly more frequent among male participants (36.5%) than female (21.6%), consistent with its known inheritance pattern.

Given the relatively high prevalence of G6PD deficiency observed in healthy blood donors, and the frequent need for blood transfusions in SCD patients, these results indicate that “SCD patients in the DRC have a high likelihood of being transfused with G-6-PD-deficient blood units,” the researchers wrote.

This raises the question of whether these blood transfusions are effective in SCD patients in the DRC, who are often taking medications that can cause oxidative stress and promote the destruction of G6PD-deficient red blood cells, the team noted.

While “it is not routine practice to screen blood donors for G-6-PD deficiency,” the researchers wrote, a previous U.S. study showed that G6PD-deficient blood units were “associated with decreased red blood cell survival after transfusion in children with SCD.”

The presence of G6PD deficiency also appeared to influence SCD severity, with patients showing greater signs of disease severity than those who were not enzyme-deficient.

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What is the effect of G6PD deficiency in sickle cell patients?

While hemoglobin levels did not significantly differ between patients with or without G6PD deficiency, patient reports and medical records revealed that those deficient for the enzyme underwent significantly more blood transfusions in the six months before the study.

In the year before the study, these patients also showed a significantly higher frequency of SCD-related hospitalizations, anemia requiring blood transfusion, and vaso-occlusive crises, or severe pain attacks characteristic of SCD.

While these findings add to previous studies that suggest a negative effect of G6PD deficiency in SCD patients, others found no such effect. Specific genetic variants prevalent in different geographic regions can influence G6PD levels and may in part account for these discrepancies, the team noted.

The results highlight a need “for prospective studies, on the one hand, to further clarify the impact of G-6-PD deficiency on the clinical course of SCD, and on the other hand, for assessing post-transfusion clinical outcomes after transfusion with G-6-PD-deficient blood units,” the researchers wrote.

Also, “a systematic screening for G-6-PD deficiency in all SCD patients in the DRC is essential,” they added.