Increased Risk of Retinal Disease Linked with G6DP Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) is an enzymatic protein which, at its most basic level, plays a supportive role in the normal function of red blood cells. From a bimolecular standpoint, G6PD’s action occurs within the first step of the pentose phosphate pathway upon converting glucose into an important nucleotide component known as ribose-5-phosphate.¹

For all those biochemistry nerds, recall that this reaction is imperative to the health of red blood cells. Within this reaction, a molecule of nicotinamide adenine dinucleotide phosphate (NADPH) is produced and utilized by red blood cells to protect against reactive oxidative species (ROS).

Importantly, red blood cells are uniquely susceptible to hemolysis in the presence of ROS and a G6PD deficiency, given their lack of other means for NADPH production and ROS protection.²

Overview of glucose-6-phosphate dehydrogenase deficiency

G6DP is regarded as the most common enzymatic deficiency worldwide, affecting nearly 400 million people.¹ It spans across many demographics and nearly all populations. Albeit, people of African descent appear to carry the greatest risk. According to Johns Hopkins, G6PD deficiency affects an estimated 1 in 10 African-American men.⁴

The genetic coding for G6PD is located along the X chromosome. It’s hypothesized that this particular mutation may prove beneficial to protect against severe cases of malaria.¹⁰ Patients who are homozygotes (genetic encoding from both parents) and heterozygotes (genetic encoding from one parent) are both at risk. Although, there is an elevated risk of severity in homozygous populations.³

As the encoding occurs along the X chromosome, genetically, there is a greater symptomatic risk within male versus female populations. The deficiency is also common among patients of Middle-Eastern, Asian, and Mediterranean descent.

The spectrum severity in G6DP deficiency

According to the American Academy of Family Physicians, the severity presents as a spectrum ranging from asymptomatic to severely symptomatic. The amount of G6PD deficiency directly correlates to symptomatic outcomes.

This is further itemized through a Class system that includes Classes I to V. Briefly, Classes I and II experience the most severe grading of enzymatic deficiency, with Class III presenting as moderate deficiency, Class IV as mild to no deficiency, and Class V as no deficiency.³

Classes II, III, and IV are important to remember; listed below is the prevalence of different classes of G6DP deficiency:^3,5

Class II deficiency is near 4% among Asian males.
Class III deficiency is estimated at 10 to 12% among African-American males.
Class IV deficiency is an estimated 4% among African-American females.

Of note, diagnoses typically present as asymptomatic to mild within patients of African-American descent. Whereas in other affected populations, although the diagnosis is less common, it typically alludes to a higher degree of severity.

Diagnosis of G6PD deficiency

Glucose-6-phosphate dehydrogenase deficiency is not likely to be on our short list of possible diagnoses. However, perhaps it should be.

To draw upon the previously stated alarming statistic, nearly 12% of African-American males are affected by this condition. It’s our duty to perform our role in reducing health disparities among patient populations.

Per Cleveland Clinic, the following is a non-exhaustive list of signs and symptoms of G2DP deficiency:⁶

Anemia, pale skin
Fatigue
Tachycardia and shortness of breath
Dark coloration of urine

Providers should be aware of particular presenting ocular symptoms, including paleness of the palpebral conjunctiva (associated with anemia) and or yellowing of the sclera (associated with jaundice). It is incumbent upon the eyecare professional to report the aforementioned findings to the patient’s primary care physician.

Further lab work up to identify a G6DP deficiency may include:⁷

Complete blood count (CBC) and observation of increased reticulocyte count (RC)
Indirect increases in lactate dehydrogenase (LDH) and bilirubin
Assessment for decreased serum haptoglobin and presence of hematuria or hemosiderin
Peripheral blood smear (PBS) for the detection of denatured hemoglobin referred to as Heinz bodies

Undiagnosed G6DP deficiency and diabetic retinal disease

It’s important to understand the risk of underestimating HbA1C measurements when considering patients with an undiagnosed G6PD deficiency. The next few paragraphs will discuss whether the reliance on HbA1C increases the concern for health disparities due to the risk of poor diabetic control and subsequent diabetic retinal complications.

The presumed pathophysiology is relatively direct. G6PD deficiency results in premature hemolysis or the early breakdown of one’s red blood cells. Recall that HbA1C measurements are collected to reflect the glycosylated hemoglobin over a 90- to 120-day period, thus presenting the clinician with a relative understanding of average blood sugar levels over that time.⁸

The problem of premature hemolysis in G6DP deficiency

The American Diabetes Association recommends that HbA1C be measured every 3 months for newly diagnosed patients and every 6 months for stable patients.⁹ The reason being, the lifespan of a typical red blood cell is 90 to 120 days. However, what happens if that lifespan is cut short by premature hemolysis in a patient with an undiagnosed G6PD deficiency?

A recent article published in the Journal of Nature Medicine expounds upon this question.¹¹ The authors analyzed a compilation of data regarding patients of non-Hispanic African descent with a G6PD risk allele to determine a correlation between HbA1C and plasma glucose at different stages of diabetic progression. The results were astounding.

In comparison, a year prior to diabetes diagnosis, the G6PD group revealed a lower HbA1C level paired with significantly higher plasma glucose. Moreover, this pattern continued prior to the introduction of insulin management, albeit in the presence of comparatively higher A1C and glucose levels.¹¹

The authors then analyzed whether these factors affected the likelihood of an increased risk of diabetic retinopathy. The findings demonstrated an increased likelihood of 2.39% in both the male and female populations carrying G6PD deficiency alleles.¹¹

It was concluded that an increased risk of retinopathy is presumably driven by suboptimal glucose control—specifically, at risk in these populations, where HbA1C provides an inaccurate portrayal of successful diabetic management.

Susceptibility to systemic manifestations

More alarming was the conclusion that these patients may suffer from other systemic manifestations.

A further analysis of the data provided by a clinic trial labeled, “The Action to Control Cardiovascular Risk in Diabetes,” determined that other undesirable outcomes, including diabetic nephropathy, were displayed at an increased rate among the population carrying the GDPD deficiency allele.¹¹Again, these findings were likely attributed to suboptimal glucose control.

Addressing disparities in diabetes

There already exists a remarkable disparity regarding diabetic prevalence in the United States. The Centers for Disease Control (CDC) notes diabetes disproportionately affects the African-American community, including 12.1% of patients currently diagnosed with the condition.¹²

To reference the study from Nature Medicine, among men and women of non-Hispanic African ancestry in the United States, ~12% of diabetic retinopathy cases may be attributed to the presence of a G6PD deficiency allele.¹¹

These disparities should not be assumed lightly. Better management requires further due diligence on behalf of the clinician to obtain an accurate portrayal of disease progression. Therefore, it is suggested to reconsider our reliance on standard HbA1C measurements when evaluating the risk of diabetic retinopathy presentation and progression as well as management of the underlying disease in our affected populations.

Conclusion

Consideration of G6PD deficiency is a “must” to ensure effective diabetic ocular management. Integration of this diagnosis will aid in reducing common health disparities due to inaccuracies between HbA1C and actual blood glucose levels.

The research is still ongoing. However, at this stage, perhaps, as the authors of the Nature Medicine article suggest, incorporating a direct assessment of blood glucose levels, G6PD screening, or eventually, G6PD allele-adjusted HbA1C measurements will aid in more dynamic management of our patients.