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BLOG: Can sickle cell retinopathy occur in a patient with sickle cell trait?
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This was the question that ran through my mind once when a resident presented a case to me saying that she noticed what she thought was a sea-fan in her sickle cell trait patient. “I thought that didn’t happen,” I believe was my response.
On my funduscopy and subsequent fundus fluorescein angiography, it was clear that this patient did indeed have three areas of sea-fan neovascularization between his two eyes.
He was a 35-year-old African American male with a past medical history of only sickle cell trait. He wasn’t able to provide much medical information about either parent but denied that he ever had any type of sickle crisis, described to him as episodes of acute pain and tenderness in the chest and/or joints. He never had any genetic testing at our hospital; his trait diagnosis was something told to him as a child. So, in addition to an appointment with our retinal specialist for laser photocoagulation, we made him an appointment with our hematology clinic.
Before we go further into this case, I think it would be wise to review the pathophysiology and clinical manifestations of sickle cell disease. Hemoglobin (Hb) is the protein we use to transport oxygen throughout our body. It’s made up of an alpha chain and a beta chain, and sickle cell disease is caused by a point mutation in the beta chain. This mutation in the Hb cell causes any picked-up erythrocyte’s membrane to stiffen, which changes the blood cell’s shape from round (or biconcave) to sickled, which means the cell can’t traverse the small capillaries and causes unpredictable episodes of microvascular occlusion. Eventually, the spleen destroys the abnormal erythrocytes, but the patient continues to make mutated Hb, which continues to sickle many red blood cells, eventually causing microinfarction of many tissues. Patients with sickle cell disease often need splenectomies for this reason, often before the age of 5 years, which puts the patient at risk for infection for the rest of their lives.
The spleen, kidneys and retina are the areas most affected; the latter two are not surprising, given their small capillary beds, prone for infarction. Sickle cell patients will also have sickle crises, which are defined as episodes of painful ischemia, with acute pain (often in the chest or joints), tenderness, fever, tachycardia and anxiety, often brought about by exercise, dehydration or hypoxia.
But the genetics of sickle cell are not as simple as positive/negative. It’s simple Mendelian genetics, and sickle cell is homozygous autosomal recessive, but there are more than two alleles for Hb. In this article we will focus on three: A (normal hemoglobin), S (sickled hemoglobin) and C (hemoglobin C).
Hb genotypes include: AA, which is normal hemoglobin; AS, which is sickle cell trait; SS, which is sickle cell anemia; SC, which is hemoglobin SC disease; and AC, which is hemoglobin C trait. In order for a patient to have HbSS (sickle cell anemia) both parents would have to give the HbS allele, meaning each parent would need to have sickle cell trait or sickle cell anemia. There is also a disease known as hemoglobin SC, where one Hb allele is S and the other is C. In SC trait, the patient will have no crises; in SC anemia, the patient will have severe crises; and in hemoglobin SC disease, the patient will have rare crises but will have much more retinopathy than trait or anemia combined. And this is why, as eye care providers, we need to know about the genetics of sickle cell disease. It’s called the Sickle Cell Paradox.
Why would patients with hemoglobin SC disease, which causes much less hemolytic anemia, splenic infarctions and pain crises, have more occlusive retinopathy? The paradox is debated, but the main theory is this: HbSC occludes the retinal circulation just enough to eventually cause areas of retinal ischemia, but not so badly that it doesn’t allow neovascularization/proliferation. In HbSS patients, the early and more complete occlusion of peripheral retinal vessels is so severe that the growth of proliferative lesions is rare, similar to the severity of ischemia and rate of proliferation of retinal artery occlusion vs. retinal vein occlusion. The difference in retinal neovascularization is dramatic between the two diseases.
A longitudinal study over 20 years in Jamaica by Downes and colleagues found that by age 24, proliferative retinopathy developed in 43% of those with HbSC, opposed to only 14% of those with HbSS. Other studies found a life-time frequency of proliferative retinopathy in more than 70% of those with HbSC (Elagouz, et al.). The difference between these HbSC numbers probably has something to do with life expectancy between the two diseases – it’s 27 years with HbSS, but a full life expectancy with HbSC.
I have one last thought about the Sickle Cell Paradox. There is an alternate hypothesis called the hematocrit theory, which is this: because HbSS disease causes such severe anemia, the overall hematocrit (percentage of red blood cells in blood) is so low that the blood viscosity is low, thus protecting from vaso-occlusion in the small capillaries of the retina. This theory would have a hard time explaining the higher rates of occlusion in larger vessels, however. Perhaps the truth lies somewhere in a combination of the two theories.
Incidentally, sickle cell disease is most common in areas of the world where malaria is endemic. The high prevalence of the sickle mutation in these regions is thought to be because HbS carriers are more resistant to malaria. According to Ryan, in patients of African descent in North America, 8.5% have HbAS (SC trait), 2.5% have HbAC (HbC trait), 0.14% have HbSS (SC anemia), and 0.20% have HbSC (HbSC disease). In patients with SC trait, the Hb composition is roughly 35% HbS (meaning 65% of their Hb is normal); compared with patients with SC anemia, the Hb composition is about 90% HbS.
It’s for this reason that patients with SC trait will have very rare sickle crises and (to answer our original question) rare retinopathy. But there are documented cases of all types of retinopathy with lab-proven SC trait patients. However, critics of these findings note that these complications occurred in patients with concomitant diseases such as hypertension, tuberculosis, diabetes and sarcoidosis. Therefore, given the large number of patients with SC trait, one might consider the presence of proliferative retinopathy coincidental. Or, in other words, like in our case in the beginning, if a resident comes to you and says there’s a sea-fan in her patient with SC trait, have the patient tested for hemoglobin SC disease.
References:
Barbosa de Melo M. Brazilian Journal of Hematology and Hemotherapy. 2014;36(5):319-321.
Downes SM, et al. Ophthalmology. 2005;112(11):1869-1875.
Elagouz M, et al. Surv Ophthalmol. 2010;55(4):359-377.
Kasper DL, et al. Harrison's Principles of Internal Medicine, 16th ed. New York, NY: McGraw Hill; 2005.
Ryan SJ. Retina, 4th ed. Philadelphia, PA: Elsevier-Mosby; 2006.