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BLOG: Why does hydroxychloroquine retinopathy look like a bull’s eye?
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Much has been written about screening for hydroxychloroquine toxicity.
In 2016 there was a major paper from the American Academy of Ophthalmology revising its recommendations on the screening for retinopathy. A Google search yields myriad case reports from all over the world.
Several recent case series have found variability in the diameter of the bull’s eye depending on the ethnicity of the patient. There are lots of papers about Plaquenil (hydroxychloroquine, Sanofi-Aventis) retinopathy, but not a lot is written about why it gets its characteristic shape. Why a bull’s eye? Why spare the fovea? Do you spell it bull’s eye or bullseye? So many questions.
I wanted to explore the pathophysiology of hydroxychloroquine (HCQ) toxicity this month. It brought me to articles from 1963 (Bernstein et al., Wetterholm et al.) and from 4 months ago (Jorge et al.). To be honest, there’s not a lot of information about it, but I’ll try to explain what we can learn from the literature.
When you look this question up, you’ll find that most of the articles insert a phrase stating something to the effect of: “The mechanism of action is not well understood.” But there is a main theory on the toxicity, and I’ll try to outline it here.
Pathophysiology
The first thing to understand is that a lot of the studies on the pathophysiology are done on chloroquine’s effect on retinal cells, not HCQ. This article will talk about HCQ, but one could attribute this to chloroquine as well.
We are inferring a relationship to HCQ toxicity, but this is not a hard leap to make. The drugs have very similar patterns of retinopathy; it’s just that chloroquine is much more toxic than HCQ. HCQ yields less retinopathy because it has a hydroxyl group added to the molecule, which limits the ability of HCQ to cross the blood-retinal barrier. It’s rare to see a patient on chloroquine today for this reason; HCQ is simply much safer for risk of vision loss.
How lysosomes work
The next thing to understand is that HCQ works by affecting lysosomes, so it’s worth an aside to recap how lysosomes work. For those who only fuzzily remember high school science class (apologies to Mr. Morris), lysosomes are organelles within a cell that help digest material and break down waste. This process is known as autophagy. Lysosomes contain lots of enzymes and typically operate in a fairly acidic (low pH) environment.
Relatedly, a major mechanism of action of HCQ is to raise the lysosomal pH. This means that with HCQ on board, lysosomes will have a harder time breaking down certain materials. If the lysosomes are mistakenly breaking down self-antigens in the joints of a patient with rheumatoid arthritis, then raising the lysosomal pH would be a good thing, and this is why HCQ works for many autoimmune diseases. If the lysosomes are providing a necessary service to vision, then raising the pH would be a bad thing.
And this is what’s happening in HCQ retinopathy: Lysosomal activity in the RPE slows down, and lipofuscin builds up in the subretinal space. This lipofuscin (just like in age-related macular degeneration) exerts cytotoxic effects on retinal pigment epithelium (RPE) cells, and RPE atrophy ensues. The process continues much like AMD, but in a specific location.
Why retinopathy starts in RPE
HCQ-related changes have been found in many layers of the retina, including the ganglion cells, photoreceptors and RPE. So why does the retinopathy start in the RPE? Because HCQ binds to melanin with a strong affinity and is, thus, present in higher concentrations in the RPE and because HCQ is a weak base and accumulates preferentially in acidic compartments such as lysosome.
Why a bull’s eye?
But what about that specific location mentioned above? Why a bull’s eye? To answer that question, one would have to answer why the foveola is spared and why the toxicity stops peripheral to a certain diameter. This is where I have to regretfully inform you, dear reader, that I just don’t know the reason and I can’t find the answer in the literature. Perhaps this is what everyone meant by “the mechanism of action is not well understood.” But I had some thoughts while pondering.
First, I thought perhaps the central macula is most affected because it’s the most metabolically active. But this doesn’t seem to work given the differences in diameter of retinopathy depending on race. Fifty percent of Asian patients present with toxicity greater than 8 degrees from the fovea, as opposed to only 2% of white patients (Melles et al.). And it’s not like Asian patients are fixating outside their foveas.
Second, perhaps the bull’s eye pattern mimics the density of rods in the macula, and perhaps having only cones is somehow protective of the fovea. But this doesn’t seem to work, either, because the maximum density of rods is typically 15 degrees to 20 degrees from the fovea, much wider than even Asian toxicity, let alone all other races (Lee et al.).
I guess we didn’t really discover the reason for the bull’s eye, but we did learn some interesting facts about the mechanism of action of HCQ toxicity. And incidentally, I looked it up, and you can spell it bull’s eye or bullseye. Bullseye seems more common in dart players in England. As they say in darts circles: “Mugs away” until next month.
References:
Bernstein HN et al. Arch Ophthalmol. 1964;71:235-245.
Jorge A, et al. Nat Rev Rheumatol. 2018;doi:10.1038/s41584-018-0111-8.
Lee DH, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2015.01.014.
Marmor MF, et al. Ophthalmology. 2002;109:1377-1382.
Marmor MF, et al. Ophthalmology. 2016;doi:10.1016/j.ophtha.2016.01.058.
Melles RB, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2014.07.018.
Wetterholm DH et al. Arch Ophthalmol. 1964;71:82-87.
Yam JCS, et al. Hong Kong Med J. 2006;12(4):294-304.
Yoon YH, et al. Invest Ophthalmol Vis Sci. 2010;doi:10.1167/iovs.10-5278.