In his blog, Doug Rett, OD, FAAO, digs deeper into questions every eye doctor has had at one point in his or her career. He sees patients and works with students and residents at the optometry clinic for the VA Boston Healthcare System and will use his blog to bring the teaching points he sees in clinic to a larger audience. Contact him at

Disclosure: Rett has no relevant financial disclosures.

BLOG: Why does hydroxychloroquine retinopathy look like a bull’s eye?

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.


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.