Ophthalmic Surgery, Lasers and Imaging Retina

Case Report 

Anti-Retinal Antibodies in Vitamin A Deficiency

Michael P. Ellis, MD; Melinda Y. Chang, MD; Glenn Yiu, MD, PhD

Abstract

Vitamin A is an important component of the visual cycle, and its deficiency causes a retinal degeneration that may be reversed with retinol supplementation. Here, the authors present a patient with vitamin A deficiency and rod-mediated retinopathy who was found to have multiple anti-retinal antibodies that gradually dissipated after vitamin A supplementation. This interesting case suggests the possibility that the photoreceptor degeneration induced by vitamin A deficiency may lead to transient immune exposure to retinal antigens and development of anti-retinal antibodies.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:723–726.]

Abstract

Vitamin A is an important component of the visual cycle, and its deficiency causes a retinal degeneration that may be reversed with retinol supplementation. Here, the authors present a patient with vitamin A deficiency and rod-mediated retinopathy who was found to have multiple anti-retinal antibodies that gradually dissipated after vitamin A supplementation. This interesting case suggests the possibility that the photoreceptor degeneration induced by vitamin A deficiency may lead to transient immune exposure to retinal antigens and development of anti-retinal antibodies.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:723–726.]

Introduction

Anti-retinal antibodies are often used in the diagnosis of autoimmune, cancer-associated, and melanoma-associated retinopathies.1 Although detection of these autoantibodies is neither sensitive nor specific,2 with anti-retinal reactivity detectable in up to one-third of normal sera,3 antibodies against certain antigens such as recoverin may improve the specificity of the diagnosis. Here, we present a patient with vitamin A deficiency who was found to have anti-retinal antibodies, but whose antibody repertoire diminished after vitamin A supplementation. We hypothesize that the humoral immune response may be triggered by the retinal degeneration induced by vitamin A deficiency.

Case Report

A 64-year-old woman with new visual field disturbance, xanthopsia (yellow-tinged vision), and nyctalopia was referred for evaluation of possible autoimmune retinopathy. Due to her history of recurrent breast cancer after mastectomy and radiation therapy, autoantibody testing had been obtained by the referring physician, and revealed several anti-retinal antibodies detected on Western blot (30-kDa, 34-kDa, 36-kDa, 42-kDa, and 46-kDa) and immunoreactivity identified for enolase, HSP60, TULP1, and GAPDH. Slit-lamp examination revealed Bitot's spots (Figure 1A), although dilated funduscopic exam showed no apparent abnormalities. Automated visual field testing demonstrated bilateral constriction (Figure 2A), and electroretinography (ERG) showed reduced scotopic responses in both eyes (Figure 3A). Upon further questioning, the patient reported a history of multiple gastrointestinal surgeries including small bowel resection after an obstruction. Serum testing revealed less than 0.06 mg/L vitamin A (normal range: 0.3 mg/L to 1.2 mg/L), confirming vitamin A deficiency. The patient was given intramuscular vitamin A injections (50,000 IU/day) for 5 days, followed by daily oral vitamin A supplementation (10,000 IU/day), with rapid improvement in symptoms and resolution of clinical, visual field, and scotopic ERG findings after 3 months (Figures 1B, 2B, and 3B). Repeat serum testing showed increased vitamin A levels to 0.3 mg/L, and reduction in anti-retinal antibody repertoire on Western blot (30-kDa and 42-kDa), but persistent immunoreactivity to the autoantibodies. Two years after sustained vitamin A supplementation, her vitamin A level stabilized at 0.3 mg/L, and almost no anti-retinal antibodies were detected, except those for TULP1 (Table 1).

Slit-lamp photographs of a patient with vitamin A deficiency (A) before and (B) 3 months after intramuscular and oral vitamin A supplementation, showing resolution of Bitot's spots.

Figure 1.

Slit-lamp photographs of a patient with vitamin A deficiency (A) before and (B) 3 months after intramuscular and oral vitamin A supplementation, showing resolution of Bitot's spots.

30-2 Humphrey visual field studies of both eyes in a patient with vitamin A deficiency (A) before and (B) 3 months after vitamin A supplementation, showing recovery of visual field constriction. MD = mean deviation.

Figure 2.

30-2 Humphrey visual field studies of both eyes in a patient with vitamin A deficiency (A) before and (B) 3 months after vitamin A supplementation, showing recovery of visual field constriction. MD = mean deviation.

Scotopic electroretinogram (ERG) waveforms of both eyes in a patient with vitamin A deficiency (A) before and (B) 3 months after vitamin A supplementation, showing recovery of both a- and b-waves.

Figure 3.

Scotopic electroretinogram (ERG) waveforms of both eyes in a patient with vitamin A deficiency (A) before and (B) 3 months after vitamin A supplementation, showing recovery of both a- and b-waves.

Serum Testing Before and After Vitamin A Supplementation in a Patient With Vitamin A Deficiency

Table 1:

Serum Testing Before and After Vitamin A Supplementation in a Patient With Vitamin A Deficiency

Discussion

Autoantibodies in visual paraneoplastic disorders such as cancer-associated and melanoma-associated retinopathies are hypothesized to arise from molecular mimicry between tumor antigens and retinal proteins. Foreign pathogens may also exhibit epitopes resembling retinal proteins triggering anti-retinal antibodies.4 In addition, infectious retinopathies and inherited retinal degenerations such as retinitis pigmentosa may develop autoantibodies, possibly as a consequence of the amplified immune response or blood-retinal barrier breakdown in these conditions.5

Vitamin A is a fat-soluble vitamin that must be obtained through diet in two forms: as retinol and retinyl ester from animal sources including meat, fish, and dairy products, or as provitamin carotenoids from plants sources such as fruits and vegetables. Because vitamin A is required for the visual cycle, including the conversion of all-trans-retinal to 11-cis-retinal, diminished vitamin A levels may result in photoreceptor damage as seen on imaging6 and animal models.7 Vitamin A deficiency also causes xerosis and conjunctival keratinization resulting in Bitot's spots, and is a leading cause of childhood blindness worldwide.

In the current case, we hypothesize that the acute retinal degeneration induced by vitamin A deficiency led to transient immune exposure to retinal antigens and development of anti-retinal antibodies. This was supported by the gradual loss of some of these autoantibodies after sustained vitamin A supplementation and recovery of symptoms. Enolase,8HSP60,9 and GAPDH10 are all expressed in photoreceptor outer segments, where acute injury may result in exposure to the immune system if there is disruption of the blood-retinal barrier. The functional consequence of these anti-retinal antibodies and the mechanism for the persistence of some autoantibodies remain unclear. Although the reproducibility of autoantibody testing is not well understood, the diminished anti-retinal antibody repertoire and clinical improvement after vitamin A supplementation suggests the possibility that some autoantibodies may be triggered by vitamin A deficiency. Further studies on the role of anti-retinal antibodies in the pathophysiology of vitamin A deficiency may prove insightful.

References

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  2. Hooks JJ, Tso MO, Detrick B. Retinopathies associated with antiretinal antibodies. Clin Diagn Lab Immunol. 2001;8(5):853–858. doi:10.1128/CDLI.8.5.853-858.2001 [CrossRef] PMID:11527791
  3. Shimazaki K, Jirawuthiworavong GV, Heckenlively JR, Gordon LK. Frequency of anti-retinal antibodies in normal human serum. J Neuroophthalmol. 2008;28(1):5–11. doi:10.1097/wno.0b013e318167549f [CrossRef] PMID: 18347451
  4. Atassi MZ, Casali P, Atassi MZ, Casali P. Molecular mechanisms of autoimmunity. Autoimmunity. 2008;41(2):123–132. doi:10.1080/08916930801929021 [CrossRef] PMID: 18324481
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  6. Aleman TS, Garrity ST, Brucker AJ. Retinal structure in vitamin A deficiency as explored with multimodal imaging. Doc Ophthalmol. 2013;127(3):239–243. doi:10.1007/s10633-013-9403-0 [CrossRef] PMID:23900584
  7. Carter-Dawson L, Kuwabara T, O'Brien PJ, Bieri JG. Structural and biochemical changes in vitamin A—deficient rat retinas. Invest Ophthalmol Vis Sci. 1979;18(5):437–446. PMID:437947
  8. Smith WC, Bolch S, Dugger DR, et al. Interaction of arrestin with enolase1 in photoreceptors. Invest Ophthalmol Vis Sci. 2011;52(3):1832–1840. doi:10.1167/iovs.10-5724 [CrossRef] PMID:21051714
  9. Tezel G, Hernandez R, Wax MB. Immunostaining of heat shock proteins in the retina and optic nerve head of normal and glaucomatous eyes. Arch Ophthalmol. 2000;118(4):511–518. doi:10.1001/archopht.118.4.511 [CrossRef] PMID:10766137
  10. Baker BY, Shi W, Wang B, Palczewski K. High-resolution crystal structures of the photoreceptor glyceraldehyde 3-phosphate dehydrogenase (GAPDH) with three and four-bound NAD molecules. Protein Sci. 2014;23(11):1629–1639. doi:10.1002/pro.2543 [CrossRef] PMID:25176140

Serum Testing Before and After Vitamin A Supplementation in a Patient With Vitamin A Deficiency

Before Vitamin A3 Months After Vitamin A12 Months After Vitamin A24 Months After Vitamin A
Vitamin A (mg/L)<0.060.30.240.38
Western Blot30, 34, 36, 42, 46 kDa30, 42 kDa
Enolase+++
HSP60+++
TULP1++++
GAPDH++
Authors

From the Department of Ophthalmology & Vision Sciences, University of California, Davis, Sacramento, California (MPE, GY); and University of Southern California Roski Eye Institute, Los Angeles, Los Angeles, California (MYC).

Presented at the Macula Society Annual Meeting in London, United Kingdom, on September 11, 2019.

Dr. Yiu is supported by NIH K08 EY026101, NIH R21 EY031108, the BrightFocus Foundation, and the Macula Society. He also has research support from Clearside Biomedical and Iridex, and is a consultant for Allergan, Alimera, Carl Zeiss Meditec, Clearside Biomedical, Genentech, Iridex, Topcon, and Verily. Dr. Ellis reports no relevant financial disclosures. Dr. Chang has received grants from Knights Templar Eye Foundation, Children's Eye Foundation of AAPOS, and Research to Prevent Blindness outside the submitted work.

Address correspondence to Glenn Yiu, MD, PhD, University of California, Davis, 4860 Y Street, Suite 2400, Sacramento, CA 95817; email: gyiu@ucdavis.edu.

Received: August 19, 2020
Accepted: October 07, 2020

10.3928/23258160-20201202-07

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