Published in Systemic Disease

Ocular Manifestations of Vitamin Deficiencies

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Review how vitamin deficiencies can impact ocular health and how optometrists can treat them with nutritional supplementation.

Ocular Manifestations of Vitamin Deficiencies
In addition to the myriad of standard-of-care treatment options optometrists have at their disposal, many off-label treatments may also benefit our patients—especially when it comes to nutrition and vitamin supplementation.
In this article, we’ll review the ocular manifestations of vitamin deficiencies and gain a better understanding of the importance of nutritional supplementation when it comes to managing ocular disease.

Vitamins: The basics

While vitamins are ubiquitous, let’s first have a review of what they actually are and how they work. Vitamins are a category of organic compounds needed for normal cell function and growth and are typically not produced by the human body. There are 13 essential vitamins that must be consumed in the diet or taken as a supplement.
As a reminder, vitamins are either fat-soluble (vitamins A, D, E, and K) or water-soluble (vitamin C and all B vitamins). Fat-soluble vitamins are best absorbed when consumed with dietary fat and can be stored in the body, while water-soluble vitamins need to be consumed regularly as they are generally not stored in the body (secreted out with urine).

The pathophysiology of vitamin deficiencies

Vitamin deficiency, or not having enough of a particular vitamin in the body—whether from poor nutrient quality of diet or poor absorption—can cause long-term health problems. We can think of all disease processes stemming from cellular damage caused by oxidation. As we’ll see, vitamin deficiencies can further exacerbate this process.
When molecules become oxidized (lose an electron), they bind to and react with unintended molecules, causing damage. Given the eye’s high level of metabolic activity, it produces a significant amount of reactive oxygen species as a metabolic byproduct during this oxidation process.
Oxidative stress leads to inflammation and damage to the entire cell, including DNA, RNA, and the mitochondria. If no intervention is provided, these cells will then undergo apoptosis and die. If we provide the essential vitamins, nutrients, and antioxidants prior to cell death, we can prevent further vision loss from a myriad of ocular diseases.1

Ocular health and vitamin deficiencies from A-Z

Vitamin A

Function

We should all be very familiar with vitamin A in the eye, as it is responsible for the formation of rhodopsin, the photopigment found in the rods. Therefore, it is crucial for night vision; as such, night blindness is one of the first signs of vitamin A deficiency.
Vitamin A deficiency is actually the leading cause of childhood blindness worldwide, although it is rare in the United States.2 In the anterior segment, vitamin A is responsible for the appropriate development of the cornea and conjunctival epithelium as well as the innate immune system and maintenance of the mucin layer of the tear film.3

Dietary sources of vitamin A

Vitamin A in the diet can be found in one of two forms: preformed vitamin A, such as retinol and retinyl esters, and provitamin A carotenoids. The main sources of preformed vitamin A are liver, dairy products, fish, and eggs.
Provitamin A carotenoids come from plant sources from foods, such as leafy green vegetables and those with bright orange, yellow, or red coloration.

At-risk patients

While vitamin A deficiency is uncommon in the developed world, there is a subset of pediatric patients we should be on the lookout for who may show signs of xerophthalmia (night blindness and corneal keratinization).
These patients include those with autism spectrum disorder (e.g., selective eating habits) and/or those with gastrointestinal problems disrupting the absorption of this fat-soluble vitamin.2
Of course, if you see patients who have immigrated to the United States from a less developed country, vitamin A deficiency should also be on your radar.

Ocular manifestations of vitamin A deficiency

Anterior segment signs of vitamin A deficiency:4
  • Corneal xerosis: A dry, hazy appearance to the cornea
  • Bitot’s spots: A triangular patch of dry conjunctiva, a classic sign of vitamin A deficiency
    • Bitot’s spots usually occur temporally and do not wet with tears
  • Corneal ulceration: Also is a possible sign
Posterior segment signs of vitamin A deficiency:5
  • Night blindness: Or difficulty seeing in low light conditions
  • Vision loss: If untreated, can lead to permanent vision loss
Fortunately, signs and symptoms typically resolve with sufficient vitamin A consumption.

Vitamin B1 (Thiamine)

Function

Thiamine is involved in many basic cellular functions and energy production.6

Dietary sources of vitamin B1

Of note, thiamine can be found in organ meat, pork, seeds, squash, fish (especially trout, mackerel, salmon, and tuna), legumes, and fortified cereals.6

At-risk patients

Those abusing alcohol, experiencing malnutrition, or severe eating disorders.7

Ocular manifestations of thiamine deficiency

Thiamine deficiency, most often caused by excessive alcohol consumption, can lead to Wernicke-Korsakoff Syndrome.
The acute phase, Wernicke encephalopathy, is characterized by confusion, ataxia, and ocular abnormalities, including double vision, nystagmus, ophthalmoplegia, and ptosis (rarely).7

Vitamin B6 (Pyridoxine)

Function

Vitamin B6 aids in the production of hemoglobin and is important in cellular metabolism.

Dietary sources of vitamin B6

Of note, vitamin B6 can be found in a wide variety of plant and animal foods, including leafy and root vegetables, fruit such as bananas, red meat, poultry, and seeds (especially sunflower and pumpkin).8

At-risk patients

Those with impaired renal function, alcohol abuse, malabsorption, and geriatric patients are at risk for vitamin B6 deficiency.9

Ocular manifestations of vitamin B6 deficiency

One case report found vitamin B6 deficiency to be the cause of Roth-type, white-centered retinal hemorrhage and non-epileptic seizures, which resolved with B6 supplementation.10

Vitamins B9 (Folic acid) and B12 (Cobalamin)

Function

Vitamin B12 is a necessary part of red blood cell maintenance and DNA formation (along with folate B9). It is absorbed in the gut from animal protein consumption with sufficient levels of stomach acid (HCl).1
Vitamin B12 and B9 deficiencies often occur together, so if you’re suspicious of one, it may be beneficial to test for both.

Dietary sources of vitamins B9 and B12

Dietary sources of vitamin B9:11
  • Organ meat
  • Green vegetables (both leafy and non-leafy)
  • Legumes
  • Beets
  • Avocados
  • Papayas
  • Strawberries
  • Pomegranates
Dietary sources of B12:12
  • Fish (especially sardines, salmon, tuna, and cod)
  • Shellfish such as shrimp and scallops, organ meat, beef, eggs, and poultry
  • Some fermented soy products like tempeh

At-risk patients

B12 deficiency is quite common in the US due to a number of factors, such as:13
  • HCl production decreases with age
  • Ubiquitous use of proton pump inhibitors to treat acid reflux (reducing HCl in the stomach)
  • Diets that avoid animal protein
  • Metformin use

Ocular manifestations of vitamin B12 deficiency

Ocular manifestations of vitamin B12 deficiency are rare. Optic atrophy has been cited, and less often, optic neuritis with only partial resolution after B12 was administered.14
One study found retinal nerve fiber layer (RNFL) thickness to be thinner in patients with vitamin B12 deficiency than those with normal B12 levels. This could be extrapolated to be of concern for patients with glaucoma or other conditions affecting the RNFL.15
B12 deficiency in one case report caused extensive retinal hemorrhaging, including Roth spots and pre-retinal hemorrhages due to pancytopenia. The retinal hemorrhages resolved with blood transfusion, a return to an omnivorous diet (the patient had been vegan), and vitamin B12 supplementation.16

Vitamin C

Vitamin C deficiency is defined as a serum concentration of less than 11.4μmol/L.17

Function

Vitamin C is one of the most important antioxidants. Antioxidants add electrons to damaged (oxidized) cells so they can retain their normal function. Given that the retina is one of the most metabolically active tissues in the body, it is prone to oxidation.
Therefore, maintaining adequate antioxidant levels can help protect and restore damaged tissue.18 Of note, vitamin C deficiency is the cause of scurvy.

Dietary sources

While everyone thinks of citrus fruits as containing high levels of vitamin C, most of us wouldn’t think that broccoli (102mg/cup) actually has more vitamin C than an orange (70mg in 1 medium orange)!
Other sources include red bell peppers (95mg/cup), strawberries (85mg/cup), all citrus fruits, dark leafy green vegetables, papaya, guava, cantaloupe, and berries.19

At-risk patients

Patients on hemodialysis, those who consume excess alcohol, use tobacco, or have poor nutritional status are at risk of vitamin C deficiency.17

Ocular signs of vitamin C deficiency

Hemorrhaging

Vitamin C plays a role in the collagen basement membrane and blood vessels. Deficiency can, therefore, lead to hemorrhaging of many organs. In the eye, this is often seen as retinal hemorrhaging and subconjunctival hemorrhages.20

Retina

Glucose competes with vitamin C for cellular binding. In the retina, that means patients with elevated glucose from diabetes are more prone to oxidative damage.
Patients with proliferative retinopathy had a 10-fold decrease in vitreous levels of vitamin C compared with controls. This may also contribute to macular ischemia in patients with proliferative diabetic retinopathy (PDR).21

Glaucoma

Patients with normal-tension glaucoma (NTG) had significantly lower levels of serum vitamin C compared with healthy controls (no ocular disease). This same study showed no difference in serum levels of vitamins A, B9, and E.22

Vitamin D

Vitamin D deficiency is defined as <20ng/ml, according to the National Institutes of Health (NIH).23

Function

Vitamin D modulates the levels of calcium and phosphorus; it also modulates the innate and adaptive immune responses.24
Sources of vitamin D include:26
  • Sunlight on bare skin
  • Oily fish (such as salmon, tuna, and mackerel)
  • Mushrooms
  • Fish roe
  • Liver
  • Eggs

At-risk patients

Many people in the general population have vitamin D deficiency, likely due to poor diet and lack of sun exposure. Groups who are at higher risk of deficiency include those who are obese, have darker skin pigmentation, and are over age 65.26
Those with kidney and liver disease are also at risk as vitamin D in the liver and kidneys help activate the vitamin D taken in by the skin via sunlight.25 
Additionally, lower levels of serum vitamin D were found in patients with more advanced glaucoma, diabetic retinopathy, and macular degeneration. This suggests that vitamin D has a protective effect against many of these inflammatory-driven conditions; however, no causation has been proven.27

Glaucoma

Observational studies have shown lower serum vitamin D levels in patients with glaucoma. While studies on primates indicated vitamin D treatment lowered intraocular pressure (IOP), studies on human subjects have not shown this same effect.
Whether or not vitamin D impacts IOP, it may have an impact on glaucoma via its role in lowering oxidative stress and inflammation—which are contributing factors in glaucoma pathogenesis.
However, this is still controversial, and one systematic review of nine studies showed no association between serum vitamin D levels and primary open-angle glaucoma (POAG), NTG, or exfoliative glaucoma.27
Figure 1 is a fundus photograph of a glaucoma patient's left eye.
Glaucoma Fundus OD
Figure 1: Courtesy of Kristin White, OD.

Cataracts

Low levels of vitamin D were shown in one study to be linked to posterior subcapsular cataracts (PSC). Patients in this study with PSC had levels of vitamin D found to be in the “vitamin D insufficiency” range (24ng/mL [+/-11SD]).
In five patients with early posterior subcapsular water cleft cysts and retro dots who were given 5,000IU of vitamin D daily, their PSC resolved completely. The time frame for this resolution was not mentioned in this study.28

Age-related macular degeneration

Vitamin D receptors and the enzymes that metabolize vitamin D are found in the retina, choroid, and retinal pigment epithelium (RPE). Low levels may be implicated in the pathogenesis of age-related macular degeneration (AMD).
One possible etiology is that vitamin D causes a decrease in amyloid beta proteins that are found in drusen. Another possible method is by reducing inflammation which is thought to be at the root of AMD. Vitamin D can inhibit angiogenesis.29
While there is controversy over whether vitamin D status is related to AMD progression, some studies do show an inverse relationship between vitamin D plasma levels and late atrophic and/or neovascular AMD.29

Diabetic retinopathy

Similarly, vitamin D may impact the development of diabetic retinopathy through its anti-inflammatory role and its effect on new blood vessel growth. Low levels of vitamin D have been thought to lead to inflammation and angiogenesis, which promotes diabetic retinopathy.30
While studies have shown conflicting data, many observational studies have shown lower serum vitamin D values associated with an increased prevalence of diabetic retinopathy and greater severity in patients with both type 1 and type 2 diabetes.30
Figure 2 shows fundus photographs of a patient with severe diabetic retinopathy.
Severe diabetic retinopathy fundus
Figure 2: Courtesy of Kristin White, OD.

Dry eye

Vitamin D’s anti-inflammatory role may also impact dry eye. One clinical trial showed improvement in tear osmolarity and tear stability when patients with clinical vitamin D deficiency (<20ng/ml) were treated with vitamin D in addition to routine dry eye therapy.31

Antioxidants

Lutein/Zeaxanthin/Meso-zeaxanthin

While not vitamins, per se, a discussion on nutrition would be remiss without the mention of antioxidants. These free radical scavengers are crucial to preventing damage by oxidative stress, arguably the main driver behind most, if not all, ocular diseases.
The most common non-vitamin A carotenoids that are important for ocular health include lutein, zeaxanthin, meso-zeaxanthin, and astaxanthin. These have been shown to slow the progression of macular degeneration. Further, lutein and zeaxanthin have also been shown to have effects benefitting cognition.33
While lutein and zeaxanthin can be found in foods like leafy green vegetables and egg yolks, it is impossible for those who are showing signs of ocular disease (e.g., macular degeneration) to consume sufficient quantities from diet alone. Meso-zeaxanthin, a metabolite of lutein and zeaxanthin, is not found in food.32
Recommended doses for antioxidants:
  • Lutein: 6 to 20mg/day
  • Zeaxanthin: 4 to 10mg/day

Astaxanthin

Astaxanthin is an extremely potent antioxidant derived from red algae, krill, and salmon. Astaxanthin has been shown to benefit AMD, cataracts, and glaucoma in addition to dry eye, eye strain, and accommodation.33
Dietary sources of astaxanthin:33
  • Red algae
  • Salmon
  • Krill
  • Shrimp
The recommended dose for astaxanthin is 4 to 6mg/day.33

Omega 3s

Fish oil, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is arguably one of the most important nutrients for ocular and systemic health. We’re all familiar with fish oil for dry eye, but did you know it can benefit retinal disease as well?
Given that over 50% of the lipid content of the photoreceptors is comprised of DHA, it’s no wonder that fish oil can improve the function of the retina. Consuming cold water, fatty fish can improve outcomes in patients with exudative AMD, diabetic retinopathy, and glaucoma.
These include “SMASH” fish, which are typically smaller and have a lower mercury content—sardines, mackerel, anchovies, salmon, and herring. Supplementing with fish, cod liver, or krill oil is also beneficial.34

Studies on omega 3s and ocular diseases

AMD

One study showed reduced levels of vitreal vascular endothelial growth factor (VEGF) in patients with wet AMD receiving intravitreal anti-VEGF injections who also took 1000mg fish oil compared with those receiving injections alone.35

Diabetic retinopathy

Fish oil not only helps increase the sensitivity of the beta cells in the pancreas, but also directly improves capillary permeability and retinal inflammation. It has been shown to reduce the onset of diabetes and improve diabetic retinopathy as well as diabetic macular edema.34

Glaucoma

Fish oil has been shown to increase circulation, which can assist with optic nerve perfusion and improve visual field indices.34 It should be considered an adjunct therapy for our POAG patients.

Table of food sources for vitamins and fatty acids5,6,8,11,12,19,25,34,32,33

Vitamin/Essential Fatty AcidFood Sources
ALiver, fish, eggs, dairy products, leafy greens, orange/yellow/red colored fruits and vegetables
B1 (Thiamine)Organ meat, pork, seeds, squash, fish (especially trout, mackerel, salmon, and tuna), and legumes
B6Wide variety of plant and animal foods, including leafy and root vegetables, fruit such as bananas, red meat, poultry, and seeds (especially sunflower and pumpkin)
B9Organ meat, green vegetables (both leafy and non-leafy), legumes, beets, avocados, papayas, strawberries, and pomegranates
B12Fish (especially sardines, salmon, tuna, and cod), shellfish such as shrimp and scallops, organ meat, beef, eggs, poultry, and some fermented soy products like tempeh also contain vitamin B12
CBroccoli (102mg/cup), red bell peppers (95mg/cup), strawberries (85mg/cup), oranges (70mg in 1 medium orange), all citrus fruits, dark leafy green vegetables, papaya, guava, cantaloupe, and berries
DSun exposure (greatest source), salmon, tuna, mackerel, wild mushrooms, fish roe, liver, and eggs
Omega 3Cold water fish such as salmon, sardines, krill, and mackerel
Lutein/XeaxanthinLeafy green vegetables, egg yolks, pistachios, orange, and yellow-colored vegetables
AstaxanthinSalmon, shrimp, krill, and red algae
Table 1: Courtesy of Kristin White, OD.

Case report of ocular disease and vitamin deficiency

A 15-year-old caucasian female presented to the optometry department of a community health center with complaints of blurry vision. She was having trouble seeing the tablet she was using for distance learning during the COVID-19 pandemic.

Findings from testing

Upon testing, her best-corrected visual acuity (BCVA) was 20/50 in each eye. Given her age, functional amblyopia was the top differential. The general stress of COVID-19 and family life stressors in an otherwise “healthy” appearing teenager may have been affecting her vision.
The patient returned for an optical coherence tomography (OCT) and visual field testing. The OCT showed full rims (although there are no age-matched controls for teens), and the visual field showed diffuse loss, but not the restricted fields necessary for a definitive diagnosis.

Relevant patient history

Upon further discussion with the family, the patient had been diagnosed a couple of years prior with a stomach disorder that caused her to be very uncomfortable whenever she ate.
At the time of her eye exam, she had been exclusively eating potatoes for several months, as this was the one food that didn’t make her stomach feel upset. When she got tested, it was found that she had multiple vitamin deficiencies.

Treatment recommendations

This is an extreme case and a difficult one to treat as she had a lot of anxiety around food after all the discomfort she had been in. This patient was prescribed vitamins/smoothies by her doctor to slowly incorporate foods and nutrients back into her diet and help restore visual (and other systemic) functions.
In the meantime, the patient was also connected with her school district’s teacher of the visually impaired to get her a larger monitor to use at home as her vision loss was affecting her ability to do her school work.
For more information on vitamins, supplements, nutrition, and the eye, check out Review of Optometry’s wellness guide and this article on nutraceutical medical food.

Conclusion

Testing vitamin status and advocating for vitamin supplementation may not be standard-of-care therapy or practical for every patient. However, a thorough understanding of vitamin status and nutrition can help eyecare providers better educate and care for their patients.
When it comes to the management of ocular disease, adjunct testing and therapy may be warranted, especially when standard-of-care treatments are not fully effective.
Testing a patient’s vitamin status and educating them on the potential benefits of appropriate supplementation may improve treatment outcomes for many common (and not-so-common) eye conditions.
Vitamin deficiencies should always be on the differential diagnosis list when striving to provide good quality patient care.
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  13. Azenha C, Costa JF, Fonseca P. You are what you eat: ophthalmological manifestations of severe B12 deficiency. BMJ Case Rep. 2017 May 6;2017:bcr2016218558. doi: 10.1136/bcr-2016-218558. PMID: 28478387; PMCID: PMC5612567.
  14. Ata F, Bint I Bilal A, Javed S, et al. Optic neuropathy as a presenting feature of vitamin B-12 deficiency: A systematic review of literature and a case report. Ann Med Surg (Lond). 2020 Nov 5;60:316-322. doi: 10.1016/j.amsu.2020.11.010. PMID: 33204422; PMCID: PMC7653199.
  15. Icel E, Ucak T. The effects of vitamin B12 deficiency on retina and optic disk vascular density. Int Ophthalmol. 2021 Sep;41(9):3145-3151. doi: 10.1007/s10792-021-01879-x. PMID: 34047909.
  16. Manoj AG, Prabhakar K. Vitamin B12 deficiency: A rare cause of Roth spot. Indian J Med Res. 2020 Nov;152(Suppl 1):S188. doi: 10.4103/ijmr.IJMR_2291_19. PMID: 35345198; PMCID: PMC8257161.
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  21. Park SW, Ghim W, Oh S, et al. Association of vitreous vitamin C depletion with diabetic macular ischemia in proliferative diabetic retinopathy. PLoS One. 2019 Jun 19;14(6):e0218433. doi: 10.1371/journal.pone.0218433. PMID: 31216331; PMCID: PMC6583975.
  22. Yuki K, Murat D, Kimura I, et al. Reduced-serum vitamin C and increased uric acid levels in normal-tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 2010 Feb;248(2):243-8. doi: 10.1007/s00417-009-1183-6. PMID: 19763599.
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  24. Aranow C. Vitamin D and the immune system. J Investig Med. 2011 Aug;59(6):881-6. doi: 10.2310/JIM.0b013e31821b8755. PMID: 21527855; PMCID: PMC3166406.
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  26. Zeratsky K. What are the risks of Vitamin D deficiency? Mayo Clinic Health Lifestyle, Nutrition and Healthy Eating. Published October 7, 2022. Accessed August 22, 2023. https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/expert-answers/vitamin-d-deficiency/faq-20058397.
  27. Chan HN, Zhang XJ, Ling XT, et al. Vitamin D and Ocular Diseases: A Systematic Review. Int J Mol Sci. 2022 Apr 11;23(8):4226. doi: 10.3390/ijms23084226. PMID: 35457041; PMCID: PMC9032397.
  28. Brown CJ, Akaichi F. Vitamin D deficiency and posterior subcapsular cataract. Clin Ophthalmol. 2015 Jun 16;9:1093-8. doi: 10.2147/OPTH.S84790. PMID: 26124632; PMCID: PMC4476482.
  29. Layana AG, Minnella AM, Garhöfer G, et al. Vitamin D and Age-Related Macular Degeneration. Nutrients. 2017 Oct 13;9(10):1120. doi: 10.3390/nu9101120. PMID: 29027953; PMCID: PMC5691736.
  30. Payne JF, Ray R, Watson DG, et al. Vitamin D insufficiency in diabetic retinopathy. Endocr Pract. 2012 Mar-Apr;18(2):185-93. doi: 10.4158/EP11147.OR. PMID: 21940279; PMCID: PMC4706181.
  31. Najjaran M, Zarei-Ghanavati S, Arjmand Askari E, Eslampoor A, Ziaei M. Effect of oral vitamin D supplementation on dry eye disease patients with vitamin D deficiency. Clin Exp Optom. 2023 Apr;106(3):257-262. doi: 10.1080/08164622.2022.2033601. PMID: 35188874.
  32. Bernstein PS, Li B, Vachali PP, et al. Lutein, zeaxanthin, and meso-zeaxanthin: The basic and clinical science underlying carotenoid-based nutritional interventions against ocular disease. Prog Retin Eye Res. 2016 Jan;50:34-66. doi: 10.1016/j.preteyeres.2015.10.003. PMID: 26541886; PMCID: PMC4698241.
  33. Richer S. Carotenoids: Front to Back Ocular Protection. Wellness Essentials for Clinical Practice: A supplement to Review of Optometry. Published October 15, 2019. https://cdn.coverstand.com/22431/627359/8d466e3fb79e95c8532799c190eb7cc532e821c1.7.pdf.
  34. Cornwell K. Fish Oil for AMD, Glaucoma, and Diabetic Retinopathy. Published February 14, 2022. Accessed August 23, 2023. https://eyesoneyecare.com/resources/fish-oil-for-amd-glaucoma-and-diabetic-retinopathy/.
  35. Rezende FA, Lapalme E, Qian CX, et al. Omega-3 supplementation combined with anti-vascular endothelial growth factor lowers vitreal levels of vascular endothelial growth factor in wet age-related macular degeneration. Am J Ophthalmol. 2014 Nov;158(5):1071-78. doi: 10.1016/j.ajo.2014.07.036. PMID: 25089351; PMCID: PMC4389631.
Kristin White, OD
About Kristin White, OD

Dr. Kristin White is a graduate of the New England College of Optometry. She is residency trained in community health optometry. Dr. White has a strong passion for providing eye care where it is most needed and has provided care on international clinics in Central and South America, on an Indian Reservation in New Mexico and in underserved communities in Boston, California and presently, South Carolina. She has helped open 2 optometry departments within community health centers and provided consulting on the topic for numerous others.

Dr. White has lectured on the topic of creating optometry departments within community health centers through collaboration with the National Association of Community Health Centers, Prevent Blindness America and the Association of Clinicians for the Underserved. She serves as co-chair of the Association of Clinicians for the Underserved Vision Services Committee. Dr. White is available for consulting for community health centers interested in opening or expanding optometry services.

Kristin White, OD
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