Celiac disease (CD) is an autoimmune disease caused by an immune-mediated reaction to gluten found in wheat, rye, and barley. It is also known as celiac sprue or gluten-sensitive enteropathy.
The global serological prevalence of CD is estimated at 1.4% for anti-tTG or anti-EMA antibody positivity and 0.7% for biopsy-confirmed cases. Prevalence ranges from 0.15% to 2.67% depending on the study region and diagnostic method 1). The incidence has been increasing worldwide in recent decades, with rising reports from Africa, Asia, and Latin America.
CD is recognized not merely as a gastrointestinal disease but as a multi-organ disorder. About 50% of patients experience extraintestinal symptoms, and up to 40% experience neurological disease or gluten neuropathy. Small intestinal dysfunction in untreated CD leads to deficiencies of many nutrients, including iron, zinc, magnesium, vitamins B12, B6, B1, B2, D, folate, and fat-soluble vitamins (A, D, E, K). These nutritional deficiencies are major causes of neuro-ophthalmic clinical manifestations. Newly diagnosed CD patients have a high frequency of vitamin and mineral deficiencies 2).
Importantly, CD-related ocular findings may appear as the initial symptom of CD. Even when gastrointestinal symptoms are not prominent, ophthalmologists should consider CD in the differential diagnosis.
QCan ocular symptoms of celiac disease appear before gastrointestinal symptoms?
A
Ocular findings related to CD can be the first manifestation of the disease. Since “atypical” or “asymptomatic” CD without prominent gastrointestinal symptoms exists, it is important to include CD in the differential diagnosis when evaluating unexplained optic neuropathy, ophthalmoplegia, or dry eye.
Symptoms vary depending on the type of vitamin deficiency.
Night blindness: Vitamin A deficiency impairs rhodopsin synthesis. Decreased vision in dim light is an early symptom.
Headache, transient visual obscurations, diplopia, visual field defects: Symptoms associated with pseudotumor cerebri (intracranial hypertension) due to vitamin A deficiency.
Decreased visual acuity: Central vision loss due to optic neuropathy (e.g., vitamin B12 or B1 deficiency), or cataract formation.
Ocular motor dysfunction, diplopia: Ophthalmoplegia due to deficiency of vitamin B1 (thiamine), B2, B12, or E.
Ptosis: Symptoms of ocular muscle/myopathy associated with vitamin E deficiency.
Nystagmus, ataxia, altered mental status: Triad of Wernicke encephalopathy (vitamin B1 deficiency). Particularly prominent when associated with alcohol abuse.
Dry eye symptoms (dryness, foreign body sensation): In an analysis of 72 CD cases, dry eye was the most common ocular complication at 32% 3).
Clinical Findings (Findings Confirmed by Physician Examination)
The main ocular findings by deficient vitamin are shown below.
Vitamin A deficiency
Night blindness: Decreased scotopic vision due to impaired rhodopsin synthesis.
Xerophthalmia: Tear film instability due to goblet cell loss. Vitamin A deficiency causes goblet cell loss and punctate superficial keratitis1).
Bitot spots and keratomalacia: Long-term deficiency leads to epithelial metaplasia and keratinization, forming Bitot spots. Further progression may result in corneal perforation1). Vitamin A deficiency is a leading cause of childhood blindness worldwide1).
Papilledema (pseudotumor cerebri): Vitamin A deficiency impairs arachnoid granulations, reducing CSF absorption and increasing intracranial pressure, leading to papilledema, visual field defects, photophobia, and transient vision loss.
Vitamin B1 (Thiamine) Deficiency
Ocular motor abnormalities in Wernicke encephalopathy: Characteristic findings include abduction limitation, lateral gaze nystagmus, and vertical nystagmus in primary position. Some cases progress from internuclear ophthalmoplegia, one-and-a-half syndrome, and horizontal/vertical gaze limitation to complete ophthalmoplegia. Most cases are bilateral but may show asymmetry.
Lesion sites: Oculomotor nucleus, vestibular nucleus, periventricular region of the thalamus, hypothalamus, periaqueductal gray matter, cerebellar vermis (glucose metabolism-dependent areas).
Corneal epithelial damage and optic atrophy: Ocular surface and optic nerve damage due to thiamine deficiency.
Vitamin B12 and folate deficiency
Nutritional optic neuropathy: Central vision loss, central scotoma/centrocecal scotoma, optic atrophy. B12 is essential for myelin synthesis; deficiency leads to myelopathy, peripheral neuropathy, and optic atrophy1).
Systemic findings: Pernicious anemia, subacute combined degeneration of the spinal cord (gait disturbance, sensory deficits), dementia.
Prevalence in the US: B12 deficiency in 3% of ages 20–39, 4% of ages 40–59, and 6% of ages 60 and older1).
Vitamin E deficiency dry eye
Vitamin E deficiency: Ophthalmoplegia, ptosis, diplopia. Accompanied by myopathy, head tremor, sensory neuropathy, loss of joint position sense, cerebellar ataxia, extrapyramidal disorders, and dementia.
Dry eye (autoimmune mechanism): In a cross-sectional study of 36 CD patients vs 35 healthy controls, decreased corneal endothelial cell density and changes in anterior chamber depth were confirmed 4). Decreased Schirmer test values and tear break-up time have been reported in pediatric CD 5). In adult CD, similar dry eye findings are observed, along with conjunctival squamous metaplasia and decreased goblet cell density 6).
QWhich vitamin deficiency most affects the eyes?
A
Vitamin A deficiency (night blindness, keratomalacia, pseudotumor cerebri), vitamin B1 deficiency (Wernicke encephalopathy → eye movement disorders), and vitamin B12 deficiency (nutritional optic neuropathy) are the three major causes. Dry eye can also occur due to autoimmune mechanisms and is the most common ocular complication in patients with CD 3).
Screening for CD should be considered in individuals who meet the following criteria.
First-degree relatives (parents, siblings, children) of patients diagnosed with CD
Carriers of HLA-DQA1/DQB1 mutations
History or comorbidity of iron deficiency anemia, osteopenia, type 1 diabetes, Down syndrome, Turner syndrome, autoimmune thyroid disease, or dermatitis herpetiformis
Autoimmune diseases associated with CD include type 1 diabetes, thyroiditis, Sjögren’s syndrome, and IgA nephropathy.
Frequency of Vitamin Deficiency in Untreated CD Patients
In newly diagnosed CD patients, the frequency of vitamin and mineral deficiencies is high 2), increasing the risk of ocular complications.
Vitamin/Nutrient
Approximate Deficiency Frequency
Vitamin A
7.5–32.5%
VitD
20–60%
VitB12
8–41%
Folic acid
20–30%
Iron (anemia only)
Approximately 40%
QIf I have a family member with celiac disease, am I also at risk?
A
First-degree relatives (parents, siblings, children) of patients diagnosed with CD are considered a high-risk group. Since carrying the HLA-DQ2/DQ8 genes is a predisposing factor, serological screening (anti-tTG antibody test) should be considered if there is a family history.
In patients diagnosed with CD who have neuro-ophthalmic symptoms or require evaluation for ocular complications, the following should be considered.
Head and orbital MRI (with/without contrast): evaluation of pseudotumor cerebri (intracranial hypertension) and orbital myositis. Also useful for excluding neuromyelitis optica.
Complete neuro-ophthalmic examination: detailed assessment of visual acuity, visual field, eye movements, and optic disc findings.
Nutritional assessment: measurement of serum vitamins (A, B1, B12, E), folate, iron, and trace elements.
The following should be considered in the differential diagnosis of neuro-ophthalmic symptoms.
Inflammatory bowel disease (IBD): Differentiation is important because the profiles of CD and ocular complications are similar.
Nutritional optic neuropathy: Optic neuropathy due to vitamin B12 or B1 deficiency is rare, but nutritional causes should be included in the differential. Ischemic optic neuropathy is differentiated by older age, presence of lifestyle-related diseases, and partial pale swelling of the optic disc.
Infectious, ischemic, inflammatory, neoplastic, and paraneoplastic diseases: Systematic search for alternative etiologies is necessary.
The only curative treatment for CD is a lifelong GFD. Strict adherence to GFD improves intestinal inflammation and restores nutrient absorption. Prognosis is favorable with correct diagnosis and strict GFD compliance. However, compliance varies due to the prevalence of gluten in foods, contamination, and labeling deficiencies.
Refractory CD occurs in up to 2–5% of cases. It is defined as persistent malabsorption with positive biopsy and no signs of malignancy despite strict GFD for at least 6–12 months. Refractory CD increases the risk of secondary lymphoma and gastrointestinal adenocarcinoma.
With the initiation of GFD, vitamins and supplements are provided for confirmed nutritional deficiencies. Long-term monitoring is necessary for anemia and nutritional deficiencies.
GFD may reduce ocular surface inflammation1). However, high-level evidence is not yet established, and it remains at the level of case reports.
QWill eye symptoms improve if I continue a gluten-free diet?
A
Strict adherence to GFD and vitamin supplementation can be expected to improve ocular complications due to vitamin deficiency. There are also reports of reduction in ocular surface inflammation with GFD 1). However, high-level evidence has not been established, and in 2–5% of refractory CD, GFD alone may not provide sufficient effect.
The causative component of celiac disease is gliadin, a protein fraction in gluten. After gluten ingestion, peptides such as α-gliadin are formed by hydrolytic enzymes in the small intestinal lumen and brush border.
Innate immune response:
Gliadin peptides stimulate the expression of inflammatory cytokines such as IL-15.
This leads to proliferation of CD8+ intraepithelial T cells bearing NKG2D receptors.
Under stress, intestinal cells express MIC-A, and NKG2D-positive CD8+ T cells attack the intestinal cells.
Adaptive immune response:
Intestinal cell damage allows gliadin to enter the lamina propria.
Deamidation of gliadin by tissue transglutaminase (tTG) occurs.
HLA-DQ2/DQ8 presents gliadin, activating CD4+ T cells, leading to cytokine production and inflammatory damage to the small intestine.
Atypical (extraintestinal symptoms): Anemia, neuropathy, ataxia, osteoporosis, infertility, liver dysfunction, etc. Ocular complications are included in this category.
Asymptomatic (subclinical): Serology positive + villous atrophy, no symptoms.
Latent and Refractory
Latent: Serology positive + normal biopsy → villous atrophy may develop in the future.
Martins et al. (2021) evaluated the ocular complication profile of 72 CD cases from a German hospital database analysis (272,873 cases) 3). Dry eye was the most common at 32%, and no cases of vitamin A deficiency were observed. This result suggests that dry eye in CD is due to autoimmune mechanisms rather than nutritional deficiency, and it has also been reported that the profile of ocular complications is similar to that of inflammatory bowel disease (IBD).
Donmez Gun et al. (2021) conducted a cross-sectional study of 36 CD patients and 35 healthy controls, confirming decreased corneal endothelial cell density and changes in anterior chamber depth in the CD patient group 4). This finding suggests that systemic autoimmune inflammation in CD affects intraocular structures.
In a pediatric CD cohort study by Karatepe Hashas et al. (2017), Schirmer values and tear break-up time (BUT) were significantly lower compared to the control group, confirming a predisposition to dry eye from a young age 5).
In the adult CD cohort of Hazar et al. (2021), similar dry eye findings were observed, along with conjunctival squamous metaplasia and decreased goblet cell density 6).
Association between Vitamin B12 Deficiency and Dry Eye
A population-based cohort study reported that vitamin B12 deficiency increases the risk of dry eye by 1.6-fold 1). This finding suggests a pathway by which vitamin B12 deficiency associated with CD may contribute to the development of dry eye.
Potential for Improvement of Ocular Complications with GFD
Tuncer et al. (2010) reported regression of conjunctival tumors in CD patients after GFD 7). Although gluten elimination may reduce ocular surface inflammation 1), high-level evidence has not yet been established, and it remains at the case report level.
Markoulli M, Kolanu S, Britten-Jones AC, et al. TFOS Lifestyle: Impact of nutrition on the ocular surface. The Ocular Surface. 2023;29:226-271.
Wierdsma NJ, van Bokhorst-de van der Schueren MA, Berkenpas M, Mulder CJ, van Bodegraven AA. Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients. Nutrients. 2013;5:3975-92.
Martins T, Miranda Sipahi A, Dos Santos FM, et al. Eye disorders in patients with celiac disease and inflammatory bowel disease: a study using clinical data warehouse. Eur J Ophthalmol. 2021:11206721211012849.
Donmez Gun R, Kaplan AT, Zorlutuna Kaymak N, et al. The impact of celiac disease and duration of gluten free diet on anterior and posterior ocular structures: ocular imaging based study. Photodiagnosis Photodyn Ther. 2021;34:102214.
Karatepe Hashas AS, Altunel O, Sevinc E, et al. The eyes of children with celiac disease. J AAPOS. 2017;21:48-51.
Hazar L, Oyur G, Atay K. Evaluation of ocular parameters in adult patients with celiac disease. Curr Eye Res. 2021;46:122-6.
Tuncer S, Yeniad B, Peksayar G. Regression of conjunctival tumor during dietary treatment of celiac disease. Indian J Ophthalmol. 2010;58:433-4.
Copy the article text and paste it into your preferred AI assistant.
Article copied to clipboard
Open an AI assistant below and paste the copied text into the chat box.
