Journal of Pediatric Ophthalmology and Strabismus

Original Article 

Assessment of Corneal and Lens Density in Children With Celiac Disease

Serdar Ozates, MD; Sibel Doguizi, MD; Ferda Ozbay Hosnut, MD; Gulseren Sahin, MD; Mehmet Ali Sekeroglu, MD; Pelin Yilmazbas, MD

Abstract

Purpose:

To assess the early changes of corneal and lens density in a pediatric population with celiac disease.

Methods:

One hundred one patients were included in this observational and prospective study. Patients with celiac disease formed the celiac disease group. Healthy individuals with no medical history formed the control group. Corneal and lens density were assessed with Pentacam HR (Oculus Optikgeräte GmbH, Wetzlar, Germany).

Results:

The mean lens and corneal density outcomes in all zones did not differ between groups (P > .05 for each). Maximum lens density outcome was significantly higher in the celiac disease group than in the control group (P = .028). The mean corneal density at the peripheral cornea was significantly higher in females than males in the celiac disease group (P < .05 for each). Compliance with a gluten-free diet, body mass index, and histological classification of celiac disease had no significant effect on lens and corneal density in patients with celiac disease (P > .05 for each).

Conclusions:

Celiac disease did not affect the mean lens and corneal density in this pediatric population, but higher maximum lens density in patients with celiac disease and higher peripheral corneal density in female patients with celiac disease may indicate early stages of ocular involvement of celiac disease.

[J Pediatr Ophthalmol Strabismus. 2019;56(6):402–406.]

Abstract

Purpose:

To assess the early changes of corneal and lens density in a pediatric population with celiac disease.

Methods:

One hundred one patients were included in this observational and prospective study. Patients with celiac disease formed the celiac disease group. Healthy individuals with no medical history formed the control group. Corneal and lens density were assessed with Pentacam HR (Oculus Optikgeräte GmbH, Wetzlar, Germany).

Results:

The mean lens and corneal density outcomes in all zones did not differ between groups (P > .05 for each). Maximum lens density outcome was significantly higher in the celiac disease group than in the control group (P = .028). The mean corneal density at the peripheral cornea was significantly higher in females than males in the celiac disease group (P < .05 for each). Compliance with a gluten-free diet, body mass index, and histological classification of celiac disease had no significant effect on lens and corneal density in patients with celiac disease (P > .05 for each).

Conclusions:

Celiac disease did not affect the mean lens and corneal density in this pediatric population, but higher maximum lens density in patients with celiac disease and higher peripheral corneal density in female patients with celiac disease may indicate early stages of ocular involvement of celiac disease.

[J Pediatr Ophthalmol Strabismus. 2019;56(6):402–406.]

Introduction

Celiac disease is an autoimmune enteropathy that is characterized by malabsorption and ingestion of a wheat protein called gluten. Several studies have reported the prevalence of celiac disease to be between 0.47% and 0.9% in children in Turkey.1–4 Specific celiac disease antibodies may bind or accumulate in extraintestinal structures, causing atypical presentations, such as autoimmune diseases, type 1 diabetes mellitus, dermatitis herpetiformis, autoimmune thyroiditis, chronic hepatitis, myasthenia gravis, and vasculitis.5 Previous studies have shown that cataract and corneal changes are extraintestinal findings of celiac disease, and celiac disease increases the risk of cataract development.6–8 However, the clinical characteristics of celiac disease may vary with the age of the patients, so further investigation is needed to determine the effect of celiac disease on the lens and cornea in the pediatric population. In this study, we aimed to assess the early changes of corneal and lens density in children with celiac disease.

Patients and Methods

This prospective and observational study was conducted at a tertiary hospital, in accordance with the ethical standards of the Declaration of Helsinki. The study protocol was approved by the institutional review board of our hospital's ethics committee. All participants and their parents provided written informed consent prior to undergoing all examinations.

Patients with celiac disease aged 18 years or younger were included in the study, which was conducted between January and May 2018. The inclusion criteria were: best corrected visual acuity (BCVA) of 20/20 or better, according to the Snellen chart; no ocular problems, other than spherical or cylindrical refractive errors of less than 1.50 diopters (D); and no systemic disease, except for celiac disease. Patients with any of the following conditions were excluded: strabismus; a history of previous ocular surgery or trauma; a history of retinopathy of prematurity; and corneal diseases, such as corneal scarring, uveitis, retinal disease, optic nerve diseases, glaucoma, and ocular media opacities, including cataracts. Patients with metabolic diseases, a history of long-term corticosteroid use, chromosomal anomalies, and any systemic diseases, except for celiac disease, were also excluded. The control subjects were aged 18 years or younger and they had no ocular problems other than spherical and cylindrical refractive errors of less than 1.50 D. Moreover, all control subjects were healthy, without any systemic diseases. Only one eye of each participant was randomly analyzed in the study. Patients with celiac disease were included in the celiac disease group and patients with no medical history of diseases were included in the control group.

Celiac disease was diagnosed according to criteria of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.9 Histological classification of celiac disease was performed according to Marsh's classification.10 Ophthalmological examination including BCVA testing with Snellen chart, non-contact tonometry, slit-lamp examination, and fundus examination were performed on all participants. Cross-sectional images of the cornea and lens were captured with Pentacam HR (Oculus Optikgeräte GmbH, Wetzlar, Germany). All measurements were performed by the same experienced blinded operator (SD) in the same room under standard dim light conditions and at the same time of the day.

We performed two consecutive measurements on each patient: the first without pupil dilation for corneal densitometric evaluation and the second after pupillary dilatation for optimal screening of the whole lens. Two drops of cyclopentolate hydrochlo-ride 1% were administered 5 minutes apart to induce pupil dilation, and the second measurements were taken approximately 45 minutes after the last drop.

Corneal and lens density were the main outcomes. The software automatically locates the corneal apex and analyzes the area around the apex with a diameter of 12 mm. Depending on the degree of light scatter, Pentacam quantifies the density of the cornea on a scale of 0 to 100 grayscale units, with “0” indicating no light scatter or no corneal haze and “100” indicating totally opaque corneas. Local densitometric analysis was done by dividing the 12-mm diameter area into four concentric radial zones available preset in the software. The central zone centered on the apex has a diameter of 2 mm. An annulus extending in a 2 to 6 mm diameter circle is the second zone. The annulus at the third zone extends from 6 to 10 mm, and the fourth zone extends from 10 to 12 mm in a circle. The output is preferred to be subdivided based on corneal depth into anterior (the anterior 120 µm), central, and posterior (the most posterior 60 µm) layers. The densitometry of the lens was measured using three-dimensional scan modes. The Pentacam densitometry software evaluates the lens' volume and density by analyzing a 12-mm diameter area within the corneal apex, using backward scatter mechanisms. The mean value was calculated in predefined three-dimensional zones centered around the pupil center, where zone 1 was 2 mm, zone 2 was 4 mm, and zone 3 was 6 mm.

Statistical analyses were performed with SPSS Statistics (version 22.0; IBM Corporation, Armonk, NY). The assumption of normal distribution of data was tested by the Kolmogorov–Smirnov test. Differences in descriptive data between groups were tested with the chi-square test. Differences in the outcomes between groups were tested with the independent samples t test and Mann–Whitney U test. A P value of less than .05 was considered statistically significant for all tests.

Results

In total, 55 patients with celiac disease were included in the celiac disease group and 46 healthy individuals were included in the control group. Of the 55 patients in the celiac disease group, 8 had type 3a, 43 had type 3b, and 4 had type 3c mucosal lesions. Disorders associated with celiac disease were present in 12 (21.8%) patients in the celiac disease group. Table 1 shows the demographic data and characteristics of the patients. Gender and mean age did not differ between the groups (P = .922 and .417, respectively). Mean body mass index was significantly lower in the celiac disease group than in the control group (P < .001).

Demographic Data and Characteristics of the Patients

Table 1:

Demographic Data and Characteristics of the Patients

Table 2 shows the mean corneal and lens density outcomes and comparison between groups. The mean lens density outcomes in all zones did not differ between groups. Maximum lens density outcome was significantly higher in the celiac disease group than in the control group. The mean corneal density outcomes in all zones did not differ between groups (P > .05 for each). Table 3 shows the mean corneal density outcomes and their comparison according to gender in the celiac disease group. The mean corneal density was similar between females and males in the control group at all zones of the cornea, but the mean corneal density at the peripheral cornea was significantly higher in females than males in the celiac disease group.

Mean Corneal and Lens Density Outcomes and Comparison Between Groups

Table 2:

Mean Corneal and Lens Density Outcomes and Comparison Between Groups

Mean Corneal and Lens Density Outcomes of the Celiac Disease Group and Comparison by Gender

Table 3:

Mean Corneal and Lens Density Outcomes of the Celiac Disease Group and Comparison by Gender

The mean lens and corneal density outcomes in all zones did not differ between patients who were compliant with a gluten-free diet and those who did not adhere to a gluten-free diet (P > .05 for each). No significant correlation was found between the disease duration and lens and corneal density outcomes in all zones (P > .05 for each). Histological classification of celiac disease had no significant effect on lens and corneal density outcomes in all zones (P > .05 for each). No significant correlation was found between the body mass index and lens and corneal density outcomes in all zones (P > .05 for each).

Discussion

Mollazadegan et al.6 showed that the mean age at diagnosis of celiac disease is an important risk factor for cataracts; however, diagnosis of celiac disease in patients younger than 20 years has not been found to be a statistically significant risk factor. In our study, the mean age at celiac disease diagnosis was 8.2 ± 3.6 years and no differences in lens density were observed between the celiac disease and control groups. Consistent with our results, Urganci and Kalyoncu11 reported no cataract in patients with celiac disease with a mean age of 6.77 ± 4.64 years. However, the maximum lens density outcome in that study was significantly higher in the celiac disease group than in the control group. Our study's result may indicate the plausible ongoing cataract development in patients with celiac disease at early stages. Due to the observational nature of our study, we could not conclude whether the lens density would increase by the time of follow-up. However, Mollazadegan et al.6 emphasized that a longer follow-up increased the risk of cataract development. Further follow-up studies with objective assessment are needed to determine whether the lens density increases in young patients with celiac disease.

Vitamin and mineral deficiency due to malabsorption is associated with cataract development.12–15 Nutrition deficiency has been well documented in patients with celiac disease, and chronic malabsorption without treatment may trigger cataract development.1,16 In our study, no clinical sign of nutrition deficiency was observed in the celiac disease group at the time of diagnosis. Good compliance with a gluten-free diet resolves both typical and atypical symptoms of celiac disease, such as malabsorption, weight loss, dermatitis herpetiformis, short stature, and chronic hepatitis.1,5,17 However, the lens and corneal density outcomes were similar between patients who were compliant with a gluten-free diet and those who were not. Consistent with our results, Urganci and Kalyoncu11 reported no cataracts in patients who did not comply with a gluten-free diet. Weight loss due to malabsorption and being overweight due to a gluten-free diet are common and trigger concerns about the body mass index of patients with celiac disease.18,19 Body mass index is an independent risk factor for cataract development.20,21 However, in our study, no significant correlation was found between body mass index and lens density.

Schuppan5 noted that long-term undiagnosed celiac disease predisposes a person to autoimmunity. Autoimmune disorders were found to be more frequent in patients with celiac disease.22,23 Cosnes et al.22 reported that the cumulative risk of autoimmune disorder was 8.1% at age 15 years and 32.5% at age 50 years. The relationship between autoimmune disorders and cataract has been documented. In our study, autoimmune disorders were present in 21.8% of the patients in the celiac disease group; however, the presence of an autoimmune disorder did not affect the lens and corneal density outcomes.

Corneal density in the peripheral cornea was significantly higher in females than in males in the celiac disease group. The peripheral cornea is the most vulnerable part to circulating immune complexes due to its anatomic relationship with the capillary network of the limbus.24,25 Deposition of immune complexes and immune activity in the adjacent conjunctiva trigger changes in the corneal stroma structure, which may result in the loss of corneal clarity.24,25 In the literature, several studies have emphasized that auto-immune diseases are more prevalent in females.26,27 Based on our study's results, we could speculate that ongoing autoimmune processes or immune complex deposition might be the reason for the higher peripheral corneal density in females with celiac disease, which also predisposes them to autoimmune disorders. However, our suggestion must be proven with pathophysiological investigations.

Celiac disease did not affect the mean lens and central corneal density in a pediatric population; however, higher maximum lens density in the patients with celiac disease and higher peripheral corneal density in the female patients with celiac disease may indicate early stages of ocular involvement of celiac disease. Further follow-up studies with objective assessment of lens density increase and pathophysiological investigation of the peripheral cornea are needed to document ocular involvement in young patients with celiac disease.

References

  1. Fasano A. Clinical presentation of celiac disease in the pediatric population. Gastroenterology. 2005;128(4)(suppl 1):S68–S73. doi:10.1053/j.gastro.2005.02.015 [CrossRef]15825129
  2. Dalgic B, Sari S, Basturk B, et al. Turkish Celiac Study Group. Prevalence of celiac disease in healthy Turkish school children. Am J Gastroenterol. 2011;106(8):1512–1517. doi:10.1038/ajg.2011.183 [CrossRef]21691340
  3. Ertekin V, Selimoglu MA, Kardas F, Aktas E. Prevalence of celiac disease in Turkish children. J Clin Gastroenterol. 2005;39(8):689–691. doi:10.1097/01.mcg.0000174026.26838.56 [CrossRef]16082278
  4. Demirçeken FG, Kansu A, Kuloglu Z, Girgin N, Güriz H, Ensari A. Human tissue transglutaminase antibody screening by immunochromatographic line immunoassay for early diagnosis of celiac disease in Turkish children. Turk J Gastroenterol. 2008;19(1):14–21.18386235
  5. Schuppan D. Current concepts of celiac disease pathogenesis. Gastroenterology. 2000;119(1):234–242. doi:10.1053/gast.2000.8521 [CrossRef]10889174
  6. Mollazadegan K, Kugelberg M, Lindblad BE, Ludvigsson JF. Increased risk of cataract among 28,000 patients with celiac disease. Am J Epidemiol. 2011;174(2):195–202. doi:10.1093/aje/kwr069 [CrossRef]21624959
  7. Karatepe Hashas AS, Altunel O, Sevinc E, Duru N, Alabay B, Torun YA. The eyes of children with celiac disease. J AAPOS. 2017;21(1):48–51. doi:10.1016/j.jaapos.2016.09.025 [CrossRef]28087348
  8. Martins TG, Costa AL, Oyamada MK, Schor P, Sipahi AM. Ophthalmologic manifestations of celiac disease. Int J Ophthalmol. 2016;9(1):159–162.26949627
  9. Husby S, Koletzko S, Korponay-Szabó IR, et al. ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136–160. doi:10.1097/MPG.0b013e31821a23d0 [CrossRef]
  10. Marsh MN, Crowe PT. Morphology of the mucosal lesion in gluten sensitivity. Baillieres Clin Gastroenterol. 1995;9(2):273–293. doi:10.1016/0950-3528(95)90032-2 [CrossRef]7549028
  11. Urganci N, Kalyoncu D. Eye disorders in children with celiac disease. Eur J Ophthalmol. 2016;26(1):85–87. doi:10.5301/ejo.5000646 [CrossRef]
  12. Bunce GE, Kinoshita J, Horwitz J. Nutritional factors in cataract. Annu Rev Nutr. 1990;10(1):233–254. doi:10.1146/annurev.nu.10.070190.001313 [CrossRef]2200464
  13. Matsushima H, Mukai K, Yoshida S, Obara Y. Effects of calcium on human lens epithelial cells in vitro. Jpn J Ophthalmol. 2004;48(2):97–100. doi:10.1007/s10384-003-0029-8 [CrossRef]15060788
  14. Fernandez MM, Afshari NA. Nutrition and the prevention of cataracts. Curr Opin Ophthalmol. 2008;19(1):66–70. doi:10.1097/ICU.0b013e3282f2d7b6 [CrossRef]
  15. Brown CJ, Akaichi F. Vitamin D deficiency and posterior subcapsular cataract. Clin Ophthalmol. 2015;9:1093–1098. doi:10.2147/OPTH.S84790 [CrossRef]26124632
  16. Kupper C. Dietary guidelines and implementation for celiac disease. Gastroenterology. 2005;128(4)(suppl 1):S121–S127. doi:10.1053/j.gastro.2005.02.024 [CrossRef]15825119
  17. Murray JA, Watson T, Clearman B, Mitros F. Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease. Am J Clin Nutr. 2004;79(4):669–673. doi:10.1093/ajcn/79.4.669 [CrossRef]15051613
  18. Kabbani TA, Goldberg A, Kelly CP, et al. Body mass index and the risk of obesity in coeliac disease treated with the gluten-free diet. Aliment Pharmacol Ther. 2012;35(6):723–729. doi:10.1111/j.1365-2036.2012.05001.x [CrossRef]22316503
  19. Dickey W, Kearney N. Overweight in celiac disease: prevalence, clinical characteristics, and effect of a gluten-free diet. Am J Gastroenterol. 2006;101(10):2356–2359. doi:10.1111/j.1572-0241.2006.00750.x [CrossRef]17032202
  20. Glynn RJ, Christen WG, Manson JE, Bernheimer J, Hennekens CH. Body mass index. An independent predictor of cataract. Arch Ophthalmol. 1995;113(9):1131–1137. doi:10.1001/archopht.1995.01100090057023 [CrossRef]7661746
  21. Kuang T-M, Tsai S-Y, Hsu W-M, Cheng CY, Liu JH, Chou P. Body mass index and age-related cataract: the Shihpai Eye Study. Arch Ophthalmol. 2005;123(8):1109–1114. doi:10.1001/archopht.123.8.1109 [CrossRef]16087846
  22. Cosnes J, Cellier C, Viola S, et al. Groupe D'Etude et de Recherche Sur la Maladie Coeliaque. Incidence of autoimmune diseases in celiac disease: protective effect of the gluten-free diet. Clin Gastroenterol Hepatol. 2008;6(7):753–758. doi:10.1016/j.cgh.2007.12.022 [CrossRef]18255352
  23. Collin P, Reunala T, Pukkala E, Laippala P, Keyriläinen O, Pasternack A. Coeliac disease—associated disorders and survival. Gut. 1994;35(9):1215–1218. doi:10.1136/gut.35.9.1215 [CrossRef]7959226
  24. Yagci A. Update on peripheral ulcerative keratitis. Clin Ophthalmol. 2012;6:747–754. doi:10.2147/OPTH.S24947 [CrossRef]22654502
  25. Dana MR, Qian Y, Hamrah P. Twenty-five-year panorama of corneal immunology: emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection. Cornea. 2000;19(5):625–643. doi:10.1097/00003226-200009000-00008 [CrossRef]11009315
  26. Quintero OL, Amador-Patarroyo MJ, Montoya-Ortiz G, Rojas-Villarraga A, Anaya JM. Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity. J Autoimmun. 2012;38(2–3):J109–J119. doi:10.1016/j.jaut.2011.10.003 [CrossRef]
  27. Gleicher N, Barad DH. Gender as risk factor for autoimmune diseases. J Autoimmun. 2007;28(1):1–6. doi:10.1016/j.jaut.2006.12.004 [CrossRef]17261360

Demographic Data and Characteristics of the Patients

CharacteristicCD GroupControl Group
No. of patients/eyes5546
Male/female34/2128/18
Mean age (y)11.8 ± 3.712.3 ± 3.5
Mean age at onset (y)8.2 ± 3.6
Duration (months)43.0 ± 34.7
Body mass index17.2 ± 3.022.1 ± 2.3
Compliance with GFD (n)
  Compliant45 (81.8%)
  Non-compliant10 (18.2%)

Mean Corneal and Lens Density Outcomes and Comparison Between Groups

ParameterCD Group (n = 55)Control Group (n = 46)Mean Difference95% CIP
Lens densitya
  Zone 17.98 ± 0.467.98 ± 0.43−0.005−0.18 to 0.17.952
  Zone 27.76 ± 0.257.74 ± 0.32−0.021−0.09 to 0.14.727
  Zone 37.62 ± 0.157.63 ± 0.33−0.008−0.11 to 0.09.871
  Average8.05 ± 0.487.95 ± 0.46−0.097−0.09 to 0.28.431
  Maximum17.93 ± 7.1615.24 ± 4.872.680.29 to 5.07.028c
Corneal densityb
  Anterior16.05 ± 1.9516.54 ± 2.58−0.049−1.39 to 0.41.282
  Central10.62 ± 2.5810.51 ± 0.790.106−0.29 to 0.50.601
  Posterior8.41 ± 1.078.16 ± 0.960.247−0.16 to 0.65.231
  Total11.77 ± 1.4011.73 ± 1.160.033−0.48 to 0.55.900

Mean Corneal and Lens Density Outcomes of the Celiac Disease Group and Comparison by Gender

Corneal ZonesCorneal Density (grayscale units)P

Female (n = 34)Male (n = 21)
Anterior
  0 to 2 mm16.4 ± 1.317.9 ± 6.1.477
  2 to 6 mm14.9 ± 1.215.8 ± 3.7.405
  6 to 10 mm14.4 ± 2.613.3 ± 2.0.094
  10 to 12 mm23.9 ± 7.719.8 ± 6.9.045a
  Average16.4 ± 2.015.4 ± 1.6.084
Central
  0 to 2 mm10.9 ± 0.611.1 ± 0.9.781
  2 to 6 mm9.9 ± 0.710.0 ± 0.9.683
  6 to 10 mm9.7 ± 1.38.8 ± 0.8.011a
  10 to 12 mm15.6 ± 5.011.6 ± 2.5.001a
  Average10.9 ± 1.310.1 ± 0.8.021a
Posterior
  0 to 2 mm8.3 ± 0.78.2 ± 0.8.609
  2 to 6 mm7.7 ± 0.87.7 ± 0.8.917
  6 to 10 mm8.2 ± 1.17.5 ± 0.9.007a
  10 to 12 mm11.6 ± 3.49.1 ± 1.6.008a
  Average8.6 ± 1.18.0 ± 0.8.064
Authors

From the Department of Ophthalmology, Kars Harakani State Hospital, Kars, Turkey (SO); the Department of Ophthalmology, Ulucanlar Eye Training and Research Hospital, Ankara, Turkey (SD, MAS, PY); and the Department of Gastroenterology, Dr. Sami Ulus Maternity, Children's Health and Diseases Training and Research Hospital, Ankara, Turkey (FOH, GS).

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: Serdar Ozates, MD, Yenisehir Mah. Ismail Aytemiz Blv. No:55, 36200 Merkez/Kars, Turkey. E-mail: serdarozates@gmail.com

Received: July 06, 2019
Accepted: September 12, 2019

10.3928/01913913-20191009-01

Sign up to receive

Journal E-contents