Prevalence of and Risk Factors for Cornea Guttata in a Population-Based Study in a Southwestern Island of Japan: The Kumejima Study

Objective  To examine the prevalence of and risk factors for cornea guttata in a rural southwestern island of Japan.

Design  Cross-sectional, population-based study. All residents of Kumejima Island, Japan, located in southwestern Japan (eastern longitude, 126° 48′; northern latitude, 26° 20′), 40 years or older were asked to undergo a comprehensive questionnaire and ocular examination, including noncontact specular microscopy of corneal endothelial cells. Of the 4632 residents, 3762 (81.2%) underwent the examination. The presence of guttata was determined when round or oval dark areas were observed in the specular microscopy images. Cornea guttata was graded from 0 to 4 depending on the total area of dark spots observed on the specular microscopy images. Diagnosis of primary cornea guttata was the main outcome measure.

Results  Of the 3060 eligible residents, 124 (4.1%; 95% confidence interval, 3.4%-4.8%) had cornea guttata in at least 1 eye. Logistic regression analysis with adjustment for age and/or sex indicated that older age, female sex, and thinner central corneal thickness were associated with an increased risk of cornea guttata.

Conclusions  The prevalence of cornea guttata is 4.1% among residents 40 years or older in Kumejima by specular microscopic criteria only, which is lower than the prevalence reported in the Reykjavik, Iceland, study. A higher prevalence may have been determined if slitlamp biomicroscopy findings had been included. Older age, female sex, and a thinner cornea were independently associated with a higher risk of cornea guttata.

Primary central cornea guttata is characterized by abnormal excrescences of collagenous basement membrane material produced by distressed endothelial cells in the central cornea. Excrescences are similar in appearance to the Hassall-Henle bodies that are observed in the peripheral cornea in older populations. Secondary guttata is a class of guttata that is associated with degenerative corneal disease, trauma, and inflammation and that usually disappears on removal of the cause.¹ Primary central cornea guttata, on the other hand, occasionally progresses to Fuchs corneal endothelial dystrophy with corneal endothelial decompensation.^1,2 Thus, primary central cornea guttata is a significant clinical sign of a predisposition for sight-threatening Fuchs corneal endothelial dystrophy.

Several studies have reported the prevalence of cornea guttata. A population-based study in Reykjavik, Iceland, reported that the prevalence of cornea guttata in 774 participants was 11% for female and 7% for male participants and that lower weight, lower body mass index, and a smoking history of longer than 20 pack-years were factors associated with a higher risk of cornea guttata.³ Another study conducted in Japan and Singapore reported that the prevalence of cornea guttata in a non–population-based setting that included 299 Japanese and 465 Singaporeans 50 years or older was 3.7% in the Japanese and 6.7% in the Singaporeans.⁴ A retrospective study in Japan found 4 patients with cornea guttata among 107 individuals ranging in age from 20 to 89 years.⁵ Lorenzetti et al⁶ reported a high prevalence of cornea guttata (31%-70%) in a hospital-based study in which participants ranging in age from 10 to 99 years underwent slitlamp examination. The present study was conducted to examine the prevalence of cornea guttata and associated factors of cornea guttata in a southwestern island of Japan.

The prevalence of cornea guttata and its associated factors were examined as part of a population-based epidemiologic survey on ocular diseases in residents of Kumejima Island 40 years or older.⁷ Kumejima is an island 63.2 km² located in the southwestern part of Japan (eastern longitude, 126° 48′; northern latitude, 26° 20′), west of the main island of Okinawa. It has a population of approximately 9000, with most residents originating from the Okinawa prefecture. The weather is warm and humid, with average daily temperatures of 22.7°C and an annual total rainfall of 2138 mm. This study was conducted from May 1, 2005, through August 31, 2006, and conformed to the tenets of the Declaration of Helsinki and the regional regulations approved by the regional council of Kumejima. According to the official household registration database, Kumejima had 5249 residents 40 years or older in 2005. After excluding residents who died, moved, or could not be located in Kumejima during the study period (n = 617), 4632 residents were eligible for the study. All these residents were asked by letter and telephone to undergo the examinations held at the public hospital of Kumejima. Home visits and examinations were performed for inpatient, paralyzed, and disabled residents.

All participants provided written informed consent before the examinations. Body weight, height, and brachial blood pressure measurements were obtained, and a structured questionnaire was administered that included questions about self-reported main lifetime occupation (farming, fishing, office worker, service industry, housewife, and other), health history, surgery and trauma history, smoking (daily number of cigarettes and pack-years of smoking), history of outdoor work (farming, fishing and others and years of working), and use of hats and sunglasses.

A detailed ophthalmic examination was performed by experienced examiners and ophthalmologists and included uncorrected and best-corrected visual acuities, refraction, ophthalmoscopy, ocular fundus photography, visual field examination, and measurement of intraocular pressure (IOP), central corneal thickness (CCT), anterior chamber depth, and axial length of the eye. Slitlamp examination was not used to detect the presence of cornea guttata. Refraction was measured using an autorefractometer (ARK-730; Topcon Corporation, Tokyo, Japan). Intraocular pressure was measured 3 times using a Goldmann applanation tonometer under topical anesthesia, and the median value was adopted. Corneal endothelial cell morphology and CCT were examined with specular microscopy (SP-2000; Topcon Corporation). Measurement of CCT with this specular microscopy was confirmed to be highly correlated with measurement with ultrasonographic pachymetry in a previous study.⁸ Anterior chamber depth and axial length of the eye were measured with a biometry system (IOL Master; Carl Zeiss Meditec, Dublin, California). Digital color fundus photographs (30° and 45°) were taken using a nonmydriatic ocular fundus camera system (Image Net TRC-NW7; Topcon Corporation). The examinations that did not require direct eye contact, including tests of refraction, visual acuity, specular microscopy, biometry, and fundus photography, were performed first. Measurement of IOP and gonioscopy were performed last.

When the participants could not visit the hospital, ophthalmologists visited their homes and performed the examinations, including IOP measurements with a portable tonometer (Perkins tonometer; Clement Clarke International Ltd, Harlow, England) or a handheld tonometer (Tonopen XL; Bio-Rad Laboratories, Hercules, California) and indirect and direct ophthalmoscopy (BS-II and BXα-13; Neitz, Tokyo). Because specular microscopy could not be performed on these participants, they were excluded from this analysis.

Only a specular microscope was used to detect cornea guttata because we thought that guttata at an early stage could be detected only with specular microscopy. The specular microscopic observation was performed in the area of approximately 0.4 × 0.2 mm at the central cornea, and the presence of guttata was determined by a masked examiner when round or oval dark areas were evident in the specular microscopy images. Owing to the large sample size, the specular microscopic observation was performed only at the central cornea. We used the modified grading method reported in the Reykjavik Eye Study³ to grade cornea guttata from 0 to 4 on the basis of the ratio of the area of dark spots seen on the specular microscopy image to the entire area of the image, with 0 indicating no dark area; 1, less than 10%; 2, 10% to 25%; 3, 26% to 50%; and 4, more than 50%.

All data were stored at the University of Ryukyus and University of Tokyo. Data analyses were performed using SPSS 15.0J for Windows statistical software (SPSS Japan Inc, Tokyo). Risk factors evaluated included sex, age, height, weight, diastolic and systolic blood pressure, diagnosis of diabetes or hypertension, smoking history, outdoor work history, self-reported main lifetime occupations, refractive error, CCT, IOP, and use of sunglasses, hat, prescription glasses, or contact lenses. Because age and sex were significantly associated with the presence of guttata in a preliminary analysis (data not shown), logistic analyses in which the explaining variables were each one of the listed risk factors and only sex (for the analysis of age), only age (for sex), and both age and sex (for the other risk factors) were included to adjust for age and/or sex. Data are expressed as mean (SD) unless otherwise specified.

Of the 4632 eligible residents, 3762 (81.2%) underwent the examination. The 3762 participants were younger than the 870 nonparticipants (mean age, 59.1 [14.9] vs 61.8 [14.0] years; P < .001, unpaired t test), and more women were among the participants (male to female ratio, 1833:1929 vs 555:315; P < .001, χ² test).

Of the 7524 eyes (3762 participants), 872 right eyes and 895 left eyes were excluded for various reasons, including history of intraocular surgery and difficulties in obtaining clear images of corneal endothelial cells with specular microscopy (Table 1). Diseases that can affect the corneal endothelium, such as iridocorneal endothelial syndrome, were not observed in any of the participants. Thus, 2890 right eyes and 2867 left eyes were included in the current analysis. At least 1 eye was eligible in 3060 residents, and both eyes were eligible in 2714. Among the 3060 included residents, more were men (50.7% vs 49.3%; P < .001, χ² test) and younger (mean age, 59.2 [12.9] vs 73.3 [12.7] years; P < .001, unpaired t test) than among the 702 excluded individuals. Of the 3060 eligible residents, 124 (4.1%; 95% confidence interval, 3.4%-4.8%) had cornea guttata in at least 1 eye, including 39 with cornea guttata in both eyes, 53 in right eyes only, and 32 in left eyes only. The prevalence in the right eyes (3.2%) was not significantly different from that in the left eyes (2.5%) (P = .11).

The prevalence of cornea guttata adjusted for sex and age is summarized in Table 2. The prevalence of cornea guttata was significantly different among subgroups of the 5 age ranges (P = .003, Fisher exact test). The grade of cornea guttata was not significantly correlated with age (P = .32; R = 0.09). The prevalence of cornea guttata was significantly different between men and women (2.4% vs 5.8%; P < .001, Fisher exact test).

Table 3 shows the results of the comparison between participants with and without cornea guttata. The univariable comparison showed that participants with cornea guttata were older, female, and shorter in stature; had a lower body weight, thinner CCT, and shallower anterior chamber; and smoked fewer pack-years compared with those without (Table 3). Logistic regression analysis with adjustment for only sex (age), only age (sex), or both sex and age (the other factors) showed that greater age, female sex, and thinner CCT were associated with increased risk of cornea guttata (Table 3).

To the best of our knowledge, ours is the first population-based study with a large population size to evaluate the prevalence of cornea guttata in an Asian population. In this study, 124 of 3060 eligible participants (4.1%) had cornea guttata in at least 1 eye. Several studies have reported the prevalence of cornea guttata. A population-based study in Reykjavik reported that the prevalence of cornea guttata was 9.2% in 774 white participants 55 years or older in whom specular microscopy was used for diagnosis.³ In a non–population-based study conducted in Japan and Singapore with a relatively small number of participants 50 years or older,⁴ the incidence of cornea guttata was 6.7% (31 of 465 participants) in Chinese Singaporeans and 3.7% (11 of 299 participants) in Japanese study participants.⁴ The prevalence of 4.1% in our study is lower than that in the Reykjavik Eye Study or the study of Chinese Singaporeans. In the study conducted in Japan and Singapore, the authors stated that environmental factors, such as UV light and temperature, may be involved in the occurrence of cornea guttata because there was a difference in the prevalence of cornea guttata in the Japanese and Chinese Singaporeans despite their racial similarity. On the other hand, the prevalence of cornea guttata in the white population reported in the Reykjavik Eye Study was even higher, suggesting that genetic factors contribute to the occurrence of cornea guttata. Moreover, primary central cornea guttata occasionally progresses to Fuchs corneal endothelial dystrophy, which is a major cause of corneal transplantation (9.3%-23.8%) in Western countries^9-13 and only a minor cause (1.7%-3.9%) in Asian countries.^14-16 This finding suggests that genetic or racial factors strongly contribute to the occurrence of Fuchs endothelial dystrophy and cornea guttata. Additional population-based studies in various geographic areas and among various ethnicities are necessary to clarify the effect of environmental and genetic factors on the occurrence of cornea guttata.

In the present study, the prevalence of cornea guttata became higher with increasing age. This finding suggests that primary cornea guttata progresses in an age-dependent manner. In the Reykjavik Eye Study with 774 participants,³ the mean age of female participants with cornea guttata was significantly higher than that of female participants without cornea guttata, but logistic regression analysis did not show age to be a significant factor associated with cornea guttata. It is possible that the number of participants in our study was large enough to detect the association between the presence of cornea guttata and higher age. On the other hand, the grade of cornea guttata was not significantly correlated with age. Only 3 cases of the highest grade were noted in the group aged 70 to 79 years, whereas none were noted in those 80 years or older. There were 201 participants in the subgroup 80 years or older, whereas there were more than 500 in the other age subgroups. In addition, only 13 persons had cornea guttata in the subgroup 80 years or older. The relatively small number of participants in the oldest subgroup might be responsible for the lack of correlation between the grade of cornea guttata and age. This point needs further investigation.

We found the prevalence of cornea guttata to be significantly different between women and men (5.8% vs 2.4%), and logistic regression analysis with adjustment for age indicated that the prevalence of cornea guttata in women was significantly higher than that in men. The Reykjavik Eye Study reported a higher prevalence of cornea guttata in women (11%) than in men (7%), although the difference was not statistically significant.³ Similarly, the study conducted in Japan and Singapore reported a higher prevalence of cornea guttata in women than in men (8.5% vs 4.4% in Chinese Singaporeans and 5.5% vs 1.5% in Japanese).⁴ Thus, a higher prevalence of cornea guttata in women is likely to be a common finding among races. This observation is consistent with the fact that Fuchs corneal endothelial dystrophy is observed more frequently in women than in men.^17-19

In the present study, logistic regression analysis demonstrated that a thinner central cornea is also associated with increased risk of cornea guttata. Higher grades of cornea guttata are likely to be associated with a thicker cornea because cornea guttata occasionally progresses to Fuchs endothelial dystrophy, in which corneal thickness is increased owing to edema. However, in most of the participants with cornea guttata in this study, the grade of cornea guttata was low, and we found no association between cornea guttata and a thicker cornea. On the contrary, cornea guttata was associated with a thinner cornea. This relationship of cornea guttata with CCT requires further investigation.

In the Reykjavik Eye Study, lower weight, lower body mass index, and a history of smoking longer than 20 pack-years were associated with a higher risk of cornea guttata.³ In the present study, participants with cornea guttata had significantly lower body weight than those without cornea guttata, but this relation was no longer significant after adjusting for age and sex. Thus, in our study, weight and body mass index were not significantly correlated with cornea guttata. Logistic regression analysis in the present study also did not indicate a significant correlation between cornea guttata and smoking.

There are a few limitations in this study. First, we used only a specular microscope to detect cornea guttata because we thought that guttata at an early stage could be detected only with that instrument. However, this could have led to underestimation of the presence of guttata in this population because only a small area in the central cornea can be observed with specular microscopy. Moreover, guttata frequently occur in the paracentral rather than the central area of the endothelium, in which a slitlamp examination is more suitable to detect guttata. In the Reykjavik Eye Study, slitlamp biomicroscopy and specular microscopy were used to detect guttata. Thus, the prevalence of guttata in the Reykjavik study and ours may not be simply compared with each other. Second, the 3762 participants were younger than the 870 nonparticipants. Because the results indicated that the prevalence of cornea guttata became higher with increasing age, it is possible that the prevalence of cornea guttata in the entire population in Kumejima Island is actually somewhat higher than 4.1%.

In conclusion, the prevalence of cornea guttata was 4.1% among individuals 40 years or older in Kumejima, a southwestern island of Japan, by specular microscopic criteria only, which is lower than the prevalence reported in the Reykjavik study. A higher prevalence may have been determined if specular microscopy had been combined with slitlamp biomicroscopy. Older age, female sex, and a thinner cornea were independently associated with a higher risk of cornea guttata.

Correspondence: Shiro Amano, MD, Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (amanos-tky@umin.ac.jp).

Submitted for Publication: December 27, 2009; final revision received July 14, 2010; accepted July 16, 2010.

Financial Disclosure: None reported.

Funding/Support: This study was supported in part by grant-in-aid 27015A from the Ministry of Health, Labor, and Welfare (Dr Araie); grant-in-aid (C) 17591845 for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (Dr Araie); and funds from the Japan National Society for the Prevention of Blindness.