Seminars in Ophthalmology, Early Online, 1–6, 2014 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2014.962169
ORIGINAL ARTICLE
Epidemiology and Associated Morbidity of Pterygium: A Large, Community-Based Case-Control Study Arie Y. Nemet1, Shlomo Vinker2,3, Ori Segal1, Michael Mimouni1, and Igor Kaiserman4
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1
Department of Ophthalmology, Meir Medical Center, Kfar Saba, Israel, 2Department of Family Medicine, Clalit Health Services, Central District, Rehovot, Israel, 3Department of Family Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, and 4Department of Ophthalmology, Barzilai Medical Center, Ashkelon, Israel, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
ABSTRACT Background: To evaluate the prevalence and risk factors of various conditions among patients with pterygium. Methods: A retrospective observational case control study of 4,037 patients who were diagnosed with pterygium in the Central District of Clalit Health Services in Israel from 2000–2009. A total of 16,054 randomly selected controls from the district HMO members. Personal, medical, and demographic information were extracted from patients’ files. We calculated the prevalence of various ocular, systemic, and demographic conditions as risk factors for pterygium. Results: The average age of pterygium patients was 58.4 ± 14 years; 56.9% were male. A significant tendency to develop pterygium was found among individuals of lower socioeconomic status (p50.001) and in populations living in rural areas (p50.001). A logistic regression model adjusted to marital status, socio-economic class, and area of living was performed. The following conditions were significantly associated with pterygium: blepharitis (OR = 1.71; 99.9% CI: 1.53–1.93), chalazia (OR = 1.46; 99.9% CI: (1.19–1.78)), anxiety (OR = 1.14, 99.9% CI: 0.98–1.33), and G6PD deficiency (OR = 1.85; 99.9% CI: 1.11–3.07). Schizophrenia (OR 0.31; 99.9% CI: 0.19–0.50) and smoking (OR 0.82; 99.9% CI: 0.76–0.89) were significantly less prevalent among pterygium patients. Conclusions: Pterygium etiology is multifactorial. Some demographic, systemic, and periocular conditions are significantly more prevalent and some are less prevalent among pterygium patients. Better understanding of the pathophysiological association between those diseases and pterygium may help in its prevention and treatment. Keywords: Anxiety, chalazia, G6PD deficiency, pterygium, risk factors
INTRODUCTION
ultraviolet (UV) light, evidence from multiple sources suggests that populations with high exposure to sunlight are at increased risk of pterygium. It is thought to be caused by reactive oxygen species (ROS) formation after exposure to UV light (e.g. sunlight), low humidity, and dust.3 Some local ocular surface changes and abnormalities in the tear film may cause a predisposition to the proliferation of fibrovascular tissue.4 Although there is a large body of literature regarding demographic risk factors for pterygium (race, age, sex, socioeconomic class, and geography5,6)
Pterygium is a common, benign, wing-shaped, fibrovascular growth of the bulbar conjunctiva. Pathology findings include elastotic degeneration and altered epithelial basal cells.1 Research into the pathogenesis of pterygium suggests a complex disease with genetic, environmental, infective, and immunological components.2 In particular, a wide variety of pro-inflammatory cytokines and angiogenic and fibrogenic growth factors have been implicated in pterygium. Since some of these factors are affected by exposure to
Received 24 May 2014; accepted 31 August 2014; published online 7 November 2014 Correspondence: Dr. Arie Y. Nemet, MD, Department of Ophthalmology, Meir Medical Center, Kfar Saba, Israel. E-mail: [email protected]
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and some targeted studies regarding the UV-B contribution to its pathogenesis, there is a relative paucity of current information about systemic diseases associated with pterygia.6,7 Smoking6–8 and diabetes have been found to be protective against pterygium. Hence, fundamental questions regarding the conditions associated with pterygium have yet to be clarified. The present study aimed to evaluate the conditions associated with pterygium in an Israeli population.
Australia—or Sephardic origin—those born in Asia and Africa (mainly the Middle East and North Africa)), place of residence (urban (410,000 inhabitants) or rural settlements), marital status, and social security economic status (members who are exempt from social security tax due to low socioeconomic status).
Outcome Measures There was a prevalence of various ocular and systemic conditions among patients diagnosed with pterygium.
METHODS
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Study Population The electronic medical records of all HMO members diagnosed with pterygium by an ophthalmologist in the Central District of the Clalit Health Services Health Maintenance Organization (HMO) in Israel between January 1, 2000, and December 31, 2009, who did not terminate their membership (for any reason) before December 31, 2009, were included in the study (n = 4,017). For each pterygium patient in the study group, four age- and gender-matched HMO members were randomly selected from all HMO members who did not discontinue membership (for any reason, including death) before December 31, 2009 (n = 16,067). The study was approved by the institutional review board of Meir Medical Center.
Observation Procedures Clalit Health Services HMO maintains a chronic disease registry database which includes information collected from a variety of sources, including primary care physician reports, medication use files, hospitalization records, and out-patient clinic records. The methods of registry acquisition and maintenance have been described elsewhere.9 In addition to the diagnosis of pterygium, information extracted from patients’ files included age, gender, region of birth (Ashkenazi origin—people born in Europe, North or South America and
Statistical Analysis Student’s t-test was used for continuous variables and 2 test with Yates’ correction for proportions. SPSS ver.12 (SPSS Inc., Chicago, IL, USA) was used to analyze the data. To account for repeated testing, only probabilities of less than 0.001 (1%) were considered statistically significant.
RESULTS A total of 4,037 patients diagnosed by an ophthalmologist to have pterygium during the study period were included, as well as 16,054 age- and gendermatched controls randomly selected from all of the HMO members in the district. Table 1 summarizes the demographic characteristics of the study populations. A significantly greater tendency to develop pterygium was found among study group members of lower socioeconomic class and those living in rural areas. Table 2 shows the prevalence of various conditions among patients who were diagnosed with pterygium versus matched controls. A logistic regression model adjusted to marital status, socio-economic class, and area of living was performed. Odds ratio and adjusted odds ratio of ocular and systemic conditions among pterygium patients and the control group showed that the following conditions were significantly
TABLE 1. Demographic characteristics of pterygium patients and control group. Characteristic Age (years, mean ± SD) Male gender Married Low socioeconomic class Living in a rural settlement
Pterygium patients (n = 4,037)
Control group (n = 16,054)
p value
58.39 ± 14.15 2,297 (56.9%) 3,053 (75.6%) 821 (20.3%) 825 (20.5%)
58.40 ± 14.15 9,127 (56.9%) 11,834 (73.7%) 2,833 (17.6%) 2,291 (14.3%)
0.96 0.92 0.014 50.001 50.001
SD = standard deviation Seminars in Ophthalmology
Risk Factors for Pterygium associated with pterygium: blepharitis, chalazia, anxiety, and G6PD deficiency. Schizophrenia and smoking were significantly less prevalent among pterygium patients.
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DISCUSSION The prevalence rates of pterygium worldwide vary greatly,8,10–12 ranging from 1% in Japanese to 29% in Samoan Islanders and 23% in Barbadian blacks.6–8,11 Generally, prevalence rates in the tropics are higher than at temperate latitudes, and several studies have shown the UV-B radiation risk of pterygium.7 The role of UV-mediated limbal damage has been extensively reviewed, and Coroneo et al. have proposed that corneal focusing of sunlight on the limbus plays a significant role.2 In the current study, some demographic findings (male, lower socioeconomic class, and people living in a rural area), some eye conditions (blepharitis and chalazia), along with some systemic conditions (anxiety and G6PD deficiency), were significantly more prevalent among pterygium patients; schizophrenia and smoking were less prevalent.
Blepharitis and Pterygium Our finding of the associations between pterygium and blepharitis indicate that the chronically inflamed ocular surface might induce pterygium growth.12 Recently, our group has shown a significant association of pterygium with blepharitis.13 Inflammation and oxidative stress may play a putative role in pterygium pathogenesis by increasing the damage caused by UV radiation on the limbal basal stem cells and accelerating the multistep mutation pathway that leads to pterygium formation.1 In blepharitis, abnormalities in the tear film may cause a predisposition to proliferation of fibro-vascular tissue. Taylor 4 had noted that aborigines with
pterygium were found to have a disruption in the marginal tear strip compared to those without pterygium. In dry eyes, increased tear osmolarity could possibly stimulate production of matrix metalloproteinases (MMPs), alter the function of limbal epithelial cells, and induce pterygium.1 However, Tongg et al. failed to find any correlation between dry eye symptoms and pterygium.14 Older subjects were also noted to be more likely to develop pterygium, for which advancing age is also a risk factor. It might be related to a depletion of stem cell reserves, as older individuals with chronic blepharitis would presumably have been exposed to chronic ocular irritation and/or low-grade inflammation for longer periods.15
Outdoor Exposure The significant association that we found in the prevalence of pterygium in rural compared to urban areas has been previously reported.7 Tropical climates are risk factors for pterygium, with strong evidence for a link to outdoor work and ultraviolet (UV) light exposure.6–8,11 Similar to our findings, a report from Australia noted that the rates of pterygium in rural residents were more than five times as high as those of urban residents, which was explained by UV-B/sunlight as the primary risk factor for pterygium.16
Socioeconomic Status We found a higher association of pterygium with low socioeconomic class. Several markers of socioeconomic status, including low income and less education, have also been identified as risk factors in other studies.5,6 Low socioeconomic status might be associated with occupations where sunlight exposure is more common. However, in their study of Singaporean Chinese people, Wong et al. found that
TABLE 2. Odds ratio and adjusted odds ratio of ocular and systemic conditions among pterygium patients and control group. Chronic condition
Pterygium patients (n = 4,037)
Control group (n = 16,054)
11.2% 3.3% 5.6% 0.5% 32.2% 0.5%
7.0% 2.4% 5.0% 0.3% 36.5% 1.3%
Blepharitis Chalazia Anxiety 1 G6PD Smoking Schizophrenia 1
Odds ratio (95% confidence interval) 1.68 1.43 1.13 1.79 0.82 0.35
(1.50–1.89) (1.17–1.75) (0.98–1.32) (1.08–2.96) (0.77–0.89) (0.22–0.56)
Adjusted* odds ratio (95% confidence interval) 1.71 1.46 1.14 1.85 0.82 0.31
G6PD-Glucose 6-Phosphate Dehydrogenase Deficiency. *A logistic regression model adjusted to marital status, socio-economic class, and area of living.
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2014 Informa Healthcare USA, Inc.
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(1.53–1.93) (1.19–1.78) (0.98–1.33) (1.11–3.07) (0.76–0.89) (0.19–0.50)
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once occupation was entered into the model, the effect of education was no longer significant.5
patients do not admit to having anxiety or feeling stress, the association of pterygium with psychological conditions might be even more significant than reported here.
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Smoking Similar to our results, smoking has been found to be protective against pterygium in several other studies,6–8 except among a Chinese population, where it was found to be a risk factor for the condition.5 The mechanism by which smoking might be protective is unclear,8 given the consistent finding of cigarette smoking upregulating cytokines and proteins responsible for cell proliferation and migration. It has been suggested that cigarette smoking may be protective by inducing immune suppression, just like the beneficial effect of smoking on ulcerative colitis and other immunologically mediated disorders. Smoking could also have a protective effect on the development of pterygium through angiogenesis. Cigarette smoke exposure inhibits hypoxia-induced angiogenesis, both in vitro and in vivo. Inhibition of the angiogenic response following cigarette smoke exposure is associated with reduced expression of the hypoxia-inducible factor1a (HIF-1a), and the vascular endothelial growth factor (VEGF) in hypoxic conditions.17 Similarly, a clinical study comparing smoking and non-smoking women has shown that smoking impairs angiogenesis, as smokers secrete significantly higher amounts of VEGF Receptors-1 than nonsmokers, which may result in decreased ovarian vascularization and reduced oocyte maturation.18
Anxiety We report here a significant association between anxiety and pterygium. We could not find any similar previous reports, and the mechanism by which stress acts on pterygium is unknown. Well-designed studies have confirmed that psychological stress, adverse life events, chronic stress, and depression increase the likelihood of relapse in patients with some diseases, such as migraine, rheumatoid arthritis, peptic ulcer disease, irritable bowel syndrome, coronary heart disease, hyperthyroidism, diabetes, asthma, and chronic obstructive pulmonary disorder.19 In a recent study, we found similar associations of anxiety with blepharitis and chalazia.13 With the evolving concept of psychoneuroimmunology, the mechanisms by which the nervous system can affect immune function are gradually becoming apparent. Recent data suggest that stress-induced inflammation might be mediated through changes in hypothalamic-pituitary-adrenal (HPA) axis function and via mucosal mast cells and mediators, such as corticotrophin releasing factor (CRF).19 Since many
Glucose-6-Phosphate Dehydrogenase (G6PD) Our finding of the association of glucose-6-phosphate dehydrogenase (G6PD) deficiency and pterygium support the findings of a recently reported study.20 G6PD deficiency is a common enzymopathy affecting more than 400 million people worldwide.21 G6PD is coded by a gene located on the long arm of the human X-chromosome. It is the key cytosolic enzyme in the pentose phosphate pathway. Since it is an X-linked disorder, G6PD is more frequently observed in males. A study by Peiretti et al. found a high prevalence of G6PD deficiency in patients affected by primary pterygium, both men and women, suggesting that this enzymatic defect is a predisposing factor for pterygium development. Oxidative stress is a possible explanation for this finding. G6PD is the only NADPH (nicotinamide adenine dinucleotide phosphate) producing enzyme that is rapidly activated in response to oxidative stress.22 Several studies have confirmed the role of oxidative stress in tumor formation.23 It has been suggested that acute oxidative stress causes selective cell death and a temporary blockage of cell growth,23 followed by a compensatory increase in cell proliferation and tissue growth stimulation. As a result, G6PD deficiency may be considered a risk factor for the development of pterygium.
Diabetes We found no association of pterygium with diabetes (OR = 1; 99.9%CI: 0.9–1.2). A slight protective effect of diabetes and pterygium was reported by West et al.24 They explained the association, as both pterygium and diabetes have been associated with pro-inflammatory cytokines, and the reported studies of increased levels of VEGF in pterygium epithelium and vascular endothelium,25,26 although the upregulation could also be explained by exposure to UV-B.2 Another given explanation was that persons with diabetes might be more likely to have indoor jobs and less sun exposure. However, the authors admit that their finding might be spurious. The low prevalence of pterygium among individuals with schizophrenia in our study might be either a true finding, secondary to indoor living and less sun exposure, or it may be just an underdiagnosed disease, since those patients tend to have less frequent eye examinations. Seminars in Ophthalmology
Risk Factors for Pterygium
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Limitations A major limitation of our study is the absence of detailed ocular sun exposure history, which might provide further evidence of the role of ocular UV-B as a primary risk factor for the high rates of pterygium in our population. Other risk factors, such as education and income, suggest sun exposure as a possible explanation, but direct measurements would be preferable. Grading of pterygium was not available, and we also recognize the difficulty in differentiating small pterygia from pingueculae, such that some misclassification might have occurred. Since this is a retrospective study, the diagnosis of pterygium could not have been. However, since we required that the definition of pterygium be made by expert ophthalmologists only, we assume that pterygium was diagnosed according to accepted clinical criteria. The main strength of our study is the large community-based population with a well-matched control group from the general population.
CONCLUSIONS The development of any pterygium is likely to be the result of a multifactorial process, including UV-B light irradiation, local and systemic conditions, as well as psychological aspects. This study shows that pterygium is associated with some demographic, periocular (blepharitis and chalazia), and systemic (anxiety, G6PD deficiency) conditions and may add to the understanding of the etiology and development of pterygium.
ACKNOWLEDGMENTS Dr. Arie Nemet had full access to all study data and takes responsibility for the integrity of the data and the accuracy of the data analysis. The statistical analysis was performed by Mrs. Nava Yelin, statistician. The manuscript was edited by Mrs. Faye Schreiber.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Dushku N, John MK, Schultz GS, Reid TW. Pterygia pathogenesis: Corneal invasion by matrix metalloproteinase expressing altered limbal epithelial basal cells. Arch Ophthalmol 2001;119:695–706. !
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2. Di Girolamo N, Chui J, Coroneo MT, Wakefield D. Pathogenesis of pterygia: Role of cytokines, growth factors, and matrix metalloproteinases. Prog Retin Eye Res 2004;23: 195–228. 3. Livingston PM, McCarty CA, Taylor HR. Visual impairment and socioeconomic factors. Br J Ophthalmol 1997;81: 574–577. 4. Taylor HR. Studies on the tear film in climatic droplet keratopathy and pterygium. Arch Ophthalmol 1980;98: 86–88. 5. Wong TY, Foster PJ, Johnson GJ, Seah SK, Tan DT. The prevalence and risk factors for pterygium in an adult Chinese population in Singapore: The Tanjong Pagar survey. Am J Ophthalmol 2001;131:176–183. 6. Luthra R, Nemesure BB, Wu SY, Xie SH, Leske MC. Frequency and risk factors for pterygium in the Barbados Eye Study. Arch Ophthalmol 2001;119:1827–1832. 7. McCarty CA, Fu CL, Taylor HR. Epidemiology of pterygium in Victoria, Australia. Br J Ophthalmol 2000;84: 289–292. 8. Gazzard G, Saw SM, Farook M, et al. Pterygium in Indonesia: Prevalence, severity and risk factors. Br J Ophthalmol 2002;86:1341–1346. 9. Rennert G, Peterburg Y. Prevalence of selected chronic diseases in Israel. Isr Med Assoc J 2001;3:404–408. 10. Cajucom-Uy HY, Tong LH, Wong TY, et al. The prevalence of and risk factors for pterygium in an urban Malay population: The Singapore Malay Eye Study (SiMES). Br J Ophthalmol 2010;94:977–981. 11. Taylor HR. Ultraviolet radiation and the eye: An epidemiologic study. Trans Am Ophthalmol Soc 1989;87:802–853. 12. Akpek EK, Merchant A, Pinar V, Foster CS. Ocular rosacea: Patient characteristics and follow-up. Ophthalmology 1997; 104:1863–1867. 13. Nemet AY, Vinker S, Kaiserman I. Associated morbidity of blepharitis. Ophthalmology 2011;118:1062–1068. 14. Tong L, Chew J, Yang H, Ang LP, Tan DT, Beuerman RW. Distinct gene subsets in pterygia formation and recurrence: Dissecting complex biological phenomenon using genome wide expression data. BMC Med Genomics 2009;2:14. 15. Goldberg L, David R. Pterygium and its relationship to the dry eye in the Bantu. Br J Ophthalmol 1976;60:720–721. 16. Taylor HR, West S, Munoz B, Rosenthal FS, Bressler SB, Bressler NM. The long-term effects of visible light on the eye. Arch Ophthalmol 1992;110:99–104. 17. Michaud SE, Menard C, Guy LG, et al. Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure: Impairment of the HIF-1alpha/VEGF pathway. FASEB J 2003;17:1150–1152. 18. Motejlek K, Palluch F, Neulen J, Grummer R. Smoking impairs angiogenesis during maturation of human oocytes. Fertil Steril 2006;86:186–191. 19. Mawdsley JE, Rampton DS. Psychological stress in IBD: New insights into pathogenic and therapeutic implications. Gut 2005;54:1481–1491. 20. Peiretti E, Mandas A, Cocco P, et al. Glucose-6-phosphatedehydrogenase deficiency as a risk factor for pterygium. Invest Ophthalmol Vis Sci 2010;51:2928–2935. 21. Luzzatto L, Battistuzzi G. Glucose-6-phosphate dehydrogenase. Adv Hum Genet 1985;14:217–329, 386–388. 22. Fico A, Paglialunga F, Cigliano L, et al. Glucose-6phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis. Cell Death Differ 2004; 11:823–831. 23. Okada F. Beyond foreign-body-induced carcinogenesis: Impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression. Int J Cancer 2007;121:2364–2372.
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24. West S, Munoz B. Prevalence of pterygium in Latinos: Proyecto VER. Br J Ophthalmol 2009;93:1287–1290. 25. Marcovich AL, Morad Y, Sandbank J, et al. Angiogenesis in pterygium: Morphometric and immunohistochemical study. Curr Eye Res 2002;25:17–22.
26. van Setten G, Aspiotis M, Blalock TD, Grotendorst G, Schultz G. Connective tissue growth factor in pterygium: Simultaneous presence with vascular endothelial growth factor: Possible contributing factor to conjunctival scarring. Graefes Arch Clin Exp Ophthalmol 2003;241:135–139.
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Notice of Correction: Changes have been made to this article since its original online publication date of 11 November 2014.
Seminars in Ophthalmology
ORIGINAL ARTICLE
Epidemiology and Associated Morbidity of Pterygium: A Large, Community-Based Case-Control Study Arie Y. Nemet1, Shlomo Vinker2,3, Ori Segal1, Michael Mimouni1, and Igor Kaiserman4
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1
Department of Ophthalmology, Meir Medical Center, Kfar Saba, Israel, 2Department of Family Medicine, Clalit Health Services, Central District, Rehovot, Israel, 3Department of Family Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, and 4Department of Ophthalmology, Barzilai Medical Center, Ashkelon, Israel, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
ABSTRACT Background: To evaluate the prevalence and risk factors of various conditions among patients with pterygium. Methods: A retrospective observational case control study of 4,037 patients who were diagnosed with pterygium in the Central District of Clalit Health Services in Israel from 2000–2009. A total of 16,054 randomly selected controls from the district HMO members. Personal, medical, and demographic information were extracted from patients’ files. We calculated the prevalence of various ocular, systemic, and demographic conditions as risk factors for pterygium. Results: The average age of pterygium patients was 58.4 ± 14 years; 56.9% were male. A significant tendency to develop pterygium was found among individuals of lower socioeconomic status (p50.001) and in populations living in rural areas (p50.001). A logistic regression model adjusted to marital status, socio-economic class, and area of living was performed. The following conditions were significantly associated with pterygium: blepharitis (OR = 1.71; 99.9% CI: 1.53–1.93), chalazia (OR = 1.46; 99.9% CI: (1.19–1.78)), anxiety (OR = 1.14, 99.9% CI: 0.98–1.33), and G6PD deficiency (OR = 1.85; 99.9% CI: 1.11–3.07). Schizophrenia (OR 0.31; 99.9% CI: 0.19–0.50) and smoking (OR 0.82; 99.9% CI: 0.76–0.89) were significantly less prevalent among pterygium patients. Conclusions: Pterygium etiology is multifactorial. Some demographic, systemic, and periocular conditions are significantly more prevalent and some are less prevalent among pterygium patients. Better understanding of the pathophysiological association between those diseases and pterygium may help in its prevention and treatment. Keywords: Anxiety, chalazia, G6PD deficiency, pterygium, risk factors
INTRODUCTION
ultraviolet (UV) light, evidence from multiple sources suggests that populations with high exposure to sunlight are at increased risk of pterygium. It is thought to be caused by reactive oxygen species (ROS) formation after exposure to UV light (e.g. sunlight), low humidity, and dust.3 Some local ocular surface changes and abnormalities in the tear film may cause a predisposition to the proliferation of fibrovascular tissue.4 Although there is a large body of literature regarding demographic risk factors for pterygium (race, age, sex, socioeconomic class, and geography5,6)
Pterygium is a common, benign, wing-shaped, fibrovascular growth of the bulbar conjunctiva. Pathology findings include elastotic degeneration and altered epithelial basal cells.1 Research into the pathogenesis of pterygium suggests a complex disease with genetic, environmental, infective, and immunological components.2 In particular, a wide variety of pro-inflammatory cytokines and angiogenic and fibrogenic growth factors have been implicated in pterygium. Since some of these factors are affected by exposure to
Received 24 May 2014; accepted 31 August 2014; published online 7 November 2014 Correspondence: Dr. Arie Y. Nemet, MD, Department of Ophthalmology, Meir Medical Center, Kfar Saba, Israel. E-mail: [email protected]
1
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and some targeted studies regarding the UV-B contribution to its pathogenesis, there is a relative paucity of current information about systemic diseases associated with pterygia.6,7 Smoking6–8 and diabetes have been found to be protective against pterygium. Hence, fundamental questions regarding the conditions associated with pterygium have yet to be clarified. The present study aimed to evaluate the conditions associated with pterygium in an Israeli population.
Australia—or Sephardic origin—those born in Asia and Africa (mainly the Middle East and North Africa)), place of residence (urban (410,000 inhabitants) or rural settlements), marital status, and social security economic status (members who are exempt from social security tax due to low socioeconomic status).
Outcome Measures There was a prevalence of various ocular and systemic conditions among patients diagnosed with pterygium.
METHODS
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Study Population The electronic medical records of all HMO members diagnosed with pterygium by an ophthalmologist in the Central District of the Clalit Health Services Health Maintenance Organization (HMO) in Israel between January 1, 2000, and December 31, 2009, who did not terminate their membership (for any reason) before December 31, 2009, were included in the study (n = 4,017). For each pterygium patient in the study group, four age- and gender-matched HMO members were randomly selected from all HMO members who did not discontinue membership (for any reason, including death) before December 31, 2009 (n = 16,067). The study was approved by the institutional review board of Meir Medical Center.
Observation Procedures Clalit Health Services HMO maintains a chronic disease registry database which includes information collected from a variety of sources, including primary care physician reports, medication use files, hospitalization records, and out-patient clinic records. The methods of registry acquisition and maintenance have been described elsewhere.9 In addition to the diagnosis of pterygium, information extracted from patients’ files included age, gender, region of birth (Ashkenazi origin—people born in Europe, North or South America and
Statistical Analysis Student’s t-test was used for continuous variables and 2 test with Yates’ correction for proportions. SPSS ver.12 (SPSS Inc., Chicago, IL, USA) was used to analyze the data. To account for repeated testing, only probabilities of less than 0.001 (1%) were considered statistically significant.
RESULTS A total of 4,037 patients diagnosed by an ophthalmologist to have pterygium during the study period were included, as well as 16,054 age- and gendermatched controls randomly selected from all of the HMO members in the district. Table 1 summarizes the demographic characteristics of the study populations. A significantly greater tendency to develop pterygium was found among study group members of lower socioeconomic class and those living in rural areas. Table 2 shows the prevalence of various conditions among patients who were diagnosed with pterygium versus matched controls. A logistic regression model adjusted to marital status, socio-economic class, and area of living was performed. Odds ratio and adjusted odds ratio of ocular and systemic conditions among pterygium patients and the control group showed that the following conditions were significantly
TABLE 1. Demographic characteristics of pterygium patients and control group. Characteristic Age (years, mean ± SD) Male gender Married Low socioeconomic class Living in a rural settlement
Pterygium patients (n = 4,037)
Control group (n = 16,054)
p value
58.39 ± 14.15 2,297 (56.9%) 3,053 (75.6%) 821 (20.3%) 825 (20.5%)
58.40 ± 14.15 9,127 (56.9%) 11,834 (73.7%) 2,833 (17.6%) 2,291 (14.3%)
0.96 0.92 0.014 50.001 50.001
SD = standard deviation Seminars in Ophthalmology
Risk Factors for Pterygium associated with pterygium: blepharitis, chalazia, anxiety, and G6PD deficiency. Schizophrenia and smoking were significantly less prevalent among pterygium patients.
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DISCUSSION The prevalence rates of pterygium worldwide vary greatly,8,10–12 ranging from 1% in Japanese to 29% in Samoan Islanders and 23% in Barbadian blacks.6–8,11 Generally, prevalence rates in the tropics are higher than at temperate latitudes, and several studies have shown the UV-B radiation risk of pterygium.7 The role of UV-mediated limbal damage has been extensively reviewed, and Coroneo et al. have proposed that corneal focusing of sunlight on the limbus plays a significant role.2 In the current study, some demographic findings (male, lower socioeconomic class, and people living in a rural area), some eye conditions (blepharitis and chalazia), along with some systemic conditions (anxiety and G6PD deficiency), were significantly more prevalent among pterygium patients; schizophrenia and smoking were less prevalent.
Blepharitis and Pterygium Our finding of the associations between pterygium and blepharitis indicate that the chronically inflamed ocular surface might induce pterygium growth.12 Recently, our group has shown a significant association of pterygium with blepharitis.13 Inflammation and oxidative stress may play a putative role in pterygium pathogenesis by increasing the damage caused by UV radiation on the limbal basal stem cells and accelerating the multistep mutation pathway that leads to pterygium formation.1 In blepharitis, abnormalities in the tear film may cause a predisposition to proliferation of fibro-vascular tissue. Taylor 4 had noted that aborigines with
pterygium were found to have a disruption in the marginal tear strip compared to those without pterygium. In dry eyes, increased tear osmolarity could possibly stimulate production of matrix metalloproteinases (MMPs), alter the function of limbal epithelial cells, and induce pterygium.1 However, Tongg et al. failed to find any correlation between dry eye symptoms and pterygium.14 Older subjects were also noted to be more likely to develop pterygium, for which advancing age is also a risk factor. It might be related to a depletion of stem cell reserves, as older individuals with chronic blepharitis would presumably have been exposed to chronic ocular irritation and/or low-grade inflammation for longer periods.15
Outdoor Exposure The significant association that we found in the prevalence of pterygium in rural compared to urban areas has been previously reported.7 Tropical climates are risk factors for pterygium, with strong evidence for a link to outdoor work and ultraviolet (UV) light exposure.6–8,11 Similar to our findings, a report from Australia noted that the rates of pterygium in rural residents were more than five times as high as those of urban residents, which was explained by UV-B/sunlight as the primary risk factor for pterygium.16
Socioeconomic Status We found a higher association of pterygium with low socioeconomic class. Several markers of socioeconomic status, including low income and less education, have also been identified as risk factors in other studies.5,6 Low socioeconomic status might be associated with occupations where sunlight exposure is more common. However, in their study of Singaporean Chinese people, Wong et al. found that
TABLE 2. Odds ratio and adjusted odds ratio of ocular and systemic conditions among pterygium patients and control group. Chronic condition
Pterygium patients (n = 4,037)
Control group (n = 16,054)
11.2% 3.3% 5.6% 0.5% 32.2% 0.5%
7.0% 2.4% 5.0% 0.3% 36.5% 1.3%
Blepharitis Chalazia Anxiety 1 G6PD Smoking Schizophrenia 1
Odds ratio (95% confidence interval) 1.68 1.43 1.13 1.79 0.82 0.35
(1.50–1.89) (1.17–1.75) (0.98–1.32) (1.08–2.96) (0.77–0.89) (0.22–0.56)
Adjusted* odds ratio (95% confidence interval) 1.71 1.46 1.14 1.85 0.82 0.31
G6PD-Glucose 6-Phosphate Dehydrogenase Deficiency. *A logistic regression model adjusted to marital status, socio-economic class, and area of living.
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(1.53–1.93) (1.19–1.78) (0.98–1.33) (1.11–3.07) (0.76–0.89) (0.19–0.50)
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once occupation was entered into the model, the effect of education was no longer significant.5
patients do not admit to having anxiety or feeling stress, the association of pterygium with psychological conditions might be even more significant than reported here.
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Smoking Similar to our results, smoking has been found to be protective against pterygium in several other studies,6–8 except among a Chinese population, where it was found to be a risk factor for the condition.5 The mechanism by which smoking might be protective is unclear,8 given the consistent finding of cigarette smoking upregulating cytokines and proteins responsible for cell proliferation and migration. It has been suggested that cigarette smoking may be protective by inducing immune suppression, just like the beneficial effect of smoking on ulcerative colitis and other immunologically mediated disorders. Smoking could also have a protective effect on the development of pterygium through angiogenesis. Cigarette smoke exposure inhibits hypoxia-induced angiogenesis, both in vitro and in vivo. Inhibition of the angiogenic response following cigarette smoke exposure is associated with reduced expression of the hypoxia-inducible factor1a (HIF-1a), and the vascular endothelial growth factor (VEGF) in hypoxic conditions.17 Similarly, a clinical study comparing smoking and non-smoking women has shown that smoking impairs angiogenesis, as smokers secrete significantly higher amounts of VEGF Receptors-1 than nonsmokers, which may result in decreased ovarian vascularization and reduced oocyte maturation.18
Anxiety We report here a significant association between anxiety and pterygium. We could not find any similar previous reports, and the mechanism by which stress acts on pterygium is unknown. Well-designed studies have confirmed that psychological stress, adverse life events, chronic stress, and depression increase the likelihood of relapse in patients with some diseases, such as migraine, rheumatoid arthritis, peptic ulcer disease, irritable bowel syndrome, coronary heart disease, hyperthyroidism, diabetes, asthma, and chronic obstructive pulmonary disorder.19 In a recent study, we found similar associations of anxiety with blepharitis and chalazia.13 With the evolving concept of psychoneuroimmunology, the mechanisms by which the nervous system can affect immune function are gradually becoming apparent. Recent data suggest that stress-induced inflammation might be mediated through changes in hypothalamic-pituitary-adrenal (HPA) axis function and via mucosal mast cells and mediators, such as corticotrophin releasing factor (CRF).19 Since many
Glucose-6-Phosphate Dehydrogenase (G6PD) Our finding of the association of glucose-6-phosphate dehydrogenase (G6PD) deficiency and pterygium support the findings of a recently reported study.20 G6PD deficiency is a common enzymopathy affecting more than 400 million people worldwide.21 G6PD is coded by a gene located on the long arm of the human X-chromosome. It is the key cytosolic enzyme in the pentose phosphate pathway. Since it is an X-linked disorder, G6PD is more frequently observed in males. A study by Peiretti et al. found a high prevalence of G6PD deficiency in patients affected by primary pterygium, both men and women, suggesting that this enzymatic defect is a predisposing factor for pterygium development. Oxidative stress is a possible explanation for this finding. G6PD is the only NADPH (nicotinamide adenine dinucleotide phosphate) producing enzyme that is rapidly activated in response to oxidative stress.22 Several studies have confirmed the role of oxidative stress in tumor formation.23 It has been suggested that acute oxidative stress causes selective cell death and a temporary blockage of cell growth,23 followed by a compensatory increase in cell proliferation and tissue growth stimulation. As a result, G6PD deficiency may be considered a risk factor for the development of pterygium.
Diabetes We found no association of pterygium with diabetes (OR = 1; 99.9%CI: 0.9–1.2). A slight protective effect of diabetes and pterygium was reported by West et al.24 They explained the association, as both pterygium and diabetes have been associated with pro-inflammatory cytokines, and the reported studies of increased levels of VEGF in pterygium epithelium and vascular endothelium,25,26 although the upregulation could also be explained by exposure to UV-B.2 Another given explanation was that persons with diabetes might be more likely to have indoor jobs and less sun exposure. However, the authors admit that their finding might be spurious. The low prevalence of pterygium among individuals with schizophrenia in our study might be either a true finding, secondary to indoor living and less sun exposure, or it may be just an underdiagnosed disease, since those patients tend to have less frequent eye examinations. Seminars in Ophthalmology
Risk Factors for Pterygium
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Limitations A major limitation of our study is the absence of detailed ocular sun exposure history, which might provide further evidence of the role of ocular UV-B as a primary risk factor for the high rates of pterygium in our population. Other risk factors, such as education and income, suggest sun exposure as a possible explanation, but direct measurements would be preferable. Grading of pterygium was not available, and we also recognize the difficulty in differentiating small pterygia from pingueculae, such that some misclassification might have occurred. Since this is a retrospective study, the diagnosis of pterygium could not have been. However, since we required that the definition of pterygium be made by expert ophthalmologists only, we assume that pterygium was diagnosed according to accepted clinical criteria. The main strength of our study is the large community-based population with a well-matched control group from the general population.
CONCLUSIONS The development of any pterygium is likely to be the result of a multifactorial process, including UV-B light irradiation, local and systemic conditions, as well as psychological aspects. This study shows that pterygium is associated with some demographic, periocular (blepharitis and chalazia), and systemic (anxiety, G6PD deficiency) conditions and may add to the understanding of the etiology and development of pterygium.
ACKNOWLEDGMENTS Dr. Arie Nemet had full access to all study data and takes responsibility for the integrity of the data and the accuracy of the data analysis. The statistical analysis was performed by Mrs. Nava Yelin, statistician. The manuscript was edited by Mrs. Faye Schreiber.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Notice of Correction: Changes have been made to this article since its original online publication date of 11 November 2014.
Seminars in Ophthalmology
