A cross-sectional study to evaluate predisposing factors for keratoconus in Saudi Arabia

doi:10.21203/rs.3.rs-1538483/v1

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A cross-sectional study to evaluate predisposing factors for keratoconus in Saudi Arabia

https://doi.org/10.21203/rs.3.rs-1538483/v1

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In cases of atopy, IgE antibodies are formed in reaction to certain environmental factors like house dust mites, pollen, or even food allergens. Some studies have shown an association between atopic diseases and keratoconus. This study aims to determine the prevalence of atopy and its associated factors among keratoconus patients. A cross-sectional study was conducted among the Jazan population attending ophthalmology clinics in PMNH regardless of their sex. Data collection started in August 2020 and finished in mid June 2021. The sample was selected using the convenience sampling technique and the total sample size was 83 participants. Data were collected via a questionnaire-based interview that contained 46 questions in the Arabic language. The data collected were analyzed using SPSS software. Family history is the leading predisposing factor for keratoconus (P < 0.001). Also, eye rubbing was a significant (P < 0.015) trigger for keratoconus. However, other factors, including demographic factors such as gender and atopic conditions, did not have any significant association. A combination of genetic and environmental factors is the leading cause of the development of keratoconus; however, family history is the most influential factor, followed by eye rubbing.

Atopic disease

Keratoconus

Prevalence

Risk factor

Jazan

Saudi Arabia

Atopy is described as a hereditary propensity to form immunoglobulin E antibodies (IgE) as a reaction to minute amounts of certain environmental factors, including house dust mites, pollen, or even food allergens¹. In addition, atopy is a hereditary propensity for developing allergic hypersensitivity. Studies show that the most prevalent representations of atopic dermatitis are allergic asthma and allergic rhinitis, followed by allergic dermatitis and food allergies¹. Allergies are the clinical expression of atopic diseases; nevertheless, not all allergies are atopic diseases². The most common characteristic of all atopic diseases is hypersensitivity of the skin and mucous membranes, and this hypersensitivity often runs in families³.

Several risk factors have been identified for atopic diseases. Risk and triggering factors such as allergens, tobacco smoke, and occupational factors are the causative agents of allergic reactions or acute asthma in atopic patients; although a distinction must be made between them, there are also connections to be found; for instance, cigarette smoke exposure as well as allergens can be long-term risk factors for allergies or even asthma development. People with atopic dermatitis have a greater propensity to respond to specific antigens in the environment⁴.

Epidemiological studies show that the incidence and prevalence of atopic diseases like asthma, hay fever, and atopic dermatitis are increasing in developing countries. However, the prevalence of atopic diseases has reached a plateau in developed western countries ¹.

Atopic involvement in a person is linked with an increased incidence of development of one or more of the atopic conditions; asthma, atopic dermatitis (eczema), allergic rhinoconjunctivitis/hay fever, as well as food allergies. However, atopy may manifest as asymptomatic sensitization, i.e., it may be seen among patients who have proven allergic sensitization but may not display a clinical allergic reaction¹.

Keratoconus is defined as an asymmetrical and worsening disease with severe effects on the acuity of vision as well as the life quality of the cases. It is also defined as a gradual thinning of the corneal stroma resulting in modification of the tissue structure. Irregular astigmatism occurs due to cone-shaped cornea. Corneal ectasia usually presents in young adults at puberty and may advance till the 3rd to 4th decade when physiological corneal cross-linking is established to be the disease's stabilizing agent⁵.

The exact causes of keratoconus are still poorly understood. While most forms of keratoconus are known to be sporadic, several researchers have revealed a significant number of hereditary family keratoconus, whether via an autosomal recessive or dominant form. LOX is recognized as the collagen cross-linking enzyme lysyl oxidase, a gene important for cross-linking collagen, while elastin is viewed as a probably reliable indicator in keratoconus formation leading to a damaged corneal architecture. Environmental causes, including eye rubbing and the use of rigid contact lenses, have been linked to the condition. Those with allergic conditions have an increased chance of keratoconus formation⁵. The most frequently noted risk factors of excessive eye rubbing in KC were allergies and atopic disorders. Nevertheless, irritation triggered by atopy, which contributes to rubbing of the eye, may be the most important contributing factor to KC⁶.

The thinning of the cornea results in unequal astigmatism and myopia, which leads to mild to severe vision problems. Keratoconus is bilateral among 90% of cases, but is typically asymmetrical in intensity as well as advancement. While no symptoms can accompany the initial stages of the disorder, as it advances, the common manifestation is mild to significant vision problems due to unequal astigmatism, myopia, and corneal scarring in some cases⁶.

Keratoconus disease is a bilateral, non-inflammatory corneal ectasia with an occurrence in the overall public of around one per 2000⁷. The frequency of keratoconus disease in the city of Asir in Saudi Arabia is twenty patients for every 100,000 people⁸. In total, 1,638 people from one of the five cities in KSA were referred to King Khaled's Eye Specialist Hospital for the treatment of keratoconus at an average annual reference rate of 136.5 cases per year. The overall distribution of people with keratoconus was almost similar among males and females, with a greater incidence of younger patients aged between 16–26⁹. Keratoconus is an unexplained etiological condition, although much research has exhibited a connection with atopy¹⁰. From the start of the twentieth century, several descriptive surveys have documented the relationship between keratoconus and atopy¹¹. In addition, Keratoconus was identified in several different clinical studies. It may be an isolated sporadic disorder, or it may be combined with other uncommon hereditary diseases as well as with Down syndrome, connective tissue diseases, Leber's congenital amaurosis, hard contact lens wear, eye rubbing, and a strong family history of the condition¹².

An association has been established between atopy and keratoconus for over 50 years, but several clinical studies have reported opposite findings. In studies carried out about 30 years ago, in 59 percent of keratoconus cases, an increased level of serum immunoglobulin E was observed. Nevertheless, as many of the people with allergic eye conditions rub their eyes vigorously, it has remained uncertain whether atopy itself or eye rubbing is the keratoconus-related cause. Harrison et al demonstrated that the condition occurs more often on the dominant hand side in atopic keratoconus cases. A case-control study published in 2000 by Bawazeer et al showed that there was an association between atopy and keratoconus, in addition to eye rubbing and keratoconus family history, in the univariate association;and demonstrated that only eye rubbing was still a strong indicator of keratoconus, in the multivariate study. They clarified that atopy may lead to keratoconus disease but most likely was a result of eye rubbing combined with atopy irritation¹³. Our study aims to estimate the prevalence of atopy and its associated factors among keratoconus patients in the Jazan region.

In determining the associated factors of keratoconus patients (Fig. 1), the findings are consistent with previous studies. Demographic characteristic and ocular parameters of keratoconus study participants is shown in Table 1. Among the genetic and environmental factors causing keratoconus, the family history was a significant determiner, with a p-value of < 0.001. Furthermore, keratoconus patients reporting eye rubbing had a p-value of 0.015, indicating a high chance of suffering from Atopic syndrome (Table 2 and Table 3). However, the risk of atopic syndrome among keratoconus patients depending on gender was not statistically significant (p-value of 0.082), and its presence was not of statistical significance on the severity of keratoconus (p-value of 0.743) either, although a significant number of patients diagnosed with atopic conditions are at risk of keratoconus. 25.5% of patients diagnosed with any atopic condition were diagnosed with keratoconus, the highest being among patients with dermatitis (7.1%), asthma (11.2%) and hay fever (13.3%). Lastly, Fig. 3 indicates an insignificant correlation between central corneal thickness (CCT) and the frequency of eye rubbing.

Table 1

Demographic characteristic and ocular parameters of keratoconus subjects.
Characteristic		N	%
Gender	Male	49	50.0
Gender	Female	49	50.0
Age Groups (years)	Less than 18	12	12.2
	18–24	27	27.6
	25–34	41	41.8
	35–49	18	18.4
Nationality	Saudi	92	93.9
Nationality	Non- Saudi	6	6.1
Educational Level	Primary	20	20.4
	Intermediate	10	10.2
	Secondary	20	20.4
	University and Postgraduate	48	49.0
Occupational Status	Students	27	27.6
	Governmental employees	18	18.4
	Private Sector employees	10	10.2
	unemployed	35	35.7
	House wife	8	8.2
Monthly Income (SR)	Less than 5000	45	45.9
	5000 to less than 10000	36	36.7
	10000 to less than 150000	11	11.2
	15000 and more	6	6.1
Marital Status	Single	62	64.6
Marital Status	Married	34	35.4
Tobacco use	Yes	9	9.2
Tobacco use	No	89	90.8
Any chronic Conditions	Yes	20	20.4
Any chronic Conditions	No	78	79.6
Descriptive ocular parameters	Total # of Eyes examined	196	100
	Corneal thickness < 500 µm	84	85.7
	n (subjects)	98	100
		Mean (SD)	MIN-Max
	Patient ages (years)	26.7(8.2)	8–48
	Duration of Keratoconus	5.5(6.0)	1–35
	CCT(Right)	457.6(67.4)	229–642
	CCT(left)	452.2(83.6)	32–655
	BDVA, decimal (Right)	044(0.33)	0.03-1
	BDVA, decimal (Left)	0.39(0.31)	0.05-1
Abbreviations: CCT = Central corneal thickness; BDVA = Best distance visual acuity; SD = Standard deviation; SR = Saudi Riyal; Min = Minimum value ; Max = Maximum value

Table 2

Characteristics of Keratoconus among the studied patients.
		Keratoconus			p value
		Right Eye	Left Eye	Both	p value
Gender	Male	6(12.2)	7(14.3)	36(73.5)	0.705
Gender	Female	8(16.3)	9(18.4)	32(65.3)	0.705
Nationality	Saudi	12(13.0)	13(14.1)	67(72.8)	0.016
Nationality	Non-Saudi	2(33.3)	3(50.0)	1(16.7)	0.016
Age Groups	Less than 18	2(16.7)	2(16.7)	8(66.7)	0.850
	18–24	3(11.1)	6(22.2)	18(66.7)
	25–34	6(14.6)	4(9.8)	31(75.6)
	35–49	3(16.7)	4(22.2)	11(61.1)
Marital Status	Single	10(16.1)	11(17.7)	41(66.1)	0.607
Marital Status	Married	4(11.8)	4(11.8)	26(76.5)	0.607
Duration of Keratoconus (years)	One year or less	3(15.0)	5(25.0)	12(60.0)	0.317
	2–4	7(19.4)	4(11.1)	25(69.4)
	5–9	2(8.0)	2(8.0)	21(84.0)
	Ten or more	2(11.8)	5(29.4)	10(58.8)
Blurred vision	Yes	2(8.7)	2(8.7)	19(82.6)	0.313
Blurred vision	No	12(16.0)	14(18.7)	49(65.3)	0.313
Had a corneal transplant	Yes	0(0.0)	1(33.3)	2(66.7)	0670
Had a corneal transplant	No	14(14.7)	15(15.8)	66(69.5)	0670
Change the measurements of your glasses and/ or lenses frequently	Yes	8(17.8)	6(13.3)	31(68.9)	0.549
	NO	6(11.3)	10(18.9)	37(69.8)	0.549
Severity of Keratoconus	Stage I	3(8.6)	3(8.6)	29(82.9)	0.060
	Stage II	1(3.6)	8(28.6)	19(67.9)
	Stage III	3(33.3)	2(22.2)	4(44.4)
	Stage IV	2(15.4)	2(15.4)	9(69.2)
● p-value based on Fisher exact test

Table 3

Atopic syndrome among keratoconus patients.
	Atopic keratoconus patients			p-value
	Atopic patients/ keratoconus Patients	Proportion	95% C.I.	p-value
Gender				0.082
Male	16/49	32.7	21.2–46.7
Female	9/49	18.4	10.0-31.4
Nationality				0.162
Saudi	25/92	27.2	19.1–37.1
Non-Saudi	0/6	0.0	-
Age Groups				0.026
Less than 18	3/12	25.0	9.1–53.8
18–24	2/27	7.4	2.3–23.5
25–34	16/41	39.0	25.6–54.4
35–49	4/18	22.2	9.4–45.6
Family History of Atopy				< 0.001
Yes	16/29	55.2	37.4–71.6
No	8/67	11.9	6.2–21.9
Eye rubbing#				0.015
Yes	21/61	34.4	23.7–47.0
NO	4/36	11.1	4.5–25.4
Severity of Keratoconus				0.743
Stage I	9/35	25.7	14.2–42.2
Stage II	9/28	32.1	17.9–50.8
Stage III	2/9	22.2	6.7–55.6
Stage IV	2/13	15.4	4.7–42.8
Overall	22/85	25.9	17.8–36.1
● p-value based on Fisher exact test ● patient self-reporting

The results of the study provide support for previous studies and conclude that the etiology of keratoconus is multifactorial and includes genetic and environmental factors. In this study, demographic attributes including gender, age groups and marital status had no statistical significance in the development of keratoconus. However, in line with findings from previous multiple studies, family history is a significant risk factor for keratoconus. There is a strong association between keratoconus and parental consanguinity/ endogamy, which suggests a strong genetic component to the etiology of keratoconus¹⁴.The establishment of a family pedigree determines the factor with the strongest influence between genetics and environmental¹⁵.

Furthermore, this study concurs that environmental factors including excessive eye rubbing and the presence of allergic disorders may contribute to keratoconus. As Figs. 1 and 2 indicate, over 75% of patients with keratoconus have an allergic disorder, especially dermatitis, hay fever or asthma. An estimated one third of patients diagnosed with keratoconus reported an allergic disorder¹³, although the allergic disorder is likely the cause of the increased frequency of eye rubbing, which aggravates the injuries to the cornea. In Fig. 3, the frequency of eye rubbing determines the thickness of the cornea. Similarly, while eye rubbing has no statistical significance to the etiology of keratoconus, it may act as a trigger to a significant number of predisposed individuals¹⁵. Thus, despite eye rubbing not being a direct contributor to the development of keratoconus, it most likely aggravates its progression.

There is still no definite cause of the etiology of keratoconus. Keratoconus is mainly a result of multifactorial factors including genetic and environmental. In genetics, a change in multiple genes is the likely cause for the development of keratoconus, and a combination of genetic and environmental factors are the leading cause of the development of keratoconus among a significant number of individuals. Family history is the most influential factor, with those individuals having a relative diagnosed with keratoconus being at a higher risk of keratoconus than those without one.

Significance of the research

The research was considered as a database for this type of research so as to identify the risk factors to avoid them and improve treatment in the future.

The design of the study is cross-sectional study. The data were collected from people in the Jazan region visiting ophthalmology clinics in PMNH after getting their permission. Data collection started in August 2020 and ended in mid June 2021.

The area where the study was carried out is Prince Muhammad bin Nasser Hospital: a government hospital that has 200 beds and holds Tumor and Hematology, Eye, and Heart centers; as well as general clinics; the children's department, the women's department, the internal department, the general surgery department, cardiac surgery, intensive care and operations; and the Oncology and Hematology department, which alone holds 29 beds for inpatients in addition to 34 beds dedicated to the day clinic for chemotherapy. The average number of daily visits is 25 cases, and the rate of follow-up and treatment cases was 700 cases during the year of this study.

The prevalence of keratoconus varies worldwide but it generally ranges from 0.0003–5%^1,2. Many studies in KSA have produced different prevalence rates in different geographical areas. A recent Saudi study reported a prevalence of KC in 4.79% of Saudi patients (6–21 years)³. Building on this estimate and using a cross-sectional study survey formula, the initial sample size used was of 76 patients. The other parameters used for sample size calculation were 95% CI and errors not more than 5%.

The inclusion criteria includes people who visited ophthalmology clinics, and have files in PMNH in Jazan during the study period, filled out a questionnaire with informed consent.

Exclusion criteria are Corneal pathologies other than keratoconus and prior corneal surgery.

Convenience sampling technique was conducted from 2019 to 2021.

Data was collected using a pre-designed questionnaire that included three sections. The first section included an introduction. The second section included items on demographic data, smoking, presence of chronic diseases, questions on the presence of any allergic disease, methods of treatment and duration, as well as items on eye health such as the presence of keratoconus and its duration, management, eye rubbing and its triggers. The third section included eye measurements and stages of severity.

Questionnaire items were derived from previous studies that assessed causes, risk factors of keratoconus and its relation to allergy^1,2,3,4,5. The questionnaire data were collected from patients after getting their permission, As no previous studies have been done using an Arabic-validated questionnaire, the questionnaire items were translated to Arabic by a health care physician and an expert translator fluent in both English and Arabic. The Arabic questionnaire was back-translated to English by another two experts who are fluent in both languages and were blinded to the original English version of that questionnaire. Then the back-translated version was also compared with the original English one to check the translation quality.

All data collected were analyzed using the Statistical Package for the Social Sciences (SPSS) software. Data were cleaned and entered into SPSS. Descriptive statistics were also calculated for these study variables (e.g., the percentage for qualitative variables, frequency, and mean and standard deviation for quantitative variables). The appropriate tests of significance, (e.g., chi Square), were finally applied and P-values of less than 0.05 were considered statistically significant. All the required Ethical approvals were obtained from The Institute Review Board (IRB) of Jazan hospital.

Data availability

All data generated or analysed during this study are included in this published article.

Ethics approval and consent to participate

This study was approved by The Jazan Health Ethics Committee, Approval number : No. 2052 dated 08/12/2020. In the current study, all methods were performed in accordance with the relevant guidelines and regulations.

Consent for publication
Not applicable

Competing interests

The authors have declared that no competing interests exist.

Fundin

The authors confirms that this research received no specific grant or funding.

Author’s Contribution

Ismail Ibrahim Abuallut: Writing of original draft, publication, conceptualization, methodology, investigation, project administration.

Abeer Rihan Alomaish, Alshaymaa Mohammad Arishy, Kholod Hadi Alfaifi, Noura Ali Alnamazi, Aisha Mansour Moafa, Abdulaziz A. Alagsam: Data collection, revision, investigation.

Mariam Asiri Mashragi, Majid A. Moafa, Sultan A. jafaari: Literature review, writing review and editing.

Mohamed S. Mahfouz : Analysis, conceptualization, Review manuscript

Mohammad A. Jareebi: Data Analysis, visualization.

Acknowledgments

The authors are grateful to all participating patients and their families. We would like to acknowledge the contributions of all personnel at the Department of ophthalmology ,located at prin mohammad bin nasser Hospital, Jazan, Saudi Arabia.

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No competing interests reported.

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A cross-sectional study to evaluate predisposing factors for keratoconus in Saudi Arabia

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