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Review Article

The Enigma of Environmental Factors in Keratoconus

Crawford, Alexandra Z. MBChB, MD∗,†; Zhang, Jie PhD; Gokul, Akilesh BOptom (Hons), PhD; McGhee, Charles N.J. DSc, FRCOphth∗,†; Ormonde, Sue E. MD, FRCOphth∗,†

Author Information
Asia-Pacific Journal of Ophthalmology: November-December 2020 - Volume 9 - Issue 6 - p 549-556
doi: 10.1097/APO.0000000000000334
  • Open

Abstract

INTRODUCTION

Definition

Keratoconus is a disorder in which the shape of the cornea becomes conical, inducing myopia, irregular astigmatism, protrusion, and vision impairment.1–3 Onset is usually at puberty, progressing to the third or fourth decade, but can also be later in life.1 A global survey of experts agreed that the essential features for diagnosis of keratoconus include posterior ectasia, abnormal corneal thickness distribution, and clinical noninflammatory corneal thinning.4 The exact values of parameters vary based on the topography or tomography machine used and the purpose (screening vs treating).4 Keratoconus should be classified as an “ectatic disease” instead of a “thinning disorder.” Experts agreed that true unilateral keratoconus does not exist.4 There is no primary pathophysiologic explanation for keratoconus.2–4

Prevalence

A meta-analysis of data from 15 countries calculated a global prevalence of 138/100,000 for keratoconus; however, the prevalence varies greatly by geographic area.5 Summarizing general population-based studies, which are more precise compared to hospital-based studies, countries ranked from the lowest to highest prevalence per 100,000 people are as follows: Russia (0.3), Finland (30), South Korea (37.4), Denmark (44 or 85), US (54.5), Netherlands (265), China (900), France (1190), Palestine (1500), Iran (760, 2500, 3300), India (2300), Israel (2340), and Lebanon (3300).6 Pediatric population-based studies yield higher prevalence because of the low age of onset of keratoconus. In New Zealand, a paediatric (high school student) population-based study estimated that people of Māori descent (2250/100,000) have a prevalence 4 times higher than the general population (520/100,000).7 Interestingly, this is reflected in corneal transplantation rates which highlight over-representation of Māori and Pasifika in Aotearoa/New Zealand.8

Hospital-based studies tend to yield lower prevalence because of selection bias, only including symptomatic patients and omitting asymptomatic patients in the community. In a hospital study from the UK, Asians (Indian, Pakistani, Bangladeshi, other Asians) had 4 times higher prevalence (229 vs 57/100,000) compared to the white population.9 The highest prevalence for keratoconus is reported from a hospital paediatric population-based study in Saudi Arabia (4790/100,000).10 Overall, the prevalence of keratoconus varies by country and ethnicity, with the Middle East, Indian subcontinent, and Māori populations having higher prevalence than Whites and East Asians.6

Comorbidities

Keratoconus is associated with many diseases including connective tissue diseases, with particularly strong associations with mitral valve prolapse and Ehlers-Danlos syndrome.2,11,12 Floppy eyelid syndrome and vernal keratoconjunctivitis are strongly associated.6,13 Tourette syndrome with obsessive-compulsive eye rubbing is also linked.14 Obesity and obstructive sleep apnea are more frequently found in the keratoconic population than the general population.15,16 Diabetes may be protective for keratoconus.17,18

Management

The nonsurgical management of ectasia aims to halt disease progression and includes guidance regarding avoidance of eye-rubbing and the use of topical antiallergic medications and lubricants to reduce itch and increase ocular comfort. Surgical prevention of progressive ectasia can be achieved with corneal collagen cross-linking.3

Methods of vision rehabilitation depend on the severity of keratoconus and include spectacles, soft contact lenses, intrapalpebral rigid gas permeable contact lenses, hybrid contact lenses, and scleral contact lenses. Once these options have been exhausted, surgical options include intrastromal corneal ring segments, deep anterior lamellar keratoplasty, and penetrating keratoplasty.3,4

ETIOLOGY

A “2-hit” hypothesis is generally considered in keratoconus, that is, that a genetic predisposition in association with an environmental event is required to trigger progressive keratoconus.2,19–21 Clearly defining possible causes and triggers is difficult due to the many confounding variables. The genetics of keratoconus is not clearly understood, and studies assessing this are often influenced by factors such as UV exposure, geographic location, eye rubbing, atopy, and contact lens wear. Similarly, studies of the effect of UV exposure are influenced by variations in ethnic background and consanguinity.

The molecular pathways responsible for the pathology of keratoconus have been proposed to involve multiple factors including inflammation and oxidative stress, keratocyte apoptosis, epithelial-stromal interactions, and extracellular matrix degradation/thinning/ectasia, although the evidence remains far from conclusive.2 Although traditionally defined as a noninflammatory condition, current evidence confirms the presence of ocular surface inflammation in keratoconus.22 Notably, the levels of a number of pro-inflammatory molecules have been demonstrated to be elevated in keratoconic corneas, including interleukin-1 (IL-1), IL-6, matrix degrading enzyme matrix metalloproteinase-9 (MMP-9), transforming growth factor-beta (TGF-β), and tumor necrosis factor-alpha (TNF-α).22–24

Increased leukocyte infiltration in the corneal stroma is also evident in keratoconus.25 It has also been suggested that increased oxidative stress could result from increased expression of inducible nitric oxide synthase, decreased activity of superoxide dismutase, and altered levels of aldehyde dehydrogenase class 3 enzyme in keratoconic eyes.26–28

Ultimately, the association of keratoconus with connective tissue diseases, atopy, and obesity suggests that this multifactorial disease may, at least in part, be a local manifestation of systemic disease.6,29

Genetics

Genes

The proportion of keratoconus patients with a family history ranges between 5% in Scotland and 28% in Turkey, with most studies estimating between 10% and 25%.30 Most familial keratoconus appears to be autosomal dominant with incomplete penetrance, but an autosomal recessive pattern has also been suggested.31 In addition, keratoconus is associated with >20 genetic syndromes such as Down Syndrome, Marfan syndrome, and Ehlers-Danlos syndrome.31

Keratoconus is genetically complex and heterogenous; therefore, identification of genetic factors through linkage and candidate gene studies has been challenging. Linkage studies have identified >19 chromosome loci with significant or suggested linkages to keratoconus,30,32 including variations in microRNA 184, DOCK9 (dedicator of cytokinesis 9), and LOX (collagen crosslinking lysyl oxidase). The physiological relevance of microRNA 184 and DOCK9 to keratoconus remains unclear.31 Candidate gene studies have been performed on a large number of genes, with the 2 that have gathered most interest being VSX1 (visual system homeobox 1) and SOD1 (superoxide dismutase 1). VSX1 was proposed as a candidate gene for keratoconus due to its linkage to posterior polymorphous corneal dystrophy, and its involvement was originally supported by multiple studies.30 However, VXS1 linkages to keratoconus remain controversial with accumulating evidence suggesting that it does not contribute to keratoconus.30 Located on chromosome 21, SOD1 linkage to keratoconus was proposed due to the association between keratoconus and Down Syndrome (Trisomy 21). However, despite multiple studies, disease-causing variants in the coding region have yet to be identified.30 Notably, rare missense mutations in the zinc finger protein gene ZNF469, which predispose to corneal thinness and may contribute to keratoconus per se, have been noted in 33% of a keratoconus population.33,34

More recently, 3 genome-wide association studies using large sample sizes suggested association of RAB3GAP1 (RAB3 GTPase activating protein subunit 1)35 and HGF (hepatocyte growth factor) to keratoconus,36 and found a significant association of PNPLA2 (patatin-like phospholipase domain-containing 2) to keratoconus.37 In addition, variations in >30 genes have been found to be associated with central corneal thickness by genome-wide association, 11 showing nominal association with keratoconus.31,32 Therefore, the genetics of keratoconus is still poorly understood, and requires larger collaborative studies that account for ethnicity and/or other factors using advanced genomic techniques, before we may see breakthroughs in the future.30

Consanguinity

An association between keratoconus and consanguinity has been suggested in several studies,20,38,39 and countries with high rates of keratoconus including Palestine, Iran, India, Israel, and Lebanon6 have a tradition of consanguinity, especially within their Muslim communities.40 A study of 70 keratoconic patients and 140 controls in Israel in 2013 looked at several risk factors including a questionnaire about their parents’ relationship. Multivariate analyses showed that first-cousin and second-cousin consanguinity confers a 4-fold risk factor for developing keratoconus, and the risk is much higher for first cousins than second cousins.41 Although a family history of keratoconus in Western countries suggests an autosomal dominant inheritance,20,42 the studies demonstrating keratoconus in consanguineous relationships suggest an additional autosomal recessive inheritance pattern. These genetic differences may be a factor in some of the geographical variations in the prevalence of keratoconus.

Environmental Factors

Eye Rubbing

Eye rubbing has been implicated as a significant independent risk factor in the development of keratoconus.43–45 A recent meta-analysis reported that the odds ratio of developing keratoconus was 3 times higher in habitual eye rubbers compared with non-eye rubbers.5 Eye rubbing is reported in around half of keratoconic patients.32 Keratoconus is usually bilateral, although frequently asymmetrical, and the role of eye rubbing is given further emphasis by reports of unilateral keratoconus developing in response to unilateral eye rubbing.43 The corollary is that conditions that segue into eye rubbing may also make patients more susceptible to keratoconus. These conditions include ocular allergy, dry eye, blepharitis, eye strain, night-time work, and “computer vision syndrome.”43

Keratoconic patients typically rub their eyes more vigorously and for much longer (from 10 to 180 seconds) than patients without any eye conditions (<5 seconds), and rubbing is often repeated.32,46 The pattern of eye rubbing may also be important, with knuckle rubbing more strongly associated with keratoconus than rubbing with the pulps of the fingers.43 Keratoconic patients tend to rub in a circular motion exerting direct pressure on the central cornea, as opposed to allergic patients who rub their eyes horizontally using the back of the hand/palm/finger pad and do not exert direct pressure on the cornea.29 Rubbing beneath the eyes has not been shown to be associated with keratoconus.43

Eye rubbing has been shown to induce immediate inflammatory cell infiltration, release of inflammatory molecules and matrix metalloproteinases in the tear film, epithelial thinning, keratocyte apoptosis, reduction in tear film break-up time, and keratometry changes. Early animal studies emulating 5 minutes of “keratoconic rubbing” demonstrated significant neutrophil and macrophage infiltration in the conjunctiva that lasted between 4 and 24 hours, after initial conjunctival vascular injection and surface alterations.47–49 In human studies, light to moderate rubbing for 15 seconds produced an immediate 18% reduction in corneal epithelial thickness in normal subjects, and took 15 to 45 minutes to recover, suggesting epithelial trauma.50 Repeated light rubbing (30 times over 30 minutes, 10 seconds each) of eyes in normal subjects is sufficient to cause elevated levels of epidermal growth factor and IL-8 in the tear film, and a 2% to 3% loss of keratocytes in the anterior and posterior stroma.51 Therefore, even gentle or short duration eye rubbing can induce corneal epithelial modifications, inflammation, and cell loss in the cornea. Moderate rubbing for 60 seconds produces elevated levels of MMP-13, IL-6, and TNF-α.29 Eye rubbing for 2 minutes using fingertips in healthy subjects induces reduction in tear film break-up time and anterior keratometry changes with a trend toward against-the-rule astigmatism.52

Eye rubbing has also been proposed to induce keratoconic changes through other mechanisms. Eye indentation from finger pressure and eyelid closure can also cause significant transient elevations in intraocular pressure (IOP).48 The area of cornea at the point of indentation may be squeezed between compressive rubbing forces and distending IOP, with the corneal apex exposed to the highest compressive forces.48 However, the evidence for IOP-related changes in keratocytes is still lacking. Such IOP spikes appear to only affect the cornea if they last for longer than 15 to 20 seconds, are repeated frequently, are at least double the IOP, happen over many years, and depend on corneal thinning or other changes in the cornea to induce cone formation.48 Therefore, elevated IOP alone may be more relevant for keratoconus progression rather than development. Other potential mechanisms of rubbing-induced corneal changes include increased corneal temperature, epithelial-stromal interactions, loss of rigidity and viscosity, and curvature transfer. These are yet to be confirmed experimentally.48

Ocular allergic conditions induce ocular inflammation by definition and can prolong the effects of eye rubbing. The level of MMP-9 in keratoconic patients with seasonal allergic conjunctivitis has been demonstrated to be 1.5 times higher than in keratoconic patients without allergy, which was in turn 1.5 times higher than the level in normal individuals.53 The level of MMP-9 correlates with keratoconus stage.53 In a study of feline-sensitive individuals, the effects of eye rubbing, including itching, chemosis, and hyperemia, were prolonged by exposure to feline dander, and the symptoms were further exacerbated by increased duration and intensity of rubbing.54 Furthermore, moderate rubbing alone is able to induce itch, which can cause further rubbing, forming a vicious cycle.54

Atopy

Atopy refers to the tendency to develop an exaggerated IgE-mediated immune response. Allergic bronchial asthma and allergic rhinitis (hay fever) are the most common manifestations of atopy, followed by atopic dermatitis (eczema) and food allergy. Atopic traits are more common in individuals with keratoconus compared with the general population,44 and there is some evidence to suggest that keratoconus manifests at a younger age in patients with atopic traits.55 Furthermore, differences in corneal topographic and pachymetric characteristics have been demonstrated in atopic keratoconic eyes compared with non-atopic keratoconic eyes.56 Collagenolysis mediated by leukocyte-derived enzymes is a proposed mechanism linking atopy/inflammation, and the development and progression of keratoconus.6

However, the independent (contributory) role of atopy in the development of keratoconus is controversial as it is difficult to extricate it from its association with eye rubbing. This is further compounded by discrepancies in the definition of atopy and differences in the severity of the atopic conditions. What is incontrovertible though is that allergy is an important cause of eye rubbing and is therefore in the multifactorial causal pathway of keratoconus.5

Floppy Eyelid Syndrome

Floppy eyelid syndrome is a well-established association of keratoconus13,57; however, the mechanism behind its contribution to the development of keratoconus is not fully understood. An interesting observation is that MMP-9 is also elevated on the ocular surface in floppy eyelid syndrome which may be the underlying mechanism of the development of keratoconus.58 Furthermore, floppy eyelid syndrome often results in dry eye including elevated tear evaporation rate and delayed tear clearance,59,60 an inherently inflammatory condition, and it has become increasingly apparent that inflammation is implicated in keratoconus development.

Contact Lens Wear

Contact lenses have been a cornerstone in providing visual rehabilitation for keratoconus for >100 years.61 However, contact lens wear has also been implicated in the development and progression of keratoconus for >50 years.62

The mechanical stimulation of the cornea by a contact lens can be considered micro-trauma, which through a complex relationship between inflammatory mediators such as IL-1 and apoptotic mediators such as the Fas-Fas ligand receptor, has been suggested to play a role in keratocyte apoptosis in keratoconus.63,64 Contact lens wear [soft hydrogel and rigid gas permeable (RGP)] and the associated mechanical stimulation to the cornea have been demonstrated to induce release of inflammatory molecules and MMPs in the tear film of normal subjects in many studies.65 Interestingly, the level of inflammatory molecules and MMPs correlates with the degree of myopia correction in orthokeratology lens wearers, suggesting their roles in corneal remodelling.65

Contact lens wear for 2 hours has been shown to induce a 2% to 3% reduction in anterior and posterior keratocyte density, compared to control eyes exposed to the same anoxic environment.51 Contact lens-induced keratocyte apoptosis has also been implicated in studies using in vivo confocal microscopy. These studies demonstrate that anterior keratocyte density is reduced in patients with keratoconus who wear contact lenses, significantly more so than those who do not.66–68 Furthermore, in vivo confocal microscopy has elucidated that sub-basal corneal nerve density is reduced in keratoconus,69,70 and sub-basal nerve density can be reduced by contact lens wear, although these changes can occur in control subjects wearing contact lenses for ametropia.71 Furthermore, orthokeratology, which utilizes a contact lens designed to mould the shape of the cornea, produces a significant and sustained reduction in sub-basal nerve density.72,73 Currently, the evidence is unclear as to whether these alterations in keratoconus are exacerbated by contact lens wear or are simply ongoing microstructural change secondary to the keratoconus disease process.

Contact lens wear is known to induce or exacerbate dry eye signs and symptoms. This has unique implications for keratoconus due to dry eye being inflammatory in nature. There is a suggestion that clinical measures of dry eye disease such as tear break-up time are affected by contact lens wear for keratoconus compared to control contact lens wearers.74,75 Contact lens wear has been demonstrated to increase eye rubbing over and above that of patients with keratoconus that do not wear contact lenses, which is thought to be in part caused by contact lens-related dry eye.76

Tear film inflammatory markers are elevated in keratoconus, and there is some evidence that some markers (including tissue inhibitors of metalloproteinases) are further elevated in contact lens-wearing patients with keratoconus compared to noncontact lens wearers.77 The increase in tear film inflammatory markers in contact lens wear is likely due to a combination of microtrauma and dry eye. Long-term (>1 year) soft or RGP lens wear results in a reduction in antibacterial enzyme lysozyme, an increase in pro-inflammatory protein S100A8, and changes in proteolytic attack modulator cystatin in the tear film compared to nonwearers.51 In long-term myopic RGP contact lens wearers (average 9 years), the tear levels of TNF-α and MMP-9 are at least double that of nonwearers.78 Keratoconic RGP lens wearers also have at least double the levels of IL-6, TNF-α, and cell adhesion molecules ICAM-1 and VCAM-1 compared to nonwearers, but whether the changes are caused by keratoconus or lens wear cannot be established.78 A positive correlation between MMP-13 levels in the tear film and keratoconus severity has been demonstrated,79 and MMP-13 levels have also been shown to be elevated by contact lens wear and eye rubbing.29,80

Overall, contemporary evidence suggests that contact lens wear modifies the surface of the cornea to a pro-inflammatory and matrix-degrading environment, induces keratocyte loss, and potentially induces stromal matrix remodeling, and thus may predispose to keratoconus development and/or progression in susceptible subjects.81 Ultimately, we have a potentially contributory pathogenic mechanism, and progression of keratoconus certainly occurs in those wearing contact lenses, often requiring regular update of contact lens fit.82 However, ongoing progression of keratoconus also occurs mid to later life in those who have relatively mild disease and have never worn contact lenses!83 This leaves the conundrum that keratoconus is a typically progressive disease that is often managed with contact lenses but progresses with or without contact lens wear; thus, the contribution of possible pathogenic contact lens-related phenomena remains speculative.

UV Exposure

The role of ultraviolet light (UV) exposure and keratoconus is not clearly understood, and the hypothesis of a causal relationship has been mainly epidemiology-driven. On the one hand, there is a higher prevalence of keratoconus in countries with hot and sunny climates such as India84 and the Middle East85 compared to countries with cooler climates and less sunshine such as Finland,86 Minnesota, USA,87 and Denmark.88 Excessive UV light may lead to oxidative stress in the cornea, which is exacerbated by the reduced amounts of superoxide dismutase and aldehyde dehydrogenase class 3 enzymes necessary to remove reactive oxygen species in keratoconic corneas.28 On the other hand, UV light is utilized during cross-linking treatment to stabilize progressive keraotoconus.89 Cross-linking involves soaking the cornea in riboflavin, and then exposing the cornea to a measured dose of UVA (370 nm) radiation. Riboflavin with an absorption peak of 366 nm acts as a photosensitizer, and during the photosensitization process free radicals are produced which result in a reaction where covalent bonds are formed between collagen molecules, thus strengthening the cornea.90

A case–control study of 73 keratoconic patients in Israel in 2015 analyzed sun exposure behavior during teenage years, and found that wearing a hat outdoors appeared to be protective, whereas limiting time in the sun and wearing sunglasses showed no association.91 A different case–control study of 70 keratoconic patients in Israel in 2013 by the same author, however, indicated that not wearing sunglasses was a significant risk factor for developing keratoconus.41 The author concluded that sun exposure in the pathogenesis of keratoconus is still unclear and warrants further research.

Although experiments in mice and rabbits have demonstrated that UV exposure leads to keratocyte apoptosis, stromal collagen degeneration, and corneal thinning, the development of keratoconus has not been observed in these animal models.92,93

It is difficult to study the specific effect of UV exposure in any given location because of the many confounding factors, including ethnic background and genetic influence. A study of keratoconic patients in Dewsbury, UK, which has a cool and cloudy climate, found that patients of Northern Pakistani origin were significantly more likely to present with keratoconus than white patients (7.5 times higher prevalence), despite having the same UV exposure.39 A study of keratoconic patients in Tehran, Iran (formerly Persia), which has a hot and sunny climate, reported a 7.9% keratoconus prevalence in non-Persians compared to a 2.5% prevalence in Persians.94

Cigarette Smoking

Cigarette smoke as a factor has been demonstrated to be either negatively associated or not associated with keratoconus in two independent studies.84,95 In a study of 180 keratoconic patients undergoing corneal collagen cross-linking, a significant correlation was found between nonsmokers and keratoconus, and the authors postulated that the by-products of cigarette smoke may lead to a beneficial cross-linking effect in the cornea.95

Personality

The existence of a particular “keratoconus personality” has long been mused upon by ophthalmologists. A behavioral profile of keratoconic patients typically includes descriptions such as “unusual,” “bizarre,” “demanding,” “untrusting,” and even “paranoid.”96 The question therefore arises: are personality and keratoconus causally linked, or does the keratoconus experience shape an individual's personality?

There are reports of comorbidity between patients affected with keratoconus and mental illness, in particular schizophrenia.6 It has been hypothesized that keratoconus is a consequence of neuroimmune dysregulation which also affects the brain; however, supporting evidence is lacking.6 Furthermore, chronic eye rubbing induced by compulsive behavior and psychiatric disorders can be associated with keratoconus.6

A recent review of the literature concluded that there is no evidence to support the perception of a unique “keratoconic personality.”97 The authors proposed that patients with keratoconus evolve maladaptive coping mechanisms as the onset of keratoconus at a young age coincides with a vulnerable period of psychosocial development.97 They further speculated that treatment providers may fail to recognize the disease burden on the patient's vision and livelihood. The development of pathological coping mechanisms combined with a perceived lack of empathy from their treatment provider may result in an altered therapeutic relationship, which in turn gives rise to the impression of a “difficult” keratoconic personality.

Sex

The influence of sex on keratoconus has been variably reported, with some studies describing a male and others a female preponderance. However, according to a recent meta-analysis, there is currently no evidence to support a gender predilection in keratoconus.5 It has been suggested that the age of onset of keratoconus differs in male and female patients, and differences in the age range of the study population may account for the incongruities between studies.5

Pregnancy

It has been proposed that hormonal changes during pregnancy can affect corneal biomechanical properties and thickness, which may result in keratoconus exacerbation and progression.98 A prospective cohort study has reported that pregnant women with keratoconus demonstrated significant progression when compared with a control group.98

Thyroid Hormones

There is increasing support for the involvement of thyroid hormones in keratoconus. A population study in Germany found an increased prevalence of thyroid gland disease (13.6%) in a keratoconic population of 154 versus the general population (2%).99 This group comprised 19 with hypothyroidism and 2 with hyperthyroidism. The levels of the thyroid hormone thyroxine in the tear film was 3 to 4 times higher in keratoconic patients with thyroid gland diseases compared to normal controls, and more importantly, keratoconic patients without thyroid diseases had similarly elevated levels of thyroxine.99 Thyroxine level affects collagen production in monkey corneal stromal organ cultures, and its accumulation in the tear film despite low serum thyroxine levels in keratoconus/hypothyroidism patients suggests a low metabolic demand for tear thyroxine in the stroma due to low collagen production.99 A recent report of bilateral keratoconic development in the sixth decade after hypothyroidism development offers more direct support for the involvement of thyroid diseases in KC.100

SUMMARY AND CONCLUSIONS

Keratoconus is a multifactorial disease that is likely caused by a genetic predisposition and a “second-hit” by environmental factors. Its prevalence varies greatly by country or geographical region. Ethnicity and consanguinity appear to be important determinants for these variations. The genetic variations associated with keratoconus are far from being fully understood and are only just beginning to be uncovered by genome-wide association studies.

Environmental factors including eye rubbing, atopy, floppy eyelid syndrome, contact lens wear, pregnancy, and thyroid hormones have been shown to be associated with keratoconus. Eye rubbing shows the strongest association with keratoconus. It can induce ocular surface inflammation, release of stromal matrix degrading enzymes, epithelial thinning, and keratocyte death consistent with the etiology of keratoconus. Atopy is an important cause of eye rubbing and hence by association with keratoconus, although atopy as an independent factor is not established. Floppy eyelid syndrome causes release of matrix-degrading enzymes and dry eye, which can also induce eye rubbing. Contact lens wear creates ocular surface inflammation, release of matrix degrading enzymes, and keratocyte death, akin to eye rubbing. It also reduces corneal nerve density, induces matrix remodeling, and induces dry eye. However, because contact lens wear is a treatment for keratoconus, it is difficult to study its role in keratoconus progression. Further studies are required to elucidate the molecular pathways involved in keratoconus in pregnancy and with thyroid hormone changes. Other proposed environmental factors that are not readily confirmed on the basis of current evidence include UV exposure, cigarette smoking, personality, and sex. Studying the effects of these factors will require careful dissection from many other confounding factors. Animal studies may allow direct assessment of the effect of individual factors.

In conclusion, despite the progress made, further studies with large sample sizes will be required to truly understand the etiology of keratoconus. Ideally, these will be sufficiently powered to allow multivariate analyses to tease out the role of each affected gene and each environmental factor on keratoconus development and progression.

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Keywords:

contact lens wear; environmental risk factors; eye rubbing; genetics; keratoconus

Copyright © 2020 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.