Hormonal Modulation of Keratoconus: A Systematic Review and Screening Strategy for At-Risk Populations.

Purpose:It was aimed to compare the levels of inflammation-related parameters, such as neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR), in patients with advanced keratoconus (KC) and healthy controls. Also, we evaluated the relationships between these parameters and several corneal topography values used in the KC diagnostic index.Methods:Forty patients with advanced and 40 healthy volunteers were included in this study. In the KC group, 20 patients were nonprogressive KC and 20 patients were progressive KC. In all participating individuals, we evaluated detailed ophthalmologic examination findings and complete blood count data, while corneal topographic measurements were also recorded in patients with KC.Results:The mean NLR value was 2.3 ± 1.19 in the progressive KC group; nonprogressive KC values were 1.99 ± 1.69 and 1.81 ± 0.72 in the control group. Mean PLR value was 113.24 ± 48.44 in the progressive KC group, nonprogressive KC values were 96.47 ± 31.04 and 104.09 ± 35.14 in the control group. No statistically significant difference was found between patients with progressive KC, nonprogressive KC, and healthy volunteers in terms of mean NLR and PLR values (P > 0.05). NLR values were found to demonstrate significant positive correlations with the corneal topography parameters, Symmetry Index front (r = 0.278, P = 0.025), KC Vertex front (r = 0.247, P = 0.048), and Baiocchi Calossi Versaci front (r = 0.273, P = 0.028); there was no significant relationship between corneal topography parameters and PLR values.Conclusion:Although there was no significant difference between the progressive KC, nonprogressive KC, and control groups in inflammation parameters such as NLR and PLR, a positive correlation was observed between the NLR value and some corneal topography findings used in the diagnosis of KC. The role of inflammation in the etiology of KC can be better understood by clinical studies and laboratory tests conducted with prospective studies involving a higher number of patients.

Protective and pathogenic role of collagen subtypes genes COL4A3 and COL4A4 polymorphisms in the onset of keratoconus in South-Asian Pakistani cohort

This comprehensive systematic review addresses how concurrent ocular surface diseases (OSDs) in patients with keratoconus (KC) affect KC's development, progression, diagnostic evaluation, and management, as well as KC's effect on ocular surface disturbance. This review integrates ocular surface findings to bridge the gap between KC pathophysiology and practical clinical management, ultimately offering a structured framework for optimizing KC treatment. This systematic review represents the effort to integrate existing knowledge on the interplay between OSDs and KC, yielding practical clinical guidance. OSDs are not only recognized contributors to KC onset but are also major factors in treatment failure, making their evaluation critical in KC management. A systematic search was conducted in Scopus, PubMed, Cochrane, Embase, and Web of Science for studies published up to February 2025. Studies were included regardless of language, provided they met predefined relevance and quality criteria. Exclusion criteria included replies, commentaries, case studies, retracted studies, ex vivo investigations, and studies scoring low on the A MeaSurement Tool to Assess systematic Reviews (AMSTAR) checklist. This systematic review is registered with PROSPERO (ID: CRD42025644883). Initially, 9572 records were identified; 5337 duplicates were removed, leaving 4235 for screening. After title and abstract review, 576 full texts were assessed, with 372 excluded based on AMSTAR scores or study type, leaving 204 studies. Findings highlight that OSDs significantly affect KC pathogenesis and clinical management. Nonectatic conditions such as dry eye and tear film instability are increasingly included in the differential diagnosis of KC, emphasizing the need for a multidisciplinary approach. OSDs not only contribute to KC progression but also complicate diagnostic interpretations and influence treatment efficacy. The ocular surface plays a pivotal role not only in KC pathogenesis but also in treatment success or failure. Thus, it is important to address concurrent OSDs in patients with KC because they can complicate its course. This is a vital consideration for treatment strategies. However, more studies on the causal link between KC and OSD are needed to help clinicians diagnose and manage these conditions better.

Keratoconus (KC), is a bilateral, noninflammatory degenerative disease of the cornea which is characterized by progressive corneal ectasia and loss of visual function. The onset of KC is commonly seen at puberty and affects approximately 1 in 2000 in the general population. The aim of this study was to assess the clinical profile of keratoconus in the tertiary eye centre in Nepal. It is a retrospective, hospital based, consecutive study from June 2017 to May 2018. A total of 66 patients (114 eyes) were diagnosed cases of Keratoconus presented in Cornea clinic of Tilganga institute of Ophthalmology. Parameters investigated included patients' demography, keratometric readings, visualacuity and manifest refraction. Classification of keratoconus was based on Amslern-Krumeich grading system (modified). The mean age of subjects was 18.73 (range: 10-65). Male/female distribution was 48 (72.7%) and 18 (27.3%) respectively. 48 (72.7%) had bilateral keratoconus and 18 (27.3%) were unilateral. Mean Uncorrected visual acuity (UCVA) was 0.80 (range: 0.01-1.00), mean visual acuity ( VA) with spectacle correction was 0.47 (range: 0.01-1.00). Mean spherical amount of refractive was -2.17 (range: -0.50 to -17.00D) and mean cylindrical amount of refraction was -2.85 (range: 0.00 to -6.00). Mean spherical equivalent (SE) of refraction was -4.26 (range: -0.50 to -22.50D). Mean flattest keratometric reading (K1) was 49.63 (range: 40.63-76.70D) and mean steepest keratometric reading (K2) was 53.14 (range: 41.63-73.21D). Mean average keratometric reading was 51.43 (range: 41.63-72.10D). Regarding disease severity, 35.68% of subjects were classified as mild keratoconus, 29.73% as moderate keratoconus, 9.73% as advance keratoconus, while 24.86% were found with the severestage of keratoconus. 78.9% of total eyes presented with minimum pachymetry of 401 to 500 mm. Clinical profile of Nepalese keratoconus patients looks similar to that reported earlier worldwide. The condition was found to manifest at a younger age and was more common in males.

The etiology of keratoconus (KC) is probably multifactorial but remains essentially unknown. Previous scientific observations have suggested that hypothyroidism might play a role in the development and progression of KC. The purpose of this study was to analyze the tomographic and biomechanical parameters in KC patients with or without hypothyroidism. Twenty-eight patients with KC and hypothyroidism (HT group) and fifty-six KC patients without thyroid dysfunction (WHT group) with matching gender and age were analyzed. Mean age was 40.3 years (range 14 - 57) in the HT group and 40.3 years (range 14 - 57) in the WHT group. Routine ophthalmic examinations consisted of corneal tomography and biomechanical parameters. We extracted the following KC parameters from the Pentacam (Pentacam HR, Oculus, Wetzlar, Germany): Keratoconus Index (KI), maximum keratometry (Kmax), astigmatism, and thinnest pachymetry (TP). From the ocular response analyzer (ORA, Reichert Ophthalmic Instruments, Depew, NY, USA), we extracted corneal hysteresis (CH), corneal resistance factor (CRF), and KC match index (KMI). The comparison of the tomographic and biomechanical values from cross-sectional and longitudinal analyses showed no significant differences between the HT and WHT groups. The severity of KC based on tomographical and biomechanical parameters does not seem to depend on the presence of hypothyroidism.

Objective To observe the therapeutic effects of riboflavin-ultraviolet A (UVA) corneal collagen cross-linking (CXL) performed with a transepithelial method for progressive keratoconus. Methods This was a prospective case series study. Thirty-six patients (54 eyes) with progressive keratoconus who underwent transepithelial corneal collagen cross-linking surgery were reviewed. The procedure was performed under topical anesthesia using a transepithelial corneal collagen cross-linking instrument (SOFT , Italy). riboflavin (0.25%) was imported into the cornea for 10 minutes (current 1.0 mA). The irradiation was performed for 9 minutes using a solid-state UVA illuminator at 370 nm and an irradiance of 10 mW/cm2. The average follow-up time was 14.1±2.3 months. Corneal epithelium healing was observed 1 day after surgery. There were no complications such as corneal ulcer, corneal dissolution, corneal epithelium mist opacity (haze) or severe pain. Uncorrected visual acuity (UCVA) ; best corrected visual acuity (BCVA) ; intraocular pressure ; corneal curvature ; corneal thickness; corneal topography; endothelial cell count; corneal biomechanical properties and in vivo confocal microscopy were evaluated at baseline and at 1, 3, 6, 12 months postoperatively. Data were analyzed using a paired samplest test. Results The day after surgery, the corneal epithelium had opaque spots due to edema but the condition improved by the second day. Postoperative 12 months, UCVA and BCVA increased from 4.27±0.23 to 4.41±0.20 (t=3.962,P<0.01) and from 4.69±0.23 to 4.82±0.14 (t=3.507,P<0.01), respectively. Interim analysis of a flattening of the steepest simulated keratometry value (K-max) and astigmatism by an average of 1.25±0.68 diopters (t=9.351, P<0.01) and 0.30±0.21 diopters (t=7.227, P<0.01) . The deformation amplitude decreased from 1.21±0.11 mm to 1.16±0.12 mm (t=4.131, P<0.01) . Intraocular pressure, endothelial cell count and central corneal thickness did not change significantly. Conclusion Transepithelial corneal collagen cross-linking can significantly control the development of progressive keratoconus and do not have any of the complications that develop from the traditional epithelium-off method. Therefore, the transepithelial corneal collagen cross-linking method is safe and effective, and is expected to replace the traditional epithelium-off method to become the preferred treatment for progressive keratoconus. Key words: Corneal collagen cross-linking; Keratoconus; Transepithelial methods

To assess keratoconus (KC) progression in patients with allergies who also tested positive to surface matrix metalloproteinase 9 (MMP-9) point-of-care test. Prospective comparative study including 100 stage I-II keratoconic patients, mean age 16.7±4.6 years. All patients underwent an anamnestic questionnaire for concomitant allergic diseases and were screened with the MMP-9 point-of-care test. Patients were divided into two groups: patients KC with allergies (KC AL) and patients KC without allergies (KC NAL). Severity of allergy was established by papillary subtarsal response grade and KC progression assessed by Scheimpflug corneal tomography, corrected distance visual acuity (CDVA) measurement in a 12-month follow-up. The KC AL group included 52 patients and the KC NAL group 48. In the KC AL group, 42/52 of patients (81%) were positive to MMP-9 point-of-care test versus two positive patients in the KC NAL group (4%). The KC AL group data showed a statistically significant decrease of average CDVA, from 0.155±0.11 to 0.301±0.2 logarithm of the minimum angle of resolution (P<0.005) at 12 months; Kmax value increased significantly, from 50.2 D±2.7 to 55.2 D±1.9 on average. The KC NAL group revealed a slight KC progression without statistically significant changes. Pearson correlation test showed a high correlation between Kmax worsening and severity of PSR in the KC AL group. The study demonstrated a statistically significant progression of KC in patients with concomitant allergies, positive to MMP-9 point-of-care test versus negative. A high correlation between severity of allergy and KC progression was documented.

Keratoconus (KC) is a corneal thinning dystrophy that leads to visual impairment. While the cause of KC remains poorly understood, changes in sex hormone levels have been correlated with KC development. This study investigated circulating gonadotropin-releasing hormone (GnRH) in control and KC subjects to determine if this master hormone regulator is linked to the KC pathology. Plasma and saliva were collected from KC subjects (n = 227 and n = 274, respectively) and non-KC controls (n = 58 and n = 101, respectively), in concert with patient demographics and clinical features. GnRH levels in both plasma and saliva were significantly lower in KC subjects compared to controls. This finding was retained in plasma when subjects were stratified based on age, sex, and KC severity. Control and KC corneal fibroblasts (HKCs) stimulated with recombinant GnRH protein in vitro revealed significantly increased luteinizing hormone receptor by HKCs and reduced expression of α-smooth muscle actin with treatment suggesting that GnRH may modulate hormonal and fibrotic responses in the KC corneal stroma. Further studies are needed to reveal the role of the hypothalamic–pituitary–gonadal axis in the onset and progression of KC and to explore this pathway as a novel therapeutic target.

Purpose Keratoconus (KTCN) is thinning and anterior protrusion of the cornea. The etiology of KTCN remains unknown. Both genetic and environmental factors are associated with the disorder. The purpose of this study was to identify novel genetic factors by analyzing mitochondrial sequences in cases and controls from Polish population. There are available only a few analyses of some mitochondrial sequences in KTCN studies.Methods A total of 96 individuals from Polish population were included into this study. Chosen mtDNA fragments of all individuals were sequenced.Results Sequencing analysis of chosen mitochondrial genome fragments have revealed numerous alterations including several novel polymorphisms. No sequence variants segregated significantly more frequent with KTCN have been identified.Conclusion Analysis of chosen fragments of mitochondrial genome in Polish patients have revealed numerous sequence variants, however our results do not support involvement of mtDNA changes in KTCN in Polish patients. The KTCN development does not depend on a single change in the gene, but on the accumulation of numerous sequence variants. The complexity of the genetic basis of KTCN causes the need to find another approach to further investigate the etiology of KTCN. Support: National Science Centre (Poland), Grant 2011/03/N/NZ5/01470

Keratoconus (KC) is classically considered a non-inflammatory condition caused by central corneal thinning that leads to astigmatism and reduced visual acuity. Previous studies have identified increased systemic levels of pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-9, suggesting that KC may have an inflammatory component in at least a subset of patients. In this study, we evaluated the levels of different immunoglobulins (light and heavy chains) based on Ig α, Ig λ, Ig κ, Ig µ, and Ig heavy chain subunits in non-KC tears (n = 7 control individuals) and KC tears (n = 7 KC patients) using tandem-liquid chromatography mass spectrometry. The most abundant Ig heavy chains detected in both control individuals and KC patients were Ig α-1 and Ig α-2 likely correlating to the higher IgA levels reported in human tears. We identified significant differences in immunoglobulin κ-chain V-II levels in KC patients compared to control individuals with no significant difference in Ig κ/Ig λ ratios or heavy chain levels. Our study supports previous findings suggesting that KC possesses a systemic component that may contribute to the KC pathology. Further studies are required to define causality and establish a role for systemic immune system-dependent factors and pro-inflammatory processes in KC development or progression.

Keratoconus (KC) is a progressive corneal degeneration characterized by structural changes consisting of progressive thinning and steepening of the cornea. These alterations result in biomechanical weakening and, clinically, in vision loss. While the etiology of KC has been the object of study for over a century, no single agent has been found. Recent reviews suggest that KC is a multifactorial disease that is associated with a wide variety of genetic and environmental factors. While KC is typically considered a disease of the cornea, associations with systemic conditions have been well described over the years. In particular, nutritional and metabolic imbalance, such as the redox status, hormones, metabolites, and micronutrients (vitamins and metal ions), can deeply influence KC initiation and progression. In this paper, we comprehensively review the different nutritional (vitamins and minerals) and metabolic (hormones and metabolites) factors that are altered in KC, discussing their possible implication in the pathophysiology of the disease.

It is accepted that progression of keratoconus (KC) should be treated by cross-linking (CXL). The accepted indications for progression of KC include: increase of 1 D of maximum K-reading (Kmax) or of manifest cylinder and/or deterioration of corrected distance visual acuity (CDVA) within 1 year, as well as contact-lens-dioptric changes which require replacement every 2 years or less. Some consider a spherical equivalent (SE) increase of ≥0.50 D or when corneal thickness decreases by ≥5 % as progression of KC which justifies CXL. At the present time, many KC patients are diagnosed earlier and referred immediately to experts without long-term topographic or refractive history to support progression of KC. It is a common bias/dilemma of waiting for progression of KC and further functional deterioration versus CXL without a delay. Decisions should consider the high-risk groups where the progression may be fast or when even small progression may cause significant functional damage. This group includes KC patients younger than 20 years old, unilateral KC, and patients with CDVA of 6/12 or with very advanced KC in which functional vision is dependent upon use of scleral lenses. KC in steroid users may also advance faster. In these groups, clinical judgment per individual case should consider the risk of functional vision loss versus the risks of the CXL procedure.

PurposeTo examine the effect of prolactin (PRL) on human corneal stromal fibroblasts (CSFs), derived from healthy individuals and from keratoconus (KC) patients, in vitro, specifically assessing physiological and elevated PRL concentrations as apparent during pregnancy.MethodsEye bank corneas of 3 female and 3 male healthy individuals as well as the corneal buttons of 3 female and 3 male KC patients were utilized for this study. The endothelium of the cornea was removed with sterile surgical scalpels, the probes were washed repeatedly with Dulbecco’s PBS and corneoscleral rims were trimmed off. Subsequently the corneal stroma was digested with collagenase type I and the harvested CSFs were cultured. We then examined (1) cell proliferation, (2) cell viability and (3) cytokine release of CSFs upon exposure to prolactin in vitro.ResultsWith respect to viability and proliferation our experiments did not show significant differences between CSFs exposed to different PRL concentrations. Our data show a significantly lower IL-8 concentration in normal CSFs exposed to 10ng/ml PRL compared to 0ng/ml and 1000ng/ml at 5 hours post exposition. Moreover, we can report significantly lower secretion of IL-8, IL-6, HGF, VEGF and FGFb in KC CSFs compared to normal CSFs, independent of PRL exposure, as determined by cytokine ELISA.ConclusionOur data in part points towards corneal cytokine secretion as a possible link between altered stromal PRL concentrations and KC progression. However, in our small dataset a significant influence of PRL concentration on cytokine secretion can only be described for IL-8 in normal CSFs. Further our results contribute to existing reports on the importance of cytokines in KC development, with an emphasis on significantly lower cytokine secretion in KC CSFs compared to normal controls.

To report variants in 26 candidate genes and describe the clinical features of Italian patients with keratoconus (KC). Sixty-four patients with a confirmed diagnosis of KC were enrolled in this genetic association study. Patients were classified into two study groups according to whether they had a confirmed diagnosis of progressive or stable KC. A purpose-developed Next Generation Sequencing (NGS) panel was used to identify and analyse the coding exons and flanking exon/intron boundaries of 26 genes known to be associated with KC and corneal dystrophies. Interpretation of the pathogenic significance of variants was performed using in silico predictive algorithms. The targeted NGS research identified a total of 167 allelic variants of 22 genes in the study population; twenty-four patients had stable keratoconus (n. 54 variants) and forty patients had progressive disease (n. 113 variants). We identified genetic variants of certain pathogenic significance in five patients with progressive KC; in addition, eight novel genetic variants were found in eight patients with progressive KC. Mutations of FLG, LOXHD1, ZNF469, and DOCK9 genes were twice more frequently identified in patients with progressive than stable disease. Filaggrin gene variants were found in 49 patients (76% of total), of whom 32 patients (80% of progressive KC group) had progressive disease. Targeted NGS research provided new insights into the causative effect of candidate genes in the clinical phenotype of keratoconus. Filaggrin mutations were found to represent a genetic risk factor for development of progressive disease in Italy.

Differential epithelial and stromal protein profiles in keratoconus and normal human corneas