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The Role of Biomarkers in Keratoconus Pathogenesis and Diagnosis

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Keratoconus

Abstract

Keratoconus is an inflammatory disease of the cornea associated with corneal thinning, ectasia and biomechanical weakness. It can lead to significant visual disturbance in more advanced cases due to the associated irregular astigmatism and even corneal scarring. The diagnosis of keratoconus is made primarily based on it’s clinical features and corneal topography or tomography. A lot is now known about the multifactorial and polygenic nature of this condition with a variety of risk factors from the environment, inflammation, hormonal imbalance, oxidative stress, genetics, eye rubbing and allergy influencing it. Dysregulated corneal extracellular matrix remodelling is key to keratoconus pathogenesis. Advances in diagnosis and management have helped improve patient care from diagnosis and treatment point of view. However, there are still many lacunae in our understanding of the etiopathogenesis of this disease. Tears have been an important source of biomarkers for keratoconus along with corneal tissue and blood. The increased knowledge about the etiopathogenesis and diagnostic markers has also opened up options for targeted therapies. This chapter discusses the various biomarkers of keratoconus which are available to us and their role in understanding disease pathogenesis, diagnosis and treatment.

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References

  1. Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42(4):297–319.

    Article  CAS  PubMed  Google Scholar 

  2. Hashemi H, Heydarian S, Hooshmand E, Saatchi M, Yekta A, Aghamirsalim M, et al. The prevalence and risk factors for keratoconus: a systematic review and meta-analysis. Cornea. 2020;39(2):263–70.

    Article  PubMed  Google Scholar 

  3. Ferrari G, Rama P. The keratoconus enigma: a review with emphasis on pathogenesis. Ocul Surf. 2020;18(3):363–73.

    Article  PubMed  Google Scholar 

  4. Matalia H, Swarup R. Imaging modalities in keratoconus. Indian J Ophthalmol. 2013;61(8):394–400.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Shetty R, D’Souza S, Khamar P, Ghosh A, Nuijts R, Sethu S. Biochemical markers and alterations in keratoconus. Asia Pac J Ophthalmol (Phila). 2020;9(6):533–40.

    Article  Google Scholar 

  6. Ahuja P, Dadachanji Z, Shetty R, Nagarajan SA, Khamar P, Sethu S, et al. Relevance of IgE, allergy and eye rubbing in the pathogenesis and management of keratoconus. Indian J Ophthalmol. 2020;68(10):2067–74.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pahuja N, Kumar NR, Shroff R, Shetty R, Nuijts RM, Ghosh A, et al. Differential molecular expression of extracellular matrix and inflammatory genes at the corneal cone apex drives focal weakening in keratoconus. Invest Ophthalmol Vis Sci. 2016;57(13):5372–82.

    Article  CAS  PubMed  Google Scholar 

  8. Wentz-Hunter K, Cheng EL, Ueda J, Sugar J, Yue BY. Keratocan expression is increased in the stroma of keratoconus corneas. Mol Med. 2001;7(7):470–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shetty R, Kaweri L, Pahuja N, Nagaraja H, Wadia K, Jayadev C, et al. Current review and a simplified “five-point management algorithm” for keratoconus. Indian J Ophthalmol. 2015;63(1):46–53.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Blackburn BJ, Jenkins MW, Rollins AM, Dupps WJ. A review of structural and biomechanical changes in the cornea in aging, disease, and photochemical crosslinking. Front Bioeng Biotechnol. 2019;7:66.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Balasubramanian SA, Pye DC, Willcox MD. Effects of eye rubbing on the levels of protease, protease activity and cytokines in tears: relevance in keratoconus. Clin Exp Optom. 2013;96(2):214–8.

    Article  PubMed  Google Scholar 

  12. Lema I, Duran JA, Ruiz C, Diez-Feijoo E, Acera A, Merayo J. Inflammatory response to contact lenses in patients with keratoconus compared with myopic subjects. Cornea. 2008;27(7):758–63.

    Article  PubMed  Google Scholar 

  13. Lema I, Duran JA. Inflammatory molecules in the tears of patients with keratoconus. Ophthalmology. 2005;112(4):654–9.

    Article  PubMed  Google Scholar 

  14. Ionescu IC, Corbu CG, Tanase C, Ionita G, Nicula C, Coviltir V, et al. Overexpression of tear inflammatory cytokines as additional finding in keratoconus patients and their first degree family members. Mediators Inflamm. 2018;2018:4285268.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Arbab M, Tahir S, Niazi MK, Ishaq M, Hussain A, Siddique PM, et al. TNF-alpha genetic predisposition and higher expression of inflammatory pathway components in keratoconus. Invest Ophthalmol Vis Sci. 2017;58(9):3481–7.

    Article  CAS  PubMed  Google Scholar 

  16. Shetty R, Ghosh A, Lim RR, Subramani M, Mihir K, Reshma AR, et al. Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. Invest Ophthalmol Vis Sci. 2015;56(2):738–50.

    Article  CAS  PubMed  Google Scholar 

  17. Fodor M, Vitalyos G, Losonczy G, Hassan Z, Pasztor D, Gogolak P, et al. Tear mediators NGF along with IL-13 predict keratoconus progression. Ocul Immunol Inflamm. 2020:1–12.

    Google Scholar 

  18. Fullwood NJ, Tuft SJ, Malik NS, Meek KM, Ridgway AE, Harrison RJ. Synchrotron x-ray diffraction studies of keratoconus corneal stroma. Invest Ophthalmol Vis Sci. 1992;33(5):1734–41.

    CAS  PubMed  Google Scholar 

  19. Meek KM, Tuft SJ, Huang Y, Gill PS, Hayes S, Newton RH, et al. Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci. 2005;46(6):1948–56.

    Article  PubMed  Google Scholar 

  20. Quantock AJ, Young RD. Development of the corneal stroma, and the collagen-proteoglycan associations that help define its structure and function. Dev Dyn. 2008;237(10):2607–21.

    Article  PubMed  Google Scholar 

  21. Radner W, Zehetmayer M, Skorpik C, Mallinger R. Altered organization of collagen in the apex of keratoconus corneas. Ophthalmic Res. 1998;30(5):327–32.

    Article  CAS  PubMed  Google Scholar 

  22. Shetty R, Sathyanarayanamoorthy A, Ramachandra RA, Arora V, Ghosh A, Srivatsa PR, et al. Attenuation of lysyl oxidase and collagen gene expression in keratoconus patient corneal epithelium corresponds to disease severity. Mol Vis. 2015;21:12–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chaerkady R, Shao H, Scott SG, Pandey A, Jun AS, Chakravarti S. The keratoconus corneal proteome: loss of epithelial integrity and stromal degeneration. J Proteomics. 2013;87:122–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sobrino T, Regueiro U, Malfeito M, Vieites-Prado A, Perez-Mato M, Campos F, et al. Higher expression of toll-like receptors 2 and 4 in blood cells of keratoconus patiens. Sci Rep. 2017;7(1):12975.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Smith VA, Rishmawi H, Hussein H, Easty DL. Tear film MMP accumulation and corneal disease. Br J Ophthalmol. 2001;85(2):147–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mazzotta C, Traversi C, Mellace P, Bagaglia SA, Zuccarini S, Mencucci R, et al. Keratoconus progression in patients with allergy and elevated surface matrix metalloproteinase 9 point-of-care test. Eye Contact Lens. 2018;44(Suppl 2):S48–53.

    Article  PubMed  Google Scholar 

  27. Mutlu M, Sarac O, Cagil N, Avcioglu G. Relationship between tear eotaxin-2 and MMP-9 with ocular allergy and corneal topography in keratoconus patients. Int Ophthalmol. 2020;40(1):51–7.

    Article  PubMed  Google Scholar 

  28. Smith VA, Matthews FJ, Majid MA, Cook SD. Keratoconus: matrix metalloproteinase-2 activation and TIMP modulation. Biochim Biophys Acta. 2006;1762(4):431–9.

    Article  CAS  PubMed  Google Scholar 

  29. Kolozsvari BL, Berta A, Petrovski G, Mihaltz K, Gogolak P, Rajnavolgyi E, et al. Alterations of tear mediators in patients with keratoconus after corneal crosslinking associate with corneal changes. PLoS One. 2013;8(10):e76333.

    Google Scholar 

  30. Balasubramanian SA, Mohan S, Pye DC, Willcox MD. Proteases, proteolysis and inflammatory molecules in the tears of people with keratoconus. Acta Ophthalmol. 2012;90(4):e303–9.

    Article  PubMed  Google Scholar 

  31. Kolozsvari BL, Petrovski G, Gogolak P, Rajnavolgyi E, Toth F, Berta A, et al. Association between mediators in the tear fluid and the severity of keratoconus. Ophthalmic Res. 2014;51(1):46–51.

    Article  PubMed  Google Scholar 

  32. Whitelock RB, Fukuchi T, Zhou L, Twining SS, Sugar J, Feder RS, et al. Cathepsin G, acid phosphatase, and alpha 1-proteinase inhibitor messenger RNA levels in keratoconus corneas. Invest Ophthalmol Vis Sci. 1997;38(2):529–34.

    CAS  PubMed  Google Scholar 

  33. Kenney MC, Chwa M, Atilano SR, Tran A, Carballo M, Saghizadeh M, et al. Increased levels of catalase and cathepsin V/L2 but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays a role in this disorder. Invest Ophthalmol Vis Sci. 2005;46(3):823–32.

    Article  PubMed  Google Scholar 

  34. Sharif R, Fowler B, Karamichos D. Collagen cross-linking impact on keratoconus extracellular matrix. PLoS One. 2018;13(7):e0200704.

    Google Scholar 

  35. Fullwood NJ, Meek KM, Malik NS, Tuft SJ. A comparison of proteoglycan arrangement in normal and keratoconus human corneas. Biochem Soc Trans. 1990;18(5):961–2.

    Article  CAS  PubMed  Google Scholar 

  36. Takaoka A, Babar N, Hogan J, Kim M, Price MO, Price FW Jr, et al. An evaluation of Lysyl oxidase-derived cross-linking in keratoconus by liquid chromatography/mass spectrometry. Invest Ophthalmol Vis Sci. 2016;57(1):126–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dudakova L, Liskova P, Trojek T, Palos M, Kalasova S, Jirsova K. Changes in Lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. Exp Eye Res. 2012;104:74–81.

    Article  CAS  PubMed  Google Scholar 

  38. Dudakova L, Sasaki T, Liskova P, Palos M, Jirsova K. The presence of Lysyl oxidase-like enzymes in human control and keratoconic corneas. Histol Histopathol. 2016;31(1):63–71.

    CAS  PubMed  Google Scholar 

  39. Jeyabalan N, Shetty R, Ghosh A, Anandula VR, Ghosh AS, Kumaramanickavel G. Genetic and genomic perspective to understand the molecular pathogenesis of keratoconus. Indian J Ophthalmol. 2013;61(8):384–8.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Bykhovskaya Y, Margines B, Rabinowitz YS. Genetics in keratoconus: where are we? Eye Vis (Lond). 2016;3:16.

    Article  Google Scholar 

  41. Li X, Rabinowitz YS, Tang YG, Picornell Y, Taylor KD, Hu M, et al. Two-stage genome-wide linkage scan in keratoconus sib pair families. Invest Ophthalmol Vis Sci. 2006;47(9):3791–5.

    Article  PubMed  Google Scholar 

  42. Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010;363(2):166–76.

    Article  CAS  PubMed  Google Scholar 

  43. Ghosh A, Zhou L, Ghosh A, Shetty R, Beuerman R. Proteomic and gene expression patterns of keratoconus. Indian J Ophthalmol. 2013;61(8):389–91.

    Article  PubMed  PubMed Central  Google Scholar 

  44. You J, Hodge C, Wen L, McAvoy JW, Madigan MC, Sutton G. Tear levels of SFRP1 are significantly reduced in keratoconus patients. Mol Vis. 2013;19:509–xxx.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Rabinowitz YS, Dong L, Wistow G. Gene expression profile studies of human keratoconus cornea for NEIBank: a novel cornea-expressed gene and the absence of transcripts for aquaporin 5. Invest Ophthalmol Vis Sci. 2005;46(4):1239–46.

    Article  PubMed  Google Scholar 

  46. Priyadarsini S, McKay TB, Sarker-Nag A, Karamichos D. Keratoconus in vitro and the key players of the TGF-beta pathway. Mol Vis. 2015;21:577–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. El-Massry A, Doheim MF, Iqbal M, Fawzy O, Said OM, Yousif MO, et al. Association between keratoconus and thyroid gland dysfunction: a cross-sectional case-control study. J Refract Surg. 2020;36(4):253–7.

    Article  PubMed  Google Scholar 

  48. Bilgihan K, Hondur A, Sul S, Ozturk S. Pregnancy-induced progression of keratoconus. Cornea. 2011;30(9):991–4.

    Article  PubMed  Google Scholar 

  49. Coco G, Kheirkhah A, Foulsham W, Dana R, Ciolino JB. Keratoconus progression associated with hormone replacement therapy. Am J Ophthalmol Case Rep. 2019;15:100519.

    Google Scholar 

  50. Suzuki T, Sullivan DA. Estrogen stimulation of proinflammatory cytokine and matrix metalloproteinase gene expression in human corneal epithelial cells. Cornea. 2005;24(8):1004–9.

    Article  PubMed  Google Scholar 

  51. McKay TB, Hjortdal J, Sejersen H, Asara JM, Wu J, Karamichos D. Endocrine and metabolic pathways linked to keratoconus: implications for the role of hormones in the stromal microenvironment. Sci Rep. 2016;6:25534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Akkaya S, Ulusoy DM. Serum Vitamin D levels in patients with keratoconus. Ocul Immunol Inflamm. 2020;28(3):348–53.

    Article  CAS  PubMed  Google Scholar 

  53. Wojakowska A, Pietrowska M, Widlak P, Dobrowolski D, Wylegala E, Tarnawska D. Metabolomic signature discriminates normal human cornea from keratoconus-A pilot GC/MS study. Molecules. 2020;25(12).

    Google Scholar 

  54. Zarei-Ghanavati S, Yahaghi B, Hassanzadeh S, Mobarhan MG, Hakimi HR, Eghbali P. Serum 25-Hydroxyvitamin D, Selenium, Zinc and Copper in patients with keratoconus. J Curr Ophthalmol. 2020;32(1):26–31.

    PubMed  PubMed Central  Google Scholar 

  55. Avetisov SE, Mamikonian VR, Novikov IA. The role of tear acidity and Cu-cofactor of Lysyl oxidase activity in the pathogenesis of keratoconus. Vestn Oftalmol. 2011;127(2):3–8.

    PubMed  Google Scholar 

  56. Ortak H, Sogut E, Tas U, Mesci C, Mendil D. The relation between keratoconus and plasma levels of MMP-2, zinc, and SOD. Cornea. 2012;31(9):1048–51.

    Article  PubMed  Google Scholar 

  57. Bamdad S, Owji N, Bolkheir A. Association between advanced keratoconus and serum levels of Zinc, Calcium, Magnesium, Iron, Copper, and Selenium. Cornea. 2018;37(10):1306–10.

    Article  PubMed  Google Scholar 

  58. Nishtala K, Pahuja N, Shetty R, Nuijts RM, Ghosh A. Tear biomarkers for keratoconus. Eye Vis (Lond). 2016;3:19.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Shetty R, Rajiv Kumar N, Pahuja N, Deshmukh R, Vunnava K, Abilash VG, et al. Outcomes of corneal cross-linking correlate with cone-specific Lysyl oxidase expression in patients with keratoconus. Cornea. 2018;37(3):369–74.

    Article  PubMed  Google Scholar 

  60. Wheeler J, Hauser MA, Afshari NA, Allingham RR, Liu Y. The genetics of keratoconus: a review. Reprod Syst Sex Disord. 2012(Suppl 6).

    Google Scholar 

  61. Giri P, Azar DT. Risk profiles of ectasia after keratorefractive surgery. Curr Opin Ophthalmol. 2017;28(4):337–42.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Molokhia S, Muddana SK, Hauritz H, Qiu Y, Burr M, Chayet A, et al. IVMED 80 eye drops for treatment of keratoconus in patients -Phase 1/2a. Invest Ophthalmol Vis Sci. 2020;61(7):2587.

    Google Scholar 

  63. Tuori AJ, Virtanen I, Aine E, Kalluri R, Miner JH, Uusitalo HM. The immunohistochemical composition of corneal basement membrane in keratoconus. Curr Eye Res. 1997;16(8):792–801.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India

    Sharon D’Souza & Rohit Shetty

  2. University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands

    Mor M. Dickman

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  1. Sharon D’Souza
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Editors and Affiliations

  1. Watany Eye Hospital, Cairo, Egypt

    Ashraf Armia

  2. Ophthalmology Unit, Department of Medical, Surgical and Experimental Sciences, Italy and Siena Crosslinking Center, Italy, University of Sassari, Siena, Italy

    Cosimo Mazzotta

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D’Souza, S., Dickman, M.M., Shetty, R. (2022). The Role of Biomarkers in Keratoconus Pathogenesis and Diagnosis. In: Armia, A., Mazzotta, C. (eds) Keratoconus. Springer, Cham. https://doi.org/10.1007/978-3-030-84506-3_3

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  • DOI: https://doi.org/10.1007/978-3-030-84506-3_3

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