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Research ArticleHypothyroidism is Not Associated with Keratoconus DiseaseAnalysis of 626 Subjects

Zsuzsa Flasko 12 Elena Zemova1 Timo Eppig3 Laszlo Modis2 Achim Langenbucher3

Stefan Wagenpfeil4 Berthold Seitz1 and Nora Szentmary15

1Department of Ophthalmology Saarland University Medical Center 100 Kirrberger Str 66421 Homburg Saarland Germany2Department of Ophthalmology Faculty of Medicine University of Debrecen 98 Nagyerdei Str 4032 Debrecen Hungary3Experimental Ophthalmology Saarland University 100 Kirrberger Str 66421 Homburg Saarland Germany4Institute of Medical Biometry Epidemiology and Medical Informatics Saarland University Medical Center 100 Kirrberger Str66421 Homburg Saarland Germany5Department of Ophthalmology Semmelweis University 39 Maria Str 1085 Budapest Hungary

Correspondence should be addressed to Zsuzsa Flasko flaskozsuzsagmailcom

Received 2 April 2019 Revised 4 September 2019 Accepted 21 September 2019 Published 31 October 2019

Academic Editor Stefano Baiocchi

Copyright copy 2019 Zsuzsa Flasko et al+is is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Purpose To analyze the association between hypothyroidism and keratoconus we examined blood thyroid hormone levels andcorneal tomographic parameters in healthy subjects and patients with keratoconus Methods We included 626 subjects (304 lefteyes 49 431 males 69 age 384plusmn 143 y) Patients with keratoconus were from our Homburg Keratoconus Center (HKC)(n 463) patients with hypothyroidism were from the Department of Internal Medicine of Saarland Medical UniversityHomburgSaar Germany (n 75) and healthy subjects were from the Department of Ophthalmology of Saarland UniversityMedical Center (n 88) We included only one randomly selected eye of each subject and the first examination data Exclusioncriteria Previous thyroid medication previous ocular surgery and patients with suspected keratoconus (topographic keratoconusclassification [TKC] 0lt 1) Patient eyes were classified (TKC) with dedicated instrument-based keratoconus detection softwareprovided with the Pentacam TKC 0 was considered ldquonormalrdquo and TKCsge 1 were considered keratoconus Subjects were alsoclassified as euthyroid or hypothyroid based on blood thyroid hormone status (ie TSH FT3 and FT4) A multiple logistic linearregression model was constructed to determine the effects of age (covariate) gender and hypothyroidism (effect sizes) on ldquoTKC-positiverdquo disease Results +e significance levels for a constant parameter sex thyroid condition and age were plt 00001plt 00001 plt 00001 and p 0003 respectively +e odds ratios for age sex and hypothyroidism were 098 305 and 334respectively Male sex and a euthyroid condition had significantly positive clinically relevant effects and age had a significantlynegative but clinically irrelevant effect on the estimated TKC index Conclusions Keratoconus appeared to occur more often inpatients classified as euthyroid than in patients with hypothyroidism +us hypothyroidism alone could not support the de-velopment of keratoconus Based on these results it should not be mandatory to screen patients with hypothyroidism forkeratoconus or patients with keratoconus for hypothyroidism

1 Introduction

Keratoconus is a bilateral ldquononinflammatoryrdquo condition ofthe corneal tissue that causes progressive stromal thinning+is condition leads to a cone-shaped centralparacentralectatic cornea Patients with keratoconus develop irregularastigmatism and myopia [1] Histopathologically kerato-conus corneas show central or paracentral stromal thinning

ruptures in Bowmanrsquos layer and ring-shaped ferritin de-positions at the basal layers of the corneal epithelium(ldquoFleischer ringrdquo) [2] Patients with keratoconus can beclassified according to severity based on Scheimpflugtechnology 0 (healthy) 1 (suspected) 2 (mild) 3 (moder-ate) and 4 (severe) Keratoconus can also be classified withkeratometric values as follows mild (lt48D) moderate(48ndash54D) and severe (gt54D) [3]

+e prevalence of keratoconus is about 1 2000 in theCaucasian population It commonly appears during pubertyprogresses until the third or fourth decade of life and then ittypically stabilizes [1] Numerous studies have suggested thathormones such as estrogen and testosterone might have aneffect on the development of corneal ectasia [4ndash8]

Keratoconus is a multifactorial disease influenced byenvironmental and genetic factors [1] It is considered to be asporadic disease but there is also evidence of autosomaldominant [9] and autosomal recessive [10] inheritanceIndeed studies have shown associations between kerato-conus and Downrsquos syndrome (05ndash15) [11ndash13] Turnerrsquossyndrome [14] Leberacutes congenital amaurosis [15] con-nective tissue disorders such as Ehlers-Danlos [16] andMarfan [17] syndromes and mitral valve prolapse In-terleukin-1 may also play a role in the development ofkeratoconus [18]

+e main environmental factor is a high-dose exposureto ultraviolet light (UV) Due to the anterior location of thecornea about 80 of UVB light which is entering the eye isabsorbed through the corneal tissue +is type of exposureleads to the local production of reactive oxygen species[2 19] In addition the risk of keratoconus increases withchronic keratocyte apoptosis or ongoing epithelial injury(eg due to contact lens wear chronic eye rubbing or atopiceye disease) [20 21]

A thyroid gland dysfunction often results in thyroid-associated ophthalmopathy [22] +e diagnosis of a thyroidgland disorder is based on changes in serum levels of freethyroxine (FT4 normal range 12ndash22 pmolL) free tri-iodothyronine (FT3 normal range 31ndash68 pmolL) andthyroid-stimulating hormone (TSH normal range 027ndash42mEL) Hypothyroidism is a pathological conditionwhere the cells of the human body do not receive the ap-propriate FT4FT3 effects In primary hypothyreosis FT4and FT3 are reduced and TSH is elevated in the bloodHypothyroidism might also be associated with keratoconusand it could be one of the causal factors [23ndash25]

+e purpose of the present study was to analyze theassociation between hypothyroidism and keratoconus byexamining blood thyroid hormone levels corneal topo-graphictomographic parameters and biomechanicalparameters

2 Patients and Methods

+is prospective single-center comparative study was con-ducted at the Department of Ophthalmology SaarlandUniversity Medical Center in Homburg Germany +estudy was approved by the local ethics committee (Number15710) and followed the tenets of the Declaration of Hel-sinki Informed written consent was obtained from allsubjects

21 Patient Selection Patients with keratoconus were en-rolled from our Homburg Keratoconus Center (HKC)which was established in 2012 at the Department of Oph-thalmology Saarland Medical University in HomburgSaar

Germany (n 463) Patients with hypothyroidism wereenrolled from the Department of Internal Medicine ofSaarland Medical University HomburgSaar Germany(n 75) Healthy subjects were enrolled from the De-partment of Ophthalmology of Saarland University MedicalCenter (n 88) For this study we acquired the examinationdata for only one randomly selected eye of each subject

We acquired data for patients examined between Jan-uary 2012 and January 2016 We only used the first exam-ination data follow-up examination data were not usedExclusion criteria were a previous thyroid medicationprevious ocular surgery and patients with suspected kera-toconus (Pentacam topographic keratoconus classification[TKC] 0lt 1) We excluded patients with previous hypo-thyroid medications to exclude a potential bias of hormonesupplementation +erefore we only included patients witha new diagnosis of hypothyreosis (which had not yet usedmedical treatment) Patients with previous ocular surgerywere excluded because surgery could influence cornealtopography Patients with suspected keratoconus were ex-cluded because a false diagnosis of keratoconus could alsoresult in a bias in the group of patients with keratoconus

+is study included 4 patient groups (1) subjects clas-sified as euthyroid without keratoconus (controls) (2) pa-tients classified as euthyroid with keratoconus (3) patientswith hypothyroidism but without keratoconus and (4)patients with hypothyroidism and keratoconus Patient eyeswere classified as keratoconus with dedicated instrument-based keratoconus detection software (topographic kera-toconus classification TKC) provided with the Pentacam(see below) A TKC of 0 was considered normal and TKCvalues of 1 or higher were considered keratoconus Howeveras mentioned above patients with suspected keratoconus(TKC 0lt 1) were excluded from the study

Patients were considered euthyroid or hypothyroidbased on blood thyroid hormone levels Normal values weredefined as follows 12ndash22 pmolL for FT4 31ndash68 pmolL forFT3 and 027ndash42mEL for TSH Patients with hormonelevels within these ranges were classified as euthyroid Pa-tients with lower FT4 and FT3 values or higher TSH valueswere classified as patients with hypothyroidism [22]

22 Examination Protocol All subjects received a completestandard ophthalmological examination In addition sub-jects were examined with a topographic modeling system forcorneal topography (TMS-5 Tomey Nurnberg Germany)and with a rotating Scheimpflug camera (Pentacam HROculus Optikgerate GmbH Wetzlar Germany) From theanterior corneal surface data we extracted the followingparameters the surface asymmetry index (SAI) surfaceregularity index (SRI) KlyceMaeda keratoconus index(KCI) SmolekKlyce keratoconus severity index (KSI) andkeratoconus prediction index (KPI) From the tomographicexamination the following parameters were extracted theindex of surface variance (ISV) index of surface asymmetry(IVA) keratoconus index (KI) center keratoconus index(CKI) index of height asymmetry (IHA) and index ofheight decentration (IHD) In addition subjects were

2 Journal of Ophthalmology

examined with the ocular response analyzer (ORA ReichertOphthalmic Instruments Buffalo NY) to measure thebiomechanical properties of the cornea including the fol-lowing parameters keratoconus match index (KMI) cornealhysteresis (CH) and corneal resistance factor (CRF) Weused the noncontact EM-3000 specular microscope (TomeyNurnberg Germany) for evaluating the endothelial celldensity (ECD) and central corneal thickness

+is study included 626 subjects (304 left eyes 49 431males 69 age 384plusmn 143 y) Subjects were classified aseuthyroid (n 458 73) or hypothyroid (n 168 27)based on blood thyroid hormone status (TSH FT3 FT4) Ofthe 458 subjects classified as euthyroid 375 (80) hadkeratoconus and 83 (20) did not have keratoconus Of thetotal study population of 626 subjects 465 (74) had ker-atoconus according to the TKC (Pentacam) and of these 90(19) had hypothyroidism Of the 161 patients withoutkeratoconus 78 (48) had hypothyroidism Of the controls5 were diagnosed with a thyroid disorder and none hadkeratoconus

23 Statistical Analysis We performed statistical analyseswith SPSS 210 software +e normality distribution waschecked for all parameters with the KolmogorovndashSmirnovtest

+e TMS-5 Pentacam ORA and EM-3000 data wereanalyzed descriptively and results are expressed as the meanand standard deviation or the median and interquartilerange for the 4 study groups A nonparametric MannndashWhitney U-test was used to evaluate differences in pa-rameters between subjects classified as euthyroid without orwith keratoconus (patient groups 1 and 2) between subjectswith hypothyroidism without or with keratoconus (patientgroups 3 and 4) between subjects classified as euthyroid orhypothyroid without keratoconus (patient groups 1 and 3)and between subjects classified as euthyroid or hypothyroidwith keratoconus (patient groups 2 and 4)

A multiple logistic linear regression model was con-structed to determine the effects of age (covariate) gender(dichotomous factor) and hypothyroidism (dichotomousfactor 1 hypothyroidism 0 euthyroidism) on TKC-positive disease (dichotomous factor 0 no keratoconus[TKC 0] 1 keratoconus [TKC 1ndash4]) +is model wastested with a receiver-operating characteristics (ROC)analysis and the area under curve (AUC) was extracted as ageneral descriptor +e maximum Youden index value wasused as the threshold for separating keratoconus fromnonkeratoconus

p values below 005 were considered statisticallysignificant

3 Results

Figure 1 shows the disease distribution in different agegroups Table 1 displays the serum FT4 FT3 and TSH levelsin different disease groups Table 2 shows results from theTMS-5 analysis of the anterior corneal surface Table 3 showsthe results from Pentacam corneal tomography Table 4

shows the corneal biomechanical properties from theORA evaluation Table 5 shows the results from the cornealendothelium evaluation with the EM-3000 specular endo-thelial microscope

We found significant differences between disease groupsin all corneal topographic tomographic and biomechanicalparameters In addition the central corneal thickness mea-sured with the EM-3000 was significantly different betweensubjects classified as euthyroid without or with keratoconusand between subjects with hypothyroidism without or withkeratoconus (plt 005 for all Tables 2ndash5) In addition subjectsclassified as euthyroid or hypothyroid without keratoconusshowed significant differences in the SRI measured with theTMS-5 the ISV the IVA and the IHD measured with thePentacam and the KMImeasured with theORA (plt 005 forall Tables 2ndash4) +e endothelial cell density was also signif-icantly different between subjects classified as euthyroidwithout or with keratoconus (plt 005 Table 5)

In the generalized linear model the absencepresence ofTKC (0 no keratoconus 1 keratoconus) was modeledwith the following effect sizes gender (1male 2 female)and hypothyroidism (0 euthyroid 1 hypothyroid) Ad-ditionally age (in years) was included as a covariate

+e model equation yielded the TKC estimation asfollows

TKCest 0557 + 11138980218(if male)0(if female) 1113899

+ 11138980231(if euthyroid)

0(if hypothyroid)1113899 minus 0003 middot age

(1)

+e significance levels for the constant term sex thyroidcondition and age were plt 00001 plt 00001 plt 00001and p 0003 respectively +e odds ratios for age sex and

200

150

100

50

0le20 years gt20 years and

le40 years

Num

ber o

f pat

ient

s

gt40 years

Euthyroid without KCHypothyroid without KC

Euthyroid with KCHypothyroid with KC

Figure 1 +e disease distribution in different age groups

Journal of Ophthalmology 3

hypothyroidism were 098 305 and 334 respectivelyBased on the linear model male sex and the euthyroidcondition had clinically relevant significantly positive effectson the estimated TKC index In addition age had a tinysignificantly negative but clinically irrelevant effect on theestimated TKC index

As proof-of-concept we used this linear TKC estimationequation to determine the best threshold for distinguishingbetween keratoconus and normal corneas with an ROCanalysis +e ROC curve had an AUC of 074 (Figure 2) +emaximum Youden index was 0422 and the respectivethreshold was 074 +e analysis yielded a sensitivity of 0656

Table 1 Serum thyroid hormones FT4 (pmolL) FT3 (pmolL) and TSH (mEL) measured in different disease groups

Disease group FT4 FT3 TSH

1 Euthyroid without keratoconus (n 83) 120plusmn 014 332plusmn 042 150plusmn 062118 022 330 060 148 083

2 Euthyroid with keratoconus (n 375) 120plusmn 013 345plusmn 045 164plusmn 057119 021 34 050 163 085

3 Hypothyroid without keratoconus (n 69) 138plusmn 027 311plusmn 047 217plusmn 174136 034 300 070a 167 243

4 Hypothyroid with keratoconus (n 86) 129plusmn 021 341plusmn 046 272plusmn 148125 024 340 050 310 220

Values represent the meanplusmn standard deviation or the median interquartile range as indicated aFor this group n 65

Table 2 Anterior corneal surface parameters measured with the TMS-5 in different disease groups

Disease group SAI SRI KCI KSI KPI

1 Euthyroid without keratoconus (n 75) 055plusmn 036 030plusmn 036 229plusmn 643 179plusmn 576 021plusmn 002044 037 019 035a 000 000 000 000 021 003

2 Euthyroid with keratoconus (n 341) 257plusmn 141 108plusmn 062 6408plusmn 3438 5383plusmn 2597 036plusmn 011252 186b 101 093 7680 5850 5690 3990 036 016b

3 Hypothyroid without keratoconus (n 57) 047plusmn 031 017plusmn 023 476plusmn 1073 272plusmn 826 021plusmn 002039 033 007 019 000 000 000 000 021 003

4 Hypothyroid with keratoconus (n 68) 255plusmn 142 115plusmn 062 6062plusmn 3471 5746plusmn 2721 035plusmn 034239 197 106 089 6965 6080 6135 4185 034 017

Difference between groups1-2 lowastlowast lowastlowast lowastlowast lowastlowast lowastlowast3-4 lowastlowast lowastlowast lowastlowast lowastlowast lowastlowast1ndash3 mdash lowastlowast mdash mdash mdash2ndash4 mdash mdash mdash mdash mdashValues represent the meanplusmn standard deviation or the median interquartile range as indicated aFor this group n 74 bfor this group n 340 lowastplt 005lowastlowastplt 001 SAI surface asymmetry index SRI surface regularity index KCI KlyceMaeda keratoconus index KSI SmolekKlyce keratoconus severity indexKPI keratoconus prediction index

Table 3 Corneal tomographic parameters measured with the Pentacam in different disease groups

Disease group ISV IVA KI CKI IHA IHD

1 Euthyroid without keratoconus (n 82) 2131plusmn 1098 018plusmn 015 102plusmn 003 107plusmn 067 642plusmn 559 002plusmn 0101800 1400 015 014 103 004 100 001 520 660 001 001

2 Euthyroid with keratoconus (n 374) 10117plusmn 5028 107plusmn 052 126plusmn 018 106plusmn 024 3465plusmn 5729 013plusmn 0119300 5900 100 072 123 019 104 009 2440 3342 011 009

3 Hypothyroid without keratoconus (n 78) 1620plusmn 625 012plusmn 007 102plusmn 002 100plusmn 0007 492plusmn 446 001plusmn 00091500 700 011 008 102 002 100 001 340 585 0008 0008

4 Hypothyroid with keratoconus (n 90) 10264plusmn 6111 100plusmn 049 125plusmn 017 106plusmn 008 3087plusmn 292 012plusmn 0079400 6675 098 065 123 022 105 008 2360 2917 011 010

Difference between groups1-2 lowastlowast lowastlowast lowastlowast lowastlowast lowastlowast lowastlowast3-4 lowastlowast lowastlowast lowastlowast lowastlowast lowastlowast lowastlowast1ndash3 lowastlowast lowastlowast mdash mdash mdash lowastlowast2ndash4 mdash mdash mdash mdash mdash mdashValues represent the meanplusmn standard deviation or the median interquartile range as indicated lowastplt 005 lowastlowastplt 001 ISV index of surface variance IVAindex of surface asymmetry KI keratoconus index CKI center keratoconus index IHA index of height asymmetry IHD index of height decentration


and a specificity of 0766 +e mean absolute estimationerror was 0210plusmn 0241

4 Discussion

+emajor finding of our study was that patients classified aseuthyroid appeared to have keratoconus more often thanpatients with hypothyroidism As commonly described KCwas more often present in males than in females Moreoverthe risk of developing keratoconus decreased by 2 witheach year of age (odds ratio 098)

Hormonal influences on the cornea have interestedresearchers for a long time During embryonic life thyroidhormone is essential for the development of cornealtransparency and it is an important factor in initiatingcorneal dehydration [26 27] +e presence of thyroxinereceptors was verified in chicken [28] and human corneas[24] Furthermore a certain quantity of thyroxine is nec-essary for the synthesis of corneal collagen [29]

During childhood serum thyroxine (T4) levels decreasein concert with a progressive reduction in thyroxine-bindingglobulin (TBG) TBG levels are lowest in puberty whenkeratoconus typically appears or progresses [30] +e thy-roxine-binding capacity of TBG is also influenced by genderhormones estrogen increases and testosterone decreasesTBG binding capacity [31] Interestingly in spontaneousmutant keratoconus mice keratoconus was observed almostexclusively in mature males but not in castrated animals [4]In spontaneous mutant keratoconus mice systemic testos-terone also led to keratoconus in females

Estrogen receptors were also identified in human cor-neas [8 32] One report hypothesized that keratoconusmight be triggered by estrogen [8] which might potentiallyexplain the keratectasia observed after refractive surgeryduring pregnancy [5 33] +e pregnancy-induced pro-gression of keratoconus was also studied by Bilgihan et al[34] Fink et al investigated the influence of gender andhormone status on the severity and progression of

Table 4 Biomechanical parameters measured with the ocular response analyzer in different disease groups

Disease group KMI CH CRF



3 Hypothyroid without keratoconus (n 72) 081plusmn 032 1028plusmn 188 1000plusmn 196088 042 995 262 960 280


Difference between groups1-2 lowastlowast lowastlowast lowastlowast3-4 lowastlowast lowastlowast lowastlowast1ndash3 lowast mdash mdash2ndash4 mdash mdash mdashValues represent the meanplusmn standard deviation or the median interquartile range as indicated lowastplt 005 lowastlowastplt 001 KMI keratoconus match index CHcorneal hysteresis CRF corneal resistance factor

Table 5 Corneal endothelium evaluated with the EM-3000 specular microscope in different disease groups

Disease group Endothelial cell density Central corneal thickness

1 Euthyroid without keratoconus2606plusmn 360 50769plusmn 99492690 452 52500 60(n 70) (n 65)

2 Euthyroid with keratoconus2523plusmn 362 45144plusmn 107992558 421 47400 73(n 302) (n 277)

3 Hypothyroid without keratoconus2586plusmn 387 51226plusmn 98752598 401 52800 41(n 68) (n 65)

4 Hypothyroid with keratoconus2501plusmn 382 45936plusmn 100332558 381 47900 83(n 62) (n 58)

Difference between groups1-2 lowast lowastlowast3-4 mdash lowastlowast1ndash3 mdash mdash2ndash4 mdash mdashValues represent the meanplusmn standard deviation or the median interquartile range as indicated lowastplt 005 lowastlowastplt 001


keratoconus +ey could not verify any significant differ-ences between midlife males ldquohormone-activerdquo females andldquohormone-inactiverdquo females [6]

Kahan et al analyzed tear and blood samples of patientswith keratoconus One-third of those patients had hypo-thyroidism half were classified as euthyroid and all patientswith both hyperthyroidism and keratoconus were males[35] In comparison in our study we found that approxi-mately 80 of patients classified as euthyroid and 20 ofpatients with hypothyroidism had keratoconus after ex-cluding data from patients with hyperthyroidism Oneprevious study claimed that keratoconus appeared after athyroidectomy [36] Others found a reversible increase incorneal thickness in patients with hypothyroidism whichdecreased with medical treatment [37]

+e association between hypothyroidism and kerato-conus is rare However this association might be foundsporadically or in specific environmental or clinical con-ditions such as pregnancy or allergy [38] +e relationshipbetween thyroid gland dysfunction and keratoconus pro-gression was described as hypothyroxinemia in one patientduring pregnancy by Gatzioufas and +anos [23] +eyfound that Kmax and corneal thickness values of this patientnormalized after giving supplementary thyroxine medica-tion [23] Similar results were found in a study by Hoo-gewound et al [39] In addition Hafezi and Iseli found thatiatrogenic keratectasia progressed in pregnancy despite theadministration of crosslinking therapy [40] More recently+anos et al described a crucial role of T4 in keratoconuspathophysiology [25] +ey found a 136 prevalence ofthyroid gland dysfunction among patients with keratoconus

which was higher than the prevalence in the general pop-ulation (sim2) [25]

Our findings that patients classified as euthyroidappeared to have keratoconus more often than patients withhypothyroidism contradicted results found in previousstudies However with the exception of the study by +anoset al all other clinical studies mentioned above were casereports which did not include data for a large patientpopulation In addition no previous study analyzed theeffect of age or gender on disease characteristics which weanalyzed in the present study We excluded biases due todifferent patient ages or genders with our multiple logisticlinear regression model

It was not surprising to find significant differences inall topographic tomographic and ORA parameters be-tween patients classified as euthyroid withwithout ker-atoconus and between patients with hypothyroidismwithwithout keratoconus [3] For example we foundsignificant differences in SRIs (TMS-5) ISVs IVAs andIHDs (Pentacam) between patients classified as euthyroidor hypothyroid in the absence of keratoconus In patientswith hypothyroidism these findings could be due to dryeye disease which was not analyzed in the present studyDry eye disease is part of thyroid-induced ophthalm-opathy [22] Moreover dry eye disease is known to causechanges in topographic and tomographic parameters[41]

We found an increase in the KMI measured with ORAamong patients with hypothyroidism compared to patientsclassified as euthyroid in the absence of keratoconus +isfinding was partly consistent with the study by Gatzioufaset al [24]+ey showed that ORA parameters might increasein patients with hypothyroidism compared to normalcontrols +ey found increases in the CH and CRF mea-sured with ORA among patients with hypothyroidismhowever unlike our findings they did not detect a differencein KMI between groups

5 Conclusion

Keratoconus appeared to occur more often in subjects clas-sified as euthyroid compared to subjects with hypothyroid-ism +us our findings showed that hypothyroidism alonecould not support the etiology of keratoconus Neverthelessin rare cases hypothyroidism has been reported in thepathogenesis of keratoconus thus it represents a risk factorduring pregnancy and in rare conditions particularly inmales due to the high levels of testosterone and dehy-droepiandrosterone sulphate +erefore hypothyroidismcould be considered an adjunctive progression factor but notan etiologic factor [4ndash8] Although these data require furtheranalysis the present results suggest that it should not bemandatory to screen patients with hypothyroidism for ker-atoconus or patients with keratoconus for hypothyroidism

Data Availability

+e data used to support the findings of this study are in-cluded within the article

00 02 04 06 08 10

10

08

06

04

02

00

Sens

itivi

ty

1 ndash specificity

Figure 2 Receiver-operating characteristics (ROC) curve for esti-mating the TKC A linear estimation equation was used to determinethe best threshold for distinguishing between keratoconus andnormal eyes with the ROC curve +e area under the ROC curve is074 (arrow) +e maximum Youden index is marked with an arrowon the graph+e Youden index is (sensitivity + specificity minus 1) 0422


Conflicts of Interest

+e authors declare no conflicts of interest related to thisstudy

References

[1] Y S Rabinowitz ldquoKeratoconusrdquo Survey of Ophthalmologyvol 42 no 4 pp 297ndash319 1998

[2] I M Cheung C N McGhee and T Sherwin ldquoA new per-spective on the pathobiology of keratoconus interplay ofstromal wound healing and reactive species-associated pro-cessesrdquo Clinical and Experimental Optometry vol 96 no 2pp 188ndash196 2013

[3] S Goebels T Eppig S Wagenpfeil A Cayless B Seitz andA Langenbucher ldquoStaging of keratoconus indices regardingtomography topography and biomechanical measurementsrdquoAmerican Journal of Ophthalmology vol 159 no 4pp 733ndash738 2015

[4] M Tachibana W Adachi S Kinoshita et al ldquoAndrogen-dependent hereditary mouse keratoconus linkage to an MHCregionrdquo Investigative Ophthalmology amp Visual Science vol 43no 1 pp 51ndash57 2002

[5] P Padmanabhan A Radhakrishnan and R NatarajanldquoPregnancy-triggered iatrogenic (post-laser in situ kerato-mileusis) corneal ectasia a case reportrdquo Cornea vol 29 no 5pp 569ndash572 2010

[6] B A Fink L T Sinnott H Wagner C Friedman K Zadnikand CLEK Study Group ldquo+e influence of gender and hor-mone status on the severity and progression of keratoconusrdquoCornea vol 29 no 1 pp 65ndash72 2010

[7] E Spoerl V Zubaty N Terai L E Pillunat and F RaiskupldquoInfluence of high-dose cortisol on the biomechanics of in-cubated porcine corneal stripsrdquo Journal of Refractive Surgeryvol 25 no 9 pp S794ndashS798 2009

[8] E Spoerl V Zubaty F Raiskup-Wolf and L E PillunatldquoOestrogen-induced changes in biomechanics in the cornea asa possible reason for keratectasiardquo British Journal of Oph-thalmology vol 91 no 11 pp 1547ndash1550 2007

[9] H Tyynismaa P Sistonen S Tuupanen et al ldquoA locus forautosomal dominant keratoconus linkage to 16q223-q231 inFinnish familiesrdquo Investigative Ophthalmology amp Visual Sci-ence vol 43 no 10 pp 3160ndash3164 2002

[10] Y Wang Y S Rabinowitz J I Rotter and H Yang ldquoGeneticepidemiological study of keratoconus evidence for majorgene determinationrdquo American Journal of Medical Geneticsvol 93 no 5 pp 403ndash409 2000

[11] N Udar S R Atilano D J Brown et al ldquoSOD1 a candidategene for keratoconusrdquo Investigative Opthalmology amp VisualScience vol 47 no 8 pp 3345ndash3351 2006

[12] M B Shapiro and T D France ldquo+e ocular features ofDownrsquos syndromerdquo American Journal of Ophthalmologyvol 99 no 6 pp 659ndash663 1985

[13] J F Cullen and H G Butler ldquoMongolism (Downrsquos syndrome)and keratoconusrdquo British Journal of Ophthalmology vol 47no 6 pp 321ndash330 1963

[14] M Macsai E Maguen and P Nucci ldquoKeratoconus andTurnerrsquos syndromerdquo Cornea vol 16 no 5 pp 534ndash536 1997

[15] M J Elder ldquoLeber congenital amaurosis and its associationwith keratoconus and keratoglobusrdquo Journal of PediatricOphthalmology and Strabismus vol 31 no 1 pp 38ndash40 1994

[16] K Pesudovs ldquoOrbscanmapping in Ehlers-Danlos syndromerdquoJournal of Cataract amp Refractive Surgery vol 30 no 8pp 1795ndash1798 2004

[17] I H Maumenee ldquo+e eye in the Marfan syndromerdquoTransactions of the American Ophthalmological Societyvol 79 pp 684ndash733 1981

[18] S E Wilson Y-G He J Weng et al ldquoEpithelial injury in-duces keratocyte apoptosis hypothesized role for the in-terleukin-1 system in the modulation of corneal tissueorganization and wound healingrdquo Experimental Eye Researchvol 62 no 4 pp 325ndash338 1996

[19] R Buddi B Lin S R Atilano N C Zorapapel M C Kenneyand D J Brown ldquoEvidence of oxidative stress in humancorneal diseasesrdquo Journal of Histochemistry amp Cytochemistryvol 50 no 3 pp 341ndash351 2002

[20] W-J Kim Y S Rabinowitz D M Meisler and S E WilsonldquoKeratocyte apoptosis associated with keratoconusrdquo Experi-mental Eye Research vol 69 no 5 pp 475ndash481 1999

[21] A J Bron and Y S Rabinowitz ldquoCorneal dystrophies andkeratoconusrdquo Current Opinion in Ophthalmology vol 7no 4 pp 71ndash82 1996

[22] H Burgi and M P Konig ldquoEndocrine ophthalmopathyrdquoSchweizerische Medizinische Wochenschrift vol 105pp 1101ndash1110 1975

[23] Z Gatzioufas and S +anos ldquoAcute keratoconus induced byhypothyroxinemia during pregnancyrdquo Journal of Endocri-nological Investigation vol 31 no 3 pp 262ndash266 2008

[24] Z Gatzioufas G D Panos E Brugnolli and F HafezildquoCorneal topographical and biomechanical variations asso-ciated with hypothyroidismrdquo Journal of Refractive Surgeryvol 30 no 2 pp 78-79 2014

[25] S +anos P Oellers M Meyer zu Horste et al ldquoRole ofthyroxine in the development of keratoconusrdquo Corneavol 35 no 10 pp 1338ndash1346 2016

[26] A J Coulombre and J L Coulombre ldquoCorneal developmentI corneal transparencyrdquo Journal of Cellular and ComparativePhysiology vol 51 no 1 pp 1ndash11 1958

[27] A J Coulombre and J L Coulombre ldquoCorneal developmentIII the role of the thyroid in dehydration and the develop-ment of transparencyrdquo Experimental Eye Research vol 3no 2 pp 105ndash114 1964

[28] A H Conrad Y Zhang A RWalker et al ldquo+yroxine affectsexpression of KSPG-related genes the carbonic anhydrase IIgene and KS sulfation in the embryonic chicken corneardquoInvestigative Opthalmology amp Visual Science vol 47 no 1pp 120ndash132 2006

[29] M Drozdzm E Kucharz and E Grucka-Mamczar ldquoIn-fluence of thyroid hormones on collagen content in tissues ofguinea pigsrdquo Endokrinologie vol 73 no 1 pp 105ndash1111979

[30] D A Fisher J Sack T H Oddie et al ldquoSerum T4 TBG T3uptake T3 reverse T3 and TSH concentrations in children 1to 15 years of agerdquo lte Journal of Clinical Endocrinology ampMetabolism vol 45 no 2 pp 191ndash198 1977

[31] M E Parslow T H Oddie and D A Fisher ldquoEvaluation ofserum triiodothyronine and adjusted triiodothyronine (freetriiodothyronine index) in pregnancyrdquo Clinical Chemistryvol 23 no 3 pp 490ndash492 1977

[32] T Suzuki Y Kinoshita M Tachibana et al ldquoExpression of sexsteroid hormone receptors in human corneardquo Current EyeResearch vol 22 no 1 pp 28ndash33 2001

[33] F Hafezi T Koller V Derhartunian and T Seiler ldquoPreg-nancy may trigger late onset of keratectasia after LASIKrdquoJournal of Refractive Surgery vol 28 no 4 pp 242-243 2012

[34] K Bilgihan A Hondur S Sul and S Ozturk ldquoPregnancy-induced progression of keratoconusrdquo Cornea vol 30 no 9pp 991ndash994 2011


[35] I L Kahan M Varsanyi-Nagy M Toth and A Nadrai ldquo+epossible role of tear fluid thyroxine in keratoconus devel-opmentrdquo Experimental Eye Research vol 50 no 4pp 339ndash343 1990

[36] E F King ldquoKeratoconus following thyroidectomyrdquo Trans-actions of the Ophthalmological Societies of the UnitedKingdom vol 73 pp 31ndash39 1953

[37] U A Bahccedileci S Ozdek Z Pehlivanli I Yetkin and M OnolldquoChanges in intraocular pressure and corneal and retinalnerve fiber layer thicknesses in hypothyroidismrdquo EuropeanJournal of Ophthalmology vol 15 no 5 pp 556ndash561 2005

[38] C Mazzotta C Traversi P Mellace et al ldquoKeratoconusprogression in patients with allergy and elevated surfacematrix metalloproteinase 9 point-of-care testrdquo Eye amp ContactLens Science amp Clinical Practice vol 44 pp S48ndashS53 2018

[39] F Hoogewoud Z Gatzioufas and F Hafezi ldquoTransitorytopographical variations in keratoconus during pregnancyrdquoJournal of Refractive Surgery vol 29 no 2 pp 144ndash146 2013

[40] F Hafezi and H P Iseli ldquoPregnancy-related exacerbation ofiatrogenic keratectasia despite corneal collagen crosslinkingrdquoJournal of Cataract amp Refractive Surgery vol 34 no 7pp 1219ndash1221 2008

[41] E Zemova T Eppig B Seitz et al ldquoInteraction betweentopographictomographic parameters and dry eye disease inkeratoconus patientsrdquo Current Eye Research vol 39 no 1pp 1ndash8 2014


+e prevalence of keratoconus is about 1 2000 in theCaucasian population It commonly appears during pubertyprogresses until the third or fourth decade of life and then ittypically stabilizes [1] Numerous studies have suggested thathormones such as estrogen and testosterone might have aneffect on the development of corneal ectasia [4ndash8]

Keratoconus is a multifactorial disease influenced byenvironmental and genetic factors [1] It is considered to be asporadic disease but there is also evidence of autosomaldominant [9] and autosomal recessive [10] inheritanceIndeed studies have shown associations between kerato-conus and Downrsquos syndrome (05ndash15) [11ndash13] Turnerrsquossyndrome [14] Leberacutes congenital amaurosis [15] con-nective tissue disorders such as Ehlers-Danlos [16] andMarfan [17] syndromes and mitral valve prolapse In-terleukin-1 may also play a role in the development ofkeratoconus [18]

+e main environmental factor is a high-dose exposureto ultraviolet light (UV) Due to the anterior location of thecornea about 80 of UVB light which is entering the eye isabsorbed through the corneal tissue +is type of exposureleads to the local production of reactive oxygen species[2 19] In addition the risk of keratoconus increases withchronic keratocyte apoptosis or ongoing epithelial injury(eg due to contact lens wear chronic eye rubbing or atopiceye disease) [20 21]

A thyroid gland dysfunction often results in thyroid-associated ophthalmopathy [22] +e diagnosis of a thyroidgland disorder is based on changes in serum levels of freethyroxine (FT4 normal range 12ndash22 pmolL) free tri-iodothyronine (FT3 normal range 31ndash68 pmolL) andthyroid-stimulating hormone (TSH normal range 027ndash42mEL) Hypothyroidism is a pathological conditionwhere the cells of the human body do not receive the ap-propriate FT4FT3 effects In primary hypothyreosis FT4and FT3 are reduced and TSH is elevated in the bloodHypothyroidism might also be associated with keratoconusand it could be one of the causal factors [23ndash25]

+e purpose of the present study was to analyze theassociation between hypothyroidism and keratoconus byexamining blood thyroid hormone levels corneal topo-graphictomographic parameters and biomechanicalparameters

2 Patients and Methods

+is prospective single-center comparative study was con-ducted at the Department of Ophthalmology SaarlandUniversity Medical Center in Homburg Germany +estudy was approved by the local ethics committee (Number15710) and followed the tenets of the Declaration of Hel-sinki Informed written consent was obtained from allsubjects

21 Patient Selection Patients with keratoconus were en-rolled from our Homburg Keratoconus Center (HKC)which was established in 2012 at the Department of Oph-thalmology Saarland Medical University in HomburgSaar

Germany (n 463) Patients with hypothyroidism wereenrolled from the Department of Internal Medicine ofSaarland Medical University HomburgSaar Germany(n 75) Healthy subjects were enrolled from the De-partment of Ophthalmology of Saarland University MedicalCenter (n 88) For this study we acquired the examinationdata for only one randomly selected eye of each subject

We acquired data for patients examined between Jan-uary 2012 and January 2016 We only used the first exam-ination data follow-up examination data were not usedExclusion criteria were a previous thyroid medicationprevious ocular surgery and patients with suspected kera-toconus (Pentacam topographic keratoconus classification[TKC] 0lt 1) We excluded patients with previous hypo-thyroid medications to exclude a potential bias of hormonesupplementation +erefore we only included patients witha new diagnosis of hypothyreosis (which had not yet usedmedical treatment) Patients with previous ocular surgerywere excluded because surgery could influence cornealtopography Patients with suspected keratoconus were ex-cluded because a false diagnosis of keratoconus could alsoresult in a bias in the group of patients with keratoconus

+is study included 4 patient groups (1) subjects clas-sified as euthyroid without keratoconus (controls) (2) pa-tients classified as euthyroid with keratoconus (3) patientswith hypothyroidism but without keratoconus and (4)patients with hypothyroidism and keratoconus Patient eyeswere classified as keratoconus with dedicated instrument-based keratoconus detection software (topographic kera-toconus classification TKC) provided with the Pentacam(see below) A TKC of 0 was considered normal and TKCvalues of 1 or higher were considered keratoconus Howeveras mentioned above patients with suspected keratoconus(TKC 0lt 1) were excluded from the study

Patients were considered euthyroid or hypothyroidbased on blood thyroid hormone levels Normal values weredefined as follows 12ndash22 pmolL for FT4 31ndash68 pmolL forFT3 and 027ndash42mEL for TSH Patients with hormonelevels within these ranges were classified as euthyroid Pa-tients with lower FT4 and FT3 values or higher TSH valueswere classified as patients with hypothyroidism [22]

22 Examination Protocol All subjects received a completestandard ophthalmological examination In addition sub-jects were examined with a topographic modeling system forcorneal topography (TMS-5 Tomey Nurnberg Germany)and with a rotating Scheimpflug camera (Pentacam HROculus Optikgerate GmbH Wetzlar Germany) From theanterior corneal surface data we extracted the followingparameters the surface asymmetry index (SAI) surfaceregularity index (SRI) KlyceMaeda keratoconus index(KCI) SmolekKlyce keratoconus severity index (KSI) andkeratoconus prediction index (KPI) From the tomographicexamination the following parameters were extracted theindex of surface variance (ISV) index of surface asymmetry(IVA) keratoconus index (KI) center keratoconus index(CKI) index of height asymmetry (IHA) and index ofheight decentration (IHD) In addition subjects were








3 Results









(1)


200

150

100

50


le40 years

Num

ber o

f pat

ient

s

gt40 years






























4 Discussion



























5 Conclusion


Data Availability


00 02 04 06 08 10

10

08

06

04

02

00

Sens

itivi

ty

1 ndash specificity





References


















































3 Results









(1)


200

150

100

50


le40 years

Num

ber o

f pat

ient

s

gt40 years






























4 Discussion



























5 Conclusion


Data Availability


00 02 04 06 08 10

10

08

06

04

02

00

Sens

itivi

ty

1 ndash specificity





References





































































4 Discussion



























5 Conclusion


Data Availability


00 02 04 06 08 10

10

08

06

04

02

00

Sens

itivi

ty

1 ndash specificity





References



















































5 Conclusion


Data Availability


00 02 04 06 08 10

10

08

06

04

02

00

Sens

itivi

ty

1 ndash specificity





References














































References












































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