vernal keratoconjunctivitis ( vkc ) is a severe inflammatory disease that commonly manifests seasonally during childhood , whereas a perennial and persistent form of the disease is less frequent . the aetiology and immunopathogenesis of vkc remain unclear ; despite the assumption that vkc is part of the family of allergic diseases , a large proportion of the patients diagnosed have no familial or personal history of atopic disease and can have negative results on the standard allergic diagnostic tests . however , antiallergic therapy is often unsuccessful . in vkc patients , the male - female ratio has been reported to range from 4  :  1 to 2  :  1 . all types of vkc are characterised by intense itching , tearing , mucous secretions , and severe photophobia . cytological , biohumoral , immunohistological , and molecular biological studies indicate that vkc is a th2 lymphocyte - mediated disease . mast cells and eosinophils , as well as their mediators , play major roles in the clinical manifestation of vkc . in addition to typical th2-derived cytokines ( il-4 , il-5 , and il-13 ) , other cytokines , such as chemokines , growth factors , and enzymes , are overexpressed in the conjunctiva of vkc patients [ 2 , 3 ] . because of the notable difference between genders and the resolution of this disease after puberty , it has been suggested that hormonal factors play a role in the development of vkc by influencing the immune deviation and the response to environmental factors , in addition to genetic , unknown , and predisposing conditions . sex hormones may also play a relevant role in the pathophysiology of allergic diseases by reciprocal interactions between the immune and endocrine systems . oestrogen and progesterone have been shown to be active players in the ocular immune system . in an immunohistochemical study of patients with vkc , oestrogen and progesterone receptors were shown to be overexpressed in eosinophils and other inflammatory cells on the conjunctiva . these hormones may bind to conjunctival receptors and exert a proinflammatory effect through the recruitment of eosinophils to the conjunctival tissue . sex hormone - related diseases , such as gynaecomastia , polycystic ovary syndrome , mammary fibroadenoma , and adiposogenital dystrophy , or autoimmune diseases have been reported in 2% of patients suffering from vkc . however , recent data reported that vkc patients may have a higher frequency of a family history of autoimmune disorders , thyroid autoantibodies , and antinuclear antibodies ( ana ) [ 6 , 8 ] . thus , the purpose of this study was to evaluate the prevalence of abnormalities of thyroid function and autoimmunity in a cohort of patients with vkc . two hundred and eighty - eight consecutive patients ( 202 males , 86 females ; median age 9.7 , range 5.5 to 16.9 years ) with vkc were recruited from july 2005 to february 2012 at the paediatric allergology unit at anna meyer children 's university hospital in florence , italy . ethical approval was obtained from the ethics committee at anna meyer children 's university hospital . after an explanation of the nature of the study , a diagnosis of vkc was established according to the presence of giant tarsal papillae and/or limbal papillae relapsing in the spring and summer . the symptoms were associated with a mild to severe cobblestone - like appearance in the upper tarsal conjunctiva , mucous discharge , epithelial keratopathy , and at least two eosinophils per optic field ( 100x , oil immersion lens ) in the conjunctival scraping . finally , each patient was evaluated to distinguish between the limbal , tarsal , and mixed forms , as well as between seasonal and perennial symptoms ( table 1 and figure 1 ) . the skin prick test , specific ige serum concentrations , and peripheral blood eosinophil count were also performed . the possible prolonged administration of either systemic or topical drugs , including antihistamines , corticosteroids , cyclosporine , and nonsteroidal anti - inflammatory drugs , was also investigated . in all of the subjects , the serum concentrations of free - t3 ( ft3 ) , free - t4 ( ft4 ) , thyroid stimulating hormone ( tsh ) , thyroperoxidase autoantibodies ( tpoa ) , thyroglobulin autoantibodies ( tga ) , and tsh - receptor ( tshr ) autoantibodies , as well as ultrasonographic data when appropriate , were evaluated . additionally , continuous data such as height , pubertal staging , weight , and body mass index ( bmi ) were collected ; the last parameter was considered as the standard deviation score ( sds ) . finally , all of the patients and control subjects and/or their parents were interviewed about their family history of autoimmune diseases up to their second - degree relatives . the following autoimmune diseases were considered : autoimmune thyroid diseases , rheumatoid arthritis and other rheumatological disorders , coeliac disease , type 1 diabetes mellitus , vitiligo , alopecia , multiple sclerosis , and inflammatory bowel disease . exclusion criteria from the study for vkc patients and controls were the presence of a history of an already diagnosed thyroid or autoimmune disease . ft4 , ft3 , and tsh serum levels were measured using immunometric assays ( immulite 2000 , third generation , dpc diagnostic products corporation , los angeles , ca , usa ) . interrun coefficients of variation were < 8.5% for tsh , < 7.5% for ft4 , and < 9.1% for ft3 . subclinical hypothyroidism was defined as a tsh level above the upper reference limit for age in conjunction with normal serum thyroid hormone levels . overt hypothyroidism was defined as persistently increased tsh levels with decreased serum thyroid hormone levels . thyroid autoimmunity was evaluated using fluorescence enzymatic immunoassays of tga and tpoa antibodies ; positive tga values were considered to be 50  iu / ml and tpoa  100  iu / ml . tshr autoantibodies were measured with thbia ( diasorin spa , vercelli , italy ) using a two - step radioreceptor assay ; tshr was considered to be positive when values were > 9 u / l . the thyroid volume and morphology , when appropriate , were investigated using an advanced technology laboratories ( atl ) high - definition imaging ( hdi ) 5000 ultrasound scanner ( atl ultrasound , bothell , wa , usa ) in combination with a 512  mhz linear transducer . thyroid sonography was performed by experienced radiologists who were unaware of the diagnosis , thyroid hormones , or antibody levels of the subjects . to compare thyroid function and autoimmunity , a group of 188 ( median age 9.5 , range 1.8 to 14.6 years , p = ns ) normal age- and sex - matched subjects with no history of atopic ocular / systemic diseases and who have been admitted to the hospital for minor surgery ( e.g. , adenotonsillectomy , phimosis , dermoid cyst , and herniotomy ) were selected from the same geographical area . studies regarding a portion of this group have been previously reported [ 10 , 11 ] . statistical analyses were performed using spssx ( spssx inc . , chicago , il , usa ) . the -test or fisher 's exact test , when appropriate , was used to compare differences between the patients and control subjects . summaries of the continuous variables are given as the mean  sd and the range . statistical tests were two - tailed and considered to be significant when p < 0.05 . the primary characteristics of thyroid function and autoimmunity in our cohort of vkc patients and controls are summarised in table 1 . associated allergic manifestations such as asthma , eczema , or rhinitis were observed in 34.9% of the patients , and a family history positive for allergic diseases was recorded in 29.5% of the vkc patients . a positive skin prick test for common allergens was observed in 52.1% of the patients , and serum containing specific ige was detected in 53.7% of the patients . twenty - seven ( 9.4% ) patients had a positive family history of thyroid disease ( 15 autoimmune thyroid diseases , 8 thyroid nodules , and 4 goitre ) , which was not significantly different compared to the control group ( 8.6% ; p = ns ) . however , 38 ( 13.2% ) of the vkc cases had a positive family history of autoimmune diseases , which was significantly higher compared to the control subjects ( 12 subjects , 6.3% , p < 0.05 ) . of these , 15 ( 5.2% ) patients had a positive family history of autoimmune thyroid diseases ( versus 3.7% of the control subjects , p = ns ) : 12 ( 4.2% ) for hashimoto 's thyroiditis and 3 ( 1.0% ) for autoimmune hyperthyroidism . subclinical hypothyroidism was diagnosed in 19 patients ( 6.6% ) and overt hypothyroidism in 2 patients ( 0.7% ) . the frequency of subclinical hypothyroidism was significantly higher than the control group ( 3 patients , 1.6% , p < 0.05 ) , whereas the frequency of overt hypothyroidism did not differ from the control group ( 0 subjects , p = ns ) . the ft3 levels were similar between the vkc patients ( 6.84  0.66  pmol / l ) and control subjects ( 6.51  0.79  pmol / l , p = ns ) . the ft4 levels were also similar between the vkc patients and control subjects ( 15.52  3.57 versus 15.13  4.31 however , the tsh levels were considerably higher in vkc patients compared to the control group ( 5.42  2.31 versus 2.81  1.24  ui / ml , p < 0.0001 ) ( figure 2 ) ; if patients with subclinical and overt hypothyroidism were excluded , the tsh levels were not significantly different compared to the control group ( 2.99  0.97 versus 2.81  1.24  ui / ml , p = ns ) . fifteen ( 5.2% ) patients were positive for thyroid autoantibodies , and this percentage was significantly higher compared to the control group ( 1 subject , 0.5% , p < 0.05 ) . no patients were positive for tshr autoantibodies . in the patients who were positive for thyroid autoantibodies , 12/15 ( 80% ) showed a heterogeneous echotexture and diffuse hypoechogenicity on their thyroid sonography , whereas the remaining 3 patients showed normal echostructure and echogenicity ( 0.5% , p < 0.05 ) . l - thyroxine treatment became necessary for one patient with autoimmune thyroiditis and overt hypothyroidism because of the persistently increased tsh levels in this patient , whereas another patient was continually followed over time . upon evaluation of the different forms of vkc , we did not find differences regarding a family history of autoimmune diseases and thyroid diseases or of thyroid autoimmunity and function . our data show , to the best of our knowledge for the first time , an increased prevalence of thyroid function abnormalities in vkc patients . however , our study confirms that patients with vkc also present a higher prevalence of thyroid autoimmunity , confirming the findings of tesse et al . , who reported a higher rate of positivity of thyroid autoantibodies in patients with vkc compared to healthy subjects , despite the fact that thyroid function in the vkc patients was not studied . the same study also discovered that , in 181 vkc children , 22% were positive for abtg , 14.6% for abtpo , and 15.8% for ana . in evaluating thyroid function and thyroid sonography in vkc , our study suggests that these patients may be at a higher risk to develop autoimmune thyroiditis compared to the general population . these data are particularly important because a high percentage of vkc patients with thyroid autoantibodies also showed a higher rate of thyroid dysfunction , primarily manifesting as subclinical hypothyroidism . we observed that 33.3% of our patients with thyroid autoantibodies also presented with either subclinical or overt hypothyroidism , which emphasises the importance of evaluating thyroid function in vkc patients . our study showed that vkc patients have a significantly higher prevalence of a family history of autoimmune diseases , confirming the data of zicari et al .   and tesse et al . . for example , tesse et al . showed that 12.2% of vkc cases had a positive family history of psoriasis ; 5.2% of the patient group was positive for thyroiditis , which suggests the role of common components associated with these immune - based diseases in the development of thyroid autoimmunity . disorders such as gynaecomastia , polycystic ovary syndrome , mammary fibroadenoma , and adiposogenital dystrophy , as well as autoimmune diseases , have been reported by 2% of patients diagnosed with vkc . it is also interesting to note that an excessive growth of eyelashes has been reported in patients with vkc , and this condition is associated with hypothyroidism in some genetic diseases . the cause of the observed higher frequency of autoimmune thyroiditis and thyroid dysfunction in vkc patients is unclear . the significant increase in the frequency of a family history of autoimmune diseases disclosed by vkc patients may also suggest a role of common components of the immune system in the pathogenesis of these disorders . autoimmune thyroid diseases ( aitd ) , which affect approximately 5% of the adult population ( with a larger incidence in women ) , result from the disruption of self - tolerance induced by environmental factors in genetically susceptible individuals   and are characterised by lymphocytic infiltration of the thyroid , the generation of antibodies against thyroid antigens , and thyroid dysfunction . the clinical spectrum of autoimmune diseases encompasses hashimoto thyroiditis ( the most common form ) , graves ' disease , postpartum thyroiditis , drug induced thyroiditis , thyroiditis within polyglandular autoimmune syndromes , and atrophic thyroiditis . phenotypic expression of thyroid autoimmunity is dependent on the pattern of the immune response that predominates at any given time . abnormal interactions between thyrocytes and immunocompetent ( e.g. , macrophages , dendritic cells , and t - cells ) and other immune cells generate autoimmunity . because these subpopulations tend to function antagonistically toward one another , the balance between th1 and th2 lymphocytes may determine the outcome of autoimmune diseases . hashimoto thyroiditis is a typical t - cell - mediated autoimmune disease and is characterised by formation of tertiary lymphoid follicles within the thyroid ( containing t - cells , increased th1 , and b cells ) , with the destruction of thyroid follicular cells generating hypofunction and the presence of anti - tpo and/or anti - tg antibodies in the serum . however , in patients with vkc , the clear abundance of th2 cytokines , the upregulated expression of their receptors , and the conspicuous paucity of t helper cell type 1 ( th1 ) cytokines in the tears and serum confirm the crucial role of these factors in the onset and perpetuation of the chronic allergic inflammation observed in these patients . the immune , nervous , and endocrine systems appear to interact with each other in the pathogenesis of vkc . although allergic diseases ( th2 disorders ) and autoimmune diseases ( th1-mediated ) are usually considered to be diametrically opposed in the immune response , this contention is now less evident because it has been found that allergy - associated mechanisms can contribute to the pathogenesis of autoimmune diseases , such as multiple sclerosis . however , an association between the presence of wheezing as a measure of asthma and the occurrence of type i diabetes   as well as between an allergic constitution ( asthma , atopic eczema ) and aitd   was observed . furthermore , there is a correlation between the elevated levels of immunoglobulin e and a slower decrease in tsh - receptor autoantibody levels , along with a lower chance of remission of the disease after antithyroid drug treatment in patients with graves ' disease [ 23 , 24 ] . additionally , patients with a relapse of graves ' hyperthyroidism had a higher rate of allergic rhinitis attacks compared to patients who went into remission . it is interesting to note that there is also an association between another allergic disease ( chronic urticaria ) and hashimoto 's thyroiditis , as tpo and/or tg autoantibodies were found more frequently in patients with chronic urticaria and angioedema compared to healthy controls . abnormalities of thyroid function and thyroid autoimmunity are present in children with vkc . the possible relationship between these disorders children with vkc should also be screened for thyroid function to evaluate possible thyroid autoimmunity in the presence of hypothyroidism .
hormones may play a role in the pathophysiology of vernal keratoconjunctivitis ( vkc ) . 
 an increased incidence of thyroid autoantibodies was recently observed in vkc , although there were no data on thyroid function . 
 two hundred and eighty - eight patients ( 202 males , 86 females ; range 5.5 to 16.9 years ) with vkc were evaluated and compared with 188 normal age- and sex - matched subjects . in all subjects , serum concentrations of free t4 , tsh , thyroperoxidase , thyroglobulin , and tshr autoantibodies were evaluated . in vkc , the family history of thyroid diseases showed no significant differences compared to the controls ( 9.4 versus 8.6% ) , whereas the family history of autoimmune diseases was significantly higher ( 13.2% versus 6.3% ; p<0.05 ) . 
 subclinical hypothyroidism was diagnosed in 6.6% ( versus 1.6% of the controls ; p<0.05 ) and overt hypothyroidism in 0.7% ( versus 0.0% of the controls ; p = ns ) . finally 
 , 5.2% of patients were positive for thyroid autoantibodies , which were significantly higher with respect to the controls ( 0.5% , p<0.05 ) . in the patients 
 positive for thyroid autoantibodies , 80% showed a sonography pattern that suggested autoimmune thyroiditis . 
 thyroid function and autoimmunity abnormalities are frequently present in children with vkc . 
 children with vkc should be screened for thyroid function and evaluated for thyroid autoimmunity .