According to our results, ocular involvement in Spanish HHT patients is more frequent in people with mutations in the endoglin gene, which is responsible for HHT subtype 1 (HHT1), than in patients with mutations in the ACVRL1/ALK1 gene, responsible for HHT subtype 2 (HHT2). HHT1 has been associated with higher frequency of arteriovenous malformations located in lungs or in brain, while patients with HHT2 are more frequently affected of telangiectasias in the liver19. Coherently, we have found that ocular manifestations of HHT are associated with lung involvement as measured via bubble contrast echocardiography or computed tomography-angiography, thus ocular telangiectasias could serve as a non-invasive marker of HHT manifestations in the respiratory tract. Other signs of HHT severity, such as oral bleeding, telangiectasias in the nostril, grade of nasal telangiectasias and epistaxis intensity are also associated with ocular telangiectasias, according to our results. In this regard Bergh et al, found that HHT1 subtype patients suffer of larger congenital lesions and, thus, they considered HHT 1 as a more severe phenotype 20. On the other hand, Lesca et al. 21 studied the association of telangiectasias in lips, fingers, tongue and nose, finding a high penetration in HHT1 with a greater number of telangiectasias in this subtype. These findings are in agreement with our results. In this same way, presumably there is an association between altered between capillaroscopy and ocular affectation in our study as a consequence of capillaroscopy is more altered in HHT1[1].
In the only previous study analysing the relationship between conjunctival telangiectasias and HHT subtype22, the percentages of patients with conjunctival involvement were 13.4% for HHT1 subtype and 14.6% for HHT2 subtype, which disagrees with our results. However, the ocular exploration in that study was not performed by ophthalmologists, which makes its prevalence values of ocular disease not completely comparable to ours. Other studies that have found mucocutaneous telangiectasias were unrelated to genetic mutations, either did not specify the telangiectasias location or studied them only in typical mucocutaneous locations that are considered in the Curaçao criteria, i.e., they did not consider ocular involvement 4,19−21,23.
Besides that, in our study, the type of ocular lesion presented by patients with HHT are mainly telangiectasias or conjunctival vascular malformations with low rate of symptoms and only 1.12% prevalence of retinal involvement. However, we have not found any patient with retinal lesion. One of the reasons for our low retinal prevalence may be due to the fact that in the ophthalmology unit the new optical coherence tomography modality, angiographic, was not available, which could have allowed detailed study of retinal and even choroid vascularization, without the needing of using contrast. Therefore, subtle vascular retinal abnormalities may have been overlooked in the subjects who did not have fundoscopic abnormalities and, consequently, were not examined by fluorescein angiography (FA) (which is an invasive test, relegated to specific cases). However, relatively well preserved visual acuity in our cohort of participants could support that there were no retinal lesions or, as a recent article with OCT-Angiography and wide-field angiography data from 24 eyes has revealed, that intraocular lesions in patients with HHT predominantly affect peripheral vasculature, while retinal vascular diseases, such as diabetes and age-related macular degeneration, typically affect the more metabolically active central vasculature of the retina 16. Further research with this technique in a greater number of subjects with HHT would be necessary to more accurately assess the presence of retinal lesions. In addition, it is noteworthy that telangiectasias seem to have predilection for certain organs, the conjunctiva being the most affected location in the eye instead of other more vascularized locations such as the choroid.
This study has some strengths. Firstly, all patients included in this study have a confirmed genetic diagnosis and have been followed by professionals specialized in the manifestations of the disease and its management. When Vase and Vase17, in 1979, and Brant et al. 13 in 1989 carried out their studies on the prevalence of ocular involvement in HHT, the diagnostic criteria of Curaçao had not been established and the techniques of current genetic diagnosis were not available, so the number of patients diagnosed with HHT in their studies does not fit the current diagnostic criteria of the disease. Secondly, the HHT Unit of Hospital de Sierrallana is a reference centre for Spanish patients with HHT and the ophthalmological examination is included in the routine protocol of the HHT Unit; therefore, patients included in our study have not been selected because of suspicion of ocular involvement, which rules out selection bias. In addition, participation of ophthalmologists in one previous study in 2007 on ocular involvement14 was carried out through questionnaires that had been submitted to the research centre.
In our series of 206 patients there are 105 patients with ocular lesions, so the prevalence of ocular involvement in our HHT population is 51%. Three studies that analysed the clinical characteristics in populations of high prevalence of HHT provided much lower prevalence of conjunctival involvement, with values of 1% 24, 14% 22 and 16% 2. However, these studies do not include the participation of ophthalmologists. On the other hand, five comparable prevalence studies have been published in the literature 13−17 with case series of 20, 75, 8, 18 and 43, patients respectively, who have been examined by ophthalmologists, so that our study represents the one with the highest number of cases published to date. These studies estimate the prevalence of ocular involvement at 43%, 35% and 38% for conjunctival lesions and 2%, 10% and 0% for retinal lesions. Notice there is a big difference between the prevalence values of ocular involvement between studies published in the literature. This highlights the importance of a good examination by an ophthalmologist to confirm or rule out the existence of ocular lesions related to HHT. In addition, according to our data, patients with ocular telangiectasias were older; although, the natural history of vascular malformations in HHT patients is not well understood, this result suggests that ocular telangiectasias may appear in later stages of HHT 16.