Pterygium, a wing-shaped (pterygos is “wing” in Greek) fibrovascular growth of conjunctiva extending into the superficial cornea, may cause irritation, redness, and tearing. Clinically, the condition involves invasive centripetal growth with associated inflammation and neovascularization. Several factors have been proposed to play a role in the pathogenesis of pterygium, such as anti-apoptosis, pro-inflammatory cytokines, growth factors, immunological responses, viral infections, extracellular matrix remodeling, and genetic factors [15
Pterygium is common in the so-called “pterygium zone”, which is defined by a geographical latitude of 40° north and south of the equator. In countries within this area as our country, the prevalence is up to 22% in the general population. In countries outside this area, the prevalence rates usually do not exceed 2% [16
The lesion mostly affects patients with an increased exposure to solar UV radiation, such as people working outdoors. A slightly higher incidence in males is reported, which may be attributed to lifestyle differences between genders (with males spending more time outdoors) in many countries [2
]. Nevertheless, in the current study, the majority of patients were female. This may be because, in México, males rarely go to the doctor for this kind of problem.
Pterygium has been documented as a fibrovascular membrane advancing on the corneal surface, often triangular in shape, sometimes bilateral and usually originating from the nasal bulbar conjunctiva, but also occasionally from the temporal conjunctiva. A study by Efstathios et al. reported that the majority of patients showed fibrovascular tissue in the nasal region [2
The pathogenesis of pterygium remains to be elucidated, and little is known about the differences between primary and recurrent pterygium. The few studies that have made a distinction between primary and recurrent pterygium determined that p53 is likely to play a role [15
]; levels of VEGF, basic fibroblast growth factor, and substance P were significantly higher in recurrent pterygium [1
], but the opposite relationship was seen by others [19
]. Similar results have been obtained with other proteins, such as L-3-phosphoserine phosphatase homolog, increases in periostin, metallopeptidase inhibitor 2 (TIMP-2), mastering eye morphogenesis and eye evolution (PAX-6), human papillomavirus and herpes simplex virus [1
Although the detailed molecular mechanism remains unclear, it has been widely accepted that chronic UV exposure is a major etiological factor, which is supported by epidemiological evidence and histological features. The noxious effects of UV radiation are either caused by direct UV radiation or by indirect stress via reactive oxygen species (ROS). Excess ROS can overwhelm the antioxidant system and cause oxidative damage to a variety of biological molecules, such as lipids, proteins and DNA [20
UV-B exposure causes oxidative stress, leading to upregulation of many potential mediators of pterygium growth. 8-hydroxydeoxyguanosine (a marker commonly used to identify oxidative damage to DNA) and human 8-oxoguanine glycosylase 1 (the enzyme that metabolizes 8-hydroxydeoxyguanosine) have been found in pterygium tissue in several studies [8
Several treatment options are available; including surgical excision techniques [21
], but postoperative recurrence is common and sometimes results in even more aggressive clinical behavior. The surgical technique used in the current study was simple closure, which has been associated with a high risk for postoperative recurrence compared with other surgical modalities [21
]. In the current study, the decision fell to the surgeon managing the patient because the aim of the study was to evaluate the effects of a complementary treatment using a-lipoic acid, not the surgical technique; although, published literature suggests that the surgical technique could probably be the single most important factor influencing recurrence, recurrent pterygium is more common in younger patients and is sometimes associated with a family history of pterygium. Its treatment often requires sophisticated surgery [21
Several studies [22
], have indicated that the oral administration of alpha lipoic acid can be useful and safe in treating human diseases, it exhibits high tissue capacity of penetration and it has been safe even being administrated for several weeks. Topical formulation of alpha-lipoic acid in eye drops (1%) has been used and has exhibited good penetration [11
]. Although this way of administration is very interesting, only a single dose has been used, so other studies should be performed in order to test efficiency and safety using repeated doses for several weeks in order to be determined on humans.
Di Geronimo et al. [23
] used alpha lipoic acid for three months at 600 mg by day and had good tolerance and safety; we decided to use this dosage and began this treatment previous to the surgery as Pajardi et al. [24
], to inhibit the process of synthesis of fibroelastic tissue responsible of the recurrence, enhanced after surgery.
In this study, all patients were treated similarly in both groups and our results indicate that recurrence was similar but with a significant decrement in size of fibroelastic tissue recurring for the a-lipoic acid group.
Another therapeutic strategy is anti-metabolite treatment, such as mitomycin C, which is often combined as an adjuvant with pterygium surgery (the recurrence rate is reported as <10%). Other agents include the alkylating agent thiotepa, and a pyrimidine analogue, 5-fluorouracil. Although very effective in reducing recurrence rates, anti-metabolite use is, nevertheless, associated with serious and potentially sight-threatening complications, such as delayed healing or even scleral melt [2
Oxidative stress caused by UV exposure may be the principal cause of pterygium development, and several protocols have been established in animals exposed to UV-B radiation to evaluate the effects of antioxidants. For example, Suh et al. [25
] demonstrated the protective effect of ascorbic acid in damaged cornea, and Demir et al. [13
] with the use of a-lipoic acid, determined the protective effect of conjunctival and corneal damage against oxidative stress in rabbits exposed to UV radiation.
Several studies, for example Golu et al. [26
] indicated an abundance of subepithelial connective tissue in pterygium tissue, a rich basic substance with numerous fibroblasts, round mononuclear cells of lymphocyte and macrophage type, and a rich network of blood vessels and numerous goblet cells. Goblet cells are observed in classical stains, having the appearance of a cup or goblet, with a dilated apical pole and a foamy cytoplasm slightly stained from synthesis and accumulation of substances rich in glycosaminoglycans. The emergence of an increased number of goblet cells in the epithelium of pterygium may be the consequence of the exposure of the anterior segment of the eye to irritant pollutants. Similarly, our results are congruent with a report by Golu in the patients treated with placebo; however, the characteristics observed diminished after treatment with a-lipoic acid, suggesting a prominent blockade of pterygium tissue recruitment.
The fibroelastic tissue demonstrated abundant extracellular matrix, with abundant fibroblastic cells present in bundle areas. The phenotype of cells within these bundles was positively stained for a-SMA, indicating “foci” of myofibroblasts that decreased with a-lipoic acid treatment. Touhami et al. [27
] reported similar results in pterygium tissue (primary and recurrent) and demonstrated the presence of contractile myofibroblast bundles in pterygium and in periorbital fibroadipose tissue.
The process of angiogenesis is governed by a complex balance of positive and negative regulatory factors. One of the most potent and specific angiogenic factors is VEGF. This growth factor is considered to be the most selective mitogen for endothelial cells (angiogenesis). Livezeanu et al. [28
] reported a strong reaction to VEGF in the pterygium for epithelial cells, except goblet cells, vascular endothelial cells, fibroblasts and stromal inflammatory cells with a granular pattern of expression and diffuse cytoplasmic disposition. Similarly, Aspiotis et al. [4
] and Marcovich et al. [5
] demonstrated an overexpression of VEGF in pterygium tissue and indicated that angiogenesis may play a role in the formation of pterygium. In the current study, we observed that a-lipoic acid treatment did not significantly inhibit the presence of VEGF in pterygium. This observation aligns with a report by Rocamonde et al. [29
] who reported that a-lipoic acid increased the VEGF content in experimental brain injury animals.
The clinical appearance definitely changed with a-lipoic acid, decreasing the excess of fibro-elastic tissue, adopting a less aggressive phenotype. However a-lipoic acid as a treatment itself couldn’t replace the surgery but it could be useful as a complementary therapy with a surgery in pterygium to avoid persistent inflammation, especially after a primary resection to avoid recurrences.
Our results indicated that the number of patients with recurrence during the 6 months following surgery was 25 (35.7%), and recurrence appeared principally within 3 months after resection. Patients that received a-lipoic acid showed no differences in recurrence; perhaps further studies with a longer period of treatment using a-lipoic acid prior the surgery will diminish these early recurrences.