Phenytoin-Induced Gingival Overgrowth: A Review of the Molecular, Immune, and Inflammatory Features

Abstract

Gingival overgrowth (GO) is a side effect associated with some distinct classes of drugs, such as anticonvulsants, immunosuppressant, and calcium channel blockers. GO is characterized by the accumulation of extracellular matrix in gingival connective tissues, particularly collagenous components, with varying degrees of inflammation. One of the main drugs associated with GO is the antiepileptic phenytoin, which affects gingival tissues by altering extracellular matrix metabolism. Nevertheless, the pathogenesis of such drug-induced GO remains fulfilled by some contradictory findings. This paper aims to present the most relevant studies regarding the molecular, immune, and inflammatory aspects of phenytoin-induced gingival overgrowth.

In vivo association of immunophenotyped macrophages expressing CD163 with PDGF-B in gingival overgrowth-induced by three different categories of medications

“…1 These medications include the immune suppressor cyclosporine-A (CsA), the anti-seizure drug phenytoin (PNT), and calcium channel blockers (CCBs). 2,3 The incidence of this side effect can be as high as 70% in transplant patients, 65% in epileptics, and 30% in hypertensive patients. 4,5 In 1997, Iacopino et al 6 reported that the clinical presentation of inflamed and hyperplastic gingival tissues are associated with specific macrophage phenotypes which express the essential platelet derived growth factor-beta (PDGF-B) in PNT-induced hyperplastic tissues.…”

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

“…Consistent with this definition, an expression profile of several mitogenic factors such as as c-Myc, PDGF-B, bFGF, and TGF-beta (Corrêa et al, 2011) and cell cycle regulators such as p53 (Saito et al, 1999) has been observed in GO tissues, and which raises the possibility of GO condition as a disease with potential to transform into malignancy (Jayaraman et al, 2012). Since p53 is overexpressed in several carcinoma tissues…”

“…Furthermore, recent investigations have identified phenytoin induced GO as rather a fibrotic condition (Subramani et al, 2012) as the tissues have been found to contain an increase amount of connective tissue stroma along with an elevated presence of collagen fibers (Corrêa et al, 2011). Under normal physiological condition, the degradation of the extracellular matrix is enabled by the enzymatic activities of collagenases and matrix metalloproteinases (MMPs) coupled with a negative regulatory control by tissue inhibitor of MMPs (TIMP), which acts to inhibit the function of MMPs.…”

“…However, administration of phenytoin even at therapeutic dosage 1 for a prolonged period may produce neuro-, hematoand dermatological side effects like horizontal gaze nystagmus, folate deficiency leading to megaloblastic anemia and hypertrichosis respectively (Fuller et al, 2012;Pandey et al, 2012;Tulloch et al, 2012). Phenytoin is also known to cause drug induced lupus and folate deficiency, which is known to be associated with gingival overgrowth (Corrêa et al, 2011). GO is a painful condition that affects about 16% to 94% of patients (Jayaraman et al, 2012) and is often associated with tenderness and bleeding, all of which cumulatively lead to speech disturbances (Lucchesi et al, 2008;Cornacchio et al, 2011).…”

Imaging in phenytoin induced neurotoxicity: a case series

“…The mechanism of gum hypertrophy, though is more complex and is a resultant of a manipulation of extracellular matrix metabolism. 9 Phenytoin has a long half-life and thus has an advantage of lesser daily dosage however; it follows non-linear pharmacokinetics which means a small increment in dose above the required maintenance dose may cause marked side effects. These properties have now led to other newer drugs such as Lamotrigine and Topiramate to take over Phenytoin in the long term treatment of epilepsy, especially in young patients where longer treatment duration is expected.…”