Dr.

Swarna Alamelu II Yr PGStudent

 Increase

in the size of gingiva is a common feature of gingival disease- terminology for this condition is GINGIVAL ENLARGEMENT or GINGIVAL OVERGROWTH. Classified according to the etiologic factors and pathologic changes : 1)Inflammatory enlargements acute and chronic. 2)Drug induced 3)Enlargements associated with systemic diseases; a)Conditioned enlargement (viz) pregnancy, puberty, Vit C deficiency, plasma cell gingivitis.

 b)Non-specific

conditioned enlargements (viz) Pyogenic granuloma Systemic diseases causing gingival enlargements; a) Leukemia, b) Wegners granulomatosis . Neoplastic a) Benign b) Malignant False enlargements

 Based

on location and distribution ; 1)Localized 2)Generalized 3)Marginal 4)Papillary 5)Diffuse and 6)Discrete

 Grade

O No signs of enlargement Grade 1 confined to interdental paiilla Grade 2 - involves papilla and marginal gingiva Grade 3 covers three quarters or more of the crown.

 The

gingiva and the associated soft tissues of the periodontium may be enlarged in response to various interactions between the host and the environment. Of the predisposing factors associated with the disfiguring and functionally compromising overgrowth of gingival tissues, selected anticonvulsant drugs, calcium channel blockers and a potent immunosuppressant have generated the most investigative attention in the scientific community.

GO secondary to the use of drugs were reviewed in the dental literature as early as the 1960s. Currently the etiology is not entirely understood, but is known to be multifactorial. Risk factors that contribute to GO are a) presence of gingival inflammation, plaque, periodontal pocket b) the dose and duration of the drug. c) Intrinsic factors (viz) susceptibility of some sub-population of fibroblasts and keratinocytes to the drugs.

 Although

prevalence rates varies greatly in different studies, GO in phenytoin- treated, noninstitutionalized patients is about 50%. Nifedipine -6% and 15% Cyclosporin -25% -30% No racial predilection No gender predilection ,but few studies show males were three times more likely than females in Ca+ antagonists. No age predilection, however phenytoin induced GO appears to be more frequent in young patients with epilepsy.

 5-Diphenyl

hydantoin is an anti- convulsive drug used in the treatment of epilepsy and other convulsive disorders. First introduced by Merritt and Putnam in 1938. On oral administration, phenytoin is absorbed from the GIT, metabolized in the liver to its metabolites, the major one being 5- Para hydroxy phenyl hydantoin.

 Selectively

depresses the motor cortex, by stabilizing neuronal discharge and limiting the progression of neuronal excitation by blocking or interfering with Ca+ influx across cell membranes. GO is the main side effect, the others being cardiac arrhythmias, CNS depression, hirsuitism and osteomalacia.

 KIMBALL

in 1939 and GLICKMAN in 1941 first to report the relationship between phenytoin and GO. Normal human gingiva contains several phenotypically distinct and different subpopulation of fibroblasts. Some synthesize large amounts of protein and collagen (high activity fibroblasts) and others only capable of low protein synthesis (low activity fibroblasts) whose proportion is genetically determined.

 In

the presence of inflammation, the high activity fibroblasts can become sensitive to the drug with subsequent increase in collagen production. It could be that phenytoin and its metabolites being cytotoxic to the low activity fibroblasts, thus facilitating an increase in the population of high activity fibroblasts. Certain sub population of fibroblasts can metabolize phenytoin, as a result of which it is available at a higher conc. In the tissues and this in turn determine the susceptibility of the patient to GO.

 PHENYTOIN

and GROWTH FACTORS ; Causes a down regulation of EGF receptor metabolism in responder fibroblasts whereas in non responders there is an up regulation. Increases the production of PDGF and that would mediate GO. Studies show an increase in the reparative/proliferative macrophage phenotype in overgrown tissues induced with phenytoin.

 Role

of inflammatory cytokines ; IL-6 on the connective tissue cells enhances proliferation and also exerts a positive regulation on collagen synthesis and GAG synthesis. Role of MMPs and their function ; related to lack of collagen breakdown than to an increase in collagen production. Gene expression of both MMP-1 and TIMP-1 in HGF is reduced by phenytoin.

 Collagen

turnover and remodeling are predominantly regulated by two pathwayscellular endocytosis and enzymatic digestion by MMPs/TIMPs. MMP substrate specificities tend to overlap and collagen degradation is controlled by MMP-1,2,3 and 11 and their antagonist. HGF were shown to express 6MMP and 4TIMP isoenzymes and phenytoin altered their gene expression (ie) MMP-1,2,3 and TIMP-2&3 were down regulated while TIMP-1 was up regulated.

 Role

of phenytoin and folic acid metabolism; Interferes with metabolism and the resulting deficiency affects the epithelium, gonads and bone marrow. As folic acid is required in DNA synthesis, tissues with high turnover (viz) the epithelium are affected and when epithelium is compromised, underlying CT is affected.

 Appears

therapy. GO normally begins at the interdental papilla and most frequently found in the anterior segment of the labial surface. Typically presents a granular or pebbly surface, with enlarge papillae extending facially or lingually, obscuring the adjacent tissue and tooth surfaces. Overgrowth diminishes as it reaches the mucogingival junction, but coronally can obscure the crowns of teeth.

1-3 months after initiation of

 Results

in malpositioning of teeth, interferes with normal masticatory function, speech and oral hygiene. In primary dentition can cause delayed eruption. Rarely beneath pontics and in edentulous patients.

Thick, stratified epithelium with long thin retepegs often acanthotic that extend deep into lamina propria. Lamina propria proliferation of fibroblasts and increased collagen production, accompanied by an increase in non-collagenous proteins. Studies by Bonnaure- Mallet et al comparing the fractional area occupied by total collagen ,type 3&4, fibroblasts, vessels and elastic fibers from GO tissue specimens showed that the area of fibroblasts in nifedipine and cyclosporin specimens was not significantly greater than those of controls, but collagen occupied a greater area in nifidipine specimens than in phenytoin or CsA.

 CsA-

first introduced in 1970 as a metabolite of the fungus species TOLYPOCLADIUM INFLATUM GAMIS. As a polypeptide with potent immunosuppressive action, CsA prolongs survival of allogenic transplants. Suppresses some humoral immnity; but to a greater extent T-cell immunity such as allograft rejection.

 Pharmacokinetics

;known to inhibit specific lymphocytes (viz) T-lymphocytes with the Thelper cells as the main target, although Tsuppressor cells may also be suppressed. CsA forms a complex with cyclophilin, a cytoplasmic receptor protein in target cells. This complex binds to calcineurin inhibiting Ca2+ stimulated dephosphorylation of the cytosolic component of NFAT.

 The

dephosphorylated NFAT translocates to the nucleus, where it complexes with the nuclear components required to activate the T-cells, including the transactivation of IL-2 and other lymphokine genes. Calcineurins enzymatic activity is inhibited following interaction with the cyclosporin complex. So blocade of NFAT dephosphorylation, gene transcription is not activated and T-cells fail to respond to specific antigenic stimulation.

CsA also increases expression of TGF- , a potent inhibitor of IL-2 stimulated T-cell proliferation and generation of cytotoxic Y-lymphocytes.(Khanna et al 1994). Clinical indications for its use ;as the agent of organ transplantation. Adverse effects include Gingival overgrowth and other systemic effects. They are dose dependant and are frequently reversible without sequelae upon decrease or discontinuance of the drug.

Apoptosis playa a major role in the maintenance of tissue homeostasis and mediators of this process may be involved in the pathogenesis of GO. Stress signals induce molecules , implicated in apoptosis (viz) the P53 protein. This induce apoptosis of transformed cells with severe DNA damage and hence known as the guardian of genome. Increased expression of P53 in gingival epithelium of treated animals was present. Degree of expression is related to the dose and treatment frequency. So expression of P53 in tissues is considered a possible marker of DNA damage from genotoxic drugs that cause gingival hyperplasia.

 Gingival

keratinocytes cultured in a low conc. of Ca2+ express Bcl- XL , an antiapoptotic factor. CsA is a well known Ca antagonist. Apoptosis involves a cascade of specific biochemical events that require a rise in the level of intracellluar Ca+. S CsA induces GO through increased keratinocyte Bcl-2 expression and a rise in serum CsAlevel.

CsA stimulates fibroblast proliferation (Colly et al 1986). Induces a significant increase in type I procollagen level.(Schincaglia et al 1992). Increased levels of non-sulfated GAGs contributes to an increased connective tissue matrix.(Zebrowski et al1994). Plaque induced inflammation also exacerbates the expression of drug induced GO.(Hallmon & Rossmann 1999). Genetic factor in the expression of GO by Pernu et al 1992 patients expressing HLA-DR1 have a protective role against GO from CsA, whereas those expressing HLA-DR2 show a increased risk for GO.

Cyclosporin induced GO is associated with enhanced macrophage PDGF- gene expression.(Plemonas & Nares et al 1996). Increased levels of PDGF in the gingiva is responsible for promoting fibroblast proliferation and production of ECM constituents. Inhibits the production of interleukins which are potent stimulators of collagenase. IL-15 causes elevation of MCP-1 by peripheral blood monocytes ,which activates mononuclear cells to produce TGF- which decrease matrix degradation and increases deposition at the same time leading to an increased amount of ECM.(Buduneli et al ).

First case reported in dental literature in 1983Rateischak et al . Begins as a papillary swelling in the labial aspects than on the palatal/lingual aspect (Tyldesly &Rotter 1984). Swelling enlarges and coalesce with adjacent papillae giving the gingiva a lobulated appearance. Restricted to the width of the attached gingiva, can extend coronally. Show marked inflammatory changes which bleeds readily on probing and more hyperemic than phenytoin induced GO.

 Positive

correlation between CsA blood conc and incidence of GO. GO develops if the plasma conc exceeds 400ng/ml(Seymour et al1998). Combined drug treatment has synergistic effets and is a significant risk factor for progression or recurrence of GO among susceptible patients.(Pernu et al 1993).

Acanthosis, with pseudo epithelimatous proliferation, focal areas of myxomatous changes in the immediate sub epithelial tissue, increase in the number of Langerhans cells intra epithelially subjacent to inflamed sites. Rete pegs penetrate deep into the connective tissue, creating irregularly arranged fibre bundles. CT is highly vascularized and focal accumulations of inflammatory cells (Rateischak-Pluss et al 1983). Distinct dilatation of the intercellular spaces in the basal and spinous layer of the epithelium.

 Group

of drugs used in the management of conditions viz hypertension, angina, coronary artery spasm and cardiac arrhythmias etc. Classified on their chemical composition as follows; Benzothiapine 6). derivatives( derivatives(Diltiazem).Phenyl alkylamine derivatives (Verapamil) Substituted dihydropyridines (Amilodipine, nifidepine). First report of occurrence of GO associated with calcium channel blockers was reported in 1984 by Ramon et al.

 Fiji

et al 1994 showed that gingival fibroblasts from responders, when tested with Ca2+ channel blockers , tended towards greater proliferation rates, DNA and collagen synthesis compared to cells from non responders

 Barclay

et al showed that the collagenolytic effects of inflammatory cels and synthesis of colaenase are ca+ dependant processes. Like the anticonvulsants and CsA , ca+ channel blockers inhibit intracelular uptake of calcium. Lucas et al suggested that GO results from overproduction of extra cellullar ground substance characterized by increased presence of GAGs and collagen and abundant active fibroblasts.

 Mckevitt

et al studied the effect f phenotypic differences in growth ,matrix synthesis and response to nifedipine on fibroblast from responders and non-responders. The responder cells presented increased growth potential and reduced greater levels of protein and collagen than did nonresponder cells. According to Robert M Lucas, IHC studies showed active fibroblasts containing secretory granules in patients with nifedipine induced GO.

There was an increase in the extra ground substance as well as increase in strongly sulfated GAGs such as chondroitin sulfate. According to Sato.N, Matsumato H, the gingival fibroblasts from nifedipine responders showed significantly higher ell proliferation rate and DNA synthesis than non-responder fibroblasts. Various drug interactions of nifedipine with other drugs have been investigated. Of these, ketaconazole, an azole antifungal agent has been implicated to increase the serum conc of nifedipine and enhance the severity of GO.(pharmacolgy 2005).

 Various

drug interactions of nifedipine with other drugs have been investigated. Of these, ketaconazole, an azole antifungal agent has been implicated to increase the serum conc of nifedipine and enhance the severity of GO.(pharmacolgy 2005).

 Interdental

papilla are initially affected, results in a lobulated or nodular morphology. Limited to attached and marginal gingiva, more frequently observed in the anterior segment of the facial surfaces. Overgrowth does not appear to affect edentulous areas (Lucas et al ). Nifedipine induced GO reported around dental implants.(Silverstein 1995). Increase in severity reported when nifedipine was administered along with CsA (Thomson et al 1995).

Although connective tissue changes are predominant, epithelium exhibits parakeratosis, proliferation an elongation of reteridges. Vander wall et al reported a10 fold increase in epithelial width, inflammatory changes accompanied by edema and infiltrates. Thickening of the spinous layer was also noted. Fibroblastic proliferation and fibrosis of the lamina propria. Fibroblasts contain strongly sulfated mucopolysaccharides and secretory granules.(similar to phenytoin inducedGO).

 Effect

of IL-1 and nifidepine on cell proliferation and DNA synthesis in cultured human gingival fibroblasts.(J ORAL SCI 2005). Another study by SATO, SAKAGAMI et al in JPR 2006also reported the effects of IL-1 and nifidepine on collagen, MMP-1 and TIMP1 in cultured human gingival fibroblasts. Role of collagen in the etiology of drug induced GO ; No increased proliferation of fibroblasts but severe accumulation of ECM , esp of type I collagen and hence apt to call it fibrosis

 Collagen

degradation occurs both by extracellular and intracellular mechanisms. The extra cellular pathway involves the secretion of collagenase and the intracellular involving the endocytosis by the fibroblasts. The former is accompanied by loss of tissue architecture eg. Inflammation, while the latter process is a part of the normal tissue turn over.

Role of integrins in GO ; Cell surface glycoproteins that mediate cell adhesion, control proliferation and regulate gene expression. Expression of 51, v1 and v6 integrins which can bind to fibronectin is induced during wound healing. The 21 integrins serve as specific receptors of type I collagen in fibroblasts. The initial binding step of collagen phagocytosis relies on the adhesive interaction between the fibroblast and collagen and that these integrins play a critical role here. Significant decreased collagen phagocytosis in fibroblasts in rat overgrown gingival tissues induced by CsA was reported and that integrin expression suppressed was also seen.(Lee et al). Integrins bind and activate latent TGF- , which upregulates fibrosis

 Role

of calcium in collagen phagocytosis ; Although the pharmacological actions and primary target tissues of the drugs are quite different, these drugs are known are basically Ca++ antagonists. Drugs inhibit intracellular Ca++ uptake by gingival fibroblast, which in turn causes Ca++ depletion, affects fibroblast activities ,synthesis and secretion of collagenase, hence the rate of collagen turn over and GINGIVAL OVERGROWTH.

 Amelioration

in susceptible patients, by elimination of local factors , meticulous plaque control, and regular periodontal maintenance therapy. Three months recall for maintenance has been recommended . Each recall appointment should include detailed oral hygiene instructions and complete periodontal prophylaxis. An animal study has shown that topically applied 0.12% CHX can reduce the severity of CsA induced enlargement.

 Drug

substitution /withdrawal ; phenytoin substitution possible with the advent of new agents like lomtrigine, gabapentin, sulthiame and topiramate. Nifedipine alternatives- diltiazem and verapamil. isradipine may result in regression of enlargement. CsA alternatives Tarcolimus.

Non-surgical treatment ; professional scaling and debridement. Application of topical anti-fungal agents. Surgical treatment ; external bevel gingivectomy and the alternative option is by internal gingivectomy. Use of CO2 laser. Recurrence rates for CsA/ nifidepine is about 40% within 18 months of active treatment. The major determinants of recurrence are younger age, inflammation and poor compliance with maintenance visits.

 Advanced

molecular approaches are needed to clearly establish the pathogenesis of GO and to provide novel information f to deisgn future preventive and rearment modalities.