Drug Induced Gingival Enlarge

7/29/2019 Drug Induced Gingival Enlarge

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Dr. Swarna Alamelu

II Yr PGStudent


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Increase in the size of gingiva is a commonfeature of gingival disease- terminology forthis condition is GINGIVAL ENLARGEMENT orGINGIVAL 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 cellgingivitis.


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b)Non-specific conditioned enlargements

(viz) Pyogenic granuloma

Systemic diseases causing gingival

enlargements; a) Leukemia, b) Wegnersgranulomatosis .

Neoplastic a) Benign b) Malignant

False enlargements


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Based on location and distribution ;

1)Localized

2)Generalized

3)Marginal

4)Papillary

5)Diffuse and

6)Discrete


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Grade O No signs of enlargement

Grade 1 confined to interdental paiilla

Grade 2 - involves papilla and marginal

gingivaGrade 3 covers three quarters or more of

the crown.


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The gingiva and the associated soft tissues ofthe periodontium may be enlarged inresponse to various interactions between thehost and the environment.

Of the predisposing factors associated withthe disfiguring and functionally compromisingovergrowth of gingival tissues, selected anti-convulsant drugs, calcium channel blockers

and a potent immunosuppressant havegenerated the most investigative attention inthe scientific community.


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GO secondary to the use of drugs werereviewed in the dental literature as early asthe 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 somesub-population of fibroblasts and keratinocytesto the drugs.


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Although prevalence rates varies greatly indifferent studies, GO in phenytoin- treated, non-institutionalized patients is about 50%.

Nifedipine -6% and 15%Cyclosporin -25% -30%

No racial predilectionNo gender predilection ,but few studies show males

were three times more likely than females in Ca+antagonists.

No age predilection, however phenytoin induced GOappears to be more frequent in young patients withepilepsy.


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5-Diphenyl hydantoin is an anti- convulsive

drug used in the treatment of epilepsy and

other convulsive disorders.

First introduced by Merritt and Putnam in1938.

On oral administration, phenytoin is

absorbed from the GIT, metabolized in the

liver to its metabolites, the major one being5- Para hydroxy phenyl hydantoin.


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Selectively depresses the motor cortex, by

stabilizing neuronal discharge and limiting

the progression of neuronal excitation by

blocking or interfering with Ca+ influx acrosscell membranes.

GO is the main side effect, the others being

cardiac arrhythmias, CNS depression,

hirsuitism and osteomalacia.


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KIMBALL in 1939 and GLICKMAN in 1941 first

to report the relationship between phenytoin

and GO.

Normal human gingiva contains severalphenotypically distinct and different

subpopulation of fibroblasts.

Some synthesize large amounts of protein

and collagen (high activity fibroblasts) andothers only capable of low protein synthesis

(low activity fibroblasts) whose proportion is

genetically determined.


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In the presence of inflammation, the highactivity fibroblasts can become sensitive tothe drug with subsequent increase incollagen production.

It could be that phenytoin and itsmetabolites being cytotoxic to the lowactivity fibroblasts, thus facilitating anincrease in the population of high activityfibroblasts.

Certain sub population of fibroblasts canmetabolize phenytoin, as a result of which itis available at a higher conc. In the tissuesand this in turn determine the susceptibilityof the patient to GO.


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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 macrophagephenotype in overgrown tissues induced with

phenytoin.


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Role of inflammatory cytokines ;

IL-6 on the connective tissue cells enhances

proliferation and also exerts a positive

regulation on collagen synthesis and GAGsynthesis.

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.


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Collagen turnover and remodeling arepredominantly regulated by two pathways-cellular endocytosis and enzymatic digestionby MMPs/TIMPs.

MMP substrate specificities tend to overlapand collagen degradation is controlled byMMP-1,2,3 and 11 and their antagonist.

HGF were shown to express 6MMP and 4TIMP

isoenzymes and phenytoin altered their geneexpression (ie) MMP-1,2,3 and TIMP-2&3 weredown regulated while TIMP-1 was upregulated.


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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 isaffected.


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Appears 1-3 months after initiation oftherapy.

GO normally begins at the interdental papillaand most frequently found in the anterior

segment of the labial surface. Typically presents a granular or pebbly

surface, with enlarge papillae extendingfacially or lingually, obscuring the adjacent

tissue and tooth surfaces.Overgrowth diminishes as it reaches the

mucogingival junction, but coronally canobscure the crowns of teeth.


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Results in malpositioning of teeth, interferes

with normal masticatory function, speech

and oral hygiene.

In primary dentition can cause delayederuption.

Rarely beneath pontics and in edentulous

patients.


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Thick, stratified epithelium with long thin retepegsoften acanthotic that extend deep into laminapropria.

Lamina propria proliferation of fibroblasts and

increased collagen production, accompanied by anincrease in non-collagenous proteins.

Studies by Bonnaure- Mallet et al comparing thefractional area occupied by total collagen ,type 3&4,fibroblasts, vessels and elastic fibers from GO tissue

specimens showed that the area of fibroblasts innifedipine and cyclosporin specimens was notsignificantly greater than those of controls, but collagenoccupied a greater area in nifidipine specimens than inphenytoin or CsA.


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CsA- first introduced in 1970 as a metabolite

of the fungus species TOLYPOCLADIUM

INFLATUM GAMIS.

As a polypeptide with potentimmunosuppressive action, CsA prolongs

survival of allogenic transplants.

Suppresses some humoral immnity; but to a

greater extent T-cell immunity such asallograft rejection.


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Pharmacokinetics ;known to inhibit specific

lymphocytes (viz) T-lymphocytes with the T-

helper cells as the main target, although T-

suppressor 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 thecytosolic component of NFAT.


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The dephosphorylated NFAT translocates tothe nucleus, where it complexes with thenuclear components required to activate theT-cells, including the transactivation of IL-2

and other lymphokine genes.Calcineurins enzymatic activity is inhibited

following interaction with the cyclosporincomplex.

So blocade of NFAT dephosphorylation, genetranscription is not activated and T-cells failto respond to specific antigenic stimulation.


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CsA also increases expression of TGF- , a potentinhibitor of IL-2 stimulated T-cell proliferation andgeneration of cytotoxic Y-lymphocytes.(Khanna et al1994).

Clinical indications for its use ;as the agent of organtransplantation.

Adverse effects include Gingival overgrowth and othersystemic effects.

They are dose dependant and are frequently reversible

without sequelae upon decrease or discontinuance ofthe drug.


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Apoptosis playa a major role in the maintenance of tissuehomeostasis and mediators of this process may be involved in thepathogenesis of GO.

Stress signals induce molecules , implicated in apoptosis (viz) theP53 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 treatmentfrequency.

So expression of P53 in tissues is considered a possible marker ofDNA damage from genotoxic drugs that cause gingival hyperplasia.


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Gingival keratinocytes cultured in a lowconc. of Ca2+ express Bcl- XL , an anti-apoptotic factor.

CsA is a well known Ca antagonist.

Apoptosis involves a cascade of specificbiochemical events that require a rise in thelevel of intracellluar Ca+.

S CsA induces GO through increased

keratinocyte Bcl-2 expression and a rise inserum CsAlevel.


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CsA stimulates fibroblast proliferation (Colly et al 1986).

Induces a significant increase in type I procollagenlevel.(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 & Rossmann1999).

Genetic factor in the expression of GO by Pernu et al 1992

patients expressing HLA-DR1 have a protective roleagainst GO from CsA, whereas those expressing HLA-DR2show a increased risk for GO.


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Cyclosporin induced GO is associated with enhancedmacrophage PDGF- gene expression.(Plemonas & Nareset al 1996).

Increased levels of PDGF in the gingiva is responsible forpromoting 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 bloodmonocytes ,which activates mononuclear cells to

produce TGF- which decrease matrix degradation andincreases deposition at the same time leading to anincreased amount of ECM.(Buduneli et al ).


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First case reported in dental literature in 1983-Rateischak et al .

Begins as a papillary swelling in the labial aspects thanon the palatal/lingual aspect (Tyldesly &Rotter 1984).

Swelling enlarges and coalesce with adjacent papillaegiving the gingiva a lobulated appearance.

Restricted to the width of the attached gingiva, canextend coronally.

Show marked inflammatory changes which bleedsreadily on probing and more hyperemic than phenytoin

induced GO.


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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).


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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 basaland spinous layer of the epithelium.


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Group of drugs used in the management ofconditions viz hypertension, angina, coronaryartery spasm and cardiac arrhythmias etc.

Classified on their chemical composition asfollows; Benzothiapinederivatives(Diltiazem).Phenyl alkylaminederivatives (Verapamil) Substituteddihydropyridines (Amilodipine, nifidepine).

First report of occurrence of GO associatedwith calcium channel blockers was reported in1984 by Ramon et al.

6).derivatives(


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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


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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 groundsubstance characterized by increased

presence of GAGs and collagen and abundant

active fibroblasts.


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Mckevitt et al studied the effect f phenotypicdifferences in growth ,matrix synthesis andresponse to nifedipine on fibroblast fromresponders and non-responders.

The responder cells presented increasedgrowth potential and reduced greater levelsof protein and collagen than did non-responder cells.

According to Robert M Lucas, IHC studiesshowed active fibroblasts containingsecretory granules in patients with nifedipineinduced GO.


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There was an increase in the extra groundsubstance as well as increase in strongly sulfatedGAGs such as chondroitin sulfate.

According to Sato.N, Matsumato H, the gingival

fibroblasts from nifedipine responders showedsignificantly higher ell proliferation rate and DNAsynthesis than non-responder fibroblasts.

Various drug interactions of nifedipine with otherdrugs have been investigated. Of these,

ketaconazole, an azole antifungal agent hasbeen implicated to increase the serum conc ofnifedipine and enhance the severity ofGO.(pharmacolgy 2005).


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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).


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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 (Thomsonet al 1995).


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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 changesaccompanied 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).


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Effect of IL-1 and nifidepine on cellproliferation and DNA synthesis in culturedhuman 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 TIMP-1 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 Icollagen and hence apt to call it fibrosis


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Collagen degradation occurs both by

extracellular and intracellular mechanisms.

The extra cellular pathway involves the

secretion of collagenase and the intracellularinvolving 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 tissueturn over.


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Role of integrins in GO ; Cell surface glycoproteins that mediate cell adhesion,

control proliferation and regulate gene expression.

Expression of51, v1 and v6 integrins which canbind to fibronectin is induced during wound healing.

The 21 integrins serve as specific receptors of type Icollagen in fibroblasts.

The initial binding step of collagen phagocytosis relies onthe adhesive interaction between the fibroblast andcollagen and that these integrins play a critical role here.

Significant decreased collagen phagocytosis in fibroblasts

in rat overgrown gingival tissues induced by CsA wasreported and that integrin expression suppressed was alsoseen.(Lee et al).

Integrins bind and activate latent TGF- , whichupregulates fibrosis


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Role of calcium in collagen phagocytosis ;

Although the pharmacological actions and

primary target tissues of the drugs are quite

different, these drugs are known arebasically 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.


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Amelioration in susceptible patients, byelimination of local factors , meticulousplaque control, and regular periodontalmaintenance therapy.

Three months recall for maintenance hasbeen recommended .

Each recall appointment should includedetailed oral hygiene instructions and

complete periodontal prophylaxis. An animal study has shown that topically

applied 0.12% CHX can reduce the severity ofCsA induced enlargement.


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Non-surgical treatment ; professional scaling anddebridement.

Application of topical anti-fungal agents.

Surgical treatment ; external bevel gingivectomy

and the alternative option is by internalgingivectomy.

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 compliancewith maintenance visits.


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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.


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