Presented by

Guru Ram Tej K

Postgraduate

Mamata dental college

Drug induced gingival enlargement

INTRODUCTIONCLASSIFICATIONPREVALENCEMEASUREMENT OF ENLARGEMENTDRUGS CAUSING ENLARGEMENTANTI CONVULSANTS

Pharmaco-dyanamics of anti epileptic drugs

Pharmaco kinetics of phenytoinPathogenesis of phenytoin induced

gingival enlargement

CONTENTS

IMMUNO-SUPPRESSANTSCyclosporine PathogenesisClinical manifestationsHistological features

CALCIUM CHANNEL BLOCKERSPathogenesisClinical manifestations

MANAGEMENT OF GINGIVAL ENLARGEMENTMedical management- drug substitutionGingivectomyLaser

CLINICAL RELEVANCE and CASE REPORTS

Contents…

Drug induced gingival enlargement

Problems

Risk factors

Age predilection

Introduction

Based on location and distributionLocalizedGeneralizedMarginalPapillaryDiffuseDiscrete

Classification

Based on etiologic factors and pathologic changes.

Inflammatory enlargement Acute Chronic

Drug induced gingival enlargement Enlargements associated with systemic diseases or

conditions Conditioned enlargement

Pregnancy Puberty Vitamin- C deficiency Plasma cell gingivitis Pyogenic granulosa (non-specified conditioned

enlargement) Systemic diseases causing gingival enlargement

Leukemia Granulomatous diseases(Wegener’s granulomatosis,

sarcoidosis

Neoplastic enlargement Benign tumors

Epulis Fibroma Papilloma Peripheral gaint cell granuloma Central gaint cell granuloma Leukoplakia Gingival cyst Other benign masses like nevus,

myoblastoma, hemangioma, neurilemmoma, neurifibroma, mucoceles, ameloblastoma

False enlargement

Malignant tumorsSquamous cell carcinomaMalignant melanomaSarcoma:

FibrosarcomaLymphosarcomaReticulum cell sarcomaKaposis sarcomaRenal cell carcinomaHypernephromaChondrosarcoma

Prevalence

Bokenkamp A. Bohnhoest BGrade 0 -No signs of gingival enlargementGrade 1 -Enlargement confined the IDPGrade 2 -Enlargement involves papilla and

marginal gingivaGrade 3 -Enlargement covers three

quarters or more of crown.

Measurement

Angel poulus and Goaz –1972 According to the amount of gingiva covering anatomic crown• Grade 0 – No hyperplasia• Grade 1 – Hyperplasia covering cervical 3rd of ant. Crown• Grade2 – Hyperplastic gingiva extending the middle 3rd of

anatomic crown of Ant. Teeth• Grade 3 – Hyperplastic gingiva covering > 2/3rd of crown of

anterior tooth.

• Nery et al (1995) modified by adding interproximal area

McGaw et al (1987)

Degree of gingival enlargement can be scored as

Grade 0: No signs of inflammation

Grade 1: GE confined to interdental papilla

Grade 2: Enlargement involves papilla &marginal gingiva.

Grade 3: Enlargement covers three quarters or more of crown.

Based on assessment of plaster study cast

Seymour et al –1985

Included both thickening and encrochment. GO assessed on a plaster model in upper and lower segments.

Grade o – Normal

Grade 1- Thickening from normal upto 2mm,

Grade 2 – Thickening >2mm

Based on Histopathologic examination

Barak et al (1985)

Grade 1 – Normal width of epithelium 0.30 to 0.50 mm

Grade 2 – Slight hyperplasia 0.50 to 1.5 mm

Grade 3 - moderate hyperplasia1.50 to 3.0 mm

Grade 4 – severe hyperplasia 3 to 4 mm

Miranda and Brunet –2001

Measured GO in buccolingual direction both for buccal and lingual/palatal papilla.

0 – papillary thickness < 1 mm

1 – papillary thickness 1-2 mm

2 – papillary thickness > 2 mm

Miranda and brunet index

Gingival overgrowth has been associated with the use of erythromycin

Valsecchi et al in 1992Lombardi et al in 1989

Oral contraceptivesNorethindroneMestranol

ResponseSeymour et al in 1998

drugs…..

Characteristics of drug induced GE (Moritti 1999)

Variation in inter-patient & intra patient patternPredilection for anterior gingivaHigher prevalence in childrenOnset within 3 monthsChange in the gingival contour leading to modification of

gingival sizeEnlargement first observed at interdental papillaNot associated with attachment lossReduction in dental plaque can limit severity of lesion.

Pathogenesis

Seymour et al 1996Multifactorial model

Inflammation from bacterial plaque is involved in the pathogenesis of DIGH

An increased amount of GAGs is involved in the pathogenesis of DIGH Immunoglobulins are involved in the pathogenesis of DIGH Phenotvpical differences within gingival fibroblasts are involved in the

pathogenesis of DIGH EGF is involved in the pathogenesis of DIGH The pharmacokinetics of inducing drugs and the gingival binding

affinities of these drugs are a determinate in the pathogenesis of DIGH

The activation of collagenase is involved in the pathogenesis of DIGH Disruption of fibroblast cellular Na/Ca flux - The influence of inducing

drugs on gingival fibroblast cellular sodium/calcium flux is involved in the pathogenesis of DIGH

Folic acid is involved in the pathogenesis of DIGH An hypothesis is proposed that involves a combination of several of

the above hypotheses

Hypotheses……

MODEER & DAHLOFF divided 59 PHT-treated non-institutionalized children into three groups

Dental prophylaxis and "good" oral hygiene can reduce or prevent the expression of DIGH

Inflammation from bacterial plaque

16 intensive

13 moderate

30 no preventive

None of the subjects in the intensive program developed GH

Dahloff- ferret- decreased degradation within the fibroblasts

GH represents neither hypertrophy, hyperplasia nor fibrosis, but is an example of uncontrolled growth of a connective tissue of apparently normal cell and fiber composition

An increased amount of GAGs

Smith et al IgA in the serum and the oral cavity

Setterstorm et al – IgG, IgA and IgM

Dahloff -T cells

It appears that immunoglobulins may be more a marker than a cause of local cellular immune reactions occuring within the gingiva during periodontal disease

Immunoglobulins

Hassell and Gilbert in 1983

Hassell and Stanek in 1974

Seymour et al in 2005Genetic heterogenecityDifferences in cellular ion fluxReceptor binding affinityCellular turnover

Gingival fibroblasts phenotype

Modeer et al- 2pts- 9 monthsEGF Receptor metabolism

The steady-state level of EGF-receptor mRNA increased significantly in the cultured fibroblasts derived from the non-responder but decreased significantly in the responder.

Modeer and Anderson

Epidermal growth factor

Salivary glands- Noach et al

Woodbury et al twice in epileptic- serum level

Conrad et al and Mcgaw et al

Pharmacokinetics

Hassell 1982- synthesis of the procollagenase

LIU & BHATNAGAR determined that Phenytoin interfers with prolyl hydroxylase, an enzyme required for the post translational hydroxylation of prolyl residues in the synthesis of collagen

Murphy 1987 and Meikle in 1989- Plasminogen- plasmin MMP cascade

Collagenase activation

Kobayashi et al- the proliferation rate of fibroblast- inhibition of calcium uptake

Colombani et al- Cs A

Disruption of sodium/calcium influx

Drew et al in 1987- folate therapy

Vogel et al in 1980 and Ariel et al- association of the phenytoin and the folate

Folic acid

Anticonvulsants Phenytoin

Introduced by Merritt & Putnam in 1938Used to control seizures in patients with epilepsyMost commonly used because of low cost ,easy

availability & effectiveHyperplasic changes were first reported in 1939 by

Kimball

Mechanism of action:Selectively depress the motor cortex of CNS

Blocks voltage dependent Na channels

Limit the progression of neuronal excitation

Blocks high frequency firing

seen in seizures

Pathogenesis

Shafer (1984) reported that the optimal rate of cell growth at phenytoin concentration 5µg/ml

Hassell & page (1992) demonstrated GO in response to

‘5-Parahydroxyphenyl-5-phenylhydantoin’

Phenytoin sensitive sub population of fibroblasts

Soreness and tendernessInitial involvement of interdental papillaGranulated lobules or pebbly surface

Clinical features

Acanthosis of squamous epithelium

Numerous young capillaries and fibroblasts and irregularly arranged collagen fibrils with occasional lymphocytes.

Histological features

Immunosuppresants

Cyclosporine, a metabolite of fungal species Beauveria Nivea

(Borel et al 1976)

The first human clinical trials of CsA in human kidney allograft recipients by CalneV and Powles' groups in 1978

Cyclosporine induced gingival overgrowth was first reported by Rateischak – Pluss et al.

Immunosuppresants

Specifically, Cyclosporin A inhibits  interleukin-2 (IL-2)

synthesis, hence inhibits the ability of cytotoxic T

lymphocytes to respond to IL-2 at oral dosages of 10-20

mg/kg.

Inhibits the activation of macrophages and preventing the

production of IL-1 receptors on the surface of T-helper

cells.

Cyclosporin A is water insoluble and absorption depends

on the presence of bile salts.

Mechanism

Wyosocki et al 1983 by fibroblasts sensitive to cyclosporine

Schincaglia et al 1992 – the anti-collagenase activity by decreasing MMPase

Enhanced macrophage platelet derived growth factor

gene expression

promotes fibroblast proliferation and production of

extracellular matrix constituents.

Pathogenesis

Plemonas et al 1996

Pennu et al 1992 - patient expressing HLA DR1 have protective role against gingival overgrowth from cyclosporine A.

Contrast..

Affects more frequently to children's & females.Enlarged gingival tissue is soft, red or bluish red,

extremely fragile & bleed easily on probing. Overgrowth is restricted to width of attached

gingiva

Clinical features

Acanthosis and parakeratinization of the epithelium with pseudoepitheliomatous proliferation.

Inflammatory cells are seen

Mariani et al found that the basal and spinous layers of epithelium show distinct dilatation of the intercellular spaces, characteristic of disease related overgrowth.

Histological features

First reported case of GH induced by nifedipine was reported

by Ramon et al

Interdental papilla become enlarged

In many areas its shows ulcerations & BOP

False periodontal pockets without bone loss

Calcium channel blockers

Fujii et al (1991) tested the effect of Ca channel blockers on cell proliferation, DNA synthesis and Collagen synthesis

Lucas et al and Jones et al(1994) suggested that GO results from overproduction of extracellular ground substance characterized by increased presence of GAG and collagen

Barelay (1999) noted that the collagenolytic effects of inflammatory cells and synthesis of collagenase are Ca dependent cellular events

Pathogenesis

Nifedipine induces gingival hyperplasia in rats through inhibition of apoptosis, which prolongs cell life……………..(Shimizu et al,2001)

Nifidepine 5.— reductase activity

Stimulates synthesis of DHT from Testosterone in gingival fibroblast 

Production of large amount of collagen + Inactive from of collagenase  Gingival overgrowth

Pathogenesis….

Epithelium exhibits para keratosis, proliferation and elongation of rete pegs that extends into lamina propria.

Increase in epithelial width, infiltrates of lymphocytes and plasma

Nander wall et al 1985 Fibroblasts contain strongly

mucopolysaccharides and secretory granules.

Histologic features

Key strategies in gingival enlargement.

Management

Plaque control

medical management

periodontal surgical procedures

multidisciplinary dental care

Drug substitutionCCB’s : Nifedipine with Isradipine ( 20 mg BD)

….(westbrook in 2001)

ACE Inhibitors like Captopril (12.5 to 50mgBD), Enalapril (2.5to20 mg OD) to control hypertension

Phenytoin with Phenobarbital(60 mg TDS), Primidone ( 100mg TDS)

Carbamezepine (200-400mg TDS)

Valproic acid (200-500mg TDS)Cyclosporin A with Tacrolimus (0.15 to 0.20/kg/d)

Rapamycin

Surgical Treatment of gingival enlargement

Gingivectomy Excision of gingiva.Simple & quick technique

Gingivectomy by Electro surgery

Advantages Permits an adequate contouring of the

tissue Controls hemorrhage

DisadvantagesUnpleasant odour Irreparable damage to bone Use limited to superficial proceduresHeat generated can cause tissue damage &

loss of periodontal support.

Laser gingivectomyCo2 lasers used for excision of gingiva

Advantages Excellent soft tissue ablationHaemostatic characteristic DisadvantagesHealing is delayedRequires precautionary measuresApplication to root surface or alveolar bone

causes carbonization & major thermal damage

Silverstain et al 1995 – Nifidepine induced gingival enlargements has been reported around dental implants

Yoon Angela et al in 2006 - Myeloid sarcoma occurring concurrently with drug induced gingival enlargement

Frederic Duffau in 2007 - Gingival enlargement originating from medication and tooth migration

Case reports….

Ronald S Brown, William T Beaver, and William K Bottomley: On the mechanism of drug induced gingival hyperplasia. J Oral Pathol Med 1991; 20: 201-9

Seymour RA and Heasmen PA: Drugs and the Periodontium. J Clin Periodontol 1998; 15: 1-16

Bettina Dannewitz: proliferation of the gingiva: aetiology risk factors and treatment modalities for gingival enlargement. Quintessence int. 2007;4(2): 83-92

Bhardwaj Amit, Bhardwaj Verma Shalu: Gingival enlargement induced by anticonvulsants, calcium channel blockers and immunosuppresants: a review: Int Res J Pharm; 2012, 3(7)

Valsecchi R, Cainelli T. Gingival hyperplasia induced by erythromycin. Acta Derm Venereol (Stockh) 1992;72: 157.

Roderick I Marshall, P Mark Bartold: A clinical review of drug induced gingival overgrowths: Aus dent Jour. 1999: 44: 4.

Thomas M Hassell and Arthur F Hefti; Drug induced gingival overgrowth: Old Problem, New Problem: critical reviews in Oral Biology and Medicine: 1991: 2(1): 103-137

P M Camargo, Philip R Melnick, Flavia Q M Pirih, R Lagos & Henry H Takei: Treatment of drug induced gingival enlargement: aesthetic and functional considerations. Perio 2000,2001: 27, 131-138

References

Kumar and Kumar et al: Drug induced gingival hyperplasia: an updated review: Int J Pharm & Toxic Science1(1): 2011, 34-42

Omid Panahi, Mohsin Seyed Arab, Kevin Tamson: Amlodipine induced gingival hyperplasia: pakisthanoral dental journal 2010: 30(2)

Barbara Anne Taylor: Management of drug induced gingival enlargement: Aust Prescr 2003; 26: 11-13

Miranda J, Brunet L, Roset et al: Reliability of two measurement indices for gingival enlargement: J O P 2012: 47(6): 776-782

Yoon Angela, Pulse Carla et al: Myeloid sarcoma occurring concurrently with drug induced gingival enlargement:J O P 2006: 77(1): 119-122

Alaaddinoglu Emine Elif, Karabay Gulten et al: Apoptosis in cyclosporine A induced gingival overgrowth: A histological study: J O P 2005: 76(2): 166-170

A defect in fibroblasts from an unidentified syndrome with gingival hyperplasia as the predominant feature: B Johnson, M E Guindy, William et al: J O P 1986: 21: 403-413.

Johnson BD, Narayanan AS. Pieters HP, Page RC: Effect of cell donor age on the synthetic properties of fihrohlasts obtained from phenytoin-induced gingival hyperplasia. J Periodont Res 1990; 25: 74-80.

references……

Frederic Duffau: Gingival enlargement originating from medication and tooth migration: quntiscence international, 2007; 4(2): 109-113

Romanos GE. Schroter-Kermani C. Hinz N, Bernimoulin J-P: Distribution of fibronectin in healthy, infiamed and drug-induced gingival hyperplasia. J Oral Pathol Med 1992; 21: 256-260.

Pradhan S, Mishra P, Joshi S: Drug induced gingival enlargement – A review

Akhthar: Drug induced gingival enlargement, Bangladesh dental journal 2012

Fatema Akhter and Shaheen:Drug induced gingival enlargement – A review; Bangladesh J Physiol Pharmacol 2009; 25(1&2): 26-29

The pathogenesis of drug induced gingival overgrowth: R A Seymour et al J C P 1996. 23(3), 165-175

references……

Thank you