Transcript Drug induced gingival enlargement

 INTRODUCTION
 CLASSIFICATION
 PREVALENCE
 MEASUREMENT OF ENLARGEMENT
 DRUGS CAUSING ENLARGEMENT
 ANTI CONVULSANTS
 Pharmaco-dyanamics of anti epileptic drugs
 Pharmaco kinetics of phenytoin
 Pathogenesis of phenytoin induced gingival
enlargement
 IMMUNO-SUPPRESSANTS
 Cyclosporine
 Pathogenesis
 Clinical manifestations
 Histological features
 CALCIUM CHANNEL BLOCKERS
 Pathogenesis
 Clinical manifestations
 MANAGEMENT OF GINGIVAL ENLARGEMENT
 Medical management- drug substitution
 Gingivectomy
 Laser
 CLINICAL RELEVANCE and CASE REPORTS
 Drug induced gingival enlargement
 Problems
 Risk factors
 Age predilection
 Based on location and distribution
 Localized
 Generalized
 Marginal
 Papillary
 Diffuse
 Discrete
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
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Malignant tumors
Squamous cell carcinoma
Epulis
Malignant melanoma
Fibroma
Sarcoma:
Papilloma
Fibrosarcoma
Lymphosarcoma
Peripheral gaint cell granuloma
Reticulum cell sarcoma
Central gaint cell granuloma
Kaposis sarcoma
Renal cell carcinoma
Leukoplakia
Hypernephroma
Gingival cyst
Chondrosarcoma
 Other benign masses like nevus,
myoblastoma, hemangioma, neurilemmoma, neurifibroma,
mucoceles, ameloblastoma
 False enlargement
Bokenkamp A. Bohnhoest B
Grade 0
-No signs of gingival enlargement
Grade 1
-Enlargement confined the IDP
Grade 2
-Enlargement involves papilla and marginal
gingiva
Grade 3
-Enlargement covers three quarters or more
of crown.
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
 Gingival overgrowth has been associated with the use
of erythromycin
Valsecchi et al in 1992
Lombardi et al in 1989
Oral contraceptives
 Norethindrone
 Mestranol
Response
Seymour et al in 1998
 Variation in inter-patient & intra patient pattern
 Predilection for anterior gingiva
 Higher prevalence in children
 Onset within 3 months
 Change in the gingival contour leading to modification of
gingival size
 Enlargement first observed at interdental papilla
 Not associated with attachment loss
 Reduction in dental plaque can limit severity of lesion.
Seymour et al 1996
Multifactorial model
 Inflammation from bacterial plaque is involved in the pathogenesis of
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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
MODEER & DAHLOFF divided 59 PHT-treated noninstitutionalized children into three groups
16 intensive
13 moderate
30 no preventive
None of the subjects in the intensive program developed GH
Dental prophylaxis and "good" oral hygiene can reduce
or prevent the expression of DIGH
 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
 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
 Hassell and Gilbert in 1983
 Hassell and Stanek in 1974
 Seymour et al in 2005
 Genetic heterogenecity
 Differences in cellular ion flux
 Receptor binding affinity
 Cellular turnover
 Modeer et al- 2pts- 9 months
 EGF 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
 Salivary glands- Noach et al
 Woodbury et al twice in epileptic- serum level
 Conrad et al and Mcgaw et al
 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
 Kobayashi et al- the proliferation rate of fibroblast-
inhibition of calcium uptake
 Colombani et al- Cs A
 Drew et al in 1987- folate therapy
 Vogel et al in 1980 and Ariel et al- association of the
phenytoin and the folate
Phenytoin
 Introduced by Merritt & Putnam in 1938
 Used to control seizures in patients with epilepsy
 Most commonly used because of low cost ,easy
availability & effective
 Hyperplasic changes were first reported in 1939 by
Kimball
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
 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 tenderness
 Initial involvement of interdental papilla
 Granulated lobules or pebbly surface
 Acanthosis of squamous
epithelium
 Numerous young
capillaries and fibroblasts
and irregularly arranged
collagen fibrils with
occasional lymphocytes.
 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.
 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.
 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.
Plemonas et al 1996
 Pennu et al 1992 - patient expressing HLA DR1 have
protective role against gingival overgrowth from
cyclosporine A.
 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
 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.
 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
 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
 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
 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.
 Key strategies in gingival enlargement.
periodontal surgical procedures
Plaque control
medical management
multidisciplinary dental care
 CCB’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
 Gingivectomy
 Excision of gingiva.
Simple & quick technique
Advantages
 Permits an adequate contouring of the
tissue
 Controls hemorrhage
Disadvantages
 Unpleasant odour
 Irreparable damage to bone
 Use limited to superficial procedures
 Heat generated can cause tissue damage &
loss of periodontal support.
 Co2 lasers used for excision of gingiva
Advantages
 Excellent soft tissue ablation
 Haemostatic characteristic
Disadvantages
 Healing is delayed
 Requires precautionary measures
 Application 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
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