Certains medications have been associated with gingival enlargement.
the seminar gives a complete analysis of etilogy and pathogenesis involved in digo as well as sequlae of it
2. 1. Introduction
2. Classification of gingival enlargement
3. Indices for gingival enlargement
4. Drugs associated with gingival enlargement
o Anticonvulsants
o Immunosuppressants
o Calcium Channel blockers
o Miscellaneous
8. Prevalence of drugs causing gingival enlargement
9. Clinical manifestations and Histopathologic features
10. Pathogenesis of Drug induced gingival enlargement
11. Risk factors for Drug induced gingival enlargement
12. Management
13. References
2
4. INCREASE IN SIZE OF GINGIVA
INFLAMMATORY TYPE
Increased cells
Decreased fibers
NON - INFLAMMATORY TYPE
Increased fibers
Decreased cells
4
5. REASONS FOR INCREASE IN SIZE OF GINGIVA
Accumulation of:
Products of inflammation
Increase in:
Cellular + fibrous + ground
substance
5
6. Various terms used previously
Gingival
Hyperplasia
Gingival
Hypertrophy
Fibrous gingival
Hyperplasia
Gingival Overgrowth
To denote excessive
gingival proliferation
secondary to drugs
Gingival
Enlargement
Preferred term
6
7. 7
SEQUELAE OF GINGIVAL OVERGROWTH
Aesthetic changes
Difficulty in maintaining good oral hygiene
Clinical symptoms such as pain
Speech disturbances
Abnormal tooth movement
Dental occlusion problem
Enhanced risk of caries & periodontitis
Brunnet et al 1996
10. 10
• Acute
• Chronic
Inflammatory enlargement
Drug induced enlargement
• Conditioned enlargement
• Pregnancy
• Puberty
• Vitamin C Deficiency
• Plasma Cell Gingivitis
• Non Specific Conditioned Enlargement (Granuloma
Pyogenicum)
• Systemic diseases causing gingival enlargement
• Leukemia
• Granulomatous Diseases (Wegner’s Granulomatosis,
Sarcoidosis, etc. )
Enlargements associated
with systemic
diseases/conditions
• Benign Tumors
• Malignant Tumors
Neoplastic Enlargement
(gingival Tumors)
False Enlargement
MODIFIEDCLASSIFICATION
According to etiology
11. SHAFER’S CLASSIFICATION
11
Inflammatory gingival
hyperplasia
Non inflammatory (fibrous)
gingival hyperplasia
Combination of inflammatory
and fibrous hyperplasia
Shafer WG, Hine M, Levy B. Shafer’s textbook of oral pathology. Elsevier. New Delhi. 5th ed, 2006.
12. 12
BASED ON DISTRIBUTION
Localized: Limited to the
gingiva adjacent to single or
group of teeth
Generalized: Involving gingiva
throughout the mouth
BASED ON LOCATION
Marginal: Confined to marginal
gingiva
Papillary: Confined to interdental
papilla
Diffuse: Involving the marginal,
attached gingiva and papillae
Discrete : An isolated sessile or
pedunculated, tumour like
enlargement
14. • Kimbal et al, 1939
• Harris & Ewall, 1942
• Robinson et al, 1945
• Babcock and Nelson, 1964
• Angelopoulos & Goaz et al, 1972
• Conrad et al, 1974
• Barak et al, 1985
• Seymour et al, 1985
• Daley et al, 1986
• Friskopp & Klintman et al, 1986
• Mc Gaw index, 1987
• Kitaneara et al, 1990
• Miller and Damm index, 1992
• King et al, 1993
• Bokenkamp et al, 1994
• Miranda et al, 1998
• New index for DIGO (Ingles et
al), 1999
• Modified Harris & Ewait index,
(Prasad et al, 2002)
VARIOUS INDICES USED TO MEASURE GINGIVAL
ENLARGEMENT
14
15. BASED ON CLINICAL APPEARANCE
1. Babcock and Nelson, 1964
GRADING OF GINGIVAL ENLARGEMENT
15
Mild No gingival enlargement or a minimal
enlargement.
Moderate Slight but definitive gingival enlargement,
not interfering with function.
Severe Gingival enlargement interfering with the
function.
16. 2. Angelopolus & Goaz –1972
Nery et al (1995) modified by adding interproximal area.
16
Grade 0 No hyperplasia
Grade 1 Hyperplasia covering cervical 3rd of anatomic
crown
Grade 2 Hyperplastic gingiva extending the middle 3rd
of anatomic crown of teeth
Grade 3 Hyperplastic gingiva covering > 2/3rd of
crown of anterior tooth.
17. 17
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.
Grade 0 No signs of gingival enlargement.
Grade I Enlargement confined to interdental papilla.
Grade II Enlargement involves papilla and marginal gingiva
Grade III Enlargement covers three quarter or more of the crown
3. Mc Gaw et al (1987)
4. Bokenkamp et al, 1994
18. BASED ON HISTOPATHOLOGICAL EXAMINATION
Barak et al (1985)
18
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 hyperplasia - 1.50 to 3.0 mm
Grade 4 severe hyperplasia - 3 to 4 mm
19. BASED ON ASSESSMENT OF PLASTER STUDY
CASTS
Seymour et al –1985
Included both gingival thickening and encroachment of gingival
tissues on the adjacent crowns.
19
Grade 0 Normal
Grade 1 Thickening from normal upto 2mm
Grade 2 Thickening >2mm
Criteria for assessing gingival thickness in a labio-lingual direction for a
gingival unit.
Criteria for assessing gingival encroachment on adjacent tooth surfaces for a
gingival unit. (MGL = Mucogingival line).
20. BASED ON PHOTOGRAPHIC ANALYSIS
Ellis & Seymour, 1993
20
0 No encroachment of interdental papilla onto tooth surface.
1 Mild encroachment of interdental papilla, producing a blunted
appearance to papilla tip.
2 Moderate encroachment, involving lateral spread of papilla across buccal
tooth surface of less than one quarter tooth width.
3 Marked encroachment of papilla, i.e., more than 1/4 tooth width. Loss of
normal papilla form.
21. INDICES FOR DRUG INDUCED
GINGIVAL ENLARGEMENT
21
0 No overgrowth
1 Early changes detectable, without encroachment on the tooth
2 Moderate changes, with increased enlargement of the interdental
papillae and slight encroachment of the gingival tissues onto the
tooth surfaces
3 Marked changes with obvious encroachment of the gingival
tissues onto the tooth surfaces.
22. Grade 0
Grade 1
NEW CLINICAL INDEX FOR DRUG INDUCED
GINGIVAL OVERGROWTH
22
1 No overgrowth; firm adaptation of the attached gingiva to the underlying
alveolar bone.
2 There is slight stippling; there is no granular appearance or a slightly granular
appearance.
3 A knife-edged papilla is present toward the occlusal surface.
4 There is no increase in density or size of the gingiva.
1 Early overgrowth, as evidenced by an increase in density of the gingiva
with marked stippling and granular appearance.
2 The tip of the papilla is rounded.
3 The probing depth is less than or equal to 3 mm.
23. Grade 2
Grade 3
23
1 Moderate overgrowth, manifested by an increase in the size of the papilla and/or
rolled gingival margins.
2 The contour of the gingival margin is still concave or straight.
3 Gingival enlargement has a bucco-lingual dimension of up to 2 mm, measured
from the tip of the papilla outward.
4 The probing depth is equal to or less than 6 mm.
5 The papilla is somewhat retractable.
1 Marked overgrowth, represented by encroachment of the gingiva onto the
clinical crown.
2 The contour of the gingival margin is convex rather than concave.
3 Gingival enlargement has a bucco-lingual dimension of approximately 3 mm or
more, measured from the tip of the papilla outward.
4 The probing depth is greater than 6 mm.
5 The papilla is clearly retractable.
24. Grade 4
24
1 Severe overgrowth, characterized by a profound thickening of the gingiva
2 A large percentage of the clinical crown is covered.
3 Same as for grade 3: The papilla is retractable, the probing depth is greater
than 6 mm, and the buccolingually dimension is approximately 3 mm.
26. PREVALENCE RATE
26
Phenytoin
50%Cyclosporine
30%
Nifedipine
20%
Drugs modify the inflammatory and immunologic
responses of the host to plaque
Goldman et al
Clinically & histologically
gingival overgrowth induced by different drugs, are
virtually indistinguishable.
Wysocki et al 1983, Tyldesley & Rotter 1984
27. ANTICONVULSANTS
27
HYDANTOINS SUCCINIMIDES VALPROIC ACID
Ethotoin (Peganone®) Ethosuximide (Zarontin®) Depakene (Depakote®)
Mephenytoin (Mesantoin®) Methsuximide (Celontin®)
Phenytoin (Dilantin®) Phensuximide (Milontin®)
Kimball 1939 - First to report gingival enlargement with chronic usage of
Phenytoin.
Children & Adolescents
Adults
Anterior region
Posterior Region
28. 28
Uses Threshold
plasma
concentration
Incidence Active
metabolite
Progression
Epilepsy –
generalized
tonic-clonic
seizures, partial
seizures.
10-20µg/ml (Rees
et al, 1993)
0 - 84.5%,
Average 50%
(Angelopoulo
s et al)
5-
parahydroxyp
henyl-5-
phenylhydant
oin
Onset – after
one month of
use.
Trigeminal &
related
neuralgias
↑ prevalence
in children
(Dahllof &
Modeer)
Maximum
severity
reached: 12-18
months
Cardiac
arrhythmias
Decreased rate
observed: in the
second year
Adverse drug effects
1. Nausea, Vomitting, Epigastric pain & anorexia.
2. Nystgmus, Diplopia, Ataxia.
3. Gingival hyperplasia (common in children on prolonged use).
4. Peripheral neuropathy.
5. Endocrine – i) Hirsuitism, acne, coarsening of facial features
ii) Hyperglycemia,
iii)Osteomalacia, hypocalcaemia
6. Hypersensitivity reactions
7. Megaloblastic Anaemia
8. Teratogenicity
PHENYTOIN
29. 29
Immunosuppressants
Cyclosporin A
Tacrolimus
Cyclosporin – A
First isolated in Switzerland – 1970, Jean Borel
First case reported by - Rateitschak Pluss,1983
Suppress some humoral immunity (B lymphocytes)
and to a much greater extent, cell-mediated
immunity (T lymphocytes) such as allograft
rejection, delayed hypersensitivity.
Inhibits IL-2 synthesis and release.
30. 30
IMMUNOSUPPRESSANTS
Uses Threshold
plasma
concentration
Incidence Active
metabolite
Progression
Immunosuppressant in
transplant rejection
(kidney, heart, liver
transplant)
> 400ng/ml 25% of renal
transplant
cases
OL-17 Progressive
enlargement
occurs over
several months
Treatment of
rheumatoid arthritis,
psoriasis
38% of
Cardiac
transplants
Reaches peak
after one year of
treatment
Severe atopic
dermatitis, chronic
autoimmune urticaria
37% of Liver
transplants
Graft-versus Host
reaction
Adverse drug effects
1. Nephrotoxicity
2. Hepatotoxicity
3. Anorexia
4. Gum hypertrophy
5. Increased susceptibility to infections
Friskopp & Klintmalm (1986)- Enlargement restricted to keratinized gingiva but can
extend coronally. Absent in edentulous areas.
31. CALCIUM CHANNEL BLOCKERS
31
Dihydropyridine
derivatives
Benzothiazine derivatives Phenylalkylamine
derivatives
Amlodipine
(Lotrel®, Norvasc ®)
Diltiazem
(Cardizem®, Dilacor®,
Tiazac®)
Verapamil HCL
(Calan®, Isoptin®,
Verelan®)
Felodipine (Plendil®)
Nifedipine
(Adalat®, Procardia ®)
Nimodipine (Nimotop®)
Lederman et al, 1984 - First to report gingival enlargement with
chronic usage of Nifedipine
32. 32
Uses Pulmonary Hypertension Raynaud’s phenomena
Threshold plasma
concentration
800ng/ml Resulted in gingival
overgrowth (rat model)
Nishikawa et al. 1995
Incidence 15% - 84% Avg: 42.5%
Severity Increases the risk of
periodontal destruction
in patients with diabetes
mellitus type 2
Does not appear to affect
edentulous areas,
Nifedipine induced gingival
enlargement is seen around
implants.
(Silverstein et al 1995)
Adverse drug effects
1. Cardiac depression
2. Facial flushing
3. Dizziness
4. Headache
5. Edema
6. Gingival enlargement
35. CLINICAL FEATURES OF DRUG INDUCED
GINGIVAL ENLARGEMENT
• Growth starts as:
o A painless beadlike enlargement of the interdental papilla
o Extends to facial & lingual gingival margins.
• On progression:
o Marginal & papillary enlargements unite
o Develop into massive tissue fold covering large part of crown
o Interfere with occlusion
• When uncomplicated by inflammation:
o Lesion is mulberry shaped
o Firm and resilient
o Pale pink
o Minutely lobulated surface
o No tendency to bleed
35
36. • Enlargement characteristically appears to:
o Project from beneath the gingival margin
o From which it is separated by a linear groove.
• Enlargement is usually generalized
• More severe in maxillary & mandibular anterior regions.
• Occurs in areas in which teeth are present & not in edentulous spaces.
• Plaque control becomes difficult due to the enlargement
Resulting
Secondary inflammatory process
(Further complicates the gingival overgrowth caused by the drug)
36
37. Resultant enlargement
Increase in size caused by the drug + plaque induced inflammation.
• Drug-induced enlargement may occur in mouths:
o With little or no plaque
o May be absent in mouths with abundant deposits.
• Enlargement is:
o Chronic
o Slowly increases in size.
o When surgically removed, it recurs.
o Spontaneous disappearance occurs within a few months after
discontinuation of the drug.
37
38. HISTOPATHOLOGY
• Pronounced hyperplasia of the connective tissue & epithelium.
• Acanthosis of the epithelium.
• Elongated rete pegs extending deep into the connective tissue.
• Densely arranged collagen bundles.
• Increase in the number of fibroblasts & new blood vessels.
• Abundance of amorphous ground substance.
Mariani et al
38
40. DRUGS CLINICAL FEATURES HISTOPATHOLOGY
PHENYTOIN • Granular or pebbly surface of affected
tissues enlarged papillae extending facially
&/or lingually.
• Formation of pseudoclefts due to
confluence of enlarged papillae
(Hallmon & Rossmann)
• Florid overgrowth of affected papillae.
• Rare cases - observed in edentulous
patients & beneath pontics of FPDs
(McCord J, Sloan P, 1992)
• Fibroblast to collagen
ratio equal to that of
normal gingiva from
normal individuals.
Florid overgrowth of affected papillae and presence of pseudoclefts
resulting from overlapping of adjacent marginal gingiva and
papillary confluence after long term Phenytoin use.
40
DRUGS CLINICAL FEATURES HISTOPATHOLOGY
CYCLOSPORIN A
• Affects children more frequently
• Enlarged gingival tissues are soft
• Extremely fragile
• Red or bluish red
• Bleed easily upon probing.
• Restricted to keratinized gingiva only, so
no interference with occlusion,
mastication or speech.
(Friskopp and Klintmalm, 1996)
• More hyperemic than phenytoin
induced enlargement.
(Seymour & Jacobs, 1992)
• Highly vascular
connective tissue with
foci of chronic
inflammatory cells,
particularly plasma
cells .
NIFEDIPINE
• Enlarged interdental papilla.
• Lobulated /nodular morphology.
• 10 fold increase in
epithelial width.
• Increase capillary
vascularity
• Slight perivascular
inflammation.
CYCLOSPORINE INDUCED GINGIVAL OVERGROWTH
41. HISTOPATHOLOGY OF DRUG–INDUCEDGINGIVALENLARGEMENT
PHENYTOIN
NIFEDIPINE
CYCLOSPORIN A
Fibroblast to collagen ratio in mature
lesion is equal to that of normal gingiva
from normal individuals
Highly vascular connective tissue with
foci of chronic inflammatory cells,
particularly plasma cells.
• Ten fold increase in epithelial width.
• Increased capillary vascularity and slight
perivascular inflammation.
41
44. DRUG METABOLITES (Phenytoin, Nifedipine, Cyclosporin)
Increased collagen production
Increased extracellular matrix synthesis
T- lymphocytes
TH2 response
IL-13, 1L4
Macrophages
TGF-β
CTGF
FGF-2
PDGF
44
INCREASED COLLAGEN SYNTHESIS
FIBROBLASTS
Proliferation of highly active fibroblasts
45. 45
DECREASED COLLAGEN DEGRADATION
Drugs associated with gingival enlargement
(Anticonvulsants, Immunosuppressants, CCB, others)
Disturbance in calcium homeostasis
Decreased influx of Ca2+ into fibroblast
Decreased uptake of Ca2+ dependant folic
acid by fibroblasts
Decreased production of active collagenase
Increased expression of TIMP
Decreased MMP 1, 2 & 3
mediated collagen degradation
46. Waxman et al, 1970
Long term phenytoin therapy
Low serum level of folic acid
Drug metabolite reduces the absorption from GIT
Blocks the transport across intestinal epithelium
Decreased folate reductase
Impaired maturation of epithelium
Connective tissue susceptible to inflammation
46
47. Decreased collagen phagocytosis
Phenytoin induced
Reduced α2β1 Integrin expression on
fibroblasts
Decreased adhesion of Type 1 Collagen
with Fibroblast
Decreased Endocytosis
Decreased phagocytosis of Type 1 collagen
Fibroblast Apoptosis
Phenytoin induced
Decreased Fibroblast apoptosis
Contribute to fibrosis
Increased number of fibroblasts
Extracellular matrix accumulation
Kantarci P A, 2007
47
INTRACELLULAR PATHWAY
α 2β1 receptors
Receptors UPARAP/ENDO 180 – One of the main
receptors responsible for collagen phagocytosis.
Not enough evidence to substantiate the role of this
receptor.
48. Joice et al: Phenytoin Induced Gingival overgrowth: A review of the cellular, molecular and inflammatory
features 10.5402/2011/497850
Modification of immune
cells by drug metabolites
Imbalance in production of
cytokines and other mediators
Increased TGFβ1, FGF-2
and others
TGFβ1
Increases synthesis and
deposit of collagen.
Regulation of TIMP.
Reduction of collagen
phagocytosis.
Myofibroblasts are
associated with
later stages of
tissue turnover.
48
50. RISK FACTORS FOR DRUG INDUCED GINGIVAL
ENLARGEMENT
RISK FACTORS
1. Age
2. Genetic factors
3. Pharmacokinetic variables
4. Alterations in the gingival connective tissue
5. Drug induced action on growth factors.
UNIFYING HYPOTHESIS
Vogel et al discussed first the possible
mechanism of pathogenesis that
grouped several current hypothesis
together.
DISSIMILAR DRUGS - SIMILAR
EFFECTS
Action on Ca2+ & Na+ influx
Link between dissimilar drugs
causing gingival enlargement
50
51. 51
AGE
Fibroblasts in areas of Inflamed gingival tissues
Androgen (Testosterone)
5 α- Dihydrotestosterone (5α DHT)
Biologically active
Stimulation of biosynthetic activity in subpopulation of fibroblasts
Increased collagen production
Children/Adolescent
Increased production of
androgen (testosterone)
Sooriyamoorthy M, Gower D, Eley BM. Androgen metabolism in gingival hyperplasia
induced by Nifedipine and Cyclosporin. JOP. 1990;25:25-30
53. 53
PHARMACOKINETIC VARIABLES
Systemic administration of drug
Local sequestration
Increased concentration
in saliva/GCF
Threshold concentration
Altered fibroblast activity
Concomitant Medication:
Higher Incidence, Severity
& Recurrence rate
Phenytoin + Cyclosporin
Bokenkamp 1994
Margiotta 1996
Prednisolone & Azathioprine -
Combined
immunosuppressant action
with Phenytoin, Cyclosporin &
Calcium channel blockers
Degree of salivary
Phenytoin & gingival
overgrowth
Babcock & Nelson1964
Cyclosporin concentration
in stimulated saliva
& extent of gingival
overgrowth
Mc Gaw et al 1987
Hefti et al 1994
Assumption:
Serum concentration of
active drug > gingival
enlargement to occur.
Threshold differs between:
o Individuals
o Drug to drug
Seymour,1988, 2000
Daley et al1986
Patients exhibiting gingival
overgrowth
Nifedipine & Amlodipine
Conclusions:
1. Can be detected in GCF
2. Significant sequestration of drug
Ellis et al. 1992
Seymour et al. 1994
Direct relationship
54. 54
ALTERATION IN CONNECTIVE TISSUE METABOLISM
HOMEOSTATIC BALANCE
Collagen production Collagen degradation
ALTERED METABOLISM
Fibroblast heterogeneity
Hyperactivity Increased TIMP (Tipton et al, 1991)
Decreased/abnormal Collagenase
Increased collagen production
(Goultchin & Shoskan 1980)
Decreased collagen breakdown
Acanthosis & accumulation of non collagenous extracellular
substances
In addition deficiency of Cathepsin B and L together with
increased levels of Hexose amine, Hyaluronic acid and total
protein content.
55. 55
.
PHENYTOIN
Responders: Up-regulation of EGF
receptor metabolism
Non responders: Down-regulation of
EGF receptor metabolism
Modeer et al 1990
d PDGF secretion from
macrophages
Dill et al. 1993
Abnormal response to plaque
induced inflammatory changes
DRUG-INDUCEDACTIONON GROWTH
FACTORS
57. MANAGEMENT OF GINGIVAL ENLARGEMENT
57
NON SURGICAL
1. Scaling and Root planing
2. Drug Substitution
3. Antimicrobials
4. Supplements
SURGICAL
1. Gingivoplasty
2. Gingivectomy
3. Periodontal flap surgery
58. 58
Mouth wash
Chlorhexidine Gluconate – 0.2 %
Metronidazole
Usage is controversial
Increases drug metabolites
of Cyclosporin in blood.
Adverse drug effects of
Cyclosporin Seen
Azithromycin
Mechanism of Action:
High intracellular accumulation (Azithromycin
metabolites):
o Endogenous defense cells
o Tissues affected by inflammatory changes
Increase phagocytosis of collagen fibres
Counter acts
Decreasing accumulation of extracellular matrix
ANTIBIOTICS
Dannewitz B, Proliferation of the gingiva: etiology, risk factors and treatment modalities for gingival
enlargement. Perio 2007;4(2):83-92
60. 60
No sufficient data exists to indicate folic acid therapy is
beneficial in Phenytoin induced Gingival enlargement
PHENYTOIN INDUCED GINGIVAL
ENLARGEMENT
Therapeutic benefits
Inove & Harrison, Prasad et al
No therapeutic
benefits
Brown et al, Majota et al
Folic acid therapy
62. 62
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