DRUG INDUCED GINGIVAL ENLARGMENT (DIGO)

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

1. DRUG INDUCED GINGIVAL ENLARGEMENT 1

2. Contents Introduction Classification of gingival enlargement Indices for gingival enlargement Drugs associated with gingival enlargement Anticonvulsants Immunosuppressants Calcium Channel blockers Miscellaneous Prevalence of drugs causing gingival enlargement Clinical manifestations and Histopathologic features Pathogenesis of Drug induced gingival enlargement Risk factors for Drug induced gingival enlargement Management References 2

3. Coral Pink Scalloped & Knife edged Surface Texture Stippled Firm & resilient consistency Size : Cellular + Intercellular + Vasculature Interdental Papilla Anterior – Pyramidal Posterior – Tent shaped Gingiva in health….. INTRODUCTION 3

4. INCREASE IN SIZE OF GINGIVA 4

5. REASONS FOR INCREASE IN SIZE OF GINGIVA 5

6. Various terms used previously 6

7. 7 SEQUELAE OF GINGIVAL OVERGROWTH Brunnet et al 1996

8. 8 CLASSIFICATION OF GINGIVAL ENLARGEMENT

9. 9 OLDER CLASSIFICATION According to etiologic factors & pathologic changes CARRANZA 9 TH EDITION

10. 10 MODIFIED CLASSIFICATION According to etiology CARRANZA 11 TH EDITION

11. Shafer’s classification 11 Shafer WG, Hine M, Levy B. Shafer’s textbook of oral pathology. Elsevier. New Delhi. 5 th 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 Margina l: 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 CARRANZA 11 TH EDITION

13. 13 INDICES FOR GINGIVAL 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 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 HARRIS et al 1942 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. INGLES 1999

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.

25. Drugs associated with gingival enlargement 25 Anticonvulsants Miscellaneous Calcium channel blockers Immunosuppressants

26. Prevalence rate 26 Angelopoulos AP & Goaz PW 1972 Seymour et al 1987 Barclay et al 1992 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. DISTRIBUTION

28. 28 Uses Threshold plasma concentration Incidence Active metabolite Progression Epilepsy – generalized tonic-clonic seizures, partial seizures. 10-20µg/ml (Rees et al, 1993) - 84.5%, Average 50% (Angelopoulos et al) 5-parahydroxyphenyl-5-phenylhydantoin 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 Nausea, Vomitting , Epigastric pain & anorexia. Nystgmus , Diplopia , Ataxia. Gingival hyperplasia (common in children on prolonged use). Peripheral neuropathy. 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. Immunosuppressants

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 Nephrotoxicity Hepatotoxicity Anorexia Gum hypertrophy 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 Nifedipine 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 Cardiac depression Facial flushing Dizziness Headache Edema Gingival enlargement

33. 33 Miscellaneous Prednisone Prednisolone Valsartan Atenolol Paracetamol Lysine acetylsalicylate Acebutalol Metoprolol Isosorbide dinitrate Trinitrine Spironolactone Allopurinol Oral contraceptives Containing : Ethinylestradiol Levonorgestrel Desogestrel

34. 34 CLINICAL FEATURES of drug induced gingival enlargement

35. CLINICAL FEATURES of drug induced gingival enlargement Growth starts as: A painless beadlike enlargement of the interdental papilla Extends to facial & lingual gingival margins. On progression: Marginal & papillary enlargements unite Develop into massive tissue fold covering large part of crown Interfere with occlusion When uncomplicated by inflammation: Lesion is mulberry shaped Firm and resilient Pale pink Minutely lobulated surface No tendency to bleed 35

36. Enlargement characteristically appears to: Project from beneath the gingival margin 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: With little or no plaque May be absent in mouths with abundant deposits. Enlargement is: Chronic Slowly increases in size. When surgically removed, it recurs. 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. E longated 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

39. 39 CLINICAL and histopathologic FEATURES of various drugs

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 –INDUCED GINGIVAL ENLARGEMENT 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 w ith foci of chronic inflammatory cells, particularly plasma cells. Ten fold increase in epithelial width. Increased capillary vascularity and slight perivascular inflammation. 41

42. 42 Pathogenesis of DRUG INDUCED GINGIVAL ENLARGEMENT

43. Pathogenesis of DIGO 43

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 DE CREASED COLLAGEN DEGRADATION EXTRACELLULAR PATHWAY Drugs associated with gingival enlargement (Anticonvulsants, I mmunosuppressants, CCB, others) Disturbance in calcium homeostasis Decreased influx of Ca 2+ into fibroblast Decreased uptake of Ca 2+ 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 α 2 β 1 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 IN TRACELLULAR PATHWAY α 2 β 1 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 TGF β 1, FGF-2 and others TGF β 1 Increases synthesis and deposit of collagen. Regulation of TIMP. Reduction of collagen phagocytosis. Myofibroblasts are associated with later stages of tissue turnover. 48

49. 49 Risk factors for Drug induced gingival enlargement

50. RISK FACTORS FOR DRUG INDUCED GINGIVAL ENLARGEMENT RISK FACTORS Age Genetic factors Pharmacokinetic variables Alterations in the gingival connective tissue 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 Ca 2+ & 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 (5 α 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

52. 52 GENETIC PREDISPOSITION PHENYTOIN/CYCLOSPORINE/CCB Altered metabolism of drug Threshold concentration of drug/metabolite Disturbance in calcium homeostasis Decreased Folate R eductase Gingival fibroblasts are activated Decreased collagen breakdown INCREASED RISK Cytochrome P450 HLA-DR2 HLA19 Genotype C807 HLAB37 Cytochrome P450 Genotype C807 DECREASED RISK HLA-DR1

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 : Individuals Drug to drug Seymour,1988, 2000 Daley et al1986 Patients exhibiting gingival overgrowth Nifedipine & Amlodipine Conclusions: Can be detected in GCF 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 . DRUG-INDUCED ACTION ON GROWTH FACTORS

56. 56 MANAGEMENT OF GINGIVAL ENLARGEMENT

57. MANAGEMENT OF GINGIVAL ENLARGEMENT 57 NON SURGICAL Scaling and Root planing Drug Substitution Antimicrobials Supplements SURGICAL Gingivoplasty Gingivectomy Periodontal flap surgery

58. 58 ANTIMICROBIALS 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): Endogenous defense cells 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

59. 59 DRUG SUBSTITUTION SUBSTITUTE FOR NIFEDIPINE SUBSTITUTE FOR CYCLOSPORIN A SUBSTITUTE FOR PHENYTOIN Isradipine 20 mg BD Tacrolimus (0.15 - 0.20/kg/d) Phenobarbital 60 mg TDS ACE Inhibitors - Captopril 12.5 - 50 mg BD - Enalapril (2.5 - 20 mg OD) Rapamycin Primidone 100 mg TDS Carbamazepine 200 – 400 mg TDS Valproic acid 200 – 500 mg TDS

60. 60 SUPPLEMENTS 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

61. 61 GINGIVECTOMY

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63. 63 Brown RS, Beaver WT, Bottomley WK. On the mechanism of drug-induced gingival hyperplasia. On the mechanism of DIGH. Oral Pathol Med. 1991; 20:201-9. Nyska A, M. Shemesh , H Tal, Dayan D. Gingival Hyperplasia Induced by Calcium Channel Blockers: Mode of Action. Medical Hypothesis. 1994; 43:115-118. Christina Popova , Antoaneta Mlachkova . Surgical approach to drug - induced gingival enlargement in renal transplant patients: Case report. J of IMAB, 2007, vol. 13, book 2. Arnold D Steinberg. Clinical management of phenytoin -induced gingival overgrowth in handicapped children. Pediatric dentistry. Volume 3, Special Issue. Chae HJ, Ha MS, Yun DH, Chung HT. Mechanism of Cyclosporine-induced Overgrowth in Gingiva. J Dent Res85(6):515-519, 2006. REFERENCES

64. 64 C A S E 1 C A S E 2

65. 65 THANK YOU  “ Knowing is not enough, we must apply, Willing is not enough, we must do” Von Goethe……