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Medically Induced Gingival Hyperplasia

1998; Elsevier BV; Volume: 73; Issue: 12 Linguagem: Inglês

10.4065/73.12.1196

1942-5546

Stephen J. Meraw, Phillip J. Sheridan,

Hedgehog Signaling Pathway Studies

Gingival hyperplasia or gingival overgrowth is a common occurrence in patients taking phenytoin, cyclosporine, or calcium channel blockers. Speech, mastication, tooth eruption, and aesthetics may be altered. Controlling the inflammatory component through an appropriate oral hygiene program may benefit the patient by limiting the severity of the gingival overgrowth. In patients in whom gingival overgrowth is present or may be anticipated, recognition of this condition and referral to a general dentist or periodontist are appropriate steps to management. The physician's awareness of the potential for development of overgrowth and the dental practitioner's role in attempting to prevent or minimize this problem are important aspects. In this article, we discuss the medications associated with gingival hyperplasia and describe appropriate recommendations. Gingival hyperplasia or gingival overgrowth is a common occurrence in patients taking phenytoin, cyclosporine, or calcium channel blockers. Speech, mastication, tooth eruption, and aesthetics may be altered. Controlling the inflammatory component through an appropriate oral hygiene program may benefit the patient by limiting the severity of the gingival overgrowth. In patients in whom gingival overgrowth is present or may be anticipated, recognition of this condition and referral to a general dentist or periodontist are appropriate steps to management. The physician's awareness of the potential for development of overgrowth and the dental practitioner's role in attempting to prevent or minimize this problem are important aspects. In this article, we discuss the medications associated with gingival hyperplasia and describe appropriate recommendations. Medically induced gingival hyperplasia or gingival overgrowth is a reactionary phenomenon that occurs because of several types of therapeutic agents. This disorder has been recognized since 1939,1Kimball OP The treatment of epilepsy with sodium diphenyl hydantoinate.JAMA. 1939; 112: 1244-1250Crossref Scopus (139) Google Scholar shortly after the introduction of phenytoin2Putnam TJ Me tritt HH Experimental determination of the anticonvulsant properties of some phenyl derivatives.Scrence. 1937; 85: 525-526Crossref Scopus (150) Google Scholar for the control of epileptic seizures. Although anticonvulsants, calcium channel blocking agents, and the immunosuppressant cyclosporine differ pharmacologically, they share an ability to induce gingival overgrowth. The occurrence of this phenomenon, particularly in advanced cases, may interfere with speech, mastication, and tooth eruption and can be aesthetically undesirable.3Jones JE Weddell JA McKown CG Incidence and indications for surgical management of phenytoin-induced gingival overgrowth in a cerebral palsy population.J Oral Maxillofac Surg. 1988; 46: 385-390Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 4Pihlstrom BL Prevention and treatment of Dilantin-associated gingival enlargement.Compendium. 1990; 11: S506-S510Google Scholar Nonpharmacologic factors such as congenital or hormone-induced or long-term poor oral hygiene may be associated with gingival overgrowth;5Rose LF Sex hormonal imbalances, oral manifestations, and dental treatment.in: Genco RJ Goldman HM Cohen DW Confemporary Periodontics. Mosby, St. Louis1990: 221-227Google Scholar however, medically induced overgrowth is more severe. This article reviews the medications associated with gingival overgrowth, treatment, and prevention. Although the association between phenytoin and gingival overgrowth is widely recognized, other anticonvulsant agents such as barbiturates, valproic acid, succinimides, and carbamazepine have been reported to induce gingival overgrowth.6Rees TD Levine RA Systemic drugs as a risk factor for periodontal disease initiation and progression.Compendium. 1995; 16 (22:26): 20PubMed Google Scholar, 7Dongari A McDonnell HT Langlals RP Drug-induced gingival overgrowth.Oral Surg Oral Med Oral Pathcl. 1993; 76: 543-548Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 8Dahllof G Prefer H Eliasson S Ryden H Kanten J Modeer T Periodontat condition of epileptic adults treated long-term with phenytoin or carbamazepine.Epilepsie. 1993; 34: 960-964Crossref Scopus (19) Google Scholar The incidence of gingival overgrowth associated with these agents is low in comparison with that of phenytoin-induced gingival overgrowth. Of the approximately 2 million patients taking phenytoin, about half will have development of some degree of gingival overgrowth.9Butler RT Kalkwarf KL Kaldahl WB Drug-induced gingival hyperplasia: phenytoin, cyclosporine, and nifedipi ne.J Am Dent Assoc. 1987; 114: 56-60PubMed Scopus (97) Google Scholar Phenytoin-induced gingival overgrowth generally begins in the anterior interdental gingival papillae, often within 1 month after initiation of the drug.10Dahllof G Modeer T The effect of a plaque control program on the development of phenytoin-induced gingival overgrowth: a 2-year longitudinal study.J Clin Periodontol. 1986; 13: 845-849Crossref PubMed Scopus (32) Google Scholar The extent of overgrowth may be related to the dose, duration, and plasma levels of the drug,7Dongari A McDonnell HT Langlals RP Drug-induced gingival overgrowth.Oral Surg Oral Med Oral Pathcl. 1993; 76: 543-548Abstract Full Text PDF PubMed Scopus (63) Google Scholar but some studies do not support this concept.10Dahllof G Modeer T The effect of a plaque control program on the development of phenytoin-induced gingival overgrowth: a 2-year longitudinal study.J Clin Periodontol. 1986; 13: 845-849Crossref PubMed Scopus (32) Google Scholar11Penarrocha-Diago M Bagan-Sebastian JV Vera-Sempere F Diphenylhydantoin-induced gingival overgrowth in man: a clinicopathc-logical study.J Periodontol. 1990; 61: 571-574Crossref PubMed Scopus (33) Google Scholar Numerous studies have detected a direct correlation between the level of plaque and calculus accumulation and the severity of gingival overgrowth.6Rees TD Levine RA Systemic drugs as a risk factor for periodontal disease initiation and progression.Compendium. 1995; 16 (22:26): 20PubMed Google Scholar7Dongari A McDonnell HT Langlals RP Drug-induced gingival overgrowth.Oral Surg Oral Med Oral Pathcl. 1993; 76: 543-548Abstract Full Text PDF PubMed Scopus (63) Google Scholar11Penarrocha-Diago M Bagan-Sebastian JV Vera-Sempere F Diphenylhydantoin-induced gingival overgrowth in man: a clinicopathc-logical study.J Periodontol. 1990; 61: 571-574Crossref PubMed Scopus (33) Google Scholar As the gingival changes gradually become more pronounced, the marginal tissues that often extend to cover portions of the clinical crowns of the teeth become involved (Fig. 1). This involvement tends to be more pronounced on the facial than on the lingual surface of the teeth. Histologically, phenytoin-induced gingival overgrowth usually demonstrates increases in connective tissue, with no change in vascularity, and a relative decrease in epithelial thickness in comparison with normal gingiva.12Angelopoulos AP Diphenylhydantoin gingival hyperplasia: a clinicopathological review. I. Incidence, clinical features and histo-pathology.J Can Dent Assoc. 1975; 41: 103-106Google Scholar Chronic inflammatory cells, mainly lymphocytes and plasma cells, may be found as gingival inflammation arises as a result of increased plaque retention.12Angelopoulos AP Diphenylhydantoin gingival hyperplasia: a clinicopathological review. I. Incidence, clinical features and histo-pathology.J Can Dent Assoc. 1975; 41: 103-106Google Scholar The association between cyclosporine and gingival overgrowth became apparent shortly after this drug was introduced as an immunosuppressant in humans in 1978.13Macoviak JA Oyer PE Stinsort EB Jamieson SW Baldwin JC Shumway NE Four-year experience with cyclosporine for heart and heart-lung transplantation.Transplant Proc. 1985; 17: 97-101Google Scholar Reports indicate a variable incidence, ranging from 13 to 85%.14Wondtmu B Dahllof G Berg U Modeer T Cyclosporin-A-induced gingival overgrowth in renal transplant children.Scand J Dent Res. 1993; 101: 282-286PubMed Google Scholar15Allmart SD McWhorter AG Seste NS Evaluation of cyclosporin-induced gingival overgrowth in the pédiatrie transplant patient.Pediatr Dent. 1994; 16: 36-40PubMed Google Scholar Part of the variability is probably due to the fact that many of the patients taking cyclosporine concurrently take other systemic medications such as calcium channel blockers, which can contribute to gingival overgrowth.6Rees TD Levine RA Systemic drugs as a risk factor for periodontal disease initiation and progression.Compendium. 1995; 16 (22:26): 20PubMed Google Scholar Cyclosporine-induced overgrowth has been reported to be less common in bone marrow transplant recipients than in solid organ transplant recipients.16Seymour RA Jacobs DJ Cyclosporin and the gingival tissues.J Clin Periodontol. 1992; 19: 111Crossref Scopus (148) Google Scholar Clinically, cyclosporine-induced gingival overgrowth is similar to phenytoin-induced gingival overgrowth.6Rees TD Levine RA Systemic drugs as a risk factor for periodontal disease initiation and progression.Compendium. 1995; 16 (22:26): 20PubMed Google Scholar16Seymour RA Jacobs DJ Cyclosporin and the gingival tissues.J Clin Periodontol. 1992; 19: 111Crossref Scopus (148) Google Scholar Initially, the anterior labial interproximal gingiva becomes involved. Subsequently, the marginal gingiva, which increases in dimension to cover portions of the clinical crowns of the teeth, becomes involved (Fig. 2). Plasma levels and dose of the drug have been suggested to be the principal factors influencing cyclosporine-induced overgrowth.17Seymour RA Smith DG Rogers SR The comparative effects of azathioprine and cyclosporin on some gingival health parameters of renal transplant patients: a longitudinal study.J Clin Periodontol. 1987; 14: 610-613Crossref PubMed Scopus (118) Google Scholar, 18Somacarrera ML Hernandez G Acero J Moskow BS Factors related to the incidence and severity of cyclosporin-induced gingival overgrowth in transplant patients: a longitudinal study.J Periodontol. 1994; 65: 671-675Crossref PubMed Scopus (135) Google Scholar, 19Morisaki I Aklyama YM Mlyawaki YN Mori Y Positive correlation between blood cyclosporin A level and severity of gingival overgrowth in rats.J Periodontol. 1997; 68: 7-11Crossref PubMed Scopus (13) Google Scholar Accumulations of bacterial plaque and chronic gingivitis may further increase the overgrowth.18Somacarrera ML Hernandez G Acero J Moskow BS Factors related to the incidence and severity of cyclosporin-induced gingival overgrowth in transplant patients: a longitudinal study.J Periodontol. 1994; 65: 671-675Crossref PubMed Scopus (135) Google Scholar Some investigators dispute the relationship between specific drug plasma levels and cyclosporine-induced overgrowth.14Wondtmu B Dahllof G Berg U Modeer T Cyclosporin-A-induced gingival overgrowth in renal transplant children.Scand J Dent Res. 1993; 101: 282-286PubMed Google Scholar, 15Allmart SD McWhorter AG Seste NS Evaluation of cyclosporin-induced gingival overgrowth in the pédiatrie transplant patient.Pediatr Dent. 1994; 16: 36-40PubMed Google Scholar, 20McGaw T Lam S Coatea J Cyclosporin-induced gingival overgrowth: correlation with dental plaque scores, gingivitis scores, and cyclosporin levels in serum and saliva.Oral Surg Oral Med Oral Pathol. 1987; 64: 293-297Abstract Full Text PDF PubMed Scopus (137) Google Scholar, 21Seymour RA Smith DG The effect of a plaque control programme on the incidence and severity of cyclosporin-induced gingival changes.J Clin Periodontol. 1991; 18: 107-110Crossref PubMed Scopus (139) Google Scholar, 22King GN Fullinfaw R Higgins TJ Walker RG Francis DM Wlesenfeld D Gingival hyperplasia in renal allograft recipients receiving cyclosporin-A and calcium antagonists.J Clin Periodontol. 1993; 20: 286-293Crossref PubMed Scopus (102) Google Scholar Clinical manifestation of cyclosporine-induced overgrowth usually begins within 1 to 3 months after initiation of cyclosporine therapy.16Seymour RA Jacobs DJ Cyclosporin and the gingival tissues.J Clin Periodontol. 1992; 19: 111Crossref Scopus (148) Google Scholar23PlatteIII A PetreIII I Fanci P Regression following reduction of the daily drug dosage in cyclosporin A-induced gingival overgrowth in bone marrow transplant recipients.Acta Stomatol Belg. 1993; 90: 171-176PubMed Google Scholar Histologically, cyclosporine-induced overgrowth generally displays increases in connective tissue with overlying irregular, multilayered, and para-keratinized epithelium of varying thickness. Controversy exists regarding the nature of increase in connective tissue, and some investigators suggest no appreciable increase occurs in numerical density of fibroblasts.24McGaw WT Porter H Cyclosporin-induced gingival overgrowth: an ultrastructural stereologic study.Oral Surg Orel Med Oral Patnol. 1988; 65: 186-190Abstract Full Text PDF PubMed Scopus (62) Google Scholar Thus, the issue involves the appropriateness of the term “hyperplasia” and the subsequent common use of the term “overgrowth.” The calcium channel blocker that is most commonly associated with gingival overgrowth is nifedipine, with a reported incidence of approximately 38%.25Steele RM Schuna AA Schreiber RT Calcium antagonist-induced gingival hyperplasia.Ann Intern Med. 1994; 120: 663-664Crossref PubMed Scopus (48) Google Scholar Other agents that have been found to have an association with gingival overgrowth include diltiazem, incidence of 20%;26Fattore L Stablein M Bredfeldt G Semia T Moran M Doherty-Greenberg: JM Gingival hyperplasia: a side effect of nifedipine and diltiazem.Spec Care Dentist. 1991; 11: 107-109Crossref PubMed Scopus (66) Google Scholar verapamil, incidence of 4 to 19%;25Steele RM Schuna AA Schreiber RT Calcium antagonist-induced gingival hyperplasia.Ann Intern Med. 1994; 120: 663-664Crossref PubMed Scopus (48) Google Scholar27Miller CS Damm DD incidence of verapamil-induced gingival hyperplasia in a dental population.J Periodontol. 1992; 63: 453-456Crossref PubMed Scopus (88) Google Scholar and amlodipine, incidence of 3%.28Jorgensen MG Prevalence of amlodipine-related gingival hyperplasia.J Periodontol. 1997; 68: 67-78Crossref PubMed Scopus (81) Google Scholar Case reports have indicated that gingival overgrowth can also occur with the use of felodipine29Lombardi T Fiore-Donno G Belter U Dl Felice R Felodi pine-induced gingival hyperplasia: a clinical and histologie study.J Oral Pathol Med. 1991; 20: 8992Crossref Scopus (42) Google Scholar and nitrendipine.30Brown RS Sein P Corio R Bottomley WK Nitrendipine-induced gingival hyperplasia: first case report.Oral Surg Oral Med Oral Pathol. 1990; 70: 593-596Abstract Full Text PDF PubMed Scopus (50) Google Scholar Clinically, calcium channel blocker-related gingival overgrowth (Fig. 3) closely resembles phenytoin-induced overgrowth. Usually, it becomes apparent 1 to 3 months after initiation of the drug.31Nishikawa S Tada H Hamaaakl A Kasahara S Kido J Nagata T et al.Nifedipine-induced gingival hyperplasia: a clinical and in vitro study.J Periodontol. 1991; 62: 30-35Crossref PubMed Scopus (71) Google Scholar Specific dose or plasma levels have been associated with this type of gingival overgrowth in animal models32Ishida H Kondoh T Kataoka M Nishikawa S Nakagawa T Morisakl I et al.Factors influencing nifedipine-induced gingival overgrowth in rats.J Periodontol. 1995; 66: 345-350Crossref PubMed Scopus (39) Google Scholar but have not been demonstrated in humans.33Nery EB Edson RG Lee KK PrutW VK Watson J Prevalence of nifedipine induced gingival hyperplasia.J Periodontol. 1995; 66: 572-578Crossref PubMed Scopus (71) Google Scholar, 34Bullon P Machuca G Martinez-Sahuqulllo A Rlos JV Rojas J Lacalle JR Clinical assessment of gingival hyperplasia in patients treated with nifedipine.J Clin Periodontol. 1994; 21: 256-259Crossref PubMed Scopus (33) Google Scholar, 35Ellis JS Seymour RA Monkman S Idle JR Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug induced gingival overgrowth.J Periodontol Res. 1993; 28: 373-378Crossref PubMed Scopus (25) Google Scholar One theory is that plaque accumulation as a result of inadequate oral hygiene may add to the severity of this type of overgrowth.33Nery EB Edson RG Lee KK PrutW VK Watson J Prevalence of nifedipine induced gingival hyperplasia.J Periodontol. 1995; 66: 572-578Crossref PubMed Scopus (71) Google Scholar34Bullon P Machuca G Martinez-Sahuqulllo A Rlos JV Rojas J Lacalle JR Clinical assessment of gingival hyperplasia in patients treated with nifedipine.J Clin Periodontol. 1994; 21: 256-259Crossref PubMed Scopus (33) Google Scholar This relationship has been questioned by some investigators.35Ellis JS Seymour RA Monkman S Idle JR Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug induced gingival overgrowth.J Periodontol Res. 1993; 28: 373-378Crossref PubMed Scopus (25) Google Scholar36Barclay S Thomason JM Idle JR Seymour RA The incidence and severity of nifedipine-induced gingival overgrowth.J Clin Periodontol. 1992; 19: 311314Crossref Scopus (120) Google Scholar Histologically, calcium channel blocker-related gingival overgrowth exhibits increases in extracellular ground substance and increased numbers of fibroblasts37Lucas RM Howell LP Wall BA Nifedipine-induced gingival hyperplasia: a histochemical and ultrastructural study.J Periodontol. 1985; 56: 211-215Crossref PubMed Scopus (89) Google Scholar that closely resemble phenytoin-induced overgrowth. Histologic changes are considered nonpathognomonic for specific drug types. Ideally, the treatment of choice for medically induced gingival overgrowth would be discontinuation of the associated medication. Regression of gingival overgrowth has been demonstrated after discontinuation of all three types of previously described drugs.23PlatteIII A PetreIII I Fanci P Regression following reduction of the daily drug dosage in cyclosporin A-induced gingival overgrowth in bone marrow transplant recipients.Acta Stomatol Belg. 1993; 90: 171-176PubMed Google Scholar38Dahliof G Axto E Modeer T Regression of phenytoin i nduced gingival overgrowth after withdrawl of medication.SwedDentJ. 1991; 15: 139-143PubMed Google Scholar39Bokenkamp A Bohnhorst B Bêler C Albere N Offner G Brodehl J Nifedipine aggravates cyclosporin A-induced gingival hyperplasia.Pediatr Nephrol. 1994; 8: 181-185Crossref PubMed Scopus (68) Google Scholar Although ideal, this approach is often not possible. In some patients, however, the use of another drug in the same class of medications could provide the appropriate medical outcomes with a reduced incidence of gingival overgrowth. This situation was demonstrated in a group of patients with mild to moderate hypertension in whom the medication was changed from nifedipine to isradipine, and the gingival overgrowth subsequently regressed.40Wostbrook P Bednarczyk EM Carlson M Sheehan M Bissada NF Regression of nifedipine-induced gingival hyperplasia following switch to a same class calcium channel blocker, isradipine.J Periodontol. 1997; 68: 645-650Crossref PubMed Scopus (45) Google Scholar Dental treatment planning with respect to medically induced gingival overgrowth commonly focuses on the prevention or minimization of the overgrowth, and the patient's oral hygiene is the primary factor. The patient must be aware of the potential for gingival overgrowth. Additionally, the patient's dentist must have an awareness of this problem in order to develop an appropriate regimen to prevent or minimize gingival overgrowth. Moderate to severe overgrowth of the gingival tissues sometimes necessitates surgical reduction of the redundant soft tissues.41Carrania Jr, FA Glickman's Clinical Periodontology. 71h ed. Saunders, Philadelphia1990: 125-148Google Scholar Although an operation provides immediate and dramatic results (Fig. 4), the gingival overgrowth has the potential to recur when the causative medications must be used for ongoing therapy. In some patients, periodic surgical reduction of the soft tissues is necessary. Thus, the dentist's role in reinforcing the importance of oral hygiene and in providing maintenance care is critical. Approximately 40 to 50% of patients taking phenytoin, cyclosporine, or calcium channel blockers will have development of some degree of gingival overgrowth. This condition can lead to problems with speech, mastication, tooth eruption, and aesthetics. Controlling the inflammatory component through an appropriate oral hygiene program may benefit the patient by limiting the severity of the gingival overgrowth.42Hall WB Dilantin hyperplasia: a preventable lesion?.Compendium. 1990; 11: S502-S505Google Scholar In a patient in whom gingival overgrowth is present or may be anticipated, referral to a general dentist or periodontist is appropriate. The physician's awareness of the potential for the development of overgrowth and the dental practitioner's role in attempting to prevent or minimize this problem are important aspects.