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Medically Induced Gingival Hyperplasia

      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,
      • Kimball OP
      The treatment of epilepsy with sodium diphenyl hydantoinate.
      shortly after the introduction of phenytoin
      • Putnam TJ
      • Me tritt HH
      Experimental determination of the anticonvulsant properties of some phenyl derivatives.
      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.
      • Jones JE
      • Weddell JA
      • McKown CG
      Incidence and indications for surgical management of phenytoin-induced gingival overgrowth in a cerebral palsy population.
      • Pihlstrom BL
      Prevention and treatment of Dilantin-associated gingival enlargement.
      Nonpharmacologic factors such as congenital or hormone-induced or long-term poor oral hygiene may be associated with gingival overgrowth;
      • Rose LF
      Sex hormonal imbalances, oral manifestations, and dental treatment.
      however, medically induced overgrowth is more severe. This article reviews the medications associated with gingival overgrowth, treatment, and prevention.

      ANTICONVULSANTS

      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.
      • Rees TD
      • Levine RA
      Systemic drugs as a risk factor for periodontal disease initiation and progression.
      • Dongari A
      • McDonnell HT
      • Langlals RP
      Drug-induced gingival overgrowth.
      • Dahllof G
      • Prefer H
      • Eliasson S
      • Ryden H
      • Kanten J
      • Modeer T
      Periodontat condition of epileptic adults treated long-term with phenytoin or carbamazepine.
      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.
      • Butler RT
      • Kalkwarf KL
      • Kaldahl WB
      Drug-induced gingival hyperplasia: phenytoin, cyclosporine, and nifedipi ne.
      Phenytoin-induced gingival overgrowth generally begins in the anterior interdental gingival papillae, often within 1 month after initiation of the drug.
      • Dahllof G
      • Modeer T
      The effect of a plaque control program on the development of phenytoin-induced gingival overgrowth: a 2-year longitudinal study.
      The extent of overgrowth may be related to the dose, duration, and plasma levels of the drug,
      • Dongari A
      • McDonnell HT
      • Langlals RP
      Drug-induced gingival overgrowth.
      but some studies do not support this concept.
      • Dahllof G
      • Modeer T
      The effect of a plaque control program on the development of phenytoin-induced gingival overgrowth: a 2-year longitudinal study.
      • Penarrocha-Diago M
      • Bagan-Sebastian JV
      • Vera-Sempere F
      Diphenylhydantoin-induced gingival overgrowth in man: a clinicopathc-logical study.
      Numerous studies have detected a direct correlation between the level of plaque and calculus accumulation and the severity of gingival overgrowth.
      • Rees TD
      • Levine RA
      Systemic drugs as a risk factor for periodontal disease initiation and progression.
      • Dongari A
      • McDonnell HT
      • Langlals RP
      Drug-induced gingival overgrowth.
      • Penarrocha-Diago M
      • Bagan-Sebastian JV
      • Vera-Sempere F
      Diphenylhydantoin-induced gingival overgrowth in man: a clinicopathc-logical study.
      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.
      • Angelopoulos AP
      Diphenylhydantoin gingival hyperplasia: a clinicopathological review. I. Incidence, clinical features and histo-pathology.
      Chronic inflammatory cells, mainly lymphocytes and plasma cells, may be found as gingival inflammation arises as a result of increased plaque retention.
      • Angelopoulos AP
      Diphenylhydantoin gingival hyperplasia: a clinicopathological review. I. Incidence, clinical features and histo-pathology.
      Figure thumbnail gr1
      Fig. 1Phenytoin-associated gingival overgrowth. Note near-complete coverage of clinical crown.

      CYCLOSPORINE

      The association between cyclosporine and gingival overgrowth became apparent shortly after this drug was introduced as an immunosuppressant in humans in 1978.
      • Macoviak JA
      • Oyer PE
      • Stinsort EB
      • Jamieson SW
      • Baldwin JC
      • Shumway NE
      Four-year experience with cyclosporine for heart and heart-lung transplantation.
      Reports indicate a variable incidence, ranging from 13 to 85%.
      • Wondtmu B
      • Dahllof G
      • Berg U
      • Modeer T
      Cyclosporin-A-induced gingival overgrowth in renal transplant children.
      • Allmart SD
      • McWhorter AG
      • Seste NS
      Evaluation of cyclosporin-induced gingival overgrowth in the pédiatrie transplant patient.
      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.
      • Rees TD
      • Levine RA
      Systemic drugs as a risk factor for periodontal disease initiation and progression.
      Cyclosporine-induced overgrowth has been reported to be less common in bone marrow transplant recipients than in solid organ transplant recipients.
      • Seymour RA
      • Jacobs DJ
      Cyclosporin and the gingival tissues.
      Clinically, cyclosporine-induced gingival overgrowth is similar to phenytoin-induced gingival overgrowth.
      • Rees TD
      • Levine RA
      Systemic drugs as a risk factor for periodontal disease initiation and progression.
      • Seymour RA
      • Jacobs DJ
      Cyclosporin and the gingival tissues.
      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).
      Figure thumbnail gr2
      Fig. 2Cyclosporine-associated gingival overgrowth.
      Plasma levels and dose of the drug have been suggested to be the principal factors influencing cyclosporine-induced overgrowth.
      • Seymour RA
      • Smith DG
      • Rogers SR
      The comparative effects of azathioprine and cyclosporin on some gingival health parameters of renal transplant patients: a longitudinal study.
      • Somacarrera 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.
      • Morisaki I
      • Aklyama YM
      • Mlyawaki YN
      • Mori Y
      Positive correlation between blood cyclosporin A level and severity of gingival overgrowth in rats.
      Accumulations of bacterial plaque and chronic gingivitis may further increase the overgrowth.
      • Somacarrera 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.
      Some investigators dispute the relationship between specific drug plasma levels and cyclosporine-induced overgrowth.
      • Wondtmu B
      • Dahllof G
      • Berg U
      • Modeer T
      Cyclosporin-A-induced gingival overgrowth in renal transplant children.
      • Allmart SD
      • McWhorter AG
      • Seste NS
      Evaluation of cyclosporin-induced gingival overgrowth in the pédiatrie transplant patient.
      • McGaw T
      • Lam S
      • Coatea J
      Cyclosporin-induced gingival overgrowth: correlation with dental plaque scores, gingivitis scores, and cyclosporin levels in serum and saliva.
      • Seymour RA
      • Smith DG
      The effect of a plaque control programme on the incidence and severity of cyclosporin-induced gingival changes.
      • King GN
      • Fullinfaw R
      • Higgins TJ
      • Walker RG
      • Francis DM
      • Wlesenfeld D
      Gingival hyperplasia in renal allograft recipients receiving cyclosporin-A and calcium antagonists.
      Clinical manifestation of cyclosporine-induced overgrowth usually begins within 1 to 3 months after initiation of cyclosporine therapy.
      • Seymour RA
      • Jacobs DJ
      Cyclosporin and the gingival tissues.
      • PlatteIII A
      • PetreIII I
      • Fanci P
      Regression following reduction of the daily drug dosage in cyclosporin A-induced gingival overgrowth in bone marrow transplant recipients.
      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.
      • McGaw WT
      • Porter H
      Cyclosporin-induced gingival overgrowth: an ultrastructural stereologic study.
      Thus, the issue involves the appropriateness of the term “hyperplasia” and the subsequent common use of the term “overgrowth.”

      CALCIUM CHANNEL BLOCKING AGENTS

      The calcium channel blocker that is most commonly associated with gingival overgrowth is nifedipine, with a reported incidence of approximately 38%.
      • Steele RM
      • Schuna AA
      • Schreiber RT
      Calcium antagonist-induced gingival hyperplasia.
      Other agents that have been found to have an association with gingival overgrowth include diltiazem, incidence of 20%;
      • Fattore L
      • Stablein M
      • Bredfeldt G
      • Semia T
      • Moran M
      • Doherty-Greenberg: JM
      Gingival hyperplasia: a side effect of nifedipine and diltiazem.
      verapamil, incidence of 4 to 19%;
      • Steele RM
      • Schuna AA
      • Schreiber RT
      Calcium antagonist-induced gingival hyperplasia.
      • Miller CS
      • Damm DD
      incidence of verapamil-induced gingival hyperplasia in a dental population.
      and amlodipine, incidence of 3%.
      • Jorgensen MG
      Prevalence of amlodipine-related gingival hyperplasia.
      Case reports have indicated that gingival overgrowth can also occur with the use of felodipine
      • Lombardi T
      • Fiore-Donno G
      • Belter U
      • Dl Felice R
      Felodi pine-induced gingival hyperplasia: a clinical and histologie study.
      and nitrendipine.
      • Brown RS
      • Sein P
      • Corio R
      • Bottomley WK
      Nitrendipine-induced gingival hyperplasia: first case report.
      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.
      • Nishikawa S
      • Tada H
      • Hamaaakl A
      • Kasahara S
      • Kido J
      • Nagata T
      • et al.
      Nifedipine-induced gingival hyperplasia: a clinical and in vitro study.
      Specific dose or plasma levels have been associated with this type of gingival overgrowth in animal models
      • Ishida H
      • Kondoh T
      • Kataoka M
      • Nishikawa S
      • Nakagawa T
      • Morisakl I
      • et al.
      Factors influencing nifedipine-induced gingival overgrowth in rats.
      but have not been demonstrated in humans.
      • Nery EB
      • Edson RG
      • Lee KK
      • PrutW VK
      • Watson J
      Prevalence of nifedipine induced gingival hyperplasia.
      • Bullon P
      • Machuca G
      • Martinez-Sahuqulllo A
      • Rlos JV
      • Rojas J
      • Lacalle JR
      Clinical assessment of gingival hyperplasia in patients treated with nifedipine.
      • Ellis JS
      • Seymour RA
      • Monkman S
      • Idle JR
      Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug induced gingival overgrowth.
      One theory is that plaque accumulation as a result of inadequate oral hygiene may add to the severity of this type of overgrowth.
      • Nery EB
      • Edson RG
      • Lee KK
      • PrutW VK
      • Watson J
      Prevalence of nifedipine induced gingival hyperplasia.
      • Bullon P
      • Machuca G
      • Martinez-Sahuqulllo A
      • Rlos JV
      • Rojas J
      • Lacalle JR
      Clinical assessment of gingival hyperplasia in patients treated with nifedipine.
      This relationship has been questioned by some investigators.
      • Ellis JS
      • Seymour RA
      • Monkman S
      • Idle JR
      Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug induced gingival overgrowth.
      • Barclay S
      • Thomason JM
      • Idle JR
      • Seymour RA
      The incidence and severity of nifedipine-induced gingival overgrowth.
      Figure thumbnail gr3
      Fig. 3Diltiazem-associated gingival overgrowth.
      Histologically, calcium channel blocker-related gingival overgrowth exhibits increases in extracellular ground substance and increased numbers of fibroblasts
      • Lucas RM
      • Howell LP
      • Wall BA
      Nifedipine-induced gingival hyperplasia: a histochemical and ultrastructural study.
      that closely resemble phenytoin-induced overgrowth. Histologic changes are considered nonpathognomonic for specific drug types.

      TREATMENT

      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.
      • PlatteIII A
      • PetreIII I
      • Fanci P
      Regression following reduction of the daily drug dosage in cyclosporin A-induced gingival overgrowth in bone marrow transplant recipients.
      • Dahliof G
      • Axto E
      • Modeer T
      Regression of phenytoin i nduced gingival overgrowth after withdrawl of medication.
      • Bokenkamp A
      • Bohnhorst B
      • Bêler C
      • Albere N
      • Offner G
      • Brodehl J
      Nifedipine aggravates cyclosporin A-induced gingival hyperplasia.
      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.
      • Wostbrook 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.
      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.
      • Carrania Jr, FA
      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.
      Figure thumbnail gr4
      Fig. 4Surgical treatment of phenytoin-associated gingival overgrowth. A, Preoperative frontal view. B, Preoperative profile view. C, Twelve-month postoperative frontal view.

      SUMMARY

      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.
      • Hall WB
      Dilantin hyperplasia: a preventable lesion?.
      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.

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        Prevention and treatment of Dilantin-associated gingival enlargement.
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        Regression following reduction of the daily drug dosage in cyclosporin A-induced gingival overgrowth in bone marrow transplant recipients.
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        Cyclosporin-induced gingival overgrowth: an ultrastructural stereologic study.
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        Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug induced gingival overgrowth.
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