Calcium Channel Blocker-Induced Gingival Hyperplasia: Case Report and Review of This Iatrogenic Disease David B

Brief Reports

Calcium Channel Blocker-Induced Gingival Hyperplasia: Case Report and Review of This Iatrogenic Disease David B. Lawrence, PharmD; C. Wayne Weart, PharmD; Jeffrey J. Laro, DM D ; and Brad W. Neville, DOS Charleston, South Carolina

Gingival hyperplasia is a common disorder associated localized folic acid deficiency. All o f the available cal with phenytoin and cyclosporine therapy. However, cium channel blockers have been reported to cause induction o f this condition by calcium channel blockers gingival hyperplasia. Treatment options include meticu is less well known. Inflammation o f the gingival tis lous plaque control, and in severe cases, gingi- sue from bacterial plaque and the subsequent de- vectomy. Gingival hyperplasia can be prevented with Ivelopment o f gingival crevicular fluid may allow meticulous plaque control or avoidance o f the offending i sequestration o f the calcium channel blocker, thus pre medication. disposing the tissue to a localized toxic effect and the development o f gingival hyperplasia. Calcium channel Key words. Gingival hyperplasia; calcium channel block blockers have cellular effects similar to those o f pheny ers; gingivitis; dental plaque; gingival crevicular fluid. toin and cyclosporine, including the production of a ( ) Fam Pract 1994; 39:483-488)

Calcium channel blockers (CCBs) have become valuable giene, contributing to periodontal disease and dental car and widely prescribed agents for the treatment of many ies. In severe cases, DIGH may even compromise the health problems. Certain CCBs are effective in the man patient’s ability to properly eat or speak. Patients who agement o f hypertension, angina, atrial arrhythmias, dia develop DIGH are at risk o f treatment failure because of stolic heart failure, and possibly renal protection in diabe noncompliance. Those who develop severe DIGH may tes. As the number of indications for CCBs continues to eventually require invasive oral surgery, such as a gingi- grow, so do the volume and number o f CCBs available for vectomy.1 use. Drug-induced gingival hyperplasia is a well-docu Drug-induced gingival hyperplasia (DIGH ) is an iat mented and widely recognized side effect of long-term rogenic dental disorder that is characterized by gums that phenytoin therapy. This manifestation o f treatment, are enlarged and inflamed, and bleed readily upon prob which occurs in approximately 50% of patients taking this ing. The gums appear lobulated from papillary enlarge medication, takes the form o f a local or generalized hy ment, and the tooth crowns may be partially covered by perplasia.2 The immunosuppressant cyclosporine fre hyperplastic tissue. Drug-induced gingival hyperplasia is quently induces a similar effect in patients who have had usually only cosmetically disfiguring; however, the forma organ transplants. In this population, the incidence of tion of tissue pockets can interfere with proper oral hy- DIGH ranges from 25% to 81%.3 Phenytoin and cyclo sporine are used primarily in the treatment o f epileptic and transplant patients, respectively; thus, DIGH can be Submitted, revised, August 5, 1994. anticipated and minimized with the institution o f preven From the Departments of Family Medicine and Community Pharmacy Practice tive oral hygiene measures. (D.B.L., C.W.W.); and the Divisions of Graduate Periodontics (J.J.L.) and Oral While recognized by the dental profession, the role Pathology (B.W.N.), Department o f Stomatology, College o f Dental Medicine, Med ical University o f South Carolina, Charleston. Requests fo r reprints should be a d o f CCBs in the development o f gingival hyperplasia is less dressed to David B. Lawrence, PharmD, Department o f Family Medicine, Medical well known in the primary care community. In susceptible University o f South C arolina, 171 Ashley Ave, Charleston, SC 29425-2302.

patients, this class o f medications has been shown to in duce gingival hyperplasia, which usually appears locally on the gums but can present more generally. The develop ment of DIGH is not unique to any one agent within this class. Combining any o f these agents with cyclosporine will likely produce an additive effect.

Case Report

In November 1987, a 78-year-old black female patient from our institution’s family medicine clinic presented to the dental clinic for a routine checkup. Localized hyper plastic gingival tissue was found adjacent to the mandib ular right canine. Her medical history included hyperten Figure 1. Hyperplastic tissue o f the mandibular canine (January 1992) in a patient who had been taking felodipine since July sion with an antihypertensive regimen of diltiazem and 1991. Note calcification due to poor dental hygiene. spironolactone with hydrochlorothiazide, both of which had been initiated in 1985. Her dental history included plastic tissue in this area has been noted since this treat routine care at the dental school since 1974. Poor oral ment. hygiene was recorded at numerous appointments; how In September 1993, examination revealed localized ever, no hyperplastic or edematous gingival lesions had erythematous hyperplasia on the gingiva adjacent to her been recorded before the initiation of diltiazem in 1985. maxillary central incisors. Her medication had been Further examination at that time revealed a localized changed to enalapril maleate in December 1992, with erythematous and raised lesion adjacent to the mandibu verapamil added in May 1993. In August 1993, verapamil lar right canine. The lesion was initially believed to be an was discontinued, and benazepril monotherapy was be abscess, but this was ruled out and the tissue was removed gun for control of her hypertension. She was seen again in by gingivectomy. The lesion recurred three times be the dental clinic in April 1994. The lesion adjacent to her tween March 1988 and October 1988. On each visit, the maxillary central incisors was still present even though she hyperplastic gingiva was excised. Flach procedure in had not taken a CCB since August 1993 (Figure 2). Signs cluded removal o f plaque and calculus from the teeth and of local chronic periodontal destruction were also present. placement o f the gingival tissue to a lower level to allow Clinically, the tissue appeared consistent with the previ for more effective patient hygiene. During the October ous hyperplastic lesions. 1988 appointment, a biopsy of the lesion was done. Mi croscopic examination showed fibrous hyperplastic tissue with chronic inflammation. Throughout this period and for 2 years thereafter, the patient continued taking dilti azem for hypertension. In January 1991, the patient presented with localized gingival inflammation and hyperplasia in the area o f the mandibular left canine. Her medication had been changed in October 1990 to nifedipine to better control her hypertension. The gingiva was reflected (gingiva pulled away from the tooth surface for the purpose of debriding), the tooth surface debrided, and a biopsy per formed. Microscopic examination again revealed chronic hyperplastic tissue. One year later, the hyperplastic tissue recurred in the areas of both mandibular canines (Figure 1). It was treated as before, and again a biopsy was obtained. At this Figure 2. Lesion adjacent to the maxillary central incisors (April time, the patient had been taking felodipine since July 1994) consistent with previously occurring hyperplastic tissue. 1991. Microscopic examination again showed hyperplas Eight months earlier, verapamil had been discontinued and ben- tic tissue with inflammation. No recurrence o f the hyper- zapril monotherapy begun.

484 The Journal of Family Practice, Vol. 39, No. 5(Nov), 1991 (XB-Induced Gingival Hyperplasia Lawrence, Wean, Laro, and Neville

Discussion Another hypothesis regarding the development of DIGH is the influence o f folic acid deficiency. Systemic Mechanism of Disease and localized folic acid deficiency can be found with the use of all the agents known to induce gingival hyperplasia, There are many theories about the pathogenesis of DIGH including CCBs.1 The alteration o f calcium and sodium at the molecular level, and specific risk factors have been ion exchange in turn affects folic acid uptake into cells. identified.1 The use o f CCBs in the presence of gingivitis Gingival tissue has a naturally high turnover rate, which or inflammation o f the gingival tissue from bacterial leads to increased demand for folic acid.14 It has been plaque may predispose patients to DIGH. Inflammation hypothesized that localized folic acid deficiency limits the from bacterial plaque causes a natural increase in connec amount of collagenase activator protein produced in the tive tissue production, leading to gingival enlargement.1 gingival tissues. This deficiency results in less efficient ca With regard to phenytoin and cyclosporine therapy, a tabolism of the excessive connective tissue produced by number o f reports have demonstrated that a bacterial the inflammation.3 inflammatory component is necessary for the expression of DIGH.3-6 The use o f a CCB in beagles led to the CCBs and DIGH observation that gingival overgrowth begins in areas dis playing signs o f previous inflammation.7 These medica There are many case reports o f GGB induced gingival tions, along with bacterial plaque and the subsequent hyperplasia in the literature. All o f the dihydropyridine onset of gingivitis, are now clearly believed to be cofactors CCBs, including the newer formulations, have a reported in the development of DIGH. association with DIGH development. Cases of DIGH Inflammation and gingivitis may play an important with nifedipine therapy are the most frequently reported, role in DIGH through the production o f gingival crevic- which may reflect the widespread use o f this popular CCB ular fluid (G C F), a serum-derived transudate produced rather than an intrinsic characteristic o f the drug. Kvalu within the gingiva in direct relationship to the extent of ation of various case reports o f D IG H with the use of inflammation.8 Gingival crevicular fluid may be important nifedipine suggests that the incidence is in excess of 10%, because o f its ability to accumulate high concentrations of with small retrospective studies reporting rates as high as CCBs within the gingival tissue when inflammation is 20% to 25% in isolated populations.13’15-16 A recent report present, predisposing tissue to the toxic effects of the found that 38% of patients receiving nifedipine for at least sequestered agent.8'9 Concentrations of GCF in patients 3 months had significant gingival hyperplasia.1 receiving nifedipine with signs o f gingival enlargement Drug-induced gingival hyperplasia has been reported have ranged from 15 to 88 times that of plasma. Concen infrequently in postmarketing surveillance of felodi trations o f amlodipine besylate within the GCF have been pine,18 nicardipine hydrochloride (personal communica shown to be 25 to 250 times that o f plasma.9 Although tion, Syntex Laboratories, Inc, Palo Alto, Calif, August 4, research related to this phenomenon is limited, sequestra 1993), and isradipine (personal communication, Sandoz tion of CCBs in the GCF is thought to be linked to Pharmaceuticals, Hast Hanover, NJ, August 4, 1993). gingivitis, localized toxic drug effects, and the develop Amlodipine, the most recently approved CCB, has not ment of DIGH . been spared association with this condition. Recently, A common feature o f phenytoin, cyclosporine, and three cases o f amlodipine-induced gingival hyperplasia CCBs is their ability in some way to influence calcium were reported in the medical literature.9 1 he infrequent metabolism. Calcium channel blockers have effects on reporting of this condition probably does not mean that cellular calcium influx, and phenytoin has been shown to the newer dihydropyridines have a lower incidence of stabilize neuronal membranes by affecting Ca- /Na DIGH. It is more likely a reflection o f their smaller share flux and decreasing intracellular calcium uptake.10 Cyclo of the CCB market. However, the association between sporine has the ability to inhibit interleukin-2-dependent amlodipine and gingival hyperplasia has not been ade T-cell proliferation by preventing a change in the intra quately evaluated in clinical studies, primarily because of cellular uptake o f calcium ions. This lowering of cytosolic- the short time this CCB has been available. An overall dihydropyridine class effect may be assumed at this point free calcium ions by cyclosporine is actually indistinguish until further evaluation is done. T he decision to use any able from that o f calcium antagonists.11-12 The reduction one dihydropyridine CCB over another in anticipation of in free cytosolic calcium may impair collagen resorption, avoiding or reducing the likelihood of this side effect is possibly by interfering with T-cell proliferation and collagenase synthesis in fibroblasts.13 The disruption of colla probably not warranted. The nondihydropyridinc CCBs, diltiazem and vera gen homeostasis may significantly influence the develop pamil, are also considered to induce gingival hyperplasia. ment of DIG H .

485 The Journal of Family Practice, Vol. 39, No. 5(Nov), 1994 CCB-Induced Gingival Hyperplasia L a w ren ce, W e a rt, L a ro , and Neville

Both have been reported to be associated with DIGH in a Treatment of Drug-Induced number o f case studies.19”24 A small retrospective chart Gingival Hyperplasia review o f 24 patients concluded that verapamil has a lower incidence of DIGH than nifedipine; however, this con The treatment of DIGH is limited to meticulous plaque clusion needs further confirmation.24 In a retrospective control and, if necessary, surgical removal of the hyper study, DIGH was reported to be present in 21% (7/33) of plastic tissue by means of gingivectomy. Because of the patients taking diltiazem and 19% (5/26) of those taking progressive nature o f this condition, surgical removal of verapamil.17 Both medications are known to induce the tissue may need to be repeated unless the medication DIGH in susceptible patients, but until adequately inves is discontinued. Although withdrawing the offending tigated, they should not be assumed to have a lower inci medication generally reverses hyperplasia, this course of dence than dihydropyridines. action may be less effective following prolonged expo Calcium channel blockers, particularly nifedipine, are sure.1-30’31 often used in the treatment of cyclosporine-induced hy The administration o f folic acid has some theoretical pertension in the organ transplant population. Among merit in the treatment o f DIG H . Although oral folic acid these patients, DIGH is a common occurrence. Although supplementation has not shown efficacy in reversing it is unknown whether the combination of nifedipine and phenytoin-induced gingival hyperplasia,32 a topical solu cyclosporine has additive or synergistic effects in promot tion of folic acid (1 mg/mL solution, with 5 mL rinse for ing DIGH, there are reports suggesting that it produces 2 minutes twice daily) has resulted in significant regres an additive increase in gingival hyperplasia.25 It is cur sion o f gingival hyperplasia as compared with both oral rently unknown whether other CCBs in combination folic acid and placebo. It has been postulated that topical with cyclosporine would have a similar or a smaller effect. folic acid may reduce hyperplasia by affecting pathogenic A recent retrospective study of 66 renal transplant pa flora or reducing inflammation.33 Further investigation tients addressed these issues.26 Patients receiving cyclo into this potential treatment of DIGH is needed. sporine alone or in combination with nifedipine or dilti Metronidazole is an interesting prospect for fixture azem were evaluated for hyperplastic development. The treatment. Four patients with cyclosporine-induced gin authors of this study concluded that there was no differ gival hyperplasia who were treated with a 7-day course of ence between the nifedipine and diltiazem groups, al metronidazole 400 mg three times per day showed im though there was a trend toward increased gingival over provement or resolution of the hyperplasia.34 Further growth in the nifedipine group. The addition of a calcium study o f this treatment option and expanded investigation antagonist also did not appear to potentiate the effect of of phenytoin-induced and calcium channel blocker- cyclosporine in this small study. In contrast, a recent study induced gingival hyperplasia are desirable. showed a significant increase in the degree o f hyperplasia in children receiving cyclosporine and nifedipine as com Prevention of Drug-Induced pared with children receiving cyclosporine alone.27 Al Gingival Hyperplasia though it is inconclusive whether CCBs potentiate the effect in combination with cyclosporine, alternative anti A key to preventing DIGH is recognizing which patients hypertensives may prevent additive hyperplasia in trans have a potential for developing this condition and insti plant patients. tuting early intervention. Several studies have demon strated that proper dental prophylaxis and good oral hy Other Causes of Gingival Hyperplasia giene can reduce or prevent the development of phenytoin-induced gingival hyperplasia.4’35-36 In subse Non-drug-induced gingival hyperplasia has been re quent investigations, a clear correlation was established ported secondary to vitamin deficiencies, particularly de between three variables and an increased risk o f develop ficiencies in vitamins A and C. Endocrine imbalances, ing DIGH in patients receiving phenytoin therapy: gingi such as those that occur in diabetes mellitus or during vitis, a visible plaque index, and the duration o f phenytoin puberty or pregnancy, have been reported to cause gingi therapy.37 val hyperplasia. In addition, Crohn’s disease and leukemia A number o f interventions have been attempted to have been implicated as a contributing factor in the de prevent recurrence of DIGH following surgical removal velopment of this form of hyperplasia.28 Gingival fibro of the hyperplastic tissue. Chlorhexidine mouthwash has matosis is an enlargement that may be familial or idio been used as secondary prevention of DIGH in patients pathic. Familial gingival fibromatosis may be either a receiving phenytoin after gingivectomy. The use of 0.1% separate finding or connected to one of many hereditary chlorhexidine gluconate mouthwash three times daily syndromes.29 along with aggressive plaque control reduced the inci-

486 The Journal of Family Practice, Vol. 39, No. 5(Nov), 1994 CCB-Induced Gingival Hyperplasia Lawrence, Weart, Laro, and Neville

dence of recurrent hyperplasia.38 Oral folic acid supple floss and brush properly, and advised to see a dental hy mentation as secondary prevention following gingivec- gienist on a regular basis. Furthermore, to rule out the tomy also has been attempted but has not proven development of gingival hyperplasia, physicians should clinically effective.39 Meticulous plaque control through perform a visual oral examination o f all patients undergo frequent brushing and flossing seems to be the most ef ing follow-up evaluation for conditions treated with fective method of reducing the chance of development of CCBs. DIGH. There has been no evaluation of the association between gingivitis and C C Bs or o f prevention and treat ment methods. However, findings regarding prevention Acknowledgments and treatm ent with phenytoin and cyclosporine can likely The authors would like to thank Deborah S. Carson and June A. Taylor be extrapolated to patients taking CCBs. for their contributions to the preparation of this manuscript.

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