Gingival overgrowth induced by diltiazem

Gingival overgrowth induced by diltiazem A case report John M. Bowman, D.M.D.,* Bernard A. Levy, D.D.S., MS.,** Richard K Grubb, D.D.S.,*** Baltimore, Md. DEPARTMENT MARYLAND

OF ORAL

PATHOLOGY,

BALTIMORE

COLLEGE

OF DENTAL

and

SURGERY,

UNIVERSITY

OF

Gingival overgrowth induced by diphenylhydantoin (Dilantin) has been well documented in the literature. Recently, there have been other medications with side effects causing Dilantin-like gingival overgrowth. This article presents a case in which diltiazem (Cardizem), a calcium-channel blocker, induced gingival overgrowth. A discussion of the clinical and histologic features and possible pathogenesis of the disorder presented. (ORAL SURG ORAL MED ORAL PATHOL 1988;65:183-5)

is

I

t was first reported by Kimball’ in 1939, as well as by other investigators -later,2.4 that diphenylhydantoin (Dilantin) can cause gingival overgrowth. The incidence of gingival overgrowth in patients treated with diphenylhydantoin can be as high as 53%’ Since that time, other medications have been associated with gingival overgrowths, such as cyclosporine,$‘O an immunosuppressive agent; sodium valproate,” an anti-epileptic agent; and nifedipine (F’rocardia),‘*-I7 a calcium-channel blocker used in the treatment of angina pectoris. This case report cites the first reported case of diltiazem, a calciumchannel blocker, inducing gingival overgrowth. CASEREPBRT

A 72-year-oldwhite manwasnoted to havean excessof gingival tissuearound a crown. In September1985, that tissuewas removedwith electrosurgery.The tissueovergrowth reappearedin the samesite, betweenthe maxillary left canineand left first premolar. The clinical appearanceof the tissuewasexophytic with an irregular surface.The tissuewassubsequentlyremoved and examinedhistologicallyin March 1986.The diagnosis was a gingival overgrowth similar to diphenylhydantoininducedgingival overgrowth. It was also noted by the clinician that other areasof gingival enlargementswere present,especiallyin the maxillary and mandibularanterior areas(Fig. 1). The patient’s medicationincluded diltiazem (Cardizem), 135 mg four times daily; isosorbide dinitrate (Isordil), 22.5 mg four *Postgraduate student, Department of Oral Pathology. **Associate Professor, Department of Oral Pathology. ***Private practice, Havre de Grace, Maryland.

Fig. 1. Arrows indicate fibrous hyperplasia of labial gingiva. Note the enlargementof the interdental papillae with increasedstipplingand lobulationsof the tissue.

times daily; and digoxin, 0.125 mg/day. The patient has beentaking thesemedicationsfor approximately 1% to 2 years. The crown wasplacedon the maxillary left first premolar in December1983. At that time, the dentist did not note any gingival enlargement.On April 29, 1986, the dentistnotedthe hyperplastictissuereturning at the siteof the biopsy(Fig. 2). The patient’smedicationhad not been changed. Histologic

examination

Histologic examination showedepithelial hyperplasia with acanthosisand parakeratosis(Fig. 3). There were elongationsof the rete pegswith a test tube pattern (Fig. 4). The connectivetissueshowedlarge bundlesof dense 183

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Fig. 2. Arrow indicateshyperplastictissuereturning at biopsysite next to crown.

Oral Surg February 1988

Fig. 4. Elongationsof rete pegswith test tube pattern (Original magnification,X25.)

DISCUSSION

Fig. 3. Epithelial hyperplasiawith acanthosisand parakeratosis.(Original magnification,x 125.)

collagenousfiberswith a moderateincreasein fibroblasts. In addition, there was an inflammatory reaction with lymphocytesand plasmacells locatedperivascularly.The bloodvesselswere dilated.

The reported case shows strong similarities to diphenylhydantoinand nifedipine-induced gingival overgrowth. Diltiazem hydrochloride is part of a group of drugs called calcium-channel blockers. Other drugs in this group are verapamil and nifedipine. These drugs act as anticalcium agents and suppress myocardial contraction and calciuminduced contraction of the smooth muscles of the coronary arteries.18 The histologic similarities between our case and those reported cases of nifedipine- and diphenylhydantoin-induced gingival overgrowth are obvious. In all of these reported induced gingival overgrowths, epithelial hyperplasia with long, slender rete pegs and a moderate to large increase in fibroblasts and collagen bundles, is seen on microscopic examination. In most cases, there was an increase in inllammation with the presence of lymphocytes, plasma cells, and leukocytes.‘** Is*I9 With phenytoin-induced gingival overgrowth, the pathogenesis remains elusive. However, HassellZo hypothesized that a small portion of the fibroblasts normally present in gingiva may inherently possess the properties of elevated protein synthesis and unusually high collagen production, as well as production of an ineffective collagenase. A unique combination of conditions ply phenytoin, existing in the gingival tissue of susceptible persons, may lead, through selective growth pressures, to amplification of the population size of cells with these properties. It has been shown on a light microscopic level that phenytoin- and nifedipine-induced gingival hyperplasia exhibited an increase in extracellular ground substance, as well as increased numbers of fibro-

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blasts containing strongly sulphated mucopolysaccharides as secretory granules.21 The possible link between phenytoin and the calcium-channel blockers may be their effect on calcium. The pharmacologic action of phenytoin is to decrease resting fluxes of sodium ions, as well as sodium currents that flow during action potential or chemically induced depolarization. In addition, influx of calcium ions during depolarization is decreased, either independently or as a consequence of reduced intracellular concentration of sodium.** The calcium-channel blockers serve to inhibit the entry of calcium into cells or its mobilization from intracellular stores. 23 Seltzer and coworkers24 implicated calcium ions in the control of mammalian collagenases, and therefore this may be part of the common pathogenesis of drug-induced gingival hyperplasia. Ramon and coworkers” reported five cases of gingival overgrowth associated with nifedipine. They noted that the labial gingivae of the anterior maxillary and mandibular teeth were most frequently involved, and this was true with our patient. With discontinuation of nifedipine, as well as with diphenylhydantoin, there is regression of the gingival hyperplasia.‘4*‘7 This was not confirmed with our patient since he remained on the medication. We thank Ms. Michele LaSpinafor preparationof this manuscript. REFERENCES 1. Kimball OP. The treatment of epilepsy with sodium diphenyl hydantoinate. JAMA 1939;112:1244-5. 2. Dallof G-, Modeer T, Reinholt FP, Wikstrom B, Hjerpe A. Proteoglycans and glycosaminoglycans in phenytoin-induced gingival overgrowth. J Periodont Res 1986;21:13-21. 3. Angelopoulas AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia. ORAL SURG ORAL MED ORAL PATHOL 1972;34:898-906.

4. Church LF, Brandt SK. Phenytoin-induced gingival overgrowth resulting in delayed eruption of the primary dentition. A case report. J Periodontol 1984;55:19-21. 5. Wysocki G, Gretzinger B, Laupcis B, Ulan R, Stiller C. Fibrous hyperplasia of the gingiva: A side effect of cyclosporin A therapy. ORAL SURG ORAL MED ORAL PATHOL 1983;55:274-8.

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14. Lederman D, Lumerman H, Reuben S, Freedman P. Gingival hyperplasia associated with nifedipine therapy. Report of a case. ORAL SURG ORAL MED ORAL PATHOL 1984;57:620-2. 15. Bencini P, Crosti C, Sala F, et al. Gingival hyperplasia by nifedipine. Report of a case. Acta Derm Venereol (Stockh) 1985;65:362-5. 16. Friskopp J, Klintmaln G. Gingival enlargement. A comparison between cyclosporine and azathioprine treated renal alloaraft recioients. Swed Dent J 1986:10:85-92. 17. Ramon Y, Behan S, Kishon Y, Engelbert IS. Gingival hyperplasia caused by nifedipine-a preliminary report. Int J Cardiol 1984;5:195-206. 18. Uchida Y. Effect of diltiazem, a new anti-Ca++ agent, on left ventricular function in patients with and without angina pectoris. A study using ultrasonic analogue conversion system. Jpn Heart J 1976;17:599-610. 19. Shafer WG, Hine MK, Levy BM, eds. A textbook of oral pathology. Philadelphia: WB Saunders Co, 1983:575-7. 20. Hassell T. Evidence for the production of an inactive collagenase by fibroblast from phenytoin enlarged human gingivae. J Oral Path01 1982;11:310-7. 21. Lucas RM, Howell L, Wall B. Nifedipine-induced gingival hyperplasia. A histochemical and ultrastructural study. J Periodontol 1985;56:21 l-5. 22. Gilman AG, Goodman LS, Rall TW, Murad F, eds. Goodman and Gilman’s The pharmacological basis of therapeutics. New York: Macmillan Publishing Co, 1985451. 23. Gilman AG, Goodman LS, Rall TW, Murad F, eds. Goodman and Gilman’s The pharmacological basis of theurapeutics. New York: Macmillan Publishing Co, 1985:816-21. 24. Seltzer J, Welgus H, Jeffrey J, Eisen A. The function of Ca++ in the action of mammalian collagenases. Arch Biochem Biophys 1976;173:355-61.