CASE REPORT

Amlodipine-Induced Gingival Overgrowth in a Patient With Uncontrolled Type 2 Diabetes Mellitus With Hypercholesterolemia: A Case Report
K. Smitha*

Introduction: Gingival overgrowth, with its potential cosmetic implications and for providing new niches for the growth of microorganisms, is a serious concern for both patients and clinicians. Amlodipine is a comparatively new calcium channel blocker and is being used with increasing frequency in the management of hypertension and angina. Although amlodipine is considered a safe drug, it may induce gingival overgrowth in some individuals. Case Presentation: A rare case of amlodipine-induced gingival overgrowth in a 60-year-old Indian woman who was on amlodipine for 3 years and subsequent periodontal management of the overgrowth is reported here. The patient did not have any gingival overgrowth for 2 years despite the fact that she was taking amlodipine, but she developed the gingival overgrowth 9 months before her initial visit, coincident with uncontrolled diabetes mellitus and use of a cholesterol-lowering drug. She was treated with drug substitution for the systemic condition and surgical treatment for the overgrowth. She was followed up for 1 year, regularly. Conclusion: We speculate that overgrowth could have been triggered by uncontrolled type 2 diabetes mellitus and by altered pharmacokinetics of amlodipine resulting from the drug interaction of amlodipine with a cholesterol-lowering drug. Clin Adv Periodontics 2012;2:115-122.
Key Words: Amlodipine, adverse effects; calcium channel blockers; diabetes mellitus, type 2; gingival overgrowth; periodontal pocket; risk factors.

Background
Gingival overgrowth (GO) has been associated with multiple factors, including inflammation, adverse drug reaction, neoplastic conditions, and systemic disorders. An increasing number of medications are associated with gingival enlargement. Currently, >20 prescription medications are associated with GO.1 Drugs associated with GO can be broadly
* Department of Periodontics, Bangalore Institute of Dental Sciences, Karnataka, India.
Submitted March 16, 2011; accepted for publication July 6, 2011 doi: 10.1902/cap.2012.110026

divided into three categories: 1) anticonvulsants; 2) calcium channel blockers; and 3) immune suppressants. Calcium channel blockers (dihydropyridine, phenylalkylamine, and benzothiazine derivatives) are used widely in the management of hypertension and in the prophylaxis of angina. Many of these drugs have been implicated in causing GO. In a study by Ellis et al.2 in 1999 on 911 patients on calcium channel blockers, a prevalence of GO of 6% for nifedipine (NIF), 1.7% for amlodipine, and 2.2% for diltiazem was reported. Amlodipine, an agent of dihydropyridine, a third-generation calcium channel blocker that is used for treatment of hypertension and angina, was first reported by Ellis et al.3 as
Clinical Advances in Periodontics, Vol. 2, No. 2, May 2012

115

C A S E

R E P O R T

causing GO as an adverse effect. Amlodipine is shown to have longer action and weaker adverse effects compared to first-generation blockers, such as NIF.2,3 The pathogenesis of GO is uncertain, and several factors may influence the relationship between drugs and gingival tissues as discussed by Seymour et al.4 These factors include: 1) age; 2) genetic predisposition; 3) pharmacokinetic variables; 4) alteration in gingival connective tissue homeostasis; 5) histopathology; 6) ultra-structural factors; 7) inflammatory changes; and 8) drug action on growth factors. The combination of periodontitis and GO presents a complicated condition. GO creates an environment conducive to easy plaque accumulation, which affects conventional periodontal therapy, so that treatment may require resective techniques. Diabetes mellitus (DM) is a well-established risk factor for periodontal disease and tissue destruction. It is reported that patients with type 2 DM were 2.8 to 4.2 times more likely to have progressive periodontal disease compared to individuals without DM.5 A previous report6 on four cases demonstrated erythematous gingival enlargement associated with hyperglycemic levels in patients with no history of taking the common drugs associated with GO. However, it remains unknown whether uncontrolled hyperglycemic levels and their effects on gingival tissue would play a synergistic role on drug-influenced gingival enlargement. A case report7 documented a conservative clinical approach to the management of felodipine-influenced gingival enlargement and reported clinical and histologic aspects of a case of felodipine-influenced GO in a patient with undiagnosed type 2 DM. A cross-sectional study8 showed that NIF intake may increase the risk of periodontal destruction in patients with type 2 DM. These data imply that there might be a possible synergistic effect of NIF intake on periodontal pathogenesis in patients with DM. NIF and DM can induce hyperresponsive monotype/macrophage phenotype and thereby increase the production of chemokines and proinflammatory cytokines.9,10 It is well recognized that calcium channel blockers, which are strong inhibitors of cytochrome P450 3A4, coadministered with statins that are metabolized by the same isoenzyme before biliary and renal excretion may lead to reduced clearance of both the drugs, with an increase in adverse effects.11 Indeed, in patients treated with verapamil and simvastatin, the serum levels of both drugs were increased,12 but as yet there is little evidence for this with dihydropyridine calcium antagonists. Nevertheless, when statins and calcium channel blockers are coprescribed, especially at high doses, there may possibly be an increase in adverse effects, such as GO. However, the exact mechanism remains an enigma. This case report presents the management of a case of a combination of drug-influenced gingival enlargement and uncontrolled DM with hypercholesterolemia.

TABLE 1 Medication History Medication Administered Period of Administration

10 mg amlodipine 80 mg gliclazide plus 500 mg metformin 25 mg atenolol 10 mg simvastatin 0.3 mg voglibose

May 2004 to September 2007 Since 2002

Since September 2007 Since October 2006 Since September 2007

Clinical Presentation
In September 2007, a 60-year-old Indian woman who complained of swollen gums for the past 9 months was referred to the Department of Periodontics, Bangalore Institute of
116
Clinical Advances in Periodontics, Vol. 2, No. 2, May 2012

Dental Sciences, affiliated with Rajiv Gandhi University of Health Sciences, Bangalore, India. She felt very uncomfortable because the swelling interfered while chewing, was unsightly, and caused gingival bleeding while brushing her teeth. She had hypertension for 3 years and was prescribed 10 mg amlodipine, daily. Table 1 shows her medication history. She also had type 2 DM for 5 years, for which she was prescribed the combination of 500 mg metformin and 80 mg gliclazide. Medical reports showed that her metabolic status was not under control for >1 year (Table 2). She had hypercholesterolemia and had been taking statinsx for 1 year. Dental history revealed that she had undergone scaling 6 months before her initial visit to this department for the same complaint of swollen and bleeding gums. Although bleeding was reduced after scaling, gingival enlargement remained. Generally, she looked well, was alert, and had central obesity. Periodontal parameters are shown in Tables 3 and 4. Intraorally, there was GO on the labial and lingual/palatal surface of the maxillary and mandibular teeth, which was more pronounced in the anterior region than the posterior region. The interdental papillae were enlarged, fibrous, and lobulated in appearance mainly around the mandibular anterior teeth (Fig. 1). Gingival enlargement was graded at six points around each tooth according to the gingival overgrowth index (GOI) originally described by Angelopoulous and Goaz13 and later modified by Miller and Damm,14 and the highest score of the three points on each surface was recorded as the grade for that surface of the tooth. Her oral hygiene showed the presence of some amount of plaque and calculus, and plaque was abundant around anterior teeth. Bleeding on probing (BOP) was detected on all affected areas. Range of probing depth (PD) of gingival sulcus was recorded from 3 to 8 mm. Grade 1 tooth mobility was noticed in teeth #2, 23, 24, 25, and 26.The examination of occlusion exhibited labioversion and diastema of anterior teeth. Panoramic radiograph examination revealed a generalized moderate horizontal bone loss (Fig. 2).
x

Amlogard, Pfizer, Mumbai, India. Diabend-M, Bal Pharma, Bangalore, India. Zocor, Merck, Mumbai, India.

Amlodipine-Induced Gingival Overgrowth

C A S E

R E P O R T

TABLE 2 Metabolic Status FBS (mg/dL) PPBS (mg/dL) Total Cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) Triglycerides (mg/dL) VLDL (mg/dL)

Time (date of investigation)

Reference value July 2006 December 2006 March 2007 September 2007 October 2007 June 2008

70 to 110 157 181 168 158 139 132

110 to 140 245 288 236 187 164 167

<200 303 278 264 253 222 197

42 to 88 36 38 40 42 42 41

<130 199 192 182 167 155 143

<150 286 256 189 163 159 158

8 to 40 68 56 53 44 45 42

FBS fasting blood glucose; PPBS postprandial blood glucose; HDL high-density lipoprotein; LDL low-density lipoprotein; VLDL very-low-density lipoprotein.

Case Management
Before local management, the patient was referred to a physician who thoroughly assessed her, substituted atenololk for amlodipine, prescribed voglibose{ (0.3 mg) along with metformin and gliclazide,# and also advised diet control and physical exercise. The treatment plan was explained, and informed written consent was obtained from the patient for the treatment, as well as for reporting of the case. She underwent thorough scaling. She was prescribed chlorhexidine mouthwash and was given oral hygiene instructions. She reported after 1 month, requesting correction of the unsightly gingival enlargement. Under local anesthesia, the enlargement was resected segment-wise by a modified flap surgical procedure. The tissue that was resected was sent for histpathologic examination. The routine hematoxylin and eosinstained sections revealed hyperplastic parakeratinized stratified squamous epithelium overlying the connective tissue. The underlying connective tissue was dense with numerous collagen bundles arranged in haphazard manner interspersed with fibroblasts. The inflammatory component was observed more toward the epithelium, with lymphocytes being the predominant cells (Fig. 3). The case was diagnosed as amlodipine-induced gingival enlargement based on clinical and histopathologic features.
Time

TABLE 3 Clinical Parameters Plaque (PCR%)24 BOP (% Sites)25

September 2007, baseline October 2007, 1 month after non-surgical treatment September 2008
PCR plague control record.

56.7 38.3

54.3 36

9.0

15

Clinical Outcomes
There were no postoperative complications, and the healing was uneventful (Fig. 4). The patient was followed up regularly for 1 year. A marginal inflammatory recurrence, however, was noticed that could easily be managed by routine therapeutic procedures. Clinical parameters 1 year post-surgery are shown in Tables 3 and 4.

manifestation of gingival enlargement frequently appears within 1 to 3 months after initiation of treatment with the associated medication.15 In the present case, although the patient was taking 10 mg amlodipine for 3 years, GO was noted only 9 months before her initial visit. Coincident with this, her medical history revealed uncontrolled DM for the past year. A previous report6 has shown cases of gingival enlargement in patients with DM. It remains unknown whether hyperglycemic status and its effects on gingival tissue would have played a synergistic role on drug-influenced gingival enlargement in this case. Furthermore, the patient was taking statins for the past year, which was coprescribed with amlodipine. This could have aggravated the adverse effects, resulting in clinically evident GO. In this case, GO was more pronounced in the anterior region and was less severe around the posterior teeth. This could be attributable to accumulation of more plaque in the anterior region especially around mandibular anteriors, due to the wasting disease noted in these teeth leading to less effective plaque removal. Gingival inflammation and
k

Discussion
GO, with its potential cosmetic implications and for providing new niches for the growth of microorganisms, is a serious concern for both patients and clinicians. Clinical
Smitha

Aten-AM, Zydus Cadila, New Delhi, India. Volgitor MD,Torrent Pharmaceuticals, Gujarat, India. # Diabend-M, Bal Pharma.
{

Clinical Advances in Periodontics, Vol. 2, No. 2, May 2012

117

C A S E

R E P O R T

TABLE 4 Periodontal Parameters Tooth # Parameter 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Maxillary (labial) BL PD (mm) BL GOI NS PD (mm) NS GOI PS PD (mm) PS GOI 4,5,6 1 4,5,5 0 3,3,3 0 7,5,8 1 6,5,6 0 5,3,5 0 8,6,6 1 6,6,6 0 4,3,3 0 3,5,5 0 3,4,5 0 2,2,3 0 6,4,6 1 6,3,5 1 4,2,3 0 5,3,6 1 4,2,5 1 3,2,3 0 6,4,6 1 5,4,6 1 2,1,2 0 6,3,5 1 5,2,5 1 2,1,2 0 5,3,5 1 5,2,5 1 2,1,2 0 5,3,4 1 5,3,4 1 3,2,2 0 5,6,7 1 5,5,6 1 3,3,3 0 6,5,6 1 5,5,6 0 3,3,4 0 6,5,6 1 5,4,5 0 4,3,4 0 6,5,7 1 6,4,6 0 4,4,5 0 7,5,6 1 6,4,5 0 5,3,5 0 7,4,5 1 5,4,5 0 4,3,3 0

Maxillary (palatal) BL PD (mm) BL GOI NS PD (mm) NS GOI PS PD (mm) PS GOI 5,5,7 1 5,5,6 1 3,3,3 0 7,6,5 1 6,6,5 1 3,3,4 0 6,5,5 1 5,5,5 1 3,3,3 0 5,4,5 0 4,4,4 0 3,2,3 0 4,4,5 0 4,3,5 0 3,2,3 0 5,5,6 1 5,5,5 1 3,3,3 0 6,6,6 1 5,5,5 1 2,2,2 0 6,4,6 1 5,4,5 1 2,1,2 0 6,5,6 1 5,4,5 1 2,1,1 0 5,4,6 1 5,4,5 1 2,2,2 0 5,4,6 1 4,4,5 1 2,2,3 0 6,5,5 0 5,5,5 0 3,3,3 0 6,6,6 0 5,5,5 0 3,3,3 0 6,5,6 0 5,5,5 0 3,3,3 0 7,6,5 1 6,5,5 0 4,3,3 0 7,5,5 0 5,4,4 0 3,3,3 0

BL baseline; NS 1 month after non-surgical treatment; PS 1 year after surgery; X extracted tooth. PDs are shown for the mesio, mid, and buccal aspects of each tooth.

presence of dental plaque have been reported as significant risk factors for development of GO.16 Calcium antagonists are almost exclusively prescribed in older patients, and these patients might have preexisting periodontitis. The combination of periodontitis and GO presents a complicated condition. The present case had periodontal pockets with the PD ranging from 3 to 8 mm. These deeper pockets serve as an ecological niches for periodonto-pathogenic bacteria leading to an increased bacterial load and concomitantly to an increased inflammation and may exacerbate the drug induced gingival enlargement.17,18 Morisaki et al.19 observed that germ-free rats infected with a strain of Streptococcus mutans had greater NIF-influenced gingival enlargement than germ-free controls. In contrast, different reports have suggested that drug induced GO may aggravate inflammatory periodontal disease with conflicting results. Recently, an epidemiologic study found greater periodontal attachment loss/bone loss in patients using NIF.8 A cross sectional study involving 4,290 individuals investigated the association between the intake of calcium antagonists and periodontitis, and concluded that calcium antagonists leads to gingival enlargement without aggravation of periodontitis.20 A consensus report of the editors of the American Journal of Cardiology and Journal of Periodontology21 stated that there are no

specific reports of the effect of calcium channel blockers on the severity of periodontitis. The most effective treatment of drug-related gingival enlargement is withdrawal or substitution of medication. When this treatment approach is taken as suggested by another case report,22 it may take from 1 to 8 weeks for resolution of gingival lesions. Unfortunately, not all patients respond to this mode of treatment especially those with long standing gingival lesions. 23 Surgical reduction of the overgrown tissues is frequently necessary to accomplish an esthetic and functional outcome. In the present case report, the antihypertensive drug was changed to atenolol by the physician. The patient was conscious of the unesthetic GO and she had moderate chronic periodontitis. Hence, surgical reduction of the enlargement was done after 1 month of non-surgical treatment. The case was followed for 1 year. Although, studies5-8,10 have shown the potential affect of uncontrolled type 2 DM on gingival tissues, it remains speculative whether the pathologic process caused by uncontrolled DM and use of cholesterol-lowering drugs may have contributed to the onset, severity, and clinical outcomes of this case. Further controlled investigations should be carried out to unravel this possible complex interaction. n

118

Clinical Advances in Periodontics, Vol. 2, No. 2, May 2012

Amlodipine-Induced Gingival Overgrowth

C A S E

R E P O R T

TABLE 4 (Continued) Periodontal Parameters Tooth # Parameter 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17

Mandibular (labial) BL PD (mm) BL GOI NS PD (mm) NS GO PS PD (mm) PS GOI 5,5,7 0 4,4,5 0 3,3,3 0 6,5,6 1 5,3,5 0 3,2,3 0 6,5,6 1 5,5,5 0 3,3,3 0 X X X X X X 5,4,5 1 4,4,4 0 3,2,3 0 5,5,5 2 4,4,4 2 2,2,2 0 6,5,6 2 5,5,5 2 2,1,2 0 6,5,6 2 5,5,5 1 2,1,2 0 5,5,4 2 5,4,4 1 3,2,2 0 5,5,5 2 4,4,4 1 3,2,3 0 7,6,7 2 5,4,6 2 3,2,3 0 6,5,6 1 5,5,5 1 2,1,2 0 6,5,6 1 6,5,5 0 2,1,2 0 5,5,6 1 5,5,5 0 2,2,2 0 8,6,7 0 6,4,5 0 5,3,4 0 7,6,4 1 6,5,3 0 4,3,3 0

Mandibular (lingual) BL PD (mm) BL GOI NS PD (mm) NS GOI PS PD (mm) PS GOI 5,5,6 0 4,4,5 0 3,3,3 0 6,6,5 1 5,5,5 0 3,4,4 0 5,5,5 0 5,4,4 0 4,3,3 0 X X X X X X 4,4,4 1 4,3,3 1 3,2,3 0 5,5,5 1 4,3,4 1 3,3,3 0 6,6,6 1 4,4,5 1 3,3,2 0 6,5,6 1 5,4,5 1 2,2,2 0 6,5,5 1 4,4,4 1 2,1,2 0 5,5,5 1 5,4,4 1 3,2,3 0 6,6,6 1 5,5,4 1 3,2,2 0 6,5,5 1 5,3,4 1 3,2,3 0 5,5,5 1 5,4,5 0 3,3,3 0 5,5,6 1 5,4,5 0 3,2,3 0 6,5,5 0 6,4,5 0 3,2,3 0 7,5,4 0 6,3,3 0 3,2,3 0

BL baseline; NS 1 month after non-surgical treatment; PS 1 year after surgery; X extracted tooth. PDs are shown for the mesio, mid, and buccal aspects of each tooth.

Smitha

Clinical Advances in Periodontics, Vol. 2, No. 2, May 2012

119

C A S E

R E P O R T

FIGURE 1 Photograph at baseline visit showing GO.

FIGURE 3 Histopathology of anterior maxillary gingival tissue. 3a hematoxylin and eosin; 4 . 3b hematoxylin and eosin; 10 .

FIGURE 2 Panoramic radiograph at baseline visit demonstrating generalized moderate periodontal involvement.

FIGURE 4 Postoperative photograph, 1 year post-surgical treatment and

drug replacement.

120

Clinical Advances in Periodontics, Vol. 2, No. 2, May 2012

Amlodipine-Induced Gingival Overgrowth

C A S E

R E P O R T

Summary
Why is this case report new information? Clinical manifestation of this case appeared to be triggered by: j poorly controlled metabolic status j interaction of drugs leading to increased adverse effects
j j j j

What are the keys to successful management of this case?

consultation with a physician alteration of the drug control of the metabolic status surgical treatment patient compliance lack of controlled investigation to unravel the complex interaction interaction is speculative

What are the primary limitations to success in this case?

j j j

Acknowledgment
The author reports no conflicts of interest related to this case report.

CORRESPONDENCE: Dr. K. Smitha, Department of Periodontics, Government Dental College and Research Institute, Bangalore 560002, Karnataka, India. E-mail: periosmitha@gmail.com.

Smitha

Clinical Advances in Periodontics, Vol. 2, No. 2, May 2012

121

C A S E

R E P O R T

References
1. Rees TD, Levine RA. Systemic drugs as a risk factor for periodontal disease initiation and progression. Compendium 1995;16:20, 22, 26 passim; quiz 42. 2. Ellis JS, Seymour RA, Steele JG, Robertson P, Butler TJ, Thomason JM. Prevalence of gingival overgrowth induced by calcium channel blockers: A community-based study. J Periodontol 1999;70:63-67. 3. Ellis JS, Seymour RA, Thomason JM, Monkman SC, Idle JR. Gingival sequestration of amlodipine and amlodipine-induced gingival overgrowth. Lancet 1993;341:1102-1103. 4. Seymour RA, Thomason JM, Ellis JS. The pathogenesis of drug-induced gingival overgrowth. J Clin Periodontol 1996;23:165-175. 5. Taylor GW. Bidirectional interrelationships between diabetes and periodontal diseases: An epidemiologic perspective. Ann Periodontol 2001; 6:99-112. 6. Van Dis ML, Allen CM, Neville BW. Erythematous gingival enlargement in diabetic patients: A report of four cases. J Oral Maxillofac Surg 1988;46:794-798. 7. Fay AA, Satheesh K, Gapski R. Felodipine-influenced gingival enlargement in an uncontrolled type 2 diabetic patient. J Periodontol 2005;76: 1217-1222. 8. Li X, Luan Q, Wang X, et al. Nifedipine intake increases the risk for periodontal destruction in subjects with type 2 diabetes mellitus. J Periodontol 2008;79:2054-2059. 9. Nurmenniemi PK, Pernu HE, Laukkanen P, Knuuttila ML. Macrophage subpopulations in gingival overgrowth induced by nifedipine and immunosuppressive medication. J Periodontol 2002;73:1323-1330. 10. Nishimura F, Iwamoto Y, Soga Y. The periodontal host response with diabetes. Periodontol 2000 2007;43:245-253. 11. Azie NE, Brater DC, Becker PA, Jones DR, Hall SD. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998; 64:369-377. 12. Donahue S, Lachman L, Norton J, Franc J, Chen L. Mibefradil significantly increases serum concentrations of atorvastatin but not pravastatin. Clin Pharmacol Ther 1999;65:179.

13. Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia. Oral Surg Oral Med Oral Pathol 1972;34:898-906. 14. Miller CS, Damm DD. Incidence of verapamil-induced gingival hyperplasia in a dental population. J Periodontol 1992;63:453-456. 15. Meraw SJ, Sheridan PJ. Medically induced gingival hyperlasia. Mayo Clin Proc 1998;73:1196-1199. 16. Miranda J, Brunet L, Roset P, Berini L, Farre M, Mendieta C. Prevalence and risk of gingival enlargement in patients treated with nifedipine. J Periodontol 2001;72:605-611. 17. Bullon P, Machuca G, Martinez Sahuquillo A, et al. Clinical assessment of gingival size among patients treated with diltiazem. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:300-304. 18. Tavassoli S, Yamalik N, Caglayan F, Caglayan G, Eratalay K. The clinical effects of nifedipine on periodontal status. J Periodontol 1998;69: 108-112. 19. Morisaki I, Kato K, Loyola-Rodriguez JP, Nagata T, Ishida H. Nifedipineinduced gingival overgrowth in the presence or absence of gingival inflammation in rats. J Periodontal Res 1993;28:396-403. 20. Meisel P, Schwahn C, John U, Kroemer HK, Kocher T. Calcium antagonists and deep gingival pockets in the population-based SHIP study. Br J Clin Pharmacol 2005;60:552-559. 21. Friedewald VE, Kornman KS, Beck JD, et al; American Journal of Cardiology; Journal of Periodontology. The American Journal of Cardiology and Journal of Periodontology editors consensus: Periodontitis and atherosclerotic cardiovascular disease. J Periodontol 2009; 80:1021-1032. 22. Khocht A, Schneider LC. Periodontal management of gingival overgrowth in the heart transplant patient: A case report. J Periodontol 1997;68:1140-1146. 23. Dongari A, McDonnell HT, Langlais RP. Drug-induced gingival overgrowth. Oral Surg Oral Med Oral Pathol 1993;76:543-548. 24. OLeary TJ, Drake RB, Naylor JE. The plaque control record. J Periodontol 1972;43:38. 25. van der Velden U. Probing force and the relationship of the tip to the periodontal tissues. J Clin Periodontal 1979:6:106-114.

indicates key references.

122

Clinical Advances in Periodontics, Vol. 2, No. 2, May 2012

Amlodipine-Induced Gingival Overgrowth