|Year : 2015 | Volume
| Issue : 3 | Page : 308-311
Prevalence of gingival overgrowth induced by antihypertensive drugs: A hospital-based study
Saumiya Gopal1, Rosamma Joseph2, Vediyera Chandroth Santhosh1, Vadakkedath Venugopal Harish Kumar1, Shiny Joseph3, Abhijeet Rajendra Shete4
1 Department of Periodontics, KMCT Dental College, Mukkom, Kerala, India
2 Department of Periodontics, Government Dental College, Calicut, Kerala, India
3 Department of Periodontics, Al Azar Dental College, Thodupuzha, Kerala, India
4 Department of Periodontics, Tatyasaheb Kore Dental College, Kolhapur, Maharashtra, India
|Date of Submission||10-Jun-2014|
|Date of Acceptance||27-Jan-2015|
|Date of Web Publication||26-Jun-2015|
Department of Periodontics, KMCT Dental College, Mukkom - 673 602, Kerala
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Gingival overgrowth (GO) is a known side-effect of calcium channel blockers. Although there have been several case reports, few studies have examined the prevalence of nifedipine, diltiazem, and amlodipine. This study was conducted to determine the prevalence and risk factors for GO in patients treated with calcium channel blockers. Materials and Methods: A cross-sectional study was conducted in out patient Department of Medicine, Government Medical College, Calicut. 133 patients taking antihypertensives were examined for the presence of GO using two different indices: Vertical GO in 6 points around each tooth and horizontal Miranda-Brunet index in the interdental area. Gingival index (GI), plaque index, and probing depth were also evaluated. Results: The frequency of GO was significantly higher in nifedipine-treated cases than other drug groups. Frequency of GO was 75% for nifedipine, 31.4% for amlodipine and 25% for amlodipine + metoprolol. Higher gingival, plaque and calculus were observed in patients taking calcium channel blockers. Among the possible risk factors, only the GI showed a significant correlation with GO. Conclusions: Patients taking antihypertensives had poor oral hygiene. Patients taking nifedipine showed a higher frequency of GO. Gingival inflammation acts as a predisposing factor.
Keywords: Calcium channel blockers, gingival overgrowth, nifedipine
|How to cite this article:|
Gopal S, Joseph R, Santhosh VC, Kumar VV, Joseph S, Shete AR. Prevalence of gingival overgrowth induced by antihypertensive drugs: A hospital-based study
. J Indian Soc Periodontol 2015;19:308-11
|How to cite this URL:|
Gopal S, Joseph R, Santhosh VC, Kumar VV, Joseph S, Shete AR. Prevalence of gingival overgrowth induced by antihypertensive drugs: A hospital-based study
. J Indian Soc Periodontol [serial online] 2015 [cited 2021 Sep 19];19:308-11. Available from: https://www.jisponline.com/text.asp?2015/19/3/308/153483
| Introduction|| |
Gingival enlargement is an overgrowth or increase in size of gingiva. Many types of gingival enlargements have been reported and can be classified according to etiologic factors and pathologic changes as inflammatory enlargement, enlargements associated with systemic diseases or conditions, neoplastic enlargements, and drug-induced enlargement. 
Drug-induced gingival overgrowth (GO) is a well-known consequence of the administration of some anticonvulsants, immunosuppressants, and calcium channel blockers. , Calcium channel blockers have been widely prescribed for the treatment of various cardiovascular diseases, mostly hypertension.  GO associated with calcium channel blockers was first described in 1984 by Lederman in patients treated with nifedipine. ,
The vast majority of published reports deal with the drug nifedipine. Although most of the literature consists of case reports, some data have been published concerning the prevalence of GO in patients taking nifedipine.  The prevalence rate of this disorder has been reported to vary; and that for nifedipine-induced GO range from 20% to 83%.  Further studies revealed the prevalence of GO in relation to other calcium channel blockers such as diltiazem, amlodipine, verapamil to be 74%, 3.3%, and 21%, respectively. ,,,, There have been no reports of GO with the use of other classes of antihypertensive drugs.
The reported prevalences varied widely, and reports regarding other antihypertensives like β blockers, diuretics and other classes of drugs have been very scant. Hence, this study is undertaken to assess the prevalence of GO in patients treated with various antihypertensive drugs and to evaluate the probable risk factors associated with gingival enlargement.
| Materials and methods|| |
A cross-sectional study was carried out at the Medicine Department of Medical College Hospital, Kozhikode, Kerala, India. Patients were included if they were currently taking an antihypertensive drug during at least the last 3 months. The presence of at least 16 permanent teeth, with a minimum of 10 anterior teeth, was required. Patients who had undergone periodontal treatment within the 6 months prior to the initiation of the study; with concomitant systemic disorders known to affect the gums (such as diabetes, endocrine disorders, leukemia, or immunodeficiency states); or taking anticonvulsants drugs, other agents associated with gingival enlargement (e.g., phenytoin or cyclosporine) and pregnant females were excluded from the study. All patients agreed to participate in the study and gave their written informed consent. Ethical approval for the study was obtained from institutional Ethics Committee, Government Dental College, Kozhikode.
Gingival enlargement was graded according to the index originally described by Angelopoulos and Goaz 1972 and later modified by Miller and Damn 1992:  GO index. The height of gingival tissue was measured from the cementoenamel junction to the free gingival margin. The following grades were scored in 6 points around each tooth: Grade 0, normal; 1, minimal enlargement (≤2 mm in size, with gingiva covering the cervical third or less of anatomic crown); 2, moderate enlargement (2-4 mm in size and/or gingiva extending into middle third of anatomic crown); and 3, severe enlargement (nodular gingiva >4 mm and/or gingiva covering more than two-thirds of tooth crown). GO was also measured in the buccal-lingual direction in all interdental papilla according to the index described by Seymour et al. 1985 and modified by Miranda et al. 1998: Miranda-Brunet (MB) index. The increase in size of papilla was measured from the enamel surface, at interdental contact point to the outer papillary surface. Two scores were obtained, one for the buccal papilla and another for lingual/palatal papilla, according to the following criteria: Grade 0, papillary thickness of <1 mm; 1, papillary thickness between 1 and 2 mm; and 2, papillary thickness >2 mm.
For both indices an average mean was calculated for whole mouth, anterior and posterior areas. GO was considered to be present when grades other than zero were recorded in one or in both GO and MB indices.
Other measures included the Loe and Silness gingival index (GI),  plaque index (PI) by Silness and Loe  and probing pocket depth (PD).  These indices were measured in 6 points around each tooth. All measurements were done by the same examiner.
All statistical analysis was performed using SPSS version 13.0 for Windows (SPSS Inc., Chicago, Illinois, USA). Means were calculated for all the variables. Means of quantitative variables were calculated and the difference for means was assessed using Student's t-test. The difference in proportions was calculated using Chi-square test. Correlation analysis was done to account for confounders. The results were considered to be statistically significant if the P < 0.05
| Results|| |
A total of 133 patients participated in the study. There was no significant difference for age, sex distribution or duration of drug therapy (P > 0.05) between the drug groups. Mean age of the patients was 56 years and consisted of 50 females and 83 males [Table 1]. Patients in the study population were taking nifedipine, amlodipine, amlodipine + metoprolol, diltiazem, losartan, atenolol, carvedilol and metoprolol [Table 2]. Of the 133 patients taking antihypertensive drugs 36 presented with GO. The frequency of occurrence of GO was 75% for nifedipine, 31.4% for amlodipine and 25% for amlodipine - metoprolol combination. Out of the 4 patients taking nifedipine three had GO that is, a frequency of 75%. There were 16 subjects taking β blockers, two diltiazem, and five losartan, but none of these patients manifested GO.
|Table 1: Demographic and medication variables of patients participating in the study |
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|Table 2: Antihypertensive drug history of patients participating in the study |
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The bivariate analysis in patients with and without overgrowth with respect to quantitative (GI, PI, PD) and qualitative variables (gender, age, smoking, oral breathing pattern) only showed a significant association between GO and GI (P < 0.05). There was no correlation between dosage of drug and duration of drug intake with GO.
Although there was no statistically significant difference between patients with overgrowth and without overgrowth with regards to the plaque, calculus, and gingival indices, scores were moderately high for both groups of patients [Table 3].
| Discussion|| |
Of the 133 patients on antihypertensive drug, 36 were diagnosed clinically as having GO. The frequency of occurrence of GO is 27.1%. GO was found in patients taking nifedipine, amlodipine and a combination of amlodipine and metoprolol. It was seen that GO was found only in patients medicated with calcium channel blockers.
The frequency of GO induced by nifedipine is much higher than in the previous studies where prevalence of nifedipine-induced GO ranged from 20% to 83%. ,, In this study, the high frequency of GO induced by nifedipine may be due to very small sample size as it was a hospital-based study and not a true representative of the population. There has been a reduction in prescription of nifedipine in the past few years, which would have contributed to the small sample size.
The frequency of amlodipine induced overgrowth in the present study is 31.4% which is again higher than previous studies. Jorgensen 1997  reported a prevalence of 3.3%; Ellis et al. 1999  reported 1.7% for amlodipine induced GO. The number of patients taking amlodipine (102 of 133) was higher than other drug users and so was for those who presented with GO. From this study, it is clear that amlodipine can induce GO.
There were 4 patients who were prescribed a combination of amlodipine and β blocker, out of which one presented with GO. There is no report of GO induced by this combination of drugs in the literature. Since there have been no reports of GO induced by β blockers, the overgrowth in this patient could have been induced by amlodipine itself.
Although there are reports of GO induced by diltiazem, , there are no reports for β blockers or losartan. The findings of previous studies ,, suggest that the dihydropyridines are more frequently cited as a cause of drug-induced GO than other types of calcium channel blockers. The nonsignificant effect of these drugs could be because of a lack of statistical power in relation to a small sample size and reduced prescription of these drugs for cardiovascular treatment.
The number of males in the present study who presented with GO is 23 (63%) and that for females 13 (36.1%). Even though, the number of males is higher than females, the difference is not statistically significant (P > 0.05). The studies by Barak et al. 1987,  Thomason et al. 1995  and Ellis et al. 1999  showed that males were at greater risk from developing gingival enlargement than females. Case reports and previous prevalence studies on calcium channel blocker induced GO have had a strong male bias since men have a higher incidence of cardiovascular disease than women. A link to androgen metabolism has been suggested, since nifedipine increases the conversion of testosterone to 5α dihydrotestosterone when added to gingival fibroblasts in culture. It was speculated that there existed a serum threshold above which overgrowth occurs and that this level was lower in males.  Obviously, more detailed pharmokinetic studies are required to substantiate this finding.
The antihypertensive that were prescribed in the study population are nifedipine, amlodipine, β blockers, diltiazem, losartan, and nicardipine. Frequency of GO was found to be greatest for nifedipine and then for amlodipine. Those subjects taking nifedipine appeared to be more at risk for developing clinically significant overgrowth than those taking amlodipine. The difference between nifedipine and amlodipine is of interest, since both drugs are dihydropyridines and hence structurally similar. Furthermore, both are sequestrated in gingival crevicular fluid. However, the two drugs differ in their physico-chemical profile. While the mechanism of drug-induced GO is considered multi-factorial,  the drug/cellular interaction is pivotal in the pathogenesis of this effect. It could be argued that nifedipine's physico-chemical profile enhances such a drug/cellular interaction within the gingival tissues. This does not occur to the same extent with amlodipine. The present study does not give a true frequency for nifedipine-induced GO as the sample size for nifedipine is much smaller than that compared for amlodipine taking patients.
The periodontal parameters assessed were GI, PI, calculus index, probing PD and GO. There was a statistically significant difference for GI between subjects with overgrowth and those without. It is now well established that gingival inflammation is an important cofactor in the expression of drug-induced GO.  However, in a cross-sectional observational study such as this, it is impossible to determine the true sequence of events with respect to the role of gingival inflammation in the development of overgrowth. Thus rather than suggesting a true causative relationship between inflammation and GO, plaque-induced gingival inflammation may simply exacerbate the effect by enhancing the gingival changes.
There was no statistically significant correlation between plaque and calculus scores with gingival enlargement although the scores for plaque and calculus scores (PI 1.46 vs. 1.29 and confidence interval 2.47 vs. 2.17) were higher for those individuals who presented with GO than those without. The plaque and calculus scores are moderately high for all the subjects in the study so there could be contribution of drug in the periodontal status of patients. Calcium channel blockers decrease salivary flow which in turn increases plaque formation. However, the actual role of drug in the increase of the amount of plaque and calculus in the study patients need to be tested by further studies using control subjects without any drugs.
The role of plaque in contributing to GO cannot be ruled out as the PI by Silness and Loe has no qualitative measure of the pathogenicity of plaque.  Rather, the PI is purely a quantitative measure of plaque, which lack the sensitivity of determining the role of micro-organisms in contributing to gingival inflammation. Further research is needed to clarify the relationship between plaque and GO by doing microbiological analysis of plaque.
The present study used two indices that recorded vertical (GO) and horizontal (MB) gingival enlargement. The MB index evaluates the nodullary papilla enlargement and results from a modification of the index.  The Seymour index uses an indirect method based on a three-dimensional study of plaster casts and evaluates only five gingival units of the upper and lower anterior segments (from the midpoint of the right canine to the midpoint of the left canine). The index scores for each gingival unit are the result of the addition of gingival thickening (graded 0-2) and gingival encroachment (graded 0-3).  The modification introduced by Miranda et al. 2001  (GO and MB index) offers the following advantages: (1) It permits the direct clinical recording of gingival enlargement (MB index) in the area of the interdental papilla, the region in which the dysmorphism first expresses itself, for the whole dentition, and (2) it records the 2 components of gingival enlargement at any site, differentiating between the degree of horizontal (MB index) and vertical (GO index) gingival enlargement. There were differences in the frequency of gingival enlargement according to the index used (vertical vs. horizontal registers). This has also been described in other studies. One possible explanation is that the MB index detects GO at earlier stages of enlargement than the GO index.
The pathogenesis of calcium channel blocker induced GO remains uncertain. However, it is believed that they all share the capacity to alter calcium metabolism at the cellular level. The influx of calcium ion across the cell membrane is thought to decrease due to reduced membrane permeability. With decreased influx of calcium, the secretory function of the affected fibroblastic cells or collagenase production is also reduced or inhibited; thus there is increased fibroblastic proliferation and collagen synthesis. , Inflammatory changes within the tissue may enhance the interaction between calcium and fibroblast. ,
Limitations of the study
one of the limitations has been that it was a hospital-based study, and hence it was not the true representation of the population. A population based or community based study would have given better results. Sample size for the study was very small, which would have masked the true prevalence for each drug. As this was only a cross-sectional analysis the causal relation of gingival inflammation, plaque and calculus cannot be definitively determined, for this clinical trial is required.
We can conclude from this study that the overall frequency of GO related to antihypertensive usage is 27.1% based on our convenience sample, with nifedipine causing the most significant GO. The frequency for nifedipine was 75%, which is considerably higher than findings from previous studies. Since the presence of gingival inflammation is an important cofactor in the expression of this effect, regular periodic periodontal health maintenance is mandatory for patients taking antihypertensives.
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[Table 1], [Table 2], [Table 3]