|Year : 2011 | Volume
| Issue : 2 | Page : 73-82
Gingival overgrowth and drug association: A review
MB Mishra1, ZY Khan2, Shanu Mishra3
1 Department of Periodontics Mahatma Gandhi Dental College and Hospital, Jaipur, India
2 Department of Pharmacology, Mahatma Gandhi Medical College and Hospital, Jaipur, Rajasthan, India
3 Registrar, Rotherham General Hospital, Rotherham, S60 3RD, South Yorkshire, United Kingdom
|Date of Web Publication||28-Nov-2012|
M B Mishra
14- A, Brij Nikunj, Friends Colony, Lal Kothi, Tonk Road, Jaipur-302 015, Rajasthan
Drugs used locally or systemically induce several alterations in micro and macroscopic tissues. However, nearly 20 drugs have been reported so far in the literature associated with gingival enlargement. Many systemic diseases have limited therapeutic options and such drugs or their metabolites have an adverse influence on different systems/organs, and one of these is that they initiate or accelerate the overgrowth of gingival tissue. The increase in size may be to the extent that teeth may be partially or completely covered, and the resultant 'gummy smile' may result in aesthetic concern for the patient.In the presence of bacterial inflammation in the gingiva, many of these drugs enhance the production of collagen by fibroblast cells, and simultaneously retard the destruction of collagen and hence increase the bulk of gingival tissue. It is apparent that there is a subpopulation of fibroblasts which is sensitive to these drugs. The exuberant growth of gingival tissue is of great aesthetic concern, which may require mechanical removal of bacterial plaque, calculus, and surgical intervention, and/or substitution of the drug with analogs. A relatively healthy oral environment provided by the dentist will reduce local microflora that will help in eliminating the major focus of infection. Physicians, general practitioners, and dentists need to make a coordinated and concise treatment plan that will be beneficial for the patients. This article will facilitate full information to physicians to involve dentists in the multidisciplinary treatment plan.
Keywords: Collagen, cyclosporine, calcium channel blockers, fibroblast, neuralgia, phenytoin
|How to cite this article:|
Mishra M B, Khan Z Y, Mishra S. Gingival overgrowth and drug association: A review. Indian J Med Sci 2011;65:73-82
| ¤ Introduction|| |
It is well understood and ubiquitously accepted that bacterial plaque is the chief etiologic factor that causes alterations in the periodontal tissue environment by inflammatory and immune responses, whereas systemic factors enhance and aggravate the underlying pathologic mechanism in the connective tissue of the gingiva. Increase in the size of the gingival marginal tissue and deepening of the gingival sulcus acts as a nidus for bacterial plaque, impairs appropriate oral hygiene, and results in increased inflammatory reaction and overgrowth.
The term 'gingival hyperplasia' was used earlier for drug-related gingival enlargement. However, this term did not reflect the histological composition of the pharmacological modified gingiva accurately; hence the terms 'gingival enlargement' or 'gingival overgrowth' are now used. Potential risk factors for drug-induced gingival overgrowth include poor oral hygiene, periodontal disease, depth of periodontal pockets, degree of microbial plaque accumulation, and duration and dose of the drug.
Among the drug-induced gingival enlargements, phenytoin (dilantin) gingival enlargement is the earliest and most commonly reported. Literature is also available on gingival overgrowth secondary to therapy with several drugs like phenobarbitone, primidone, carbamazepine, sodium valproate, mephenytoin, contraceptives, cyclosporine A, calcium channel blockers, and many others. Several studies have shown the interaction of phenytoin, cyclosporine, and nifedipine with epithelial keratinocytes, fibroblasts, and collagen, which can lead to an overgrowth of gingival tissue in susceptible individuals. Phenytoin has been shown to induce gingival overgrowth by its interaction with a subpopulation of sensitive fibroblasts. Cyclosporine affects the metabolic function of fibroblasts (e.g., collagen synthesis and degradation), whereas nifedipine potentiates the effect of cyclosporine, and reduces protein synthesis by fibroblasts. A review of the existing literature reveals clearly that a cofactor is needed to induce gingival overgrowth. In fact, there are several observations suggesting a modulation of inflammatory processes.
The prevalence of phenytoin-induced gingival overgrowth is estimated at 15-50% in patients taking the medication, whereas prevalence by cyclosporine in transplant-recipient patients is 27%. The incidence of gingival enlargement has been reported as 10-20% in patients treated with calcium channel blockers in the general population. However, these numbers should be interpreted with caution and clinicians need to observe the population represented within each particular study (i.e., young persons with epilepsy, recipients of transplants). There are other intrinsic risk factors including the susceptibility of some subpopulations of fibroblasts and keratinocytes to phenytoin, cyclosporine, and/or nifedipine, and the number of Langerhan's cells present in gingival epithelium. The latter appears to be related to the presence of dental plaque and inflammation. Extensively studied and documented are the following three drugs that have been commonly found associated with gingival overgrowth, and are reviewed here with emphasis on pathogenesis.
Phenytoin-associated gingival overgrowth
Since its introduction in 1930s by Merrit and Putnam, phenytoin (dilantin) has been the drug of choice as an anticonvulsant in the treatment of grand mal, temporal lobe, and psychomotor seizures.  Verifying degrees of gingival hyperplasia is one of the most common side effects of phenytoin therapy which was first described by Kimball in 1939.  For more than 60 years, literature has been available on the association between gingival enlargement and phenytoin.  The incidence of enlargement reported by several investigators ranges from 40 to 50% and has been found more in teenagers. In India, 57% of the children aged 8-13 years, who were on monotherapy of phenytoin, developed gingival overgrowth, generally within six months of commencement of the treatment. It is observed that within two to three months of starting phenytoin therapy, clinical sings of gingival enlargement appear as thickening of papillary and marginal gingiva with progression of lesions forming lobules and clefts and eventually covering the crown of the teeth. Clinically, the gingiva becomes firm and pale-pink with slightly inflamed margins and a lobulated or pebbled surface. Enlargement is profound in the anterior region in contrast to posteriors and occurs in teeth-bearing areas. Contrarily, a few cases have been documented in the edentulous areas. Increased gingival bulk may be a limitation to maintaining good oral hygiene, and thereby  increase accumulation of bacterial plaque and inflammation. Edema, redness, and gingival bleeding are the secondary manifestations [Figure 1].
|Figure 1: Phenytoin-associated gingival overgrowth, pronounced enlargement in anterior teeth. Gingiva is firm, leathery, and lobulated.|
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Other anticonvulsant drugs which are prescribed include ethotoin, mephenytoin, valproic acid, ethosuxamide, succinimides, and so on. Drugs like valproic acid, carbamazepine, and phenobarbitone that have been found to influence gingival morphology are commonly prescribed for therapy, and hence have been extensively investigated and documented for their association with gingival enlargement. ,,, Vigabatrin, a relatively newer antiepileptic drug has also been reported to cause gingival overgrowth.  In a 34-year-old male patient having gingival enlargement due to phenytoin, squamous cell carcinoma in relation to maxillary molar roots has been reported, but its association of cause could not be established. 
The major metabolite of phenytoin is 5-parahydroxyphenylhydratoin (5-PHPPH). The mechanism of phenytoin-induced gingival enlargement is not understood clearly, but it has been hypothesized that the increase in the gingival connective tissue occurs probably due to the proliferation of fibroblast cells and increased production of type-1 collagen.
Hassell et al. have suggested that high-activity fibroblasts become sensitive to phenytoin, and this results in subsequent increased production of collagen. Different subpopulations of fibroblast cells in this kind of enlarged gingiva have been postulated.  One of the subpopulations of fibroblasts may become sensitive to phenytoin in the presence of microbial plaque-induced inflammation, resulting in  an increased synthesis of collagen.  Moreover, the enzyme collagenase secreted by phenytoin-sensitive fibroblasts is relatively inactive to degrade collagen. An imbalance in production and degradation results in the overaccumulation of collagen and hence in an increase in the bulk of connective tissue. Changes in the density of the epidermal growth factor receptor (EGFR) has also been reported as an alternative cause, due to the direct effect of the drug or its metabolites on folic acid metabolism and adrenal function. ,
Good oral hygiene and significant control of plaque will reduce the gingival inflammation and help in limiting further increase in gingival enlargement. Phenytoin gingival overgrowth is confined more to the anterior teeth and compromises the aesthetics of the patient. Gingivectomy and gingivoplasty are the treatments of choice, followed by an intensive home care program of oral hygiene. Phenytoin is still a drug of choice for grand mal and psychomotor epilepsy, and epileptic patients require regular medication; discontinuation or substitution may always not be possible. A study conducted by Prasad et al. concluded that systemic folic acid prescribed along with phenytoin delays the onset and reduces the incidence and severity of gingival overgrowth. 
Nifedipine-induced gingival hyperplasia
Calcium channel blockers are also called calcium antagonists and their use has been associated with gingival over growth. Nifedipine (calcium channel blocker) is extensively used for the treatment and prophylaxis of certain cardiovascular conditions and is a known calcium antagonist which inhibits the influx of calcium into the cardiac and smooth muscle cells. This results in a reduction in the contractile process of the cardiac muscle leading to a reduction in arterial blood pressure. The number of prescriptions for calcium channel blockers has been increasing in recent years. Gingival enlargement associated with nifedipine was first reported in the early 1980s.  Gingival overgrowth has been reported in 1-10% of the patients on calcium channel blockers. Ramon et al.  , Heijl et al.  and Shaftic et al.  reported the prevalence of overgrowth as 0.5 to 83% for nifedipine and 74% for diltiazem, whereas Miller et al. observed 4% enlargement with verapamil therapy.  Some of the calcium channel blockers prescribed for different cardiovascular aliments are listed below and have been found to cause enlargement of gingiva:
Lacidipine and nitrendipine 
Nitrendipine, an analog of nifedipine, has also been reported to induce gingival enlargement.  Clinical features of nifedipine-associated gingival overgrowth are similar to those of phenytoin-induced enlargement. Gingival enlargement due to nifedipine shows extensive inflammation that bleeds on slight provocation [Figure 2]. Gingival enlargement is one of the many side effects of this drug; other side effects, though rare, include hypotension, peripheral edema, flushing, palpitation, headache, dizziness, nausea, tiredness, and syncope. These side effects usually occur at the beginning of the treatment and decrease as the treatment progresses.
The possible hypothesis to explain this overgrowth is that the fibroblasts contain strongly sulfated mucopolysaccharides that are precursors of ground substance. After an interaction between nifedipine and gingival fibroblasts, overproduction of collagen and extracellular ground substance occurs and leads to an increase in the size of the gingiva. The drug interferes with the calcium metabolism of fibroblast cells and hence reduces the production of the degrading enzyme collagenase. It has been suggested that there may be subpopulations of fibroblasts which are sensitive to nifedipine and cause an increase in the production of collagen. 
Gingival overgrowth caused by nifedipine decreases following the withdrawal of the drug. Exacerbation occurs when the drug is reintroduced and decreases the second time  with the withdrawal of the drug. The dosage of nifedipine has no correlation with gingival enlargement. Control of bacterial plaque may lead to the resolution of inflammation, but the enlargement does not completely regress. Excision of gingival overgrowth becomes mandatory to overcome aesthetic concerns.
Cyclosporine A-associated gingival enlargement
Cyclosporine, a potent immunosuppressant has been widely used since the early 1980s in recipients of organ transplants  and in the treatment of psoriasis and other autoimmune disorders.
Cyclosporine A (CsA) causes gingival enlargement in 30% patients receiving the drug. Successful use of CsA in transplant medicine has been limited by the development of prominent renal, cardiac, and gingival fibrosis.  Several patients on CsA have been documented with gingival overgrowth. Renal and cardiac fibrosis may be severe enough to cause transplant failure.  Pediatric recipients of heart-lung transplants on CsA appear to be more susceptible to CsA-associated enlargement. Ninety-seven percent of these children have been reported to develop some degree of overgrowth.  A significant role is played by T lymphocytes in the rejection of the graft (transplant). By inhibiting the production and function of T helper lymphocyte cells (Th), CsA suppresses the immune response. At the same time the B-lymphocyte cell system is unaffected by cyclosporine, allowing the patient to maintain a humoral immune response to potential pathogens.
Other than CsA, basiliximab (monoclonal antibody of IL-2 receptor) is also a commonly used immunosuppressant drug, but has not been documented for gingival enlargement. Tacrolimus, another  analog of CsA, has been documented to induce gingival overgrowth, but this effect appears to be time related. 
The onset of cyclosporine-induced gingival enlargement is rapid and initial gingival changes may appear within one to two weeks of therapy. Children and adolescents have a greater risk of developing gingival enlargement in comparison to adults. It has been observed that increase in gingival size and stabilization of growth may occur after a few months of therapy. CsA-associated overgrowth is more hyperemic and bleeds more easily in contrast to gingival overgrowth due to phenytoin, but the clinical appearance of both is identical [Figure 3].
|Figure 3: Cyclosporine-associated gingival overgrowth. Gingiva is more fragile and bleeds on gentle provocation.|
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In the edentulous area, cyclosporine-associated enlargement has not been reported. In patients of bone marrow transplants, the incidence of gingival enlargement is 2% as compared to 81% in renal transplants.
Varga et al. have reported a case of carcinoma arising in the cyclosporine-associated gingival hyperplasia. 
It is not understood whether poor oral hygiene is responsible for initial gingival inflammation which is enhanced subsequently by CsA, or the drug initiates enlargement and facilitates accumulation of bacterial plaque, impairs oral hygiene, and precipitates inflammation.
Some studies on CsA-induced enlargement found no correlation between the oral dose of CsA and severity of gingival enlargement. Examination of tissue-typing  data in transplant recipients have shown that HLA B37-positive patients are significantly more likely to show severe gingival enlargement, whereas the opposite is true for HLA DR1-positive patients. CsA-treated patients are often prescribed prednisolone or azathioprine additionally, which can modify the severity of gingival enlargement.  It was found that CsA could react with a phenotypically distinct subpopulation of gingival fibroblasts to enhance protein synthesis. 
The histological appearance of the tissue shows an increase in the collagen fibers in the connective tissue of the gingiva. The drug may reach the connective tissue of the gingiva through the blood stream and/or from the oral cavity through the crevicular epithelium. In the presence of inflammation, the permeability of the sulcular epithelium increases, resulting in the increased concentration of CsA in the connective tissue. The hypothesis is supported by the fact that the concentration of CsA is higher in whole saliva than in serum.
There is no effective and predictable method of managing this condition. Complete resolution of gingival enlargement following reduction of dosage of CsA in one patient has been reported. Treatment may involve optional drug therapy, for example, replacing cyclosporine with tacrolimus (an alternative immunosuppressant).  Overgrowth can be minimized by measures to control bacterial plaque. However, excess fibrotic tissue unresponsive to regress on withdrawal of the drug needs excision. Gingivectomy with carbon dioxide or Neodymium-droped: yttrium aluminium garnet crystal (Nd: YAG) laser is  recommended for moderate to severe cases. CsA-induced hyperplasia is more hyperemic than a phenytoin one; therefore, it is necessary to control excessive bleeding during surgery. Recent observations suggest that roxithromycin, a macrolide antibiotic, may have a therapeutic role in reducing cyclosporine-induced gingival overgrowth, owing to its inhibitory action in the production of the transforming growth factor-β. Azithromycin, in association with oral prophylaxis, significantly reduces cyclosporine-induced gingival enlargement.
Firm, leathery, fibrous enlargement of gingival tissue can also be associated with heredity, hormones, idiopathic syndromes, and drug factors.
Hereditary gingival enlargement has a definite family history and is an isolated abnormality. Gingival enlargement is inherited as an autosomal dominant trait or, rarely, as an autosomal recessive trait.  There may a spontaneous gene mutation; hence, a negative family history alone cannot dismiss hereditary gingival enlargement from differential diagnosis completely. Oral pathologists prefer the term 'hereditary gingival fibromatosis' (HGF) for this kind of enlargement. Other characteristic features of HGF are hypertrichosis, mental retardation, and coarse and thickened facial appearance simulating acromegaly.
In leukemic infiltration, the gingival tissue often is purple-red with secondary inflammation. There is acute onset of hemorrhagic gingival oozing, and the consistency of the gingiva is soft and fragile and dark red to purple in color.
Tuberculosis and other granulomatous diseases, including orofacial granulomatosis, Crohn's disease, and sarcoidosis, can also mimic drug-induced gingival enlargement.
Gingival enlargement may have a rare association with the following conditions:
- Inclusion-cell disease (mucolipidosis II) 
- Acanthosis nigricans
- Borrone-Di Rocco-Crovato syndrome
- Cantu syndrome
- Winchester syndrome
| ¤ Discussion|| |
The prevalence of gingival enlargement in the healthy population has been estimated to be between 4.0 and 7.5 %. , Kimball (1939) was among the first to report gingival overgrowth associated with phenytoin, reporting that 57% of the patients taking this drug had gingival overgrowth.  Phenytoin, nifedipine, cyclosporine, and other similar drugs mentioned above or analogs, despite their therapeutic dose, are found to cause gingival enlargement. It has also been observed that nifedipine potentiates the adverse effect (i.e., gingival overgrowth) of cyclosporine. Morbidity can be severe in some cases because of gross overgrowth of the gingival tissue, which can lead to gingival bleeding, pain, displacement of teeth, and periodontal disease, but mortality has not been reported. Racial and gender predilection has not been found for drug-induced gingival overgrowth, although one study reported that males are three times more likely than females to develop gingival overgrowth with calcium antagonists.  Similarly, no age predilection exists for the onset of drug-induced gingival overgrowth; however, phenytoin-induced gingival overgrowth appears to be more frequent in young patients with epilepsy. Most likely, this may be related to the age of the population, the nature of the disease, and poor oral hygiene. The probable explanation is that clinical and epidemiologic studies are primarily retrospective, and they are unable to clarify this association fully. The prevalence of phenytoin induced gingival overgrowth is Estimated 15-50%, while that of cyclosporine induced over growth in transplant patients is 27%. Incidence of gingival hyperplasia has been reported as 10-20% in patients treated with calcium antagonists. However, these numbers should be interpreted with caution, and clinicians should look at the population represented within each particular study (i.e., young persons with epilepsy, recipients of transplants). 
Fibroblasts are the predominant cells in the connective tissue of gingiva, the cells responsible for the synthesis of fibers (collagen and elastin) and ground substance (proteoglycans and glycoprotein). However, collagenase is also produced by fibroblasts to degrade old collagen and thus maintain the turnover of collagen in the connective tissue. Fibroblast cells are calcium dependent for the production of collagen. These drugs interfere with the calcium transport and cause imbalance in the synthesis and degradation of the extracellular matrix by interfering with the synthesis and function of collagenase.
Although the pharmaceutical effects and primary target tissues of antiepileptic, immunosuppressant, antidepressant, and calcium channel blocker medication are different, they act in a similar way on gingival connective tissue, causing fibrous gingival enlargement. In cases involving gingival enlargement, gingival connective tissue does not necessarily exhibit an increased number of fibroblasts histologically. , These findings indicate that at a molecular level, one etiologic factor of drug-induced gingival enlargement may be the inhibition of collagen phagocytosis by means of reducing the expression of the a2B1 integrin. Research suggests that the integrin transducer conveys information from the extracellular matrix to the inside of the cell by triggering intracellular signaling pathways.  The above-stated drugs are known to act as calcium antagonists. Intracellular calcium plays a significant role in the regulation of a2B1 integrin-mediated collagen phagocytosis by alternating integrin affinity. 
Furthermore the actin-binding protein gelsolin is considered an important factor in gingival enlargement. Gelsolin contributes to maintain normal integrity of the tissue by regulating collagen phagocytosis through its integrin-binding affinity for collagen. 
In orthodontic patients, gingival overgrowth has been suggested to be due to the accumulation of nickel in epithelial cells. Substitution of phenytoin with a different anticonvulsant has long been suggested as the treatment of choice for severely affected gingival enlargement. With the introduction of the new generation  of anticonvulsant drugs like lamotrigine, gabapentin, sulthiame and topiramate, the possibility of gingival enlargement can be reduced. Replacing CsA with tacrolimus (an alternative immunosuppressive drug) may cause a significant regression of gingival enlargement in recipients of renal transplants. 
All these drug-induced enlargements mentioned in the literature so far have similarities of clinical and histological characteristics. Substantial evidence in the dental literature indicates that gingival enlargement can be controlled successfully, even under the continuous administration of calcium antagonists, by meticulous professional and individual oral hygiene, initiated prior to commencing therapy.
| ¤ Conclusion|| |
Several clinical studies concluded that in the relatively healthy oral cavity with optimal control of plaque, drug-associated gingival overgrowth is clinically unnoticeable. The drugs discussed here accentuate the overgrowth in pre-existing gingival inflammation due to the accumulation of microbial plaque.
There are two concrete recommendations as protocol for the management of the drug-induced gingival overgrowth:
- Physician and dentist should make a co-ordinated treatment plan for the patients indicated for these drug therapies.
- Established gingival overgrowth renders esthetic insult, which may be a primary concern and require intervention. Therefore, excision of the enlarged gingiva becomes an inevitable choice. All patients need to be helped to practice improved oral hygiene.
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[Figure 1], [Figure 2], [Figure 3]