Drug-induced gingival overgrowth: The nemesis of gingiva unravelled.

Drug-induced gingival overgrowth or enlargement manifests as abnormal growth of the gingiva due to an adverse drug reaction (ADR) in patients treated with anticonvulsants, immunosuppressants, and calcium channel blockers. As gingival enlargement develops, it affects the normal oral hygiene practice and may interfere with masticatory functions. It gradually becomes a source of pain and the condition often leads to disfiguration. Within the group of patients that develop this unwanted effect, there appears to be variability in the extent and severity of the gingival changes. It would seem pertinent to identify and explore possible risk factors and relating them with the treatment plan. This article throws light on respective drugs and their association with gingival overgrowth and approaches to treatment based on current knowledge and investigative observations.

INTRODUCTION

Drug-induced gingival overgrowth or enlargement occurs in whole or in part from systemic drug use. It occurs as a side effect following the administration of drugs used mainly for non-dental treatments and thus, the overgrowth cannot be explained as a variation of the intended pharmacological action of the drug.[1] Several factors namely; age, genetic predisposition, presence of preexisting plaque, and gingival inflammation influence the relationship between the drugs and gingival tissue.[2] There is a variable gingival response in patients taking drugs. Indeed, the term “responders” and “nonresponders” appear in the literature. Furthermore, within the group of patients that develop this unwanted effect, there appears to be variability in the extent and severity of the gingival changes.[3] On the contrary, there is infinitesimal awareness about this effect of drugs on gingival tissues in medical community.

To date there has been no clear cut literature which could consolidate the pathogenesis, clinical manifestations, and the management of affected patients. There is a need of exposition which would refine our knowledge about known drugs and familiarize with the newer drugs. The aim of this literature review is to bring to a focus the integrated knowledge about drug-induced gingival overgrowth and ameliorate about the concepts of its treatment.

Different systemic medications can cause gingival overgrowth [Table 1].[1415161718]

Table 1

Drugs causing gingival overgrowth

Other drugs

Erythromycin: A single case of gingival overgrowth has been associated with the use of erythromycin in a young boy (Valsecchi and Cainelli, 1992). The condition resolved with withdrawal of the drug and returned upon repeat challenge. The authors were unable to suggest any possible mechanism for the phenomenon.[1]

PATHOGENESIS

Despite their pharmacological diversity, the three major drugs causing gingival overgrowth, namely; anticonvulsants, calcium channel blockers, and immunosuppressants; have similar mechanism of action at the cellular level, where they inhibit intracellular calcium ion influx. The action of these drugs on calcium and sodium ion flux may prove to be the key in understanding why three dissimilar drugs have a common side effect upon a secondary target tissue, such as gingival connective tissue. An appraisal of the various investigations into the pathogenesis of drug-induced gingival overgrowth supports the hypothesis that it is multifactorial [Figure 1].[3419] Plaque scores and gingival inflammation appear to exacerbate the expression of drug-induced gingival overgrowth, irrespective of the initiating drug. The severity of gingival enlargement in patients taking medications correlates well with poor plaque control and is commensurate with the degree of plaque-induced inflammation. The importance of plaque as a cofactor in the etiology of drug-associated gingival enlargement has been recognized in the most recent classification system for periodontal diseases. In this classification, “drug-induced gingival enlargements” are categorized as plaque-induced gingival diseases modified by medications.[19]

Figure 1

Schematic diagram to illustrate the potential multifactorial features and interactions involved in the pathogenesis of drug-induced gingival overgrowth

Role of fibroblasts

It has also been proposed that susceptibility or resistance to pharmacologically induced gingival overgrowth may be governed by the existence of differential proportions of fibroblast subsets in each individual which exhibit a fibrogenic response to these medications. In support of this hypothesis, it has been shown that functional heterogeneity exists in gingival fibroblasts in response to various stimuli.[19]

Role of inflammatory cytokines

A synergistic enhancement of collagenous protein synthesis by human gingival fibroblasts was found when these cells were simultaneously exposed to nifedipine and interleukin-1β (IL-1β), a proinflammatory cytokine that is elevated in inflamed gingival tissues. In addition to IL-1β, IL-6 may play a role in the fibrogenic responses of the gingiva to these medications. IL-6 appears to target connective tissue cells such as fibroblasts both by enhancing proliferation and by exerting a positive regulation on collagen and glycosaminoglycans synthesis.[19]

Role of matrix metalloproteinase

Because most types of pharmacological agents implicated in gingival overgrowth have negative effects on calcium ion influx across cell membranes, it was postulated that such agents may interfere with the synthesis and function of collagenases.[19]

Kantarci et al.,[20] demonstrated that there are significantly higher numbers of basement membrane discontinuities in overgrowth tissues, sometimes containing epithelial-like cells. Disrupted basal membrane structure in gingival overgrowth tissues is accompanied by a discontinuous collagen type IV expression pattern and decreased laminin-5. These findings provided a new additional support for the hypothesis that epithelial plasticity and epithelial to mesenchymal transition promote gingival overgrowth, resulting in compromised basal membrane structure and increased interactions between epithelial and connective tissue layers that contribute to fibrotic pathology.[2021]

Recently, Subramani et al.,[22] observed that mast cells participate in many inflammatory oral diseases, particularly those associated with fibrosis. They possess very diverse roles ranging from proinflammatory to immunomodulatory. Upon their activation, they promote the local renin angiotensin system generation consequently able to stimulate endothelin and other profibrotic mediators. Cyclosporin can modulate local expression of renin angiotensin system components such as angiotensinogen, angiotensin II and its receptors in gingival tissues, and gingival fibroblast cells.[2223]

CLINICAL MANIFESTATIONS

Clinical manifestation of gingival enlargement frequently appears within 1-3 months after initiation of treatment with the associated medications:[19]

The growth starts as a painless, beadlike enlargement of the interdental papilla, and extends to the facial and lingual gingival margins. As the condition progresses, the marginal and papillary enlargements unite; they may develop into a massive tissue fold covering a considerable portion of the crowns[24]

When uncomplicated by inflammation; the lesion is mulberry-shaped, firm, pale pink, and resilient; with a minutely lobulated surface and no tendency to bleed. The enlargement characteristically appears to project from beneath the gingival margin, from which it is separated by a linear groove[24]

Presence of enlargement makes plaque control difficult, often resulting in a secondary inflammatory process that complicates the gingival overgrowth caused by the drug. Secondary inflammatory changes not only add to the size of the lesion caused by the drug, but also produce a red or bluish red discoloration, obliterate the lobulated surface demarcations, and increase bleeding tendency[24]

The enlargement is usually throughout the mouth, but is more severe in the maxillary and mandibular anterior regions. It occurs in area in which teeth are present, not in edentulous spaces, and the enlargement disappears in areas from which teeth are extracted. Hyperplasia of the mucosa in edentulous mouths has been reported but is rare.[24]

HISTOPATHOLOGY OF THE LESION

An ultrastructural study demonstrated that the increase in gingival tissue volume is primarily due to a connective tissue response rather than epithelial cell layer involvement. The histopathology of the lesions in all drug categories is similar and is characterized by excessive accumulation of extracellular matrix proteins such as collagen or amorphous ground substance. Varying degrees of inflammatory infiltrate exist, while an increase in the number of fibroblasts remains controversial. The predominant type of infiltrating inflammatory cell is the plasma cell. Parakeratinized epithelium of variable thickness covers the connective tissue stroma and epithelial ridges may penetrate deep into the connective tissue, creating irregularly arranged collagen fibres.[19]

DRUGS WHICH CAUSE GINGIVAL OVERGROWTH

Anticonvulsants

Phenytoin (PHT; 5,5-diphenylhydantoin) was first introduced as an antiepileptic drug in 1938. Within a year of its initial clinical use, reports linking PHT to gingival overgrowth appeared in the literature.[5] Since then, other anticonvulsant agents have been introduced that have frequently been linked to clinically significant forms of gingival overgrowth. For example, gingival overgrowth cases after chronic use of valproic acid, carbamazepine, or phenobarbitone in adult patients have been reported but are rare or have been poorly documented.[1925] In addition, valproic acid can affect the fetus also. A congenital case has been described in a child exposed to valproic acid in utero.[26] Vigabatrin is a relatively new antiepileptic agent that can also cause gingival overgrowth. Immunohistochemical study suggested that vigabatrin induced an increase in epithelial cell proliferation due to overexpression of antigen Ki-67 and slight underexpression of the CDK-inhibitors p27KIP1 and p21WAF1.[27] Administration of multiple anticonvulsants in children also has an additive effect on gingival overgrowth. PHT, primidone, and phenobarbitone are all metabolized to 5-(4-hydroxyphenyl) 5-phenylhydantoin (4-HPPH). The increased serum concentration of this metabolite might explain the additive effect of multiple anticonvulsant therapy to gingival overgrowth.[28] Other drugs known to induce gingival overgrowth include are ethotoin, mephenytoin, ethosuximide, methosuxinimide.[24]

Immunosuppressants

Cyclosporin is a powerful immunosuppressant widely used for prevention of transplant rejection as well as for management of a number of autoimmune conditions.[19] However, cyclosporin may have damaging side effects, such as nephrotoxicity, hepatotoxicity, hypertension, and gingival overgrowth.[29] The first time gingival overgrowth with cyclosporin therapy was described in the dental literature in 1983 by both Rateitschak-Plüss et al., and Wysocki et al.[5] Recently, Greenberg et al.,[30] studied a sample of 115 patients that underwent kidney transplants and found a gingival overgrowth prevalence of 53% among those who were treated with cyclosporin.

Tacrolimus or FK506, is a macrolide molecule which has been shown to have major potential as an alternative immunosuppressant to cyclosporin.[31] Tacrolimus has similar side effects when compared with cyclosporin, but where gingival overgrowth is concerned, the results appear to differ. It is also nephrotoxic, but it results in much less severe hypertension and hypertrichosis.[2432] Various studies have demonstrated less frequent association of gingival overgrowth with the use of tacrolimus than with cyclosporin.[3334] Synergistic effects have been reported when cyclosporin is administered concurrently with calcium channel blockers of dihydropyridine derivatives.[35]

Furthermore, gingival overgrowth is also demonstrated in transplant subjects under sirolimus based regimens, but within a nonsignificant clinical threshold.[789]

Calcium channel blockers

Antihypertensive drugs in the calcium channel blocker group are used extensively in elderly patients who have angina or peripheral vascular disease.[19] The first case of nifedipine-induced gingival enlargement was reported in mid 1980s by Lederman et al., and Ramon et al., and was soon also described with diltiazem, verapamil, and in cases with amlodipine and felodipine.[519] Ikawa K et al.,[11] presented a case report of severe gingival overgrowth induced by manidipine in a female patient. The choice of the calcium channel blocker used in conjunction with cyclosporin can also affect the prevalence or severity of gingival enlargement. It has been reported that the prevalence of gingival overgrowth in renal transplant recipients maintained on cyclosporin and amlodipine is higher than those receiving cyclosporin and nifedipine. In addition, when effects of a combined treatment of cyclosporin and nifedipine or diltiazem were tested in an animal model, cyclosporin was found to synergistically enhance gingival growth with nifedipine and to a lesser degree with diltiazem.[19]

DIFFERENTIAL DIAGNOSIS

A differential diagnosis requires thorough medical and dental histories, a careful evaluation of nature of enlargement, and an identification of the etiologic factors. A biopsy specimen may be required to confirm diagnosis.

Drug-induced gingival overgrowth must be differentiated from

Inflammatory enlargement: Acute inflammatory enlargement appears as a localized gingival swelling characterized by acute pain of rapid onset suggesting an abscess. Chronic inflammatory enlargement appears as deep red or bluish red, soft, friable with smooth, shiny surface along with bleeding tendency. Inflammatory enlargements usually are a secondary complication to any of the other types of enlargement, creating a combined gingival enlargement[24]

Idiopathic or familial or hereditary gingival enlargement: It affects the attached gingiva, as well as the gingival margin and interdental papillae. The facial and lingual surfaces of the mandible and maxilla are generally affected, but the involvement may be limited to either jaw. The enlarged gingiva is pink, firm, and almost leathery in consistency and has a characteristic minutely pebbled surface. Its cause is not known. However, some cases show a hereditary basis[24]

Conditioned enlargement: It occurs when the systemic condition of the patient exaggerates or distorts the usual gingival response to dental plaque. It includes hormonal (pregnancy, puberty), nutritional (associated with vitamin C deficiency), and allergic (plasma cell gingivitis). The gingiva shows features of chronic inflammatory enlargement especially interproximally. Plasma cell gingivitis consists of lesion located in the oral aspect of attached gingiva[24]

Systemic diseases induced gingival enlargement: Several systemic diseases viz. leukemia, sarcoidosis, tuberculosis, and other granulomatous diseases can result in gingival enlargement. Hematological investigations (as in leukemia) and histopathological examination (leukemic infiltrate in leukemia, foreign body giant cell in sarcoidosis, tuberculosis) are useful in establishing the diagnosis[24]

Neoplastic enlargement or gingival tumors: It may appear as slowly growing spherical mass that tends to be firm and nodular or hard, wart-like protuberance from gingival surface[24]

False enlargement: These are not true enlargements of the gingival tissues but appear as such. These result due to increase in size of the underlying osseous or dental tissues. The gingiva usually presents with no abnormal clinical features except the massive increase in size of area.[24]

Gingival overgrowth induced by various drugs is differentiated from one another as

In phenobarbitone treated patients, the gingiva may be enlarged uniformly without lobulations of the interdental papillae, and severity of the clinical lesions has been reported to be greater in the posterior as compared to the anterior regions[19]

In individuals, immunosuppressed with cyclosporin, sometimes pebbly or papillary lesions appear on the surface of larger lobulations, which have been associated with the presence of Candida hyphae invading the gingival epithelium. Other investigators have reported that tissues affected by cyclosporin are generally more hyperemic and bleed more readily upon probing than tissues affected by phenytoin.[19]

TREATMENT

Nonsurgical

The primary aim of nonsurgical approaches is to reduce the inflammatory component in the gingival tissues and thereby avoid the need for surgery.

Meticulous removal of plaque on a frequent basis helps in the maintenance of attachment levels. Patients at risk from, or who have developed drug-induced gingival overgrowth will benefit from effective oral hygiene measures, professional tooth cleaning, scaling, and root surface instrumentation. For some patients these measures alone could reduce the gingival overgrowth to acceptable levels, for others, it could make surgical correction easier.[363738]

In addition, in chronically immunosuppressed patients, papillary lesions present on the surface of the enlarged gingiva have been reported to resolve using topical antifungal medications (e.g. nystatin lozenges).[19] A review of clinical trials suggests that there are some benefits associated with the use of systemic azithromycin in the management of gingival overgrowth. Lu et al.,[39] considered that drug-induced gingival overgrowth may be either prevented or treated through a pharmaceutical strategy using nonsteroidal antiinflammatory agents to control IL-1-mediated inflammation, or by treatment with a reassuringly safe profile of low dose androgen receptor antagonists to block the androgen receptor CTGF/CCN2-collagen cascade and decrease collagen production.[39]

Consideration should be given to the possibility of discontinuing the drug or of changing medication. These possibilities should be consulted with the patient's physician. Simple discontinuation of the offending agent is usually not a practical option but replacing it with another medication might be. Alternative medications to PHT include carbamazepine and valproic acid, both of which have been reported to have a lesser impact in inducing gingival enlargement.[40] Recently, the feasibility of PHT substitution has increased with the addition of a new generation of anticonvulsants such as lomatrigine, gabapentin, sulthiame, and topiramate.[5] Drug substitution options for cyclosporin are more limited due to the fact that few of these options exist. Earlier, it was said that cyclosporin-induced gingival enlargement can spontaneously resolve if the drug is substituted by tacrolimus.[40] However, mycophenolic acid and azathioprine showed a protective effect against the development of gingival hyperplasia in kidney transplant patients. The protective effect of Azathioprine on the risk of gingival hyperplasia is explained through its antiproliferative and antiinflammatory action.[41] The dihydropyridine derivative isradipine can replace nifedipine in some cases and does not induce gingival overgrowth.[42] Consideration may be given to the use of another class of antihypertensive medications than calcium channel blockers, none of which are known to induce gingival enlargement.[24]

If any drug substitution is attempted, it is important to allow for 6-12 months to elapse between discontinuation of the offending drug and the possible resolution of gingival enlargement before a decision to implement surgical treatment is made.[40]

Surgical

Gingival enlargement may persist, despite drug substitution attempts and good plaque control. These cases need to be treated by periodontal surgery. Before any surgical procedure, precautions and consultations with physician regarding underlying systemic disease should be taken into consideration. The surgical management of drug-induced gingival overgrowth includes the scalpel gingivectomy, periodontal flap surgery, electrosurgery, and laser excision. The clinician's decision to choose gingivectomy or periodontal flap surgical techniques must be made on a case-by-case basis and should take into consideration the extent of area to be involved in surgery, the presence of periodontitis, the presence of osseous defects combined with the gingival enlargement lesions, and the position of the bases of the pockets in relation to the existing mucogingival junction. Nevertheless, surgical intervention using conventional means (scalpel) may sometimes be technically difficult and/or impractical for example in children or mentally handicapped, or in patients suffering from impaired hemostasis. In these situations the use of electrosurgery may be advantageous. The use of lasers has shown some utility for reducing gingival enlargement, an approach which provides rapid postoperative hemostasis [Figure 2].[3640]

Figure 2

Decision tree in the treatment of drug-induced gingival overgrowth

Maintenance

Chlorhexidine gluconate rinses and professional cleaning can decrease the rate and the degree at which recurrence occurs. A hard, natural rubber, fitted bite guard worn at night may also assist in the control of recurrence. Recurrence may occur as early as 3-6 months after the surgical treatment, but in general, surgical results are maintained for at least 12 months.[40]

CONCLUSION

Drug induced gingival overgrowth is one of the most widespread unwanted effect of systemic medication on the periodontal tissues. However, our understanding of the pathogenesis of gingival overgrowth is incomplete at best. Hence, it would be pertinent to identify and explore possible risk factors relating to both prevalence and severity of drug-induced gingival overgrowth. Newer molecular approaches are needed to clearly establish the pathogenesis of gingival overgrowth and to provide novel information for the design of future preventive and therapeutic modalities.