Background
Several causes of gingival hyperplasia are known. Congenital gingival enlargement can be caused by various hereditary and metabolic disorders (eg, fetal valproate syndrome). [1] However, the most recognized form of gingival hyperplasia is drug-induced gingival enlargement (or drug-induced gingival overgrowth [DIGO]). [2] (See the image below.) The term gingival hyperplasia is something of a misnomer here, in that enlargement results not from an increase in the number of cells but, rather, from an increase in extracellular tissue volume.
Swelling of gingival mucosa around right lower canine and multiple areas of erythema, erosions, and bleeding throughout upper gingival mucosa.
DIGO was first reported in the dental literature in the early 1960s in institutionalized epileptic children who were receiving therapy with phenytoin for the treatment of seizures. [3, 4] It was also reported in adults receiving phenytoin or phenobarbital for treatment of epilepsy. [5, 6]
Cyclosporine, a potent immunosuppressant widely used since the early 1980s in organ transplant recipients and for treatment of psoriasis, has also been associated with gingival overgrowth, as have numerous calcium-channel blockers (CCBs; eg, nifedipine and amlodipine). [7, 8, 9, 10, 11, 12] Amlodipine is frequently used as an antihypertensive and for treatment of angina; it is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Nifedipine appears to have an additive effect when used together with cyclosporine in transplant recipients with hypertension. [13]
There are several hypotheses about the mechanisms by which CCBs induce gingival hyperplasia, but there remains a need for further investigation. A leading explanation has been that these agents inhibit the influx of calcium ions needed for the degradation and synthesis of collagen, and that this accumulation of collagen and extracellular matrix that has not broken down gives rise to the gingival hyperplasia.
Although phenobarbital-induced gingival overgrowth has been reported as well, it is relatively rare; further study is warranted. [14]
Because not all patients who take phenytoin, cyclosporine, or CCBs develop gingival overgrowth, it is important to identify patients who are at risk for this condition so that all the necessary measures can be taken to minimize its onset and severity. [15]
Among the risk factors known to contribute to gingival overgrowth is the presence of gingival inflammation (ie, gingivitis) resulting from poor oral hygiene. Furthermore, the presence of dental plaque may provide a reservoir for the accumulation of phenytoin or cyclosporine. In orthodontic patients, gingival overgrowth may be due to nickel accumulation and epithelial cell proliferation. [15, 16]
Other intrinsic risk factors include the susceptibility of some subpopulations of fibroblasts and keratinocytes to phenytoin, cyclosporine, or nifedipine, as well as the number of Langerhans cells present in oral epithelium. [17, 18] The latter appears to be related to the presence of inflammation and dental plaque.
Because most of the studies reported to date have evaluated patients who had gingival overgrowth at the time of the study, it has been quite difficult to determine the true effect of the medication, independent of cofactors such as severity of underlying disease, oral health status before the onset of gingival overgrowth (eg, premature tooth loss, periodontal disease, routine oral hygiene), socioeconomic status, and education. It is clear, however, that both oral health status prior to onset of gingival overgrowth and medication effects are involved in the onset of drug-induced gingival hyperplasia. [19, 20, 21]
Treatment is primarily nonsurgical, with surgical measures employed only when necessary. [2] (See Treatment.) The simplest means of treating DIGO is to discontinue or change the inducing drug, if possible.
Pathophysiology
Several studies have shown that the interaction of phenytoin, cyclosporine, and nifedipine with epithelial keratinocytes, fibroblasts, and collagen can lead to an overgrowth of gingival tissue in susceptible individuals. [22]
Phenytoin has been shown to induce gingival overgrowth through its interaction with a subpopulation of sensitive fibroblasts.
Cyclosporine may affect the metabolic functioning of fibroblasts (eg, collagen synthesis, breakdown). The mechanism of cyclosporine-induced fibroblast overgrowth in both adults and children may be linked to the steps involving fibroblast proliferation and the cytokine network, including interleukin (IL)-6, IL-8, IL-1β, transforming growth factor (TGF)-β1, and prostaglandin E2. [18]
Nifedipine, which potentiates the effect of cyclosporine, reduces protein synthesis of fibroblasts. Studies have indicated that a cofactor is clearly needed to induce gingival overgrowth. [5, 17, 18, 23, 24, 25]
Several lines of evidence have pointed to a modulation of inflammatory processes. A study by Palmieri et al suggested a link between drugs that cause DIGO and M1 proinflammatory macrophage polarization. [26]
Etiology
The etiology of DIGO has not been fully defined but is clearly multifactorial. There has been debate as to whether DIGO is due to hyperplasia of the gingival epithelium or of submucosal connective tissue, or both. Furthermore, the effects of age, sex, and the duration and dosage of drug use on the pathogenesis of gingival overgrowth are not clearly understood. One of the main reasons for this lack of clarity is that clinical and epidemiologic studies are primarily retrospective and are unable to clarify the association fully. [15]
Potential risk factors for DIGO include the following:
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Poor oral hygiene
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Periodontal disease
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Periodontal pocket depth
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Gingival inflammation
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Degree of dental plaque
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Duration and dose of cyclosporine
Epidemiology
US and international statistics
Gingival overgrowth is a rare condition, and population-based or epidemiologic studies are not available for the United States. Incidence figures are reported from case-series studies.
The prevalence of phenytoin-induced gingival overgrowth has been estimated at 15-50% in patients taking the medication. The prevalence of gingival hyperplasia in transplant recipients treated with cyclosporine has been reported to be 27%; however, these numbers should be interpreted with caution. The incidence of gingival hyperplasia has been reported to be 10-20% in patients treated with calcium antagonists in the general population. When considering a particular study, clinicians should look at the population represented within that study (eg, young persons with epilepsy or transplant recipients).
No epidemiologic data on the worldwide incidence or prevalence of gingival overgrowth are available. In a study from India, 57% of epileptic children aged 8-13 years who were undergoing phenytoin monotherapy were found to have gingival overgrowth within 6 months of treatment.
Age-, sex-, and race-related demographics
No age predilection exists for the onset of DIGO. However, phenytoin-induced gingival overgrowth appears to be more frequent in young patients with epilepsy. This observation may be related to the age of the population, the nature of the disease, and poor oral hygiene. The prevalence and intensity of DIGO are greater in pediatric patients. [18]
No sex predilection has been established for DIGO, though in one study, males were three times more likely to develop gingival overgrowth with calcium antagonists than females were.
No racial predilection exists for the onset of DIGO.
Prognosis
No mortality is associated with gingival enlargement. Morbidity can be severe in some cases, because gross overgrowth of gingival tissue can lead to gingival bleeding, pain, displacement of teeth, and periodontal disease. The prognosis is better if patients maintain regular oral hygiene and plaque control.
Patient Education
Patients should be informed of the risk of developing gingival enlargement secondary to therapy and educated regarding the role of oral health in minimizing complications from therapy.
Patients should be advised to see a pedodontist, a periodontist, and an oral medicine dentist for a baseline evaluation, full-mouth x-ray films, tooth extractions (if needed), and dental hygiene before undergoing a transplant procedure or using any drug known to induce gingival overgrowth.
For patient education resources, see the Oral Health Center, as well as Gingivitis and When to Visit the Dentist.
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Swelling of gingival mucosa around right lower canine and multiple areas of erythema, erosions, and bleeding throughout upper gingival mucosa.
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Enlarged upper and lower gingival mucosa in partially edentulous patient. Notice how overgrown tissue tends to engulf teeth. Poor oral hygiene and poor dentition are most likely contributing factors in this patient receiving immunosuppressive therapy.
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Palatal view of enlarged upper and lower gingival mucosa in partially edentulous patient. Note severity of gingival enlargement. If left untreated, patients develop severe periodontal disease and lose teeth.
