Background
Several causes of gingival hyperplasia are known, and the most recognized is drug-induced gingival enlargement. Furthermore, causes of congenital gingival enlargement include hereditary and metabolic disorders, such the fetal valproate syndrome. [1] See the image below.
Swelling of the gingival mucosa around the right lower canine and multiple areas of erythema, erosions, and bleeding throughout the upper gingival mucosa.
See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to help identify the causes of abnormalities of the oral cavity.
Drug-induced gingival overgrowth, also known as gingival hyperplasia secondary to drugs, was first reported in the dental literature in the early 1960s in institutionalized epileptic children who were receiving therapy with phenytoin (Dilantin) for the treatment of seizures [2, 3, 4] This gingival overgrowth has also been reported in the adult population with epilepsy on phenytoin and phenobarbital drugs. [5, 6]
Cyclosporine, a potent immunosuppressant widely used since the early 1980s in organ transplant recipients and for psoriasis, and numerous calcium channel blocker agents, including nifedipine and amlodipine, have also been associated with gingival overgrowth. [2, 7, 8, 9, 10, 11, 12] Amlodipine is frequently used as an antihypertensive and for the treatment of angina; it is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. There are several hypotheses about the mechanisms by which calcium antagonists induce gingival hyperplasia, but further investigation is still needed. [13] Currently, the leading explanation is that calcium antagonists inhibit the influx of calcium ions needed for the degradation and synthesis of collagen. [14] This accumulation of collagen and extracellular matrix that has not broken down is proposed to be the reason of gingival hyperplasia. [13] Nifedipine appears to have an additive effect when used together with cyclosporine in transplant recipients with hypertension. [15]
In addition, phenobarbital-induced gingival overgrowth has been reported but is rare and needs further evaluation. [16]
Because not all patients on phenytoin, cyclosporine, and/or calcium antagonists develop gingival overgrowth, identifying patients at risk is important in order to take all the necessary measures to minimize the onset and severity of this condition. [17]
Currently, the etiology of drug-induced gingival overgrowth is not entirely understood but is clearly multifactorial. Debate is ongoing regarding whether drug-induced gingival overgrowth is due to hyperplasia of the gingival epithelium or of submucosal connective tissue, and/or both. Furthermore, the effect of age, sex, and duration and dosage of the drug in the pathogenesis of gingival overgrowth is not clearly understood. One of the main reasons is that clinical and epidemiologic studies are primarily retrospective, and they are unable to fully clarify this association. [17]
Some of the risk factors known to contribute to gingival overgrowth include 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 has been suggested to be due to nickel accumulation and epithelial cell proliferation. [17, 18]
Other intrinsic risk factors include the susceptibility of some subpopulations of fibroblasts and keratinocytes to phenytoin, cyclosporine, and/or nifedipine, and the number of Langerhans cells present in oral epithelium. [19, 20, 21] The latter appears to be related to the presence of inflammation and dental plaque.
Because most of the studies reported to date observed patients who had gingival overgrowth at the time of the study, determining the true effect of the medication independent of cofactors such as severity of the underlying disease, oral health status prior to the onset of gingival overgrowth (eg, premature tooth loss, periodontal disease, routine oral hygiene), socioeconomic status, and education is quite difficult. However, the status of oral health prior to onset of gingival overgrowth combined with the medication are both clearly involved in the onset of drug-induced gingival hyperplasia. [22, 23, 24]
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. Phenytoin has been shown to induce gingival overgrowth by its interaction with a subpopulation of sensitive fibroblasts. Cyclosporine has been suggested to affect the metabolic function of fibroblast (eg, collagen synthesis, breakdown). The mechanism of a 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-β1, and prostaglandin E2. [21] Nifedipine, which potentiates the effect of cyclosporine, reduces protein synthesis of fibroblasts. A review of existing literature shows that a cofactor clearly is needed to induce gingival overgrowth. [5, 19, 21, 25, 26, 27, 28, 29, 30] In fact, several lines of evidence point to a modulation of inflammatory processes.
Etiology
Potential risk factors for drug-induced gingival overgrowth 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
Frequency
United States
Gingival overgrowth is a rare condition, and no population-based or epidemiologic studies exist in the United States. Incidence rates are reported from case-series studies. The prevalence of phenytoin-induced gingival overgrowth is estimated at 15-50% in patients taking the medication. The prevalence for cyclosporine transplant recipient patients is 27%; however, these numbers should be interpreted with caution. The incidence of gingival hyperplasia has been reported as 10-20% in patients treated with calcium antagonists in the general population. Clinicians should look at the population represented within each particular study (ie, young persons with epilepsy, recipients of transplants).
International
No incidence or prevalence epidemiologic data is available on gingival overgrowth worldwide. In India, 57% of epileptic children aged 8-13 years who were undergoing phenytoin monotherapy developed gingival overgrowth within 6 months of treatment.
Race
No racial predilection exists for the onset of drug-induced gingival overgrowth.
Sex
No sexual predilection exists for drug-induced gingival overgrowth, although in one study, males were 3 times more likely than females to develop gingival overgrowth with calcium antagonists.
Age
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 prevalence and intensity of drug-induced gingival overgrowth is more serious in pediatric patients. [21]
Prognosis
No mortality is associated with gingival enlargement. Morbidity can be severe in some cases because of gross overgrowth of gingival tissue, which can lead to gingival bleeding, pain, teeth displacement, and periodontal disease. The prognosis is better if patients maintain regular oral hygiene and plaque control.
Patient Education
Inform patients of the risk of developing gingival enlargement secondary to therapy and the role of oral health in minimizing complications from therapy.
Advise patients 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 transplant or the use of 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 the gingival mucosa around the right lower canine and multiple areas of erythema, erosions, and bleeding throughout the upper gingival mucosa.
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Enlarged upper and lower gingival mucosa in a partially edentulous patient. Notice how the overgrown tissue tends to engulf the teeth. Poor oral hygiene and poor dentition are the most likely contributing factors in this patient receiving immunosuppressive therapy.
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A palatal view of enlarged upper and lower gingival mucosa in a partially edentulous patient. Notice the severity of the gingival enlargement. If left untreated, patients develop severe periodontal disease and lose teeth.
