Drug-Induced Gingival Hyperplasia 

Updated: Mar 26, 2019
Author: Lina M Mejia, DDS, MPH; Chief Editor: Jeff Burgess, DDS, MSD 

Overview

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 l 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:

  • Poor oral hygiene

  • Periodontal disease

  • Periodontal pocket depth

  • Gingival inflammation

  • Degree of dental plaque

  • 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.

 

Presentation

History

The onset of drug-induced gingival overgrowth in susceptible individuals is insidious. Gingival overgrowth is asymptomatic, except in the presence of poor oral hygiene and dental plaque because patients may develop bleeding with tender and swollen gums. Patients with mal-positioned teeth, periodontal disease, and poor oral hygiene are at risk of developing gingival overgrowth. Severity varies depending on the oral health prior to the beginning of therapy; however, not all patients with poor oral hygiene develop drug-induced gingival overgrowth.

Phenytoin-induced gingival overgrowth

This is more likely to occur in patients with gingivitis and dental plaque.

Increased dental plaque has been suggested to induce local inflammation and to serve as a reservoir for phenytoin.

Cyclosporine-induced gingival overgrowth

In susceptible patients (ie, presence of dental plaque, swollen gums, high dose of cyclosporine), gingival overgrowth may develop by the third month of therapy.

Patients with poor oral hygiene and displaced teeth tend to develop bleeding gums upon probing.

Aggressive plaque control and routine oral hygiene help in maintaining gums but may not prevent the onset of gingival overgrowth in susceptible individuals.

Cyclosporine-induced gingival overgrowth is reversible once therapy is discontinued or when the dose is reduced.[31, 32]

Cyclosporine- and nifedipine-induced gingival overgrowth

Nifedipine potentiates the adverse effect (ie, gingival overgrowth) of cyclosporine.[33, 34]

Calcium antagonist–induced gingival overgrowth

Oral hygiene plays a decisive role in the development of gingival enlargement.[35]

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.

Physical Examination

Gingival enlargement occurs primarily on the labial gingival mucosa and in between the teeth (interdental papillae area). Gingival overgrowth is more pronounced on the labial aspect of the maxillary gingiva and in the interdental papillae.

See the images below.

Enlarged upper and lower gingival mucosa in a part 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.
A palatal view of enlarged upper and lower gingiva 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.
 

DDx

Diagnostic Considerations

Also consider the following:

 

Workup

Laboratory Studies

CBC count is indicated in patients with severe gum bleeding to rule out anemia and leukemia.

Imaging Studies

Periapical (full mouth series) or Panorex (panoramic view) radiographs are indicated prior to treatment to evaluate the status of the periodontal tissue or any compromised teeth.

Other Tests

Culture is recommended to rule out oral candidiasis.

Procedures

Tissue biopsy may be indicated if gingival overgrowth has an unusual clinical presentation or if the patient is not on a medication known to induce gingival overgrowth.

Periodontal examination is necessary to evaluate for the presence of periodontal disease.

Dental hygiene is required to remove dental plaque.

Root planning may be indicated.

Dental extraction of periodontically compromised teeth is indicated if those teeth may interfere with subsequent medical treatment. It also may be considered if the patient cannot perform prophylactic dental care (eg, young epileptic patient).

Histologic Findings

Histologic changes are similar in gingival overgrowth that is caused by either phenytoin or cyclosporine. The term gingival hyperplasia is inappropriate because enlargement does not result from an increase in the number of cells but rather an increase in extracellular tissue volume.

A highly vascular connective tissue is observed histologically with focal accumulation of inflammatory cells, primarily plasma cells. The overlying epithelium is of variable thickness, irregular, and multilayered. Acanthosis and parakeratosis with pseudoepitheliomatous proliferation have been reported.

Immunohistologic studies have demonstrated an increase in the number of Langerhans cells within the epithelium and adjacent to inflamed sites.

 

Treatment

Medical Care

For dental care, refer patients to a general dentist and/or oral medicine specialist for evaluation.

Surgical Care

Gingivectomy with carbon dioxide, YAG,[37] or diode laser[38] is recommended for patients who have moderate-to-severe gingival enlargement that does not resolve when the dose is reduced, proper oral hygiene is maintained, or after a short course of antibiotics. They can be effective for the removal of hyperplastic gingival tissue and result in fast healing with only mild discomfort. Low-level laser therapy (LLLT),[39] photobiomodulation diode laser, and dual-wavelength (904/650-nm) laser treatments have been reportedly used as adjuvants in the management of drug-induced gingival hyperplasia. In the majority of patients for whom drug discontinuation or substitution is not possible and for whom prophylactic measures have failed, surgical excision of gingival tissue remains the only treatment option.[11, 24]

Consultations

For evaluation and treatment planning, refer patients to a dental practitioner and/or an oral medicine specialist familiar with the oral care of medically complex patients.

An oral medicine specialist and a periodontist should monitor patients with gingival overgrowth for as long as they receive therapy with cyclosporine, phenytoin, or calcium channel blockers to evaluate and treat oral complications from medical therapy.

Diet

No diet restrictions are recommended for patients with gingival overgrowth other than minimizing the consumption of sweets, starch, soft drinks, and simple carbohydrates.

Activity

No activity restrictions are reported.

Complications

Severe gingival overgrowth in patients with poor oral health can lead to early tooth loss.

Chlorhexidine 12% mouthwash might cause teeth staining; however, brushing teeth prior to rinsing out with chlorhexidine can prevent it. The stain can be removed by routine oral prophylaxis.

Prevention

Ensure healthy periodontal tissue prior to any organ transplantation or the use of phenytoin or calcium channel blocker.

Consider alternative drugs (ie, mycophenolate [CellCept], or tacrolimus [Prograf] in organ transplant recipients, verapamil in place of calcium channel blockers) for patients at high risk.[40] One study showed that in a case of pediatric renal transplantation, gingival overgrowth was improved after switching from cyclosporine A to tacrolimus.

Use lower doses of cyclosporine.

Educate patients about the importance of good oral hygiene and routine dental care, not only to minimize gingival overgrowth but also to reduce risk of systemic complications, including organ rejection.

Long-Term Monitoring

To monitor for gingival overgrowth–associated oral complications (eg, bleeding gums, poor oral hygiene, gingivitis, oral candidiasis), oral medicine specialists should provide follow-up care twice a year for patients taking drugs known to induce gingival overgrowth.

Dental hygiene is recommended every 3 months to control dental plaque.

Patients should practice thorough oral hygiene twice a day (ie, before breakfast, before going to bed) and rinse mouth with plain water after each meal.

 

Medication

Medication Summary

Recent observations suggests that roxithromycin, a macrolide antibiotic, may have a therapeutic role in reducing cyclosporine-induced gingival overgrowth, owing to its inhibitory effect on transforming growth factor-beta production.[41] Azithromycin has been used successfully.[42, 43, 44, 45]

In addition, tacrolimus, a commonly used immunosuppressive agent, can become an alternative to cyclosporine-A use.[46] However, tacrolimus can also induce gingival overgrowth, but this effect appears to be time related.[47]

Clinical studies comparing oral hygiene programs versus azithromycin indicate that azithromycin plus oral hygiene significantly reduces cyclosporine-induced gingival hyperplasia, while oral hygiene alone reduces oral symptoms but does not affect cyclosporine-induced gingival hyperplasia.[48]

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Azithromycin (Zithromax)

Azithromycin is used to treat mild-to-moderate oral microbial infections. Clinical studies comparing oral hygiene programs versus azithromycin indicate that azithromycin plus oral hygiene significantly reduces cyclosporine-induced gingival hyperplasia, while oral hygiene alone reduces oral symptoms but does not affect cyclosporine-induced gingival hyperplasia.

Azithromycin is a macrolide antibiotic that acts by suppressing protein synthesis of gram-positive and gram-negative aerobes. Take 1-2 hours after eating.

Mouthwash antiseptics

Class Summary

Antiseptic agent for oral bacterial and fungal infections.

Chlorhexidine oral (Peridex, PerioChip, PerioGard)

Chlorhexidine gluconate is an effective, safe, and reliable mouthwash antiseptic. It is a polybiguanide with bactericidal activity, usually supplied as a gluconate salt. At physiologic pH, the salt dissociates to a cation that binds to bacterial cell walls.