eMedicine Specialties > Dermatology > Diseases of the Oral Mucosa

Drug-Induced Gingival Hyperplasia

Lina M Mejia, DDS, Assistant Professor, Oral Medicine and Diagnostic Sciences, College of Dental Medicine, Nova Southeastern University
Francina Lozada-Nur, DDS, MS, MPH, Professor Clinical Oral Medicine (Emerita), University of California at San Francisco School of Dentistry

Updated: Oct 23, 2009

Introduction

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
 

Swelling of the gingival mucosa around the right lower canine and multiple areas of erythema, erosions, and bleeding throughout the upper gingival mucosa.

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), whereas 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.^{5,7,8,9,10,11,12} In fact, several lines of evidence point to a modulation of inflammatory processes.

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.

Mortality/Morbidity

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.

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.

Clinical

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.^13,14
• Cyclosporine- and nifedipine-induced gingival overgrowth: Nifedipine potentiates the adverse effect (ie, gingival overgrowth) of cyclosporine.
• Calcium antagonist–induced gingival overgrowth
  • Oral hygiene plays a decisive role in the development of gingival enlargement.
  • 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

• 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.

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 same patient as in Image 2. Notice the severity of the gingival enlargement. If left untreated, patients develop severe periodontal disease and lose teeth.

Causes

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

Differential Diagnoses

Other Problems to Be Considered

Leukemia (bleeding gums) 
Pyogenic granuloma
Pregnancy tumor
Warts (Warts, Nongenital)
Monomorphic B-cell post-transplantation
Lymphoproliferative disease (Posttransplant Lymphoproliferative Disorder)

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 or YAG laser 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. 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.

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.

Medication

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.¹⁵ Azithromycin has been used successfully.^16,17,18

In addition, tacrolimus, a commonly used immunosuppressive agent, can become an alternative to cyclosporine-A use.¹⁹ However, tacrolimus can also induce gingival overgrowth, but this effect appears to be time related.²⁰

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.²¹

Antibiotics

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

Azithromycin (Zithromax)

Used to treat mild-to-moderate oral microbial infections. Clinical studies comparing oral hygiene programs vs 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 h pc.

Dosing

Adult

Day 1: 500 mg PO
Days 2-5: 250 mg PO qd

Pediatric

>6 months
Day 1: 10 mg/kg PO once; not to exceed 500 mg/d
Days 2-5: 5 mg/kg PO qd; not to exceed 250 mg/d

Interactions

May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with administration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when administered with cyclosporine

Contraindications

Documented hypersensitivity; hepatic impairment; do not administer with pimozide

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Site reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in patients who are hospitalized, geriatric, or debilitated

Mouthwash antiseptics

Antiseptic agent for oral bacterial and fungal infections.

Chlorhexidine gluconate (Peridex)

Effective, safe, and reliable mouthwash antiseptic. Polybiguanide with bactericidal activity; usually is supplied as a gluconate salt. At physiologic pH, the salt dissociates to a cation that binds to bacterial cell walls.

Dosing

Adult

15 mL rinse and expectorate/spit bid after thoroughly brushing teeth to prevent staining

Pediatric

5-10 mL rinse and expectorate/spit bid after thoroughly brushing teeth to prevent staining

Interactions

None reported

Contraindications

Documented hypersensitivity; avoid in the presence of any oral ulcers or if patient presents with mucositis secondary to radiation or chemotherapy, if alcohol is present in chlorhexidine

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Irritation if open ulcers are seen in the mouth; dental deposits, staining of teeth, taste changes, and parotitis have been reported

Lysozyme, lactoferrin, glucose oxidase, lactoperoxidase (Biotene)

Alcohol-free mouthwash antiseptic.

Dosing

Adult

Rinse mouth BID/TID

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

None reported

Follow-up

Further Outpatient Care

• 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.

Inpatient & Outpatient Medications

• Chlorhexidine 12% once before going to bed or Biotene mouthwash after meals is recommended for those patients known to be at risk for gingivitis.

Deterrence/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.²² 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.

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.

Prognosis

• 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 excellent patient education resources, visit eMedicine's Teeth and Mouth Center. Also, see eMedicine's patient education articles Gingivitis and When to Visit the Dentist.

Miscellaneous

Medicolegal Pitfalls

• Failure to perform appropriate diagnostic procedures (ie, periodontal evaluation, full mouth x-ray film, routine histology)
• Failure to appropriately identify and monitor patients at risk for the development of gingival overgrowth secondary to systemic therapy known to induce gingival overgrowth (ie, regular oral hygiene, frequent visits to dental professional)

Special Concerns

• Emphasize the importance of good oral hygiene and routine dental care.
• In a patient who is pregnant, rule out pregnancy tumor/pyogenic granuloma.
• Refer all patients, regardless of sex and age, to their dentists prior to therapy with medications known to induce gingival overgrowth.

Multimedia

Media file 1: Swelling of the gingival mucosa around the right lower canine and multiple areas of erythema, erosions, and bleeding throughout the upper gingival mucosa.

Media file 2: 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.

Media file 3: A palatal view of same patient as in Image 2. Notice the severity of the gingival enlargement. If left untreated, patients develop severe periodontal disease and lose teeth.

References

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Keywords

drug-induced gingival hyperplasia, gingival hyperplasia, drug-induced gingival overgrowth, gingival overgrowth, gingival enlargement, gum overgrowth, gum enlargement, gum hyperplasia, cyclosporine, phenytoin, calcium antagonist-induced gingival hyperplasia

Contributor Information and Disclosures

Author

Lina M Mejia, DDS, Assistant Professor, Oral Medicine and Diagnostic Sciences, College of Dental Medicine, Nova Southeastern University
Lina M Mejia, DDS is a member of the following medical societies: American Academy of Oral Medicine, American Dental Association, and California Dental Association
Disclosure: Nothing to disclose.

Coauthor(s)

Francina Lozada-Nur, DDS, MS, MPH, Professor Clinical Oral Medicine (Emerita), University of California at San Francisco School of Dentistry
Francina Lozada-Nur, DDS, MS, MPH is a member of the following medical societies: American Academy of Oral Medicine
Disclosure: Nothing to disclose.

Medical Editor

Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, University of Florida College of Medicine
Franklin Flowers, MD is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Drore Eisen, MD, DDS, Consulting Staff, Department of Dermatology, Dermatology Research Associates of Cincinnati
Drore Eisen, MD, DDS is a member of the following medical societies: American Academy of Dermatology, American Academy of Oral Medicine, and American Dental Association
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Piamkamon Vacharotayangul, DDS, PhD, and previous Chief Editor, William D. James, MD, to the development and writing of this article.

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