Drug Induced Gingival Overgrowth (DIGO)

Article Author:
Sujata Tungare
Article Editor:
Arati Paranjpe
Updated:
4/27/2019 10:26:36 PM
PubMed Link:
Drug Induced Gingival Overgrowth (DIGO)

Introduction

Drug-induced gingival overgrowth (DIGO), also referred to as drug-induced gingival enlargement, was previously referred to as drug-induced gingival hyperplasia. It is a noted side-effect of certain drugs given for non-dental uses where the gingival tissue is not the intended target organ. The chief amongst them being anticonvulsants, immunosuppressants and calcium channel blockers.[1] This is of great importance as gingival overgrowth impedes proper dental hygiene and apart from the cosmetic disfigurement, causes painful chewing and eating. Hence, patient education and information about the condition and its management are required.

Etiology

Drugs are the commonest reason behind gingival enlargement. Drug-induced enlargement is associated with a patients genetic predisposition, and the presence of existing plaque or gingival inflammation.[2] The drugs that cause DIGO are mainly the anticonvulsants, immunosuppressants, and the calcium channel blockers.

Anticonvulsants

Phenytoin (PHT, or 5,5-diphenylhydantoin), sodium valproate, phenobarbitone, vigabatrin, primidone, mephenytoin, and ethosuximide are some of the drugs that cause gingival hypertrophy. At times, multiple drugs are given together which could act synergistically and aggravate the condition. Drugs like PHT, phenobarbitone, and primidone are metabolized to 5-(4-hydroxyphenyl)5-phenyl hydantoin(4-HPPH) which is responsible for the overgrowth of gingival tissue.

Immunosuppressants

Cyclosporin, tacrolimus, and sirolimus are some of the immunosuppressants that cause gingival hypertrophy. The commonest one is Cyclosporin, the indications for use being autoimmune diseases and after organ transplantation like post renal transplants.[3] Highly toxic, one study found the incidence of gingival overgrowth apart from other side effects to be nearly 53% in patients of renal transplant on cyclosporin.[4] Tacrolimus is another immunosuppressant sometimes used in place of cyclosporin. It is less toxic than cyclosporin, causing less hepatotoxicity and renal toxicity and less severe gingival overgrowth than cyclosporin.[5][6] Sirolimus is another immunosuppressant that has shown to predispose to gingival enlargement.[7][8][9]

Calcium Channel Blockers

These include nifedipine, nitrendipine, felodipine, amlodipine, nisoldipine, verapamil, and diltiazem. The indications for use are hypertension, angina pectoris or peripheral vascular disease.[3] Renal transplant patients who are on immunosuppressants like cyclosporin show a greater propensity to develop gingival hypertrophy when put on nifedipine or diltiazem, though the extent of hypertrophy is greater with the former.[3] Combinations of these drugs could act synergistically, causing exaggerated hypertrophy of gingival tissue. Seymour et al. reported the first case of gingival overgrowth attributed to the use of Amlodipine in 1994. Lafzi et al reported gingival hypertrophy in patients receiving 10 mg. of Amlodipine daily within 2 months of onset of treatment.[10]

Epidemiology

The drug-induced gingival overgrowth caused by drugs like phenytoin, nifedipine, cyclosporine causes an overgrowth of the connective tissue matrix. Studies have shown that it is more commonly seen in male children and adolescents. Genetic heterogeneity also plays a vital role and the extent and the degree of overgrowth depends on the drugs. Hereditary gingival fibromatosis is the most common type of gingival enlargement seen in children usually seen during the eruption of the permanent dentition. Neurofibromatosis type 1 causes plexiform neurofibromas in the connective tissue in the gingiva and is most commonly seen in mentally handicapped patients. This type of gingival overgrowth consists of hypertrophic nerves arranged in a lobulated form in the connective tissue of the gingiva.[11]

Pathophysiology

In 1996, Seymour et al. postulated the theory of genetic predisposition for the etiopathology of DIGO.[2][12] This is substantiated by the fact that some individuals develop gingival hyperplasia and some do not whilst on the same drug. The usual inflammatory response of gingival fibroblasts and subsequent proliferation of connective tissue matrix emphasizes the heterogenetic character of the individual’s gingival fibroblasts in response to the inducing drugs. The common mechanism of action at the cellular level of all these three categories of dissimilar drugs appears to be inhibition of cation influx, particularly sodium and calcium ions. CLinicians believe that gingival overgrowth is multifactorial.[12][13][3] Bacterial plaque appears to be a contributory factor and the severity of gingival overgrowth is believed to be directly proportional to the degree of plaque buildup and plaque-induced inflammation. Decreased cation dependant folic acid (FA) active transport within gingival fibroblasts causes reduced FA uptake by the cells, causing changes in the metabolism of matrix metalloproteinases and inability to activate collagenase. This results in accumulation of connective tissue and collagen due to lack of collagenase causing DIGO.

Gingival Fibroblasts and Cellular Folate Uptake

Inducing drugs act as a trigger to activation and proliferation of gingival fibroblasts causing increased connective tissue production of GAGs (glycosaminoglycans). These drugs decrease cellular uptake of folate by genetically predisposed fibroblasts. Reduced intracellular folate translates into reduced synthesis or activation of MMPs( matrix metalloproteinases), which are required for the conversion of inactive collagenase to active collagenase, allowing an excessive of connective tissue to build up. Brown et al. (1991) postulated that bacterial plaque contributes to gingival inflammation which completes the vicious cycle.

Matrix Metalloproteinases

These are a group of more than 20 enzymes that bring about the degradation of connective tissue and cause tissue remodeling. These include collagenases, gelatinases, stromelysins. Inhibition of activation of these can result in the accumulation of extracellular matrix and collagen and cause DIGO.

Inflammatory Cytokines

Inflamed gingival tissue exhibits higher levels of Interleukin-1 beta (IL-1beta), a proinflammatory cytokine. Likewise, IL-6 too causes fibroblastic proliferation and increased production of collagen and GAG synthesis.[3]

Na+/ Ca++ Ion Flux Drug Mechanisms

Fugi and Kobayashi (1990) reported inhibition of Ca++ uptake within gingival fibroblasts by PHT and several calcium channel blockers(CCBAs). Thomas and Petrou(2013) reported a reduction in Na+ channel availability and therefore a decrease in the action potential amplitude. This causes reduced Ca++ entry, and a decrease in Ca ++ activated K+ channels. All 3 types of DIGO inducing drugs act on Ca++ flux similarly.

Plaque Buildup

 The concentrated drug in crevicular gingival fluid or bacterial plaques exerts a direct toxic effect on the gingival tissue. Dental plaque causes inflammation, which causes gingival overgrowth. Inflammation causes upregulation of transforming growth factor beta 1(TGF-beta 1). Hence, control of dental plaque is effective in the treatment and prevention of DIGO over time.

Histopathology

In DIGO, the target cell is the gingival fibroblast. The pathology lies in the matrix or connective tissue and not the epithelial cells of the gingiva. Histopathology reveals excessive accumulation of extracellular matrix like collagen with varying amounts of inflammatory infiltrates, predominantly plasma cells. Fibroblastic proliferation may not be evident. Erratic columns of collagen fibers are seen interspersed with penetrating epithelial ridges.

History and Physical

The patient of gingival enlargement is typically one with hypertension or angina or an epileptic or a renal transplant recipient, on medication from any of the DIGO inducing drugs, reporting with hypertrophy of the gums since a variable period (which is generally a few weeks from the start of medication) and complaining of pain during mastication or cosmetic disfigurement.

Possible Findings

  1. Firm, painless, nodular enlargement of the interdental papilla, limited to the keratinized portions of the gingiva and extending to the facial and lingual gingival margins.
  2.  In severe cases, a huge fold of hypertrophied gingival tissue is observed covering the crowns.
  3. At times, it appears firm and pale pink with minute lobulations, pouting from underneath the gingival margin, delineated by a groove of tissue which does not bleed on touch.
  4. If secondary inflammation exists, the gingiva appears smooth, and The enlargement is greater in the maxillary and anterior mandibular regions. Typically, it is not seen in edentulous areas of the gingiva.

Evaluation

The following tests should be done to evaluate this condition:

  • A complete blood count (CBC) is indicated in patients with gingival enlargement if there is a presence of profuse gingival bleeding even if it is drug induced to rule out anemia and leukemia.
  • Full mouth periapical radiographs or OPG (orthopantomograph) are to be taken before beginning any treatment to rule out periodontal disease or dental disease.
  • Candidiasis and other infections must be ruled out by taking a culture.
  • Tissue biopsy should be carried out in case the presentation of the disease is unusual.
  • A periodontal examination is necessary to evaluate for the presence of periodontal disease.
  • The removal of dental plaque maintains oral hygiene.
  • Scaling and root planning must be carried out.

Treatment / Management

The aim of treatment in DIGO is to alleviate the discomfort and make simple acts like eating and chewing pain-free, to treat the inflammation and reduce the swelling, and also give a better cosmetic appearance to the gingiva.

The modalities of treatment are medical and surgical.

Medical management is the first line of treatment, and surgery is reserved for recurrences or cases that persist despite good medical treatment.

Plaque removal including periodic scaling, tooth surface cleaning.[14][15][16]

Control of inflammation including non-steroidal anti-inflammatory agents, antibiotics to control infection and topical application of antifungal medication like nystatin.[17]

Discontinuation of the drug or switching over to another drug without the same side-effects can be considered.[18][19]

Folate supplementation to be started.

Surgical treatment is to be considered in patients not responding to medical management, or cases that recur despite adequate plaque control. An adequate period should be allowed to elapse after medical therapy or discontinuation of the inducing drug before surgery is considered.

The surgical methods include traditional scalpel gingivectomy and periodontal flap surgery.

Electrocautery may be used in difficult cases, children, or where the gingiva is fragile and likely to bleed.

CO2 Laser has a wavelength of 10600 nm; hence, it is readily absorbed by water and therefore is very effective in surgery of soft tissues with high water content like the gingiva. Blood vessels up to a diameter of 0.5 mm can be sealed effectively and provides a dry field for better visibility of the surgical field. A laser is preferred over the scalpel as it has strong bactericidal and hemostatic effects.[14][18]

Differential Diagnosis

  1. False enlargement of gingival tissue: This is pseudo-enlargement of the gingiva, which is actually because of enlarged underlying bony tissue. The gingiva here has no abnormality.
  2. Inflammation: An abscess presents as a localized painful swelling which is tender. Chronically inflamed gingival tissue is red or violaceous smooth and bleeds on touch.
  3. Familial or hereditary: The tendency runs in the family. The gingiva is pink, non-tender, involves the attached gingiva, the gingival margin and the interdental papillae, and has a firm and leathery consistency.
  4. Tumors: These are localized, hard in consistency, wart-like, friable and bleed on touch.
  5. Physiological states: Puberty and pregnancy are at times associated with gingival enlargement.
  6. Scurvy: Vitamin C deficiency can produce very tender bleeding gingiva.
  7. Systemic diseases: Leukemias, tuberculosis, sarcoidosis. Can be corroborated hematologically to confirm the diagnosis.

In all these conditions, a thorough history, physical examination, and investigations including a biopsy may be required to confirm the etiology.

Conditions Similar to Gingival Enlargement

  1. Fibrous epulis/peripheral fibroma
  2. Angiogranuloma/Pyogenic granuloma 
  3. Gingival cysts
  4. Neoplasms: They can be benign or malignant. Benign are fibroma, peripheral and central giant cell granuloma, papilloma, leukoplakia, nevus, hemangioma,  leukoplakia, nevus, myoblastoma, hemangioma, neurilemoma, neurofibroma, ameloblastoma. Malignant tumors are squamous cell carcinoma, Kaposi's sarcoma, etc.
  5. Others like palatal mucocele or lateral periodontal cyst[20]

Complications

Complications due to Drug-Induced Gingival Enlargements

  • Functional difficulties
  • Esthetic concerns
  • Increased incidence of caries
  • Delayed eruption of teeth
  • Pathological drifting of teeth
  • Prolonged retention of the primary dentition
  • Diastemas and spacing problems
  • Poor plaque control leading to periodontal complications[11]

Enhancing Healthcare Team Outcomes

Since this condition is entirely drug-induced, patient education about the side-effects of these drugs before the start of treatment is warranted. In cases where these drugs have no substitute, thorough knowledge about the situation has to be explained to the patient and the various treatment options discussed. Good dental hygiene has to be stressed upon, for which the regular use of chlorhexidine gluconate rinses and periodic dental checkups with scaling and control of inflammation has to be instituted.[18] Drug-induced gingival enlargement has a good prognosis and is generally reversible on stopping the usage of the offending drug or changing the drug. (Level V)



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References

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[3] Dongari-Bagtzoglou A, Drug-associated gingival enlargement. Journal of periodontology. 2004 Oct;     [PubMed PMID: 15562922]
[4] Greenberg KV,Armitage GC,Shiboski CH, Gingival enlargement among renal transplant recipients in the era of new-generation immunosuppressants. Journal of periodontology. 2008 Mar;     [PubMed PMID: 18315427]
[5] Sekiguchi RT,Paixão CG,Saraiva L,Romito GA,Pannuti CM,Lotufo RF, Incidence of tacrolimus-induced gingival overgrowth in the absence of calcium channel blockers: a short-term study. Journal of clinical periodontology. 2007 Jul;     [PubMed PMID: 17433046]
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