Drug Induced Gingival Enlargement

A review

Literature Review, 2005
73 Pages


Library Desertation

Drug Induced Gingival Enlargement:

Introduction: Increase in the size of the gingiva is a common feature of gingival disease. Accepted current terminology for this condition is gingival enlargement and gingival overgrowth. These are strictly clinical descriptive terms and avoid the erroneous pathologic connotations of terms used in the past such as hypertrophic gingivitis or gingival hyperplasia. The gingiva and associated soft tissues of the periodontium may be enlarged in response to various interactions between the host and the environment. Although such enlargement usually represents an inflammatory response to bacterial plaque59, increased susceptibility as a result of systemic factors or conditions should always be considered during the course of patient evaluation90. Systemically related gingival enlargements include, but are not limited to, scurvy, leukemia, puberty, pregnancy, multisystem syndromes and selected drugs and/or agents. In addition, fibrotic gingival enlargement has been reported and is believed to be the result of a genetic predisposition (for example hereditary or familial gingival enlargement). However an idiopathic variant that has not been associated with genetic linkage or cause has been described. Of the predisposing factors associated with the gingival enlargement, selected anticonvulsant drug, Calcium channel blockers and a potent immunosuppressant (Cyclosporine A) have generated the most investigative attention in the scientific community91.

Since the first report of Phenytoin induced gingival overgrowth by Kimball in 1939, many clinical and investigative studies have been carried out to determine the pathogenesis of this disorder. Although these studies yielded various pathogenetic data, it is still unknown why drugs with such different pharmacological actions induce similar gingival changes. Furthermore different views concerning the interrelationships between blood drug levels and/or duration of drug intake and the severity of growth, sex predilection, effect of local inflammation and incidence has been reported in the literature99.

The genetically determined capacity of the host to deal metabolically with chronically administered drugs; the responsiveness of gingival tissues to the drugs and the pre-existing gingival condition may differ among individuals. Moreover, Calcium channel blockers are mainly prescribed for post-middle aged patients to control hypertension or myocardial events, whereas Phenytion and Cyclosporine A are prescribed for a wide range of patients due to their wide spectrum of efficacy47. These factors make it difficult to evaluate the etiology of drug induced gingival overgrowth caused by Phenytoin, Cyclosporin A and Calcium channel blockers and to compare the factors involved. Many investigators have attempted experimental induction of gingival overgrowth. Despite all these intense clinical and laboratory investigations, the underlying pathogenic mechanism that mediates gingival overgrowth in affected individuals remains undefined.

From the treatment standpoint, the clinician should be particularly concerned with cases where there is evidence of gingival enlargement and patients taking one or more of these drugs because:

- It poses a plaque control problem;
- It may affect mastication;
- It may alter tooth eruption;
- It may interfere with speech and
- It may cause aesthetic concerns.


Gingival enlargement can be classified according to etiologic factors and pathologic changes as follows:15

I. Inflammatory enlargement
A. Chronic
B. Acute

II. Drug-induced enlargement

III. Enlargement associated with systemic diseases
A. Conditioned enlargement
1. Pregnancy
2. Puberty
3. Vitamin C deficiency
4. Plasma cell gingivitis
5. Non specific conditioned enlargement (Granuloma pyogenicum)
B. Systemic diseases causing gingival enlargement
1. Leukemia
2. Granulomatous diseases (Wegeners granulomatosis, sarcoidosis and so on)

IV. Neoplastic enlargement (gingival tumors)
A. Benign tumors
B. Malignant tumors

V. False enlargement

Using the criteria of location and distribution, gingival enlargement is designated as follows:

Localized: Limited to the gingiva adjacent to a single tooth or group of teeth.

Generalized: Involving the gingiva throughout the mouth.

Marginal: Confined to the marginal gingiva.

Papillary: Confined to the interdental papilla.

Diffuse: Involving the marginal and attached gingiva and papillae.

Discrete: An isolated sessile or pedunculated tumor like enlargement.

The degree of gingival enlargement can be scored as follows:

Grade O: No signs of gingival enlargement.

Grade I: Enlargement confined to interdental papillae.

Grade II: Enlargement involves papillae and marginal gingiva.

Grade III: Enlargement covers three quarters or more of the crown.

Review of Literature:


Clinical Features:

The growth starts as a painless beadlike enlargement of the interdental papillae and extends to the facial and lingual margins. As the condition progresses, the marginal and papillary enlargements unite; they may develop into a massive tissue fold covering a considerable portion of the crowns and they may interfere with occlusion. When uncomplicated by inflammation, the lesion is mulberry shaped, firm, pale pink and resilient, with a minutely lobulated surface and no tendency to bleed. The enlargement characteristically appears to project from beneath the gingival margin, from which it is separated by a linear groove.

The enlargement is usually generalized throughout the mouth but is more severe in the maxillary and mandibular anterior regions. It occurs in areas in which teeth are present, not in edentulous spaces and the enlargement disappears in areas from which teeth are extracted. Hyperplasia of the mucosa in edentulous mouth has been reported but is rare. The enlargement is chronic and slowly increases in size. When surgically removed it recurs. Spontaneous disappearance occurs within a few months after discontinuation of the drug.

Drug induced enlargement may occur in mouths with little or no plaque and may be absent in mouths with abundant deposits. However, the presence of the enlargement makes plaque control difficult, often resulting in a secondary inflammatory process that complicates the gingival overgrowth caused by the drug. The resultant enlargement is then a combination of the increase in size caused by the drug and the complicating inflammation caused by the bacteria. Secondary inflammatory changes add to the size of the lesion caused by the drug but also produce a red or bluish-red discoloration, obliterate the lobulated surface demarcations, and result in an increased tendency toward bleeding.


The enlargement consists of a pronounced hyperplasia of the connective tissue and epithelium. There is an acanthosis of the epithelium and elongated retepegs extend deep into the connective tissue, which exhibits densely arranged collagen bundles with an increase in the number of fibroblasts and new blood vessels. An abundance of amorphous ground substance has also been reported. Structural changes in the outer epithelial cell surface have been reported in Cyclosporine enlargement.

The enlargement begins as a hyperplasia of the connective tissue core of the marginal gingiva and increase by its proliferation and expansion beyond the crest of the gingival margin. Sometimes particularly in Cyclosporine enlargements, the connective tissue appears more highly vascularized and with foci of chronic inflammatory cells, particularly plasma cells.

The “mature” Phenytoin enlargement has a fibroblast – to – collagen ratio equal to that of normal gingiva from normal individuals, suggesting that at some point in the development of the lesion there must have been an abnormally high fibroblastic proliferation. Oxytalan fibers are numerous beneath the epithelium and in areas of inflammation. Inflammation is common along the sulcular surface of the gingiva.

Recurring enlargements appear as granulation tissues composed of numerous young capillaries and fibroblasts and irregularly arranged collagen fibrils with occasional lymphocytes.


Historical perspective:

In 1939, Kimball first reported gingival hyperplasia in association with chronic Phenytoin therapy in epileptic patients. Since then the mechanism of pathogenesis of gingival overgrowth is an enigma that has intrigued researchers for decades. In 1939, Faurbye and in 1959, Strean and Leon suggested that the alkalinity of Phenytoin might be the cause of the gingival side effect.14

Frankel (1940) reported a correlation between decreased serum ascorbic acid and gingival enlargement. Merritt and Foster disputed the results.

Thoma (1942) regarded gingival enlargement as a form of Stomatitis Medicamentosa. Houck et al disputed this concept

Brandon (1948) suggested Phenytion has a direct effect on the gingival tissues.

Houck et al reported that human fibroblasts were stimulated with 2-10mg per ml of Phenytoin.

Shafer and Nease also reported a direct stimulating effect of Phenytoin.

Hassell reported that 10mg per ml did not stimulate the proliferation of any of 15 different strains of human gingival fibroblasts derived from normal subjects and from Phenytoin responders and non-responders.

Kasai and Yoshizumi were unable to detect proliferative enhancement of human gingival cells with any concentration of Phenytoin.

Keith et al, Hassel and Stanek published studies disputing any stimulation.

Brandon (1948), Scarzella and Bellatti suggested that the byproducts of Phenytoin were the causes of the cellular proliferation.

Conrad postulated that the failure of the gingival fibroblasts to convert Phenytoin into its metabolite 5 – (p – hydroxyphenyl) – 5 – phenylhydantion resulted in an increased cellular response.

Hassel et al showed that 5 – (p – hydroxyphenyl) – 5 – phenylhydantion (p-HPPH) itself stimulated the gingival fibroblast cellular response.

Sigmund (1949) stated that Phenytoin induced gingival overgrowth was related to brain damage and the gingiva was under the influence of the Central Nervous System.

Staple (1951) suggested a connection between Pituitary and Adrenal Glands and Phenytoin induced gingival overgrowth.

Haim (1955) believed that the connective tissue in Phenytoin induced gingival hyperplasia was immature. Tsutsumi et al disputed this theory.

Van der kwast (1956) suggested that the immune system was involved in Phenytoin induced gingival hyperplasia.

Aarli and Tonder and Aarli suggested IgA is a factor in Phenytoin induced gingival overgrowth.

Noach (1958) et al and Woodbury et al suggested the importance of a relationship between Phenytoin parotid uptake and Phenytoin gingival binding and Phenytoin induced gingival overgrowth. Steinbergh et al disputed this relationship.

Korff (1963) and Mutschel knaus suggested that Phenytoin induced a disturbance of glucocorticoid synthesis by the adrenal cortex.

Nenning furthered this concept by suggesting that concurrent with a depression of ACTH production, Phenytoin causes an enhancement of somatotropic hormone production and somatotropic hormone causes fibroblast proliferation.

Milli chap (1975) claimed that Phenytoin should be administered as a capsule instead of an uncoated pill or elixir to avoid the topical effect of phenytoin.

Angelopoulous (1975) suggested that Phenytoin induces degranulation of Mast cells, which results in the generation of a substance that increases collagen formation.

Larmas (1976) suggested that Phenytoin has a proliferating effect primarily on the basal cell layer of the oral epithelium thus increasing the epithelium-connective tissue interface area. Also the oral epithelium may have an inducing effect on the underlying fibroblasts.

Vogel (1977) suggested that Phenytoin-induced enlargement was due to an end organ folic acid deficiency.

Schneir (1978) et al determined that the collagen I to collagen III ratio was unchanged in Phenytoin induced gingival overgrowth when compared to inflamed gingiva. Narayanan and Hassell disputed this..

Southren (1978) et al reported a significant increase in the number of 5-alpha-dihydrotestosterone receptor binding site per mg protein in Phenytoin induced gingival hyperplasia.

Javed (1980) proposed that Phenytoin therapy prompted growth of Bacteroides . Smith and Hinrichs contradicted this.

Pernu (1989) et al reported that incubation of fibroblast in the presence of Verapamil reduced protein and collagen synthesis.

Yahia (1990) et al reported increased cAMP levels in Cyclosporine A induced gingival overgrowth

Phipps and Buchanan (1990) examined chromosomal protein phosphorylation in Cyclosporine A induced gingival overgrowth.

Review of Hypothesis:

1. Inflammation from bacterial plaque:

Inflammation from bacterial plaque is involved in the pathogenesis of Drug induced gingival overgrowth.

A bacterial inflammatory component is necessary for the expression of the side effect. Several studies have demonstrated that dental prophylaxis and “good” oral hygiene can reduce, bad oral hygiene can present the expression of drug induced gingival overgrowth.

Oneil and Figures demonstrated the efficacy of chlorhexidine, in the treatment of Phcnytoin induced gingival overgrowth81.

Daley et al determined that cyclosporin A subjects with excellent dental hygiene scores exhibited at worst very mild gingival overgrowth and typically presented no obvious clinical evidence of gingival overgrowth28.

Modeer et al, in a study of non-institutionalized epileptic children reported a significant correlation between Phenytoin induced gingival overgrowth and 3 variables – gingivitis, visible plaque index and duration of Phenytoin therapy.

Modeer and Dahllof divided 59 Phenytoin treated non-institutionalized epileptic children into 3 groups:

16 Subjects – Intensive preventive program group

13 Subjects – Moderate preventive program group

30 Subjects – No preventive program group

INTENSIVE PROGRAM GROUP – 0 gingival overgrowth

MODERATE GROUP – 46% gingival overgrowth

NO PROGRAM GROUP – 40% gingival overgrowth

A relationship between bacterial plaque – induced inflammation and drug induced gingival overgrowth has been clearly established73.

2. Increased Sulfated Glycosaminoglycans (GAGs):

An increased amount of GAGs is involved in the pathogenesis of drug-induced overgrowth.

Phenytoin induced gingival overgrowth represents neither hypertrophy, hyperplasia nor fibrosis, but is an example of uncontrolled growth of a connective tissue of apparently normal cell and fiber composition. Ultra structural quantification of connective tissue changes in phenytoin induced gingival overgrowth in ferrets suggested that the amount of interstitial ground substance or GAGs increases and this may be due to decreased degradation within fibroblasts. When the collagen content and composition of human gingiva, enlarged due to Phenytoin, normal and inflamed gingiva were compared Phenytoin induced enlarged gingiva contained significantly higher amounts of collagen per weight.

However, Dahllof et al demonstrated decreased relative collagen and increased GAGs and uronic acid in Phenytoin induced gingival overgrowth compared to normal gingiva24.

Ultra structural studies by Lucas et al on Nifedipine induced gingival overgrowth and by Deliliers et al and Yamasaki et al on Cyclosporine A induced gingival overgrowth found an increase in GAGs, collagen and fibrous connective tissue.

Effect and side effects of Phenytoin with regard to collagen also support the concept of a decrease in collagen catabolism.

One side effect of chronic Phenytoin therapy in growing children is coarse facies. Both Phenytoin and Cyclosporine A induce Hirsutism58. Pretreatment with Phenytoin greatly accelerates fibroplasia in wound repair.


Immunoglobulins are involved in the pathogenesis of drug induced gingival overgrowth.

Smith et al noted that phenytoin induced a significant decrease in serum IgA levels and a significant increase in both salivary IgA levels and IgA secretion by parotid gland. They concluded that IgA in the serum and saliva are at least partially under independent control and that Phenytoin does not appear to cause a deficiency in oral IgA or that Phenytoin induced changes in oral IgA play a role in gingival overgrowth.

Setterstrom et al looked at IgA, IgG and IgM in Phenytoin induced gingival overgrowth, idiopathic gingival overgrowth and normal gingiva. IgA levels did not differ significantly in the 3 types of gingiva.

A significant increase of IgG in Phenytoin induced gingival overgrowth tissue compared to Idiopathic but not normal gingiva. This would be related to the inflamed condition of the tissues in Phenytoin mediated over growth.

IgM was detected 90% - Phenytoin induced overgrowth

75% - Idiopathic specimens

40% - normal tissue

It appears that immunoglobulins may be more a marker than a cause of level cellular immune reactions occurring within the gingiva97.

Dahllof et al utilized

7 children with Phenytoin induced overgrowth

3 children with gingivitis

3 children control group

They analyzed gingival biopsies to define T – lymphocyte subpopulations, Blymphocytes and Monocytes. The Phenytoin group had substantial number of mononuclear cells. The gingivitis and control groups demonstrated only a few mononuclear cells. Majority of them were T cells25.

Dahllof et al suggested immunological reaction mediated by T cells might play a role in the pathogenesis of Phenytoin induced gingival overgrowth. Both Phenytoin and Cyclosporine A have an effect on the immune system including the induction of lymphoid hyperplasias and lymphomas.

4. Gingival fibroblast phenotype population differences:mediated over growth Phenotypical differences within gingival fibroblasts are involved in the pathogenesis of drug induced gingival overgrowth.

Hassell and Gilbert postulated that the reason that not all the Phenytoin related patients developed gingival overgrowth is predicated upon the presence of a Phenytoin sensitive subpopulation of gingival fibroblasts. They observed a large invitro fibroblast interstrain differences in the magnitude of protein and collagen synthesis after pretreatment with Phenytoin42.

Hassell and Stanek reported significant differences among several cultures derived from a single biopsy of normal gingival tissue in regard to proliferation rates, replicative life spans and cell – size distributions. From this data they suggested that functional heterogeneity exists among phenotypically stable fibroblast subpopulation or subpopulation mixtures from normal tissue44.

Cockey et al obtained gingival biopsies from the maxillary arch of Monozygous (MZ) and Dizygous (DZ) twin pairs. The differences between proliferation rate and collagen and protein production in MZ and DZ twin pair fibroblasts on exposure to Phenytoin were significant Twin analyses indicated that genetic variation accounted for the most inter-individual heterogeneity with genetic factors influencing protein production more than collagen production18.

Schnier et al examined tissue sampled from both subjects with Phenytoin induced gingival overgrowth and inflamed gingiva and confirmed that collagen phenotype is unaltered in phenytoin induced gingival overgrowth.

Genetic heterogeneity may exist along several parameters

Difference in receptor biding affinity, cellular ion flux,

Cellular turnover rate,

Cellular GAG,


Collagenase and

Collagen production capacity – are all possibilities96.

5. Epidermal Growth Factor (EGF):

EGF is involved in the pathogenesis of drug induced gingival overgrowth.

Modeer et al studied gingival fibroblasts from two patients who have been on Phenytoin therapy for 9 months. Responder had and non-responder did not have gingival enlargement. They concluded that Phenytoin results in down regulation of Epidermal Growth Factor receptor metabolism in fibroblasts derived form the responder patient in contrast to up-regulation in the non-responder.

Modeer and Andersson examined gingival fibroblasts derived from 5 children. The fibroblasts were cultured in the presence of EGF alone or in combination with Phenytoin. DNA synthesis, EGF binding to its cell – surface receptor and internalization of EGF – receptor ligand was studied. The number of EGF receptors in fibroblasts increased significantly after Phenytoin treatment. They concluded that Phenytoin regulated EGF – receptor metabolism in human gingival fibroblasts by increasing the number of cell surface EGF receptor, which may contribute to, Phenytoin induced gingival overgrowth72.

The conclusions of these two studies are in conflict. As there were only fibroblasts from two patients in the Modeer et al study, the results may not be reproducible.

Modeer and Andersson caution that increase in cell surface receptors may be related to the effects of Phenytoin on Ca2+. Phenytoin increases total intra cellular Ca2+ accumulation in gingival fibroblasts. Calcium may influence other receptors such as the 5 – alpha – dihydrotestosterone receptors, which are up regulated after Phenytoin therapy also72. Further more, whether EGF stimulates collagen synthesis is not clear since it has been reported that the proportion of collagen in confluent cultures of gingival fibrosis was decreased by EGF.

6. Pharmacokinetics and tissue – binding:

The pharmacokinetics of inducing drugs and the gingival binding affinities of these drugs are a determinate in the pathogenesis of drug induced gingival overgrowth.

Noach et al reported a high concentration of Phenytoin on salivary glands.

Woodbury et al reported that Phenytoin levels in gingival tissues of nine epileptic patients were approximately twice those of serum levels.

Conrad et al confirmed a significant correlation between phenytoin content of saliva and the occurrence of gingival overgrowth21.

Steinberg et al found no correlation between the degree of gingival overgrowth and the concentration of Phenytoin in the gingiva of ferrets.

Mc GAW et al confirmed the results of Conrad et al looking at Cyclosporine A. Cyclosporine A levels of whole saliva were significantly higher in the responder group. Interestingly, he found no significant correlation between Cyclosporine A levels in whole saliva and the corresponding Cyclosporine A levels in parotid saliva or submandibular saliva. It would appear that secondary salivary gland Cyclosporine A secretion may play a role in Cyclosporine A induced gingival overgrowth67.

Daley et al determined that study subjects with mean serum trough Cyclosporine A concentrations greater than 155 ng/ml exhibited at least mild gingival overgrowth.

These data also indicated that there was no direct correlation between serum Cyclosporine A trough concentration in the therapeutic range and the severity of the gingival hyperplasia. The results of Mc Gaw et al appear to be in agreement with both Conrad et al and Steinberg et al. Once the inducing drug attains a certain concentration, the occurrence of the side effect of gingival overgrowth is reasonably certain, however the degree of hyperplasia is independent of the concentration.

6.Collagenase activation

The activation of collagenase is involved in the pathogenesis of drug induced gingival overgrowth.

Hassell observed that Phenytoin induced gingival Overgrowth was related to reduced collagenase activity. There is a strong correlation between production of inactive collagenase and responding fibroblasts (fibroblasts producing more connective tissue than normal after exposure to Phenytoin). Every responder fibroblast synthesized and secreted considerably more total collagenase (active and inactive) than did any strain of non-responding human gingival fibroblast45. From Hassell’s results, it appears that a negative feedback loop prevents further synthesis of the activatable proenzyme (inactive collagenase) after activation by an activator enzyme. Liu and Bhatnagar determined that Phenytoin interferes with Prolyl Hydroxylase, an enzyme required for the posttranslational hydroxylation of prolylyl residues in the synthesis of collagen.

Abbildung in dieser Leseprobe nicht enthalten

Moy et al reported that Phenytoin in fibroblast cell cultures reduces prolyl hydroxylase and also markedly decreases the activity of collagenase. Stromelysin purified from human gingival fibroblasts has been shown to activate procollagenase in vitro in the presence of trypsin a plasminogen – plasmin metalloproteinase cascade may be involved in the activation of metalloproteinases (collagenases) and their subsequent action on matrix macro molecules. Prolyl hydroxylase may activate stromelysin. Either one or both of these proteins may be necessary for collagenase activation75. Prolyl hydroxylase stromelysin Inactive collagenase Active collagenase

8. Disruption of fibroblast cellular Na+/Ca2+ flux:

The influence of inducing drugs on gingival fibroblast cellular sodium/calcium flux is involved in the pathogenesis of drug induced gingival overgrowth.

Phenytoin, Cyclosporine A and Calcium channel blocking agents (CCBAS) all these drugs may influence Ca2+/Na+ flux. Phenytoin decreases resting fluxes of Na+ ions as well as Na+ currents that flow during action potentials or chemically induced depolarization.

Colombani et al described the potential of Cyclosporine A to interfere with the interaction of intracellular calcium and calmodulin20.

Fujii and Kobayashi reported that Phenytoin, Verapamil and Nifedipine all inhibited Ca2+ uptake of gingival fibroblast in cell culture. The proliferation rate on the fibroblasts correlated with the inhibition of Ca2+ uptake38.

9. Folate:

Folic acid is involved in the pathogenesis of drug induced gingival overgrowth.

Drew et al conducted a pilot study and demonstrated the efficacy of topical folate in the treatment of Phenytoin induced gingival overgrowth32.

Vogel In an animal study found that high (0.4mg/kg) i.v.doses of folic acid gave some protection against the occurrence of. Phenytoin induced gingival overgrowth119.

Abbildung in dieser Leseprobe nicht enthalten

Ariel et al observed that inhibited the Phenytoin uptake of folic acid into isolated chick intestinal cells through both the Na+ dependent and Na+ independent uptake components. A 50% inhibition of cellular folate uptake with a concentration between 10 & 20 mcg was noted3. It has been suggested that folic acid is taken up primarily in a Na+ coupled, Na+ dependent active transport mechanism and secondarily through passive diffusion. The favorable results of topical administration and the negative results of systemic administration of folic acid in the treatment of Phenytoin induced gingival overgrowth support the concept of an end organ deficiency.

The topical administration of folic acid would be more likely than systemic administration to produce an increased extra cellular concentration of folic acid necessary to over-ride the decreased active transport uptake with increased passive diffusion.

Abbildung in dieser Leseprobe nicht enthalten

10. A Combination hypothesis:

A hypothesis is proposed that involves a combination of several of the above hypothesis.

In this hypothesis, bacterial plaque, folic acid, Na+/Ca2+ flux, and collagenase activation are involved. It is established that human skin and gingival fibroblast collagenase is secreted as a trypsin (or trypsin-like) activated proenzyme. Activation with trypsin is dependent on trypsin concentration and incubation time. Recent data suggests that trypsin (or tryspin-like enzyme) activates procollagenase by initiating an intramolecular autoproteolytic reaction resulting in the formation of a stable 42 Kda active enzyme species.

Inflammation causes proliferative increase in connective tissue, particularly with the “walling off” effect. This phenomenon is usually countered with increased catabolism of connective tissue after the connective tissue proliferation and return to a steady state. The influence of dental plaque on drug induced gingival overgrowth is well documented.

With all the above information in mind a hypothesis based on a cascade of biochemical events is presented.

Abbildung in dieser Leseprobe nicht enthalten

Catabolism remains static because Active collagenase utilization is saturated.

3 entities are necessary for drug induced gingival overgrowth they are:

I. Drug – Phenytoin, Cyclosporine, Nifedipine, Diltiazem, Verapamil or Nitrendipine.
II. Bacteria and bacterial inflammation (dental plaque)
III. Teeth (Sulcular epithelium)

The drug causes a decrease in sodium flux (directly or indirectly due to calcium – sodium exchange), which causes a decrease in cellular folic acid uptake producing a localized folate deficiency. The bacterial plaque causes inflammation, which in turn causes, an increase gingival connective tissue production that is a normal physiologic response. Because of the localized folate deficiency, the production of the activator protein (trypsin or trypsin like collagenase activator), a precursor or secondary activator(s) is limited. The activation of trypsinogen to trypsin is also a multi step process with the decreased amount of collagen are activator, only a limited saturable amount of active collagenase is available. The result is a decreased efficiency in the process of gingival connective tissue catabolism, which presents clinically as drug induced gingival overgrowth.

Several of the reviewed hypotheses are well documented such as the bacterial component and an increased amount of GAGs in drug induced gingival overgrowth. Other hypotheses are controversial and less established. There are presently large voids in the understanding of many of the mechanisms involved with drug induced gingival overgrowth. The past hypotheses concerning drug induced gingival overgrowth pathogenesis have tended to be exclusionary; denying the possibility of other rationale.

Vogel was the first to discuss a possible mechanism of pathogenesis that grouped several current hypotheses together. He suggested that folic acid, bacterial plaque and an increased GAGs were involved in Phenytoin induced gingival overgrowth118.

Hall and Squire and Dahllof et al suggested that both increased GAGs and a defect in tissue degradation might be issues.

Bowman et al later suggested that besides a bacterial plaque component, an increase in GAGs, an effect of collagenase activation and a disruption of calcium flux were common to all drugs causing drug induced gingival overgrowth11.

Brown et al suggested the combination hypothesis suggesting the involvement of bacterial plaque, decreased GAGs, decreased active collagenase and a decrease in catabolism13.

The combination hypothesis explains some inconsistencies within the literature .

Risk Factors for drug – induced gingival overgrowth 105 .

The various identifiable risk factors that have been elucidated for drug induced gingival overgrowth can be considered under the following headings:

i) Age and other demographic factors
ii) Drug variables
iii) Concomitant Medications
iv) Periodontal variables
v) Genetic factors

Age and other Demographic variables:

Age has been considered an important risk factor for drug induced gingival overgrowth with particular reference to Phenytoin and cyclosporine. Early studies on the prevalence of Phenytoin induced gingival overgrowth identified that teenagers were particularly at risk from this unwanted effect. Many of these studies could be criticized for the sampling technique and as such did not represent a true reflection of the problem. Two community-based studies have reported a (Cassetta 1997, Thomsan 1992) lower prevalence of Phenytoin induced gingival overgrowth (15% and 40% respectively). The latter study reported that a combination of younger age and poor oral hygiene seemed to predispose to severest level of gingival involvement.

Age has been reported as a risk factor for cyclosporine induced gingival overgrowth. These observations have been supported by animal studies110.


Excerpt out of 73 pages


Drug Induced Gingival Enlargement
A review
Rajiv Gandhi University  (Yenepoya Dental college)
Master of Dental Surgery
Catalog Number
ISBN (eBook)
ISBN (Book)
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713 KB
Gingival enlargement is an enigma to the researchers as it is not completely understood. This Literature review critically analyses various hypothesis put forward regarding the etiopathogenesis and treatment.
Drug induced gingival enlargement, gingival overgrowth, fibroblast, hyperplasia, cyclosporine, phenytoin. nifedepine
Quote paper
Dr. Rajesh Hosadurga (Author), 2005, Drug Induced Gingival Enlargement, Munich, GRIN Verlag, https://www.grin.com/document/215797


  • Rajesh Hosadurga on 6/7/2013

    Thank you GRIN for publishing the book. Hope It will be helpful for interested people

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