CLINICAL FEATURES OF DRUG INDUCED GINGIVAL ENLARGEMENT
PATHOGENESIS OF DRUG INDUCED GINIGVAL ENLARGEMENT
HISTOPATHOLOGY OF DRUG INDUCED GINGIVAL ENLARGEMENT
ETIOLOGY OF DRUG-INDUCED GINGIVAL ENLARGEMENT
DRUGS ASSOCIATED WITH GINGIVAL ENLARGEMENT
SUMMARY AND CONCLUSION
Gingival enlargement is the term used to describe medication-related gingival overgrowth or gingival hyperplasia, a condition commonly induced by three main classes of drugs: Anticonvulsants, antihypertensive calcium antagonists, and immunosuppressant cyclosporine. Drug-induced gingival enlargement was first reported in 1939 by Kimball, with chronic usage of the anti-epileptic drug phenytoin. The prevalence of drug-induced gingival overgrowth (GO) varies among medications, and a variety of risk factors have been identified and reviewed recently, including age and sex of the patient, drug variables, concomitant medication, genetic factors, and the inflammatory status of the periodontal tissues1.
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 plaque, increased susceptibility as a result of systemic factors or conditions should always be considered during the course of patient evaluation. Systemically related gingival enlargements include, but are not limited to, scurvy, leukemia, puberty, pregnancy, multisystem syndromes and selected drugs and/or agents1. 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 community.
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 pathogenic 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 literature2.
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 efficacy. 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 undefined3.
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:
I. Inflammatory enlargement
II. Drug-induced enlargement
III. Enlargement associated with systemic diseases
A. Conditioned enlargement
3. Vitamin C deficiency
4. Plasma cell gingivitis
5. Non specific conditioned enlargement (Granuloma pyogenicum)
B. Systemic diseases causing gingival enlargement
2. Granulomatous diseases (Wegeners granulomatosis, sarcoidosis and so on)
IV. Neoplastic enlargement (gingival tumors)
A. Benign tumors
B. Malignant tumors
V. False enlargement
2. According to location and distribution, gingival enlargement :
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.
3. The degree of gingival enlargement can be scored as follows:
Grade 0: 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 crown4.
CLINICAL FEATURES OF DRUG INDUCED GINGIVAL ENLARGEMENT
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 bleeding5.
Risk Factors for Drug Induced Gingival Enlargement
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 factors5.
PATHOGENESIS OF DRUG INDUCED GINIGVAL ENLARGEMENT
Despite their pharmacological diversity, the three major drugs causing gingival overgrowth, namely; anticonvulsants, calcium channel blockers, and immunosuppressants; have similar mechanism of action at the cellular level, where they inhibit intracellular calcium ion influx. The action of these drugs on calcium and sodium ion flux may prove to be the key in understanding why three dissimilar drugs have a common side effect upon a secondary target tissue, such as gingival connective tissue. An appraisal of the various investigations into the pathogenesis of drug-induced gingival overgrowth supports the hypothesis that it is multifactorial. Plaque scores and gingival inflammation appear to exacerbate the expression of drug-induced gingival overgrowth, irrespective of the initiating drug. The severity of gingival enlargement in patients taking medications correlates well with poor plaque control and is commensurate with the degree of plaque‑induced inflammation. The importance of plaque as a cofactor in the etiology of drug-associated gingival enlargement has been recognized in the most recent classification system for periodontal diseases. In this classification, “drug‑induced gingival enlargements” are categorized as plaque-induced gingival diseases modified by medications6.
Role of fibroblasts- It has also been proposed that susceptibility or resistance to pharmacologically induced gingival overgrowth may be governed by the existence of differential proportions of fibroblast subsets in each individual which exhibit a fibrogenic response to these medications. In support of this hypothesis, it has been shown that functional heterogeneity exists in gingival fibroblasts in response to various stimuli.
Role of inflammatory cytokines -A synergistic enhancement of collagenous protein synthesis by human gingival fibroblasts was found when these cells were simultaneously exposed to nifedipine and interleukin-1β (IL-1β), a proinflammatory cytokine that is elevated in inflamed gingival tissues. In addition to IL‑1β, IL‑6 may play a role in the fibrogenic responses of the gingiva to these medications. IL-6 appears to target connective tissue cells such as fibroblasts both by enhancing proliferation and by exerting a positive regulation on collagen and glycosaminoglycans synthesis.
Role of matrix metalloproteinase (MMP)- Because most types of pharmacological agents implicated in gingival overgrowth have negative effects on calcium ion influx across cell membranes, it was postulated that such agents may interfere with the synthesis and function of collagenases.
Kantarci et al., demonstrated that there are significantly higher numbers of basement membrane discontinuities in overgrowth tissues, sometimes containing epithelial-like cells. Disrupted basal membrane structure in gingival overgrowth tissues is accompanied by a discontinuous collagen type IV expression pattern and decreased laminin‑5. These findings provided a new additional support for the hypothesis that epithelial plasticity and epithelial to mesenchymal transition promote gingival overgrowth, resulting in compromised basal membrane structure and increased interactions between epithelial and connective tissue layers that contribute to fibrotic pathology7.
Recently, Subramani et al., observed that mast cells participate in many inflammatory oral diseases, particularly those associated with fibrosis. They possess very diverse roles ranging from proinflammatory to immunomodulatory. Upon their activation, they promote the local renin angiotensin system generation consequently able to stimulate endothelin and other profibrotic mediators. Cyclosporin can modulate local expression of renin angiotensin system components such as angiotensinogen, angiotensin II and its receptors in gingival tissues, and gingival fibroblast cells8.
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Figure 5- Schematic representation of potential multifactorial features and interactions.
HISTOPATHOLOGY OF DRUG INDUCED GINGIVAL ENLARGEMENT
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 cells9.
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 lymphocytes10.
ETIOLOGY OF DRUG-INDUCED GINGIVAL ENLARGEMENT
Kimball (1939) 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 effect2,.
Frankel (1940) reported a correlation between decreased serum ascorbic acid and gingival enlargement. Merritt and Foster disputed the results11.
Thoma (1942) regarded gingival enlargement as a form of Stomatitis Medicamentosa. Houck et al disputed this concept and reported that human fibroblasts were stimulated with 2-10mg per ml of Phenytoin12,34.
Brandon (1948) suggested Phenytion has a direct effect on the gingival tissues13.
Shafer and Nease also reported a direct stimulating effect of Phenytoin14.
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-responders15.
Kasai and Yoshizumi were unable to detect proliferative enhancement of human gingival cells with any concentration of Phenytoin16.
Keith et al, Hassel and Stanek published studies disputing any stimulation17.
Brandon, Scarzella and Bellatti (1948) suggested that the byproducts of Phenytoin were the causes of the cellular proliferation13.
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 response8.
Sigmund (1949) stated that Phenytoin induced gingival overgrowth was related to brain damage and the gingiva was under the influence of the Central Nervous System19.
Staple (1951) suggested a connection between Pituitary and Adrenal Glands and Phenytoin induced gingival overgrowth20.
Haim (1955) believed that the connective tissue in Phenytoin induced gingival hyperplasia was immature. Tsutsumi et al disputed this theory21.
Van der kwast (1956) suggested that the immune system was involved in Phenytoin induced gingival hyperplasia22.
Aarli suggested IgA is a factor in Phenytoin induced gingival overgrowth23,24,25.
Noach et al and Woodbury et al (1958) suggested the importance of a relationship between Phenytoin parotid uptake and Phenytoin gingival binding and Phenytoin induced gingival overgrowth. Steinbergh et al disputed this relationship26,27.
Korff and Mutschel knaus(1963) suggested that Phenytoin induced a disturbance of glucocorticoid synthesis by the adrenal cortex28.
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 proliferation29.
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 phenytoin30.
Angelopoulous (1975) suggested that Phenytoin induces degranulation of Mast cells, which results in the generation of a substance that increases collagen formation31.
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 fibroblasts32.
Vogel (1977) suggested that Phenytoin-induced enlargement was due to an end organ folic acid deficiency33.
Schneir et al(1978) 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 this34.
Southern et al(1978) reported a significant increase in the number of 5-alpha-dihydrotestosterone receptor binding site per mg protein in Phenytoin induced gingival hyperplasia35
Javed (1980) proposed that Phenytoin therapy prompted growth of Bacteroides . Smith and Hinrichs contradicted this36.
Pernu et al (1989) reported that incubation of fibroblast in the presence of Verapamil reduced protein and collagen synthesis37.
Yahia et al (1990) reported increased cAMP levels in Cyclosporine A induced gingival overgrowth38.
Phipps and Buchanan (1990) examined chromosomal protein phosphorylation in Cyclosporine A induced gingival overgrowth39.
Various hypothesis have been given for drug induced gingival enlargement. They are described as follows:
1. Inflammation from bacterial plaque:
Inflammation from bacterial plaque is involved in the pathogenesis of Drug induced gingival overgrowth.
Oneil demonstrated the efficacy of chlorhexidine, in the treatment of Phcnytoin induced gingival overgrowth40.
Daley et al observed that subjects having cyclosporin A with excellent dental hygiene scores exhibited very mild gingival overgrowth and typically presented no obvious clinical evidence of gingival overgrowth41.
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
Intense 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 established42.
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 43,44.
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 Hirsutism. 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 45.
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 46.
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 gingiva.
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 cells.
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 47.
4. Gingival fibroblast phenotype population differences:
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 Phenytoin 48.
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 tissue8.
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 production 49.
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 39.
Genetic heterogeneity may exist along several parameters -Difference in receptor biding affinity, cellular ion flux, Cellular turnover rate,Cellular GAG,Protein,Collagenase and Collagen production capacity – are all possibilities 50.
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 overgrowth.
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.
They also stated 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 also. 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 EGF51.