Diphenylhydantoin-induced gingival overgrowth in man: a clinico-pathological study

In a cross-sectional, epidemiological study of diphenylhydantoin-induced gingival overgrowth (DGO) in 60 epileptic patients, gingival lesion severity was statistically compared with other clinical, laboratory, and histopathological findings. Evident DGO was observed in 50% of patients, and positive correlations were detected between overgrowth severity and oral debris, calculus accumulation, plaque score, gingival inflammation, and probing depth. However, no valid correlation was observed between lesion and patient age, mouth breathing, daily drug dose, plasma diphenylhydantoin level, or duration of drug intake. Also, there were no significant correlations between connective fiber richness and the intensity of epithelial hyperplasia and severity of gingival overgrowth.     

Connective tissue growth factor in drug-induced gingival overgrowth

BACKGROUND: Drug-induced gingival overgrowth is a known side effect of certain chemotherapeutic agents used for the treatment of systemic disorders. The pathogenesis and mechanisms responsible for this condition are not fully understood. This study assesses for the presence and localization of connective tissue growth factor (CTGF) in drug-induced gingival overgrowth tissues. CTGF immunostaining was compared with sections stained with transforming growth factor (TGF)-beta1 and CD31 antibodies in order to investigate possible pathogenic mechanisms. METHODS: Gingival overgrowth samples were obtained from patients undergoing therapy with phenytoin (n = 9), nifedipine (n = 4), cyclosporin A (n = 5), and control tissues from systemically healthy donors (n = 9). Tissue sections were subjected to peroxidase immunohistochemistry and were stained with CTGF and TGF-beta1 polyclonal primary antibodies. Possible relationships between CTGF staining and angiogenesis were also studied using an anti-CD31 antibody as a marker for endothelial cells. Staining was analyzed by computer-assisted quantitative and semiquantitative methodology at 5 defined sites in all samples based on the location of specific landmarks including epithelium and underlying connective tissues. RESULTS: Cellular and extracellular CTGF content in phenytoin gingival overgrowth tissues was significantly (P<0.05) higher compared to the other gingival overgrowth tissues and the controls. Higher CTGF staining in phenytoin gingival overgrowth tissues was accompanied by an increased abundance of fibroblasts and connective tissue fibers. No strong association of CTGF staining with TGF-beta1 or CD31 staining was found. CONCLUSIONS: The data from the present study show significantly higher CTGF staining in phenytoin-induced gingival overgrowth tissues compared to controls, cyclosporin A-, or nifedipine-induced gingival overgrowth. Moreover, semiquantitative analyses of histologic samples support the concept that the phenytoin overgrowth tissues are fibrotic. These associations suggest a possible role for CTGF in promoting development of fibrotic lesions in phenytoin-induced gingival overgrowth.     

New clinical index for drug-induced gingival overgrowth.

The numbers of patients using medications that induce gingival overgrowth are expanding rapidly. The tremendous increase in the number of organ transplants being performed, each requiring treatment with the immunosuppressive drug of choice, cyclosporine, has created a new dilemma in management of the gingival tissues. Additionally, cyclosporine-induced hypertension is frequently treated with calcium channel blockers, such as nifedipine, both drugs acting synergistically to induce gingival overgrowth. At present, the profession lacks a well-defined and easy-to-use clinical index for classifying overgrown gingival tissue. This article describes a comprehensive, yet simple, scoring system for enlarged tissues that may provide direction to the clinician and standardize evaluation. This system may also give guidance for the most appropriate time for surgical treatment of drug-induced gingival overgrowth.     

Tuberous sclerosis with gingival overgrowth.

A case of tuberous sclerosis with gingival overgrowth is presented. A brief literature review and diagnostic criteria of tuberous sclerosis are discussed. The patient had a full-mouth gingivectomy with frequent post-operative maintenance visits. After 6 months, the overgrowth in conjunction with the tuberous sclerosis returned.     

Risk factors for drug-induced gingival overgrowth

Background/Aims: Drug‐induced gingival overgrowth remains a significant problem for the periodontologist. Many patients medicated with the drugs implicated in this unwanted effect experience significant, recurrent gingival problems that require repeated surgical excisions. In this review, we attempt to identify and quantify the various “risk factors” associated with both the development and expression of the drug‐induced gingival changes. Method: The risk factors appraised include age, sex, drug variables, concomitant medication, periodontal variables and genetic factors. Elucidation of such factors may help to identify “at risk patients” and then develop appropriate treatment strategies. Results: Of the factors identified, the only one that can be affected by the periodontologist is the patents' periodontal condition. However, drug variables and concomitant medication do impact upon the expression of gingival overgrowth. Conclusion: The identificatioin of risk factors associated with both the prevalence and severity of drug‐induced gingival overgrowth is important for all parties involved with this unwanted effect. Both periodontologist and patient have an important rôle to play in improving oral hygiene and gingival health. Likewise, there is always an opportinity to establish a close liaison between the patient's physician and the periodontologist to try and identify alternative drug regimens that can help reduce the impact of this unwanted effect.     

Nitrendipine-induced gingival overgrowth in dogs

This study assessed the development of gingival overgrowth in dogs given nitrendipine, a new antihypertensive dihydropyridine. Nine male Beagle dogs with established plaque and gingivitis were used. Following a baseline examination, which involved assessment of plaque, gingivitis, and gingival enlargement, six dogs (test) received nitrendipine twice daily in a high dose, while 3 dogs (control) received placebo. Clinical scorings were repeated after 10 and 20 weeks. At termination of the study gingival biopsies were excised and examined morphometrically. Already at the 10-week examination definite changes in gingival size had occurred, and following 20 weeks of nitrendipine treatment the gingival enlargement had markedly increased. In none of the control dogs were there any signs of gingival size changes. The histopathological examination showed that the only principal changes in histopathological morphology were that areas of non-infiltrated connective tissue in test specimens showed an increase in vascularity and appeared more loose compared with the dense tissue in control specimens. The morphometric analysis demonstrated minor differences between test and control specimens in regard to all tissue fractions observed; however, such differences were numerically very small, and were not considered biologically significant. Thus, the results demonstrated that nitrendipine administered to Beagle dogs during a 20-week period causes marked overgrowth of gingival tissue of apparently normal composition. The fact that cases of gingival overgrowth have been reported among patients receiving other dihydropyridines suggest that the observed gingival overgrowth is an effect of this class of drugs.     

Cyclosporin-induced gingival overgrowth in children

Cyclosporin is a potent immunosuppressant drug commonly used to prevent organ transplant rejection. In recent years, there has been a widening of its therapeutic use and an increase in the number of patients undergoing transplantation. Gingival overgrowth is one of several oral side-effects of cyclosporin, with a quoted prevalence of between 8% and 100%. There is continued debate over the factors which modify the degree of overgrowth, including individual sensitivity, age, dose of drug, duration of drug therapy and the presence of dental plaque. The exact mechanism of gingival overgrowth is still being debated, but appears to be caused by a combination of the proliferation of fibroblasts within the gingival tissue, an increase in the deposition of collagen and extracellular matrix, and a decrease in phagocytosis with a net gain in gingival tissue mass. A number of treatment options are utilized in the treatment of gingival overgrowth, including CO2 laser surgery, improved oral hygiene, the use of antibiotics such as metronidazole and azithromycin, and surgical intervention. In the clinical application of cyclosporin, there is little correlation between cyclosporin dose, serum trough levels and total exposure to the drug, making it difficult to achieve the desired therapeutic response. These problems were previously further complicated by the variability of absorption of the drug via the gastrointestinal tract. The original cyclosporin formulation, Sandimmune, was replaced by a new formulation, Neoral, which has a more reliable absorption, and gives a closer correlation between trough concentration levels and individual bioavailability. There is a conflict of opinion over whether or not the side-effect profile of Neoral varies from its precursor Sandimmune. It has yet to be seen whether the increased bioavailability of Neoral will result in an increased severity and prevalence of gingival overgrowth. An alternative immunosuppressant drug, tacrolimus, which is a macrolide antibiotic with a different side-effect profile, has emerged as a substitute for cyclosporin in organ transplantation. However, there have been conflicting reports of its side-effects and its capacity to cause gingival overgrowth.     

Human gingival glycosaminoglycans in cyclosporin-induced overgrowth

Glycosaminoglycans in normal and cyclosporin‐induced gingival overgrowth were extracted by papain digestion and purified by Mono Q‐FPLC chromatography. The purified glycosaminoglycans were analyzed by agarose gel electrophoresis and by the pattern of degradation products formed by chondroitin lyases on HPLC chromatography. Our results on the glycosaminoglycan composition showed presence of chondroitin 4‐ and 6‐sulfate, dermatan sulfate, heparan sulfate and hyaluronic acid in both normal gingiva and cyclosporin‐induced gingival overgrowth. The total and relative amounts of glycosaminoglycans were similar between normal and overgrown gingiva. This suggests that the glycosaminoglycan composition is not changed in cyclosporin‐induced gingival overgrowth. Our present biochemical results conflict with histochemical and biosynthetic data previously reported by other groups. Those studies suggested that the affected tissues contained higher levels of glycosaminoglycans and that cyclosporin induced comparably high levels of these compounds in in vitro cultures of gingival fibroblasts. Therefore, these discrepant results suggest that a cyclosporin‐induced increase on gingival glycosaminoglycans still remains an open question. The implications of these conflicting results are discussed.     

Cyclosporine-induced gingival overgrowth in beagle dogs

Development of gingival overgrowth during daily long-term cyclosporine A treatment was studied in 2-yr-old beagles. Gingival enlargement developed in five of 12 dogs (42%), primarily in the mandibular anterior area. The earliest gingival changes occurred by 3 wk as an increase in the size of the interdental papillae. The lesions progressively became more severe, in some cases obscuring portions of teeth by wk 6. The redundant tissue exhibited an increase in connective tissue components and an inflammatory infiltrate primarily of plasma cells. Severity of the overgrowth varied in responding animals; both incidence and severity were related to the CSA concentration in blood. The mean CSA blood levels of responders were significantly greater than nonresponders at wk 3, 6 and 10. Since beagles develop gingival overgrowth similar to humans, they provide an excellent model to investigate the roles of local and systemic factors in the induction of gingival overgrowth.     

Immunohistochemical analysis of epidermal growth factor receptor in cyclosporin A-induced gingival overgrowth

Cyclosporin A (CsA)-induced gingival overgrowth represents a tissue of fibrosis and epidermal growth factor (EGF) has been shown to induce extracellular matrix synthesis by fibroblasts. The purpose of this study was to evaluate the expression of EGF-receptor (EGF-r) in frozen sections of CsA-induced overgrown gingival tissue using immunohistochemical and semiquantitative techniques. Gingival biopsies were obtained from 12 renal transplant patients receiving CsA as well as 9 systemically and periodontally healthy individuals. Immunohistochemical staining procedures were carried out in frozen sections of gingival tissue and the expression of EGF-r was compared between the two study groups. The expression of EGF-r was more pronounced in the oral gingival epithelium of CsA-induced overgrown gingiva as compared to those of the clinically healthy gingival specimens. The reactivity in the inflammatory infiltrate and connective tissue cells of both of the study groups was similar. In conclusion, the results of the present study may suggest that CsA affects EGF-r metabolism in gingival keratinocytes resulting in an increased number of cell surface receptors, which may eventually play a role in the pathogenesis of gingival tissue alterations.     

Immunohistochemical analysis of epidermal growth factor receptor in cyclosporin A-induced gingival overgrowth

Cyclosporin A (CsA)induced gingival overgrowth represents a tissue of fibrosis and epidermal growth factor (EGF) has been shown to induce extracellular matrix synthesis by fibroblasts. The purpose of this study was to evaluate the expression of EGF-receptor (EGF-r) in frozen sections of CsA-induced overgrown gingival tissue using immunohistochemical and semiquantitative techniques. Gingival biopsies were obtained from 12 renal transplant patients receiving CsA as well as 9 systemically and periodontally healthy individuals. Immunohistochemical staining procedures were carried out in frozen sections of gingival tissue and the expression of EGF-r was compared between the two study groups. The expression of EGF-r was more pronounced in the oral gingival epithelium of CsA-induced overgrown gingiva as compared to those of the clinically healthy gingival specimens. The reactivity in the inflammatory infiltrate and connective tissue cells of both of the study groups was similar. In conclusion, the results of the present study may suggest that CsA affects EGF-r metabolism in gingival keratinocytes resulting in an increased number of cell surface receptors, which may eventually play a role in the pathogenesis of gingival tissue alterations.     

Cyclosporine A-induced gingival overgrowth: a comprehensive review.

Cyclosporine A, an extremely effective immunosuppressant, is also associated with various untoward effects, including gingival overgrowth. Despite intense clinical and laboratory investigation, the cellular-molecular mechanism through which cyclosporine A simultaneously acts as a selective immunosuppressant while it elicits a connective tissue reaction in the gingiva remains poorly understood. In recent years, cellular and molecular biologic techniques have elucidated a variety of growth factors that control connective tissue homeostasis. Two growth factors known to be major elements in wound repair and connective tissue homeostasis are platelet-derived growth factor and transforming growth factor-beta 1. Increased gingival levels of these factors may be responsible for promoting fibroblastic proliferation and fibroblastic production of extracellular matrix constituents in overgrown gingival tissues. Expression of these factors has recently been shown to be upregulated in these tissues. The results of these recent studies may provide a foundation for understanding the molecular mechanism involved in the pathogenesis of cyclosporine A-induced gingival overgrowth.     

Expression of fibronectin-binding integrins in gingival epithelium in drug-induced gingival overgrowth

BACKGROUND AND OBJECTIVE: Gingival overgrowth is a side-effect of nifedipine and cyclosporin medications. Integrins are transmembrane glycoproteins that mediate cell adhesion, regulate cell proliferation and participate in the regulation of tissue fibrosis. The aim of this study was to investigate whether expression of epithelial cell integrins is linked to the development of drug-induced gingival overgrowth. MATERIAL AND METHODS: Human gingival biopsies of patients taking nifedipine, cyclosporin, or a combination of both medications, were used. Expression of the alpha5beta1, alphavbeta1 and alphavbeta6 integrins, and of cellular extra domain A of fibronectin, was localized in frozen sections using immunohistochemistry. RESULTS: The activated conformation of the beta1, alpha5beta1 and alphavbeta6 integrins were more frequently expressed in distinct locations in the oral epithelium in the combined drug group. Cellular extra domain A of fibronectin, a ligand for both alpha5beta1 and alphavbeta6 integrins, was expressed within the connective tissue of all groups. It was also expressed around the basal keratinocytes of the control, nifedipine and cyclosporin-induced gingival overgrowth groups, but not in the combined medication group. No relationship between the presence of inflammation and integrin expression was found. CONCLUSION: The results indicate that expression of certain integrins is up-regulated in the epithelium of drug-induced gingival overgrowth where they could participate in controlling the formation of elongated rete ridges and tissue fibrosis.     

Proteoglycans and glycosaminoglycans in phenytion-induced gingival overgrowth

Proteoglycans and glycosaminoglycans in normal gingival and phenytoin-induced gingival overgrowth were studied by gel electrophoresis and HPLC methods after extration with guanidinium hydrochloride and subsequent cesium chloride gradient centrifugation. The results showed that normal gingival. The relative collagen content was decreased in the phenytoin lesion. These results are in agreement with our revious stereological study, which reported an accumulation of the non-collagenous matrix chondroitin sulfates Containing non-sulfated, 4-sulfated and 6-sulfated disaccharide units, dermatan sulfate, hyaluronic acid and presumably also heparan sulfate in both normal gingival. and phenyton-induced gingival overgrowth. The increased amounts of PGs seen in the PHT lesion were associated with an increase mainly in chondroitinase sensitive glycosaminoglycans of high molecular weight and with a relative increase in iduroinc acid content. This study is consistent with the view that the PHT-lesion represents a tissue with an altered composition of the connective tissue.     

Phenytoin induced gingival overgrowth in institutionalized epileptics

In a cross-sectional, epidemiological study of phenytoin induced gingival overgrowth in 77 institutionalized persons with epilepsy, the severity of the gum lesions was quantified by means of a precise new technique. Lesion severity was then compared statistically to other clinical and laboratory parameters. Positive correlations were detected between overgrowth severity and gingival inflammation, probing depths, calculus accumulation, plaque score and the measurement gingival margin to mucogingival junction (GM-MGJ). No correlation was observed between lesion severity and patients age, daily drug dosage, plasma or saliva phenytoin level, or salivary concentration of the major phenytoin metabolite.     

Cyclosporin-a-induced gingival overgrowth in heart transplant patients

Abstract The incidence of gingival overgrowth secondary to the administration of cyclosporine A (CsA) is widely reported in renal transplant recipients, while there is no information about periodontal conditions in heart transplant patients. In the present cross-sectional investigation the relationship between clinical periodontal conditions and pharmacological profiles of CsA was determined in 39 patients (31 male and 8 female, aged 18–63 years, mean 45.6±15.2 years) who possessed their 6 upper and 6 lower anterior teeth. All patients had been on a CsA-based immunosoppression regimen for at least 6 months (6–101. mean 39.3±30.1). 2 periodontal parameters (recorded on the 12 anterior teeth only) relating to gingival overgrowth were considered: hyperplastic index and % of sites with probing depth >3 mm. These parameters were always recorded by the same observer at first appointment and 2 months after an oral hygiene programme. Both non parametric statistical analysis (Kruskal-Wallis one-way analysis by rank. Wilcoxon signed rank-test and Mann Whitney U-test) and parametric analysis (stepwise multiple regression analysis, one-sample and two-sample t-test) were used to investigate the relationship between the periodontal parameters (dependent variables) and a series of independent variables: age. sex. plaque index (PI), gingival index (GI), CsA dose, CsA blood level, duration of therapy (months since allograft). Results failed to demonstrate any significant correlation between gingival overgrowth and age, sex, CsA dose or CsA blood level, PI. A positive significant correlation was found between periodontal conditions and GI and a significant inverse correlation between periodontal conditions and duration of therapy, suggesting that the relation between CsA therapy and gingival overgrowth in heart-transplant patients could be time-related and the negative influence of the drug on the periodontal status could spontaneously decrease over time.