Hyperplasia refers to an enlargement of tissue caused by an increase in number of cells. Gingival overgrowth may be acquired due to a fibrous and granulomatous inflammatory response associated with the use of certain systemic drugs. Although gingival inflammation is a feature of GH similar to CIPDs, however, whilst matrix components are degraded in CIPDs they accumulate in GH. Furthermore, in CIPD there is a mixture of destruction, repair and regeneration and the presence of hyperplasia may correspond to an exaggerated phase of repair. GH is a common, serious and recurrent side- effect associated with the use of certain type of drugs (Brown at al., 1991; Seymour at al., 1996; Nishikawa at al., 1996). Although reported first in 1939 (Kimball, 1939) in patients being treated with phenytoin (PHT) for epilepsy, a number of other drugs subsequently have been identified as causing this lesion, including the immunosuppressive cyclosporin A (CsA) (Thomasson at al., 1993; O'Valle at al., 1994; Seymour at al., 1997) prescribed for patients who have undergone organ transplants to prevent rejection. Nifedipine (NIP), belonging to a family of calcium channel-blockers, has been extensively used in the treatment of cardiovascular conditions including hypertension, angina and cardiac arrhythmia is also implicated in GH (Nishikawa at al,. 1991; Fujii at al., 1994; Ishida at ai, 1995).
1.2.2.1 Histopathology
Although all three types of drugs have different pharmacological properties, they nevertheless all elicit a similar clinical gingival appearance and histologically they are almost indistinguishable. Generally, GH occurs within three months of the start of drug therapy and affects predominantly the buccal and interdental gingiva of the upper and lower anterior teeth (Thomasson et al.,
1996) and often regressing after discontinuation of the drug. Several studies have shown that one of the features of GH is enhanced proliferation of normal fibroblasts, which show well-developed RER characteristic of protein synthesis and secretion, the cells resembling myofibroblasts (Yamasaki et a/., 1987). The cells showed an increased connective tissue components of the ECM but quantitative analysis of different ECM proteins showed differences using histocytochemical analysis, with type I and type III collagens, and FN showing strong expression in the NIP group than in other periodontal pathologies (Bonnaure-Mallet et al., 1995; Seymour et al., 1996). The epithelium of the enlarged gingiva tends to be parakeratinised and there is usually marked epithelial down-growths into the underlying connective tissue, with elongated rete pegs. There is also considerable evidence to indicate that plaque and gingival inflammation influence the initiation and progression of GH (Thomason
et al., 1993). Inflammatory cells are present in the connective tissue, mainly plasma cells and lymphocytes, the amount depending on the extent of inflammation. Clinically, these lesions may become so extensive that the teeth are displaced and/or their crowns covered with overgrown gingival tissue. Despite extensive studies, the pathogenesis of GH is uncertain and treatment is mainly confined to surgical removal of the overgrown tissue and to the maintenance of adequate oral hygiene.
A number of factors influence the occurrence and severity of the disease. Several clinical studies using PHT and CsA have suggested that children and adolescents are more prone to GH than adults, but there are no data available on the use of calcium-channel blockers in children as this group of drugs is used only for treating the adult population (Seymour et al., 1996). However, animal studies have supported an age-related effect of calcium-
channel blockers (Nishikawa et al., 1996). Epidemiological studies have shown that not all patients receiving these drugs develop GH. The prevalence rate for patients treated with PHT is approximately 50%, whilst those medicated with NIF and CsA show incidences of 30% and 20% respectively (Seymour et al.,
1987; Barclay et al., 1992). The drugs appear to have a synergistic effect on gingival tissue when used in combination (Thomasson et al., 1993). The terms ‘responders’ and ‘non-responders’ have been proposed to describe patients who are either susceptible or not susceptible to the drugs (Modeer et al., 1990).
1.2.2.2 Possible mechanisms of GH
Many hypotheses have been proposed to explain GH. It has been suggested that functional heterogeneity exist in GF since these cells are known to show a markedly heterogeneous response to various stimuli (Cockey et al.,
1989). Studies with GF obtained from monozygous and dizygous twin pairs also indicated genetic variation in terms of proliferation rates and protein synthesis (Cockey et al., 1987). Cells from dizygotic twins showed greater variation than those from monozygotic twins in response to PHT, further confirming the influence of genetic factors in the pathogenesis of GH. A common feature of most of the drugs that cause GH is that they are calcium (Ca"""") antagonists. Calcium is essential in many of the biological processes and influx of Ca”""" leads to activation of a cascade of biochemical reactions including a phenomenon known as apoptosis. This is a form of programmed cell death that occurs under numerous developmental and physiological conditions that require elimination of cells from tissues and organs. It is a mechanism that plays an important role in the control of tissue overgrowth by eliminating unnecessary cells in a controlled manner without inducing an inflammatory response. Therefore, one possible mechanism of GH could be the abrogation of the apoptic programme as result of the blockage of Ca'"'" influx (McConkey and Orrenius, 1977).
Many studies have demonstrated an increased synthesis of ECM proteins in GH but these are degraded during CIPD. This increase in ECM may be due to either the matrix overproduction or to reduction in the degradation of
ECM. Degradation is a highly regulated process, however, it can become excessive during inflammation, and may be impaired in hyperplasia. Several metabolic pathways are associated with matrix changes. Degradation of matrix by a family of enzymes called metal loproteinases (MMPs) is one pathway involved in remodelling of ECM (Birkedal-Hansen, 1993). These enzymes are expressed at low levels in normal adult tissues but are up-regulated in normal and pathological remodelling processes such as embryonic development, tissue repair, inflammation and metastasis. They degrade all known ECM proteins and have overlapping substrate specificities. Their activity is further regulated by tissue inhibitors of metal loproteinases (TIMPs) which bind to the enzymes forming non-covalent complexes (Birkedal-Hansen, 1993). Both PTH and CsA have been shown to affect collagenase (MMP-1) and TIMP activity (Hassell, 1982; Tipton et al., 1991).
As mentioned previously, plaque-induced inflammation may be an aggravating factor in GH suggesting that cytokines may have a role in the progression of the disease. However, the significance of these cytokines remains to be determined. Whilst several cytokines including IL-ip and IL-6
have been shown to play a significant role in CIPD, very few studies h^ve examined these factors in GH. The effects of IL-1 on androgen metabolism have been investigated in gingival tissues and the cytokine caused increased conversion of androgens to the active metabolite dihydrotestosterone (DHT) (Kasasa and Soory, 1995). This finding may be relevant in GH as DHT bps been shown to affect matrix synthesis in connective tissues. However, lacopino
et ai. (1997) examined the effects of CsA and PHT on IL-1 expression- in macrophages, both in vitro and in vivo, and found no significant up-regulation of the cytokine at the mRNA and protein levels. This indicated that, although IL-1 is up-regulated in inflammatory conditions causing tissue destruction, it may not be directly associated with GH. Similarly, Williamson et ai. (1994) analysed IL-
6 expression, by in situ hybridisation and radioimmunoasay, in gingival tissue from CsA-induced GH patients and compared it with normal tissue. These workers showed an increase in IL-6 expression, at both the mRNA and protein levels, in GH compared to the normal tissue. This result is in contrast to a
report by Yashimura et al. (1991) which showed that CsA significantly reduced serum IL-6 suggesting that the drug may inhibit IL-6 production in peripheral mononuclear cells whereas it may stimulate local synthesis of IL-6 by GF.