Volume 4 Number 1 December 1999

Periodontitis Modied by Systemic Factors

Denis F. Kinane*
* Glasgow Dental Hospital and School, Glasgow, Scotland.

Microbial dental plaque is the initiator of periodontal disease but whether it affects a particular subject, what form the disease takes, and how it progresses, are all dependent on the host defenses to this challenge. Systemic factors modify all forms periodontitis principally through their effects on the normal immune and inammatory defenses. Some good examples of this effect exist such as when there is a reduction in number or function of polymorphonuclear leukocytes (PMNs) that may result in an increased rate and severity of periodontal destruction. Many other systemic factors are much less clear cut and are difcult to causally link to periodontitis. In many cases the literature is insufficient to make definite statements on links between systemic factors and periodontitis. It is also at times difcult to be precise regarding the causative agent in systemic exposures such as smoking and even prescribed drug therapy. The possible role of systemic diseases and systemic exposures in initiating or modifying the progress of periodontal disease is clearly a complex issue. It is however generally agreed that several conditions may give rise to an increased prevalence, incidence, or severity of gingivitis and periodontitis. The categorization of the systemic modifying factors causing periodontitis and the evidence to support the role of these factors are the focus of this review. An attempt has been made to consider the conditions under broad headings, but it will be clear that many conditions fall within more than one category and that for several conditions only case reports exist whereas in other areas an extensive literature is present. Ann Periodontol 1999;4:54-63. KEY WORDS Periodontitis/etiology; risk factors; systemic diseases; systemic factors.

DIABETES MELLITUS Periodontal disease has been called the sixth complication of diabetes,1 an observation supported by several reviews which conclude that the bulk of evidence indicates there is a direct relationship between diabetes mellitus and periodontal disease.2,3 Another report also concluded that the preponderance of evidence from studies conducted throughout the world suggests that some diabetics are at increased risk of periodontitis.4 A crosssectional study of 1,426 subjects reported that diabetes mellitus was the only systemic disease positively associated with attachment loss, with an odds ratio of 2.32.5 Some caution has to be adopted in this interpretation, however, as there are numerous conicting studies which do not support this association between periodontal disease and diabetes.6 The relationship appears to be very strong within special populations such as the Pima Indians. Insulin (IDDM) and non-insulin (NIDDM) dependent diabetics appear to be equally at risk of periodontitis.7 A study involving 75 diabetic patients (IDDM and NIDDM) aimed to evaluate the association between long-term control of diabetes, as evaluated from multiple glycosylated hemoglobin measurements and periodontitis.7 In this study, the prevalence, severity, and extent of periodontitis increased with poorer control of diabetes. Thus, there are studies that suggest that the level of diabetic control and disease onset are relevant factors to consider in categorizing this patient group. A 1995 report confirmed that metabolic control may be the most important factor between periodontal health and IDDM.8 Thorstensson and Hugoson9 investigated periodontal disease experience in 83 adult long-duration insulin-dependent diabetic patients compared with 99 age-

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and sex-matched controls. Using periodontal bone levels as the main variable, they concluded that diabetics aged 40 to 49 years had more extensive bone loss and suggested that the age of onset was an important risk factor for future periodontal destruction. A more recent review,6 however, concluded that the duration of diabetes does not inuence periodontal severity, a view supported by a 5-year longitudinal study.10 Thus it would appear that diabetes (IDDM and NIDDM) is associated with an increased risk of periodontitis; that the level of diabetic control is an important factor in this relationship; and that duration of diabetes per se does not appear to be important. Further studies have suggested that periodontal treatment inuences diabetic control positively and that diabetics with severe periodontal disease were much more at risk of renal and cardiovascular complications.11 MEDICATIONS Membrane Ion-Channel Blockers This group of drugs work on the ion channels of human cells and have profound effects through this route. They have relatively similar effects in that they are considered to influence gingival fibroblasts to overproduce collagen matrix and ground substance when stimulated by gingival inammation following plaque build-up.12 They clearly have major effects in terms of gingival overgrowth and, although it could be argued that an unfavorable gingival form and false pocketing may be plaque retentive and thus might be local modiers of periodontitis (i.e., increased susceptibility may ensue) this has not been shown in published studies. Thus it is important to bear in mind that, although there is evidence supporting the effects of these drugs on gingival overgrowth, there is as yet no evidence linking the use of these medicines with periodontitis. Anti-Epileptic Drugs Some degree of gingival enlargement is present in 36% to 67% of patients who take the anticonvulsant drug sodium 5,5-diphenylhydantoinate (DPH, phenytoin, Dilantin).13 Generally the gingival tissue around the labial surfaces of the anterior teeth is more severely affected than around the posterior teeth.11 It occurs primarily in young individuals and is reported to be seen rarely in persons over 40 years of age.14,15 The onset of gingival overgrowth is generally 3 months after the commencement of phenytoin therapy16 and approximately 50% of phenytoin users develop these lesions,11 although this incidence is higher in institutionalized epileptics.17 More recent studies have also implicated alternative anti-epileptic drugs such as valproic acid18 and vigabatrin19 as also causing gingival overgrowth. Antihypertensive Calcium Antagonists Nifedipine is used extensively in the management of angina and occassionally hypertension and gingival

overgrowth often accompanies its use. The overgrowth associated with nifedipine is clinically and histochemically similar to phenytoin-inuenced overgrowth. Other calcium antagonists such as diltiazem have been shown to have similar effects.20 Cyclosporin Cyclosporin is an immunosuppressant which acts solely on the cell-mediated immune responses.21 A widely recognized side effect of cyclosporin is gingival overgrowth.22,23 Clinically and histopathologically it resembles phenytoin-inuenced overgrowth. Other similarities are that the overgrowth occurs in 30% of individuals, is related to the serum concentration of the drug, and tends to appear within 3 months of commencing the drug regimen.24 Combination Therapies Combination therapy of cyclosporin and nifedipine is widely used in the management of organ transplant patients. One study examined the prevalence and severity of gingival overgrowth in cardiac transplant patients and found signicantly higher gingival overgrowth scores and periodontal probing depths in patients medicated with the combination of cyclosporin and nifedipine than those medicated with cyclosporin alone.12 Calcium channel blockers will result in gingival overgrowth in a proportion of patients and may increase periodontal destruction in patients otherwise susceptible to the disease, but whether they actually increase the risk of periodontitits in non-risk patients is not known.25 Steroids Studies relating steroid therapy to periodontal disease and alveolar bone loss are conflicting. One reported that, although long-term prednisone therapy may predispose the patient to osteoporosis, no loss of alveolar bone was observed.26 In contrast, another study27 concluded that hydrocortisone-induced periodontal breakdown by impairing collagen and mucopolysaccharide synthesis in bone. Hydrocortisone acetate signicantly decreased the gingival concentrations of hyaluronic acid, chondroitin sulfate, and heparin in rats.28 The effects of prednisone therapy on gingival inammation and periodontitis have been investigated in a group of patients taking steroids for up to 4 years.29 Comparisons were made between this group and non-steroidal therapy patients and healthy controls and showed no differences in either the frequency or severity of periodontal disease, indicating the lack of inuence of steroids on periodontal disease. SEX HORMONES It is well established that pregnancy causes a modication in the hosts response to dental plaque but this is largely conned to the soft tissues and manifests as
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an increase in chronic gingivitis. Several studies have shown that the incidence and severity of gingival redness, swelling, bleeding, and exudation increase from the second month of gestation to the eighth month and then decrease.30-32 It is evident that with more gingival overgrowth, false pocketing will increase and thus the quantity and anaerobicity of the microora will increase, but there are no published studies which might implicate periodontitis as a sequelae to sex hormone-induced chronic gingivitis.33 Other clinical indications of a hormonal effect include the effects of oral contraceptives on the gingiva and uctuations in gingivitis with phases of the menstrual cycle.34,35 Furthermore, puberty is often accompanied by increased gingival inammation and this heightened response to plaque has been attributed to the concentration of circulating sex hormones.36 An alternative explanation for increased gingivitis during puberty is that this is a period of mixed dentition where erupting and exfoliating teeth present many sites for plaque retention. The fact that gingivitis decreases after puberty may reflect the general improvement seen in children as they improve their dexterity and become more aware of oral hygiene. Evidence suggests that sex hormone levels may alter the inammatory response to plaque and, although this predominantly results in gingivitis alone, an increased risk of periodontitis in these patients cannot be ignored.37,38 Osteoporosis Several recent papers have drawn attention to a possible link between osteoporosis and periodontal disease.39 In a cross-sectional study of 28 women aged between 23 and 78 years of age, subjects were divided into 2 groups, an older postmenopausal group on estrogen replacement therapy and a younger premenopausal group.40 The older group had reduced alveolar bone density from which the authors concluded that menopause may cause reductions in alveolar bone density. Clearly the effect of aging will have a major inuence here and the choice of the control group in this study is highly questionable. An animal study of sheep with estrogen deciency suggests that reduced estrogen levels may inuence periodontal disease progression41 although another study42 on hamsters showed that hormones did not inuence alveolar bone loss in this model. A study of human subjects with osteopenia and osteoporosis has suggested that alveolar crestal height and tooth loss in postmenopausal women were related.43 It is clear that large and, ideally, longitudinal studies or carefully controlled cross-sectional studies are needed to elucidate the possible relationship between chronic periodontitis and osteoporosis. IMMUNOSUPPRESSION Clarication of the role of immunological processes in the pathogenesis of chronic periodontal disease is pro56

vided by studies involving individuals with primary immunodeficiencies or those receiving immunosuppressive therapy. Cross-sectional studies on patients receiving immunosuppressive therapy44,45 failed to show differences between these patients and healthy controls in the prevalence or severity of periodontitis. These reports suggest that immunological deciencies do not predispose to periodontal disease, but it must be remembered that patients on immunosuppressive therapy often take repeated and intensive antimicrobial therapy, which may compensate for the reduced immune response. HIV Infection Among the oral lesions associated with acquired immunodeciency syndrome (AIDS) are several periodontal ndings. HIV-infected individuals may exhibit the following conditions: 1) linear gingival erythema; 2) necrotizing ulcerative gingivitis (NUG); 3) severe localized periodontitis; and 4) severe destructive necrotizing stomatitis affecting gingiva and bone (similar to noma or cancrum oris).46-49 It is possible that these lesions are not HIV or AIDS specic, but that they are necrotizing forms of periodontal disease which may be more exaggerated in immunosuppressed patients although many HIV-infected individuals do not have any form of periodontitis. Interestingly, HIV-infected individuals with CD4+ cell counts <200 cells/mm3 may have more severe and extensive attachment loss related to chronic periodontitis.50,51 This suggests that in immunocompromised HIV patients, prexisting periodontitis may be exacerbated and thus HIV infection can be considered a modier of periodontitis. EXPOSURES Certain environmental conditions or exposures may modify periodontitis and these include smoking and emotional stress. Smoking Numerous investigations of the relationship between smoking and periodontal diseases have been performed over the past 15 years and both cross-sectional and longitudinal studies provide strong epidemiological evidence that smoking confers a considerably increased risk of periodontal disease. Numerous studies of the potential mechanisms whereby smoking tobacco may predispose to periodontal disease have been conducted and it appears that smoking may effect the vasculature, the humoral immune, the cellular immune, and the inflammatory systems. A 10-year longitudinal radiographic study of alveolar bone loss showed that smoking was a significant predictor of future bone loss,52 and in a 5-year study of attachment loss, smokers were found to be at an increased risk of attachment loss.53 In a further 1-year longitudinal study, smokers exhibited both greater attachment

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loss and bone loss when compared with their nonsmoking counterparts.54 Smokers were also shown to be at signicantly greater risk of further attachment loss when compared to non-smokers. Thus both crosssectional and longitudinal studies indicate a strong relationship between smoking and increased risk of periodontal breakdown. A study examining the relationship between smoking and attachment loss5 demonstrated a dose-dependent response; the odds for more severe attachment loss in smokers compared to non-smokers ranging from 2.05 for light smokers to 4.75 in heavy smokers. This supports the ndings of a later study which reported that probing depth was signicantly correlated with smoking pack years.55 Furthermore, years of exposure to tobacco products have been shown to be a statistically signicant risk factor for periodontal disease in 1,156 community dwelling New England elders, regardless of other social and behavioral factors.56 Thus factors such as quantity of cigarettes smoked and duration of the habit may need to be considered in assessing risk of periodontitis due to smoking. Emotional Stress The incidence of acute necrotizing ulcerative gingivitis (ANUG) increases during periods of physiological57 and emotional stress.58 Green et al.59 studied individual life events such as divorce and bereavement and concluded that increased stressful events led to a greater prevalence of periodontal disease. These conclusions are supported by a more recent study60 which looked at the relationship between life events and adult (chronic) periodontitis and found that both psychosocial factors and oral health risk behaviors, such as poor oral hygiene and smoking, clustered together as important determinants of periodontitis. The intervening physiological mechanisms between stress and increased susceptibility to periodontal disease are not well documented but are probably related to impaired immune function during stress. It is recognized that stress may increase the levels of circulating corticosteroids,61 which may have effects on the periodontium. Stress is not an easily measured factor, but corticosteroid levels in urine can be measured and were found to be higher in ANUG patients.62 Maupin and Bell63 found signicant elevation of 17-hydroxycorticosteroids in ANUG patients and reductions when the disease was resolved. Recent studies suggest that stress may inuence the inammatory response to Porphyromonas gingivalis infection in mice.64 More severe and extensive periodontitis was also seen in psychologically depressed human subjects who smoked and had high titres of IgG against Bacteroides forsythus. The authors explained this by the negative inuence depression has on the immune system.65 Further studies with experimental gingivitis volunteers suggested that proin-

ammatory cytokine levels are increased in stressed subjects.66 A study of adults with periodontitis patients found that those resistant to therapy were more stressed than those who responded to therapy, which highlights the potential contribution of stress to periodontitis.67 Genco et al.68 evaluated the association of stress, distress, and coping behaviors with periodontal disease in 1,426 subjects, aged 25 to 74. They found that psychosocial measures of stress associated with nancial strain are signicant risk indicators for periodontal disease in adults. Interestingly, stress may also significantly change behavior and behavior-related parameters such as oral hygiene, which may further affect the periodontal condition. HEMATOLOGICAL DISORDERS The polymorphonuclear leukocytes (PMNs) in periodontal disease may cause tissue damage,69,70 but there is much evidence from studies of hematological diseases where periodontitis susceptibility is increased to suggest a protective role for these cells. To exert this protective function, several activities of PMNs must be integrated, namely chemotaxis, phagocytosis, and killing or neutralization of the ingested organism or substance. Individuals with either quantitative (neutropenia or agranulocytosis) or qualitative (chemotactic or phagocytic) PMN deciencies exhibit severe destruction of the periodontal tissues. Quantitative deciencies are generally accompanied by destruction of the periodontium of all teeth, whereas qualitative defects are often associated with localized destruction affecting only the periodontium of certain teeth.71 Quantitative Leukocyte Disorders Neutropenia. Patients with neutropenia present with a variety of periodontal manifestations. In the malignant form there is ulceration and necrosis of the marginal gingiva. This is associated with bleeding and occasional involvement of the attached gingiva.72 In more protracted forms of the disease such as cyclic, chronic, and familial benign neutropenia the lesions are frequently severe with deep periodontal pockets and extensive, generalized bone loss involving the permanent dentition.73-75 Occasionally bone resorption may be seen in the deciduous dentition.76,77 In familial benign chronic neutropenia, periodontitis is not always inevitable78 and not all subjects are affected either by recurrent infections or by periodontal disease. These findings might be explained by the variable expressivity of the disorder between the siblings, or on the interaction of the environment (e.g., oral hygiene) on this disorder. Leukemia. Periodontal lesions have been frequently observed in patients with leukemia, particularly those with an acute form. Generalized gingival enlargement
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was apparent in 36% of the individuals with acute and in 10% of those with chronic forms.79 Gingival swelling due to inltration by leukemic cells is usually a feature of acute monocytic leukemia, although it has been reported as a feature of other forms, including chronic lymphocytic leukemia.80 Gingival bleeding is also a common sign of the disease in both acute and chronic leukemia and may relate to the associated thrombocytopenia.81 Qualitative Functional Leukocyte Disorders Various disorders of neutrophil function are also associated with severe forms of periodontal destruction. Chediak-Higashi syndrome (CHS) is a rare genetic disease transmitted as an autosomal recessive trait. Those affected are extremely susceptible to bacterial infections and this appears to be related to alterations in the functional capacity of the neutrophil resulting in generalized, severe gingivitis, extensive loss of alveolar bone, and premature loss of teeth.82 CHS, chronic granulomatous disease and leukocyte adhesion deciency syndrome are functional deciencies of leukocytes and are discussed within the genetic diseases section of this review. Other Blood Disorders Red blood cell disorders and platelet bleeding disorders and clotting disorders will inuence the management of periodontal disease but there is no evidence that these conditions increase susceptibility to periodontal disease.83 HISTIOCYTOSIS SYNDROMES The histiocytosis syndromes comprise a group of diseases which may affect infants, children, and adults. In a series of 50 patients, 36% had oral involvement and 16% were first diagnosed by the dentist.84 The periodontal features of histiocytosis are punched-out necrotic ulcers with considerable granulation tissue, tissue necrosis, and marked bone loss. These lesions may clinically resemble necrotizing ulcerative periodontitis lesions and biopsy of the associated granulation tissue assists the diagnosis of this condition. The only form that appears to have a genetic component is familial erythrophagocytic lymphohistiocytosis. The diagnostic management should include hematological and immunological investigations at an early stage and may be assisted by a biopsy of the granulation tissue associated with the deep lesions.85 Skeletal surveys and chest radiographs will help determine the extent of the disease. GENETIC DISORDERS By and large these disorders manifest early in life and may clinically manifest very similarly to early-onset forms of periodontitis. That is not to say that such early periodontal destruction will not continue into adult
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life, nor to claim that the form of the disease in these inherited disease cases follows that of localized or generalized early-onset periodontitis. A further consideration is that susceptibility to chronic or adult periodontitis itself may be an inherited condition and although there are twin, family, and genetic polymorphism studies supporting this contention, susceptibility to chronic periodontitis is likely to be a multigene disorder with major environmental inuences such as smoking and microbial plaque levels. Downs Syndrome Periodontal disease in Down syndrome is characterized by a generalized early periodontitis, which commences in the deciduous dentition86-88 and continues into the adult dentition. The prevalence and severity of periodontal disease in individuals with Down syndrome is extremely high when compared to either their siblings89 or other mentally subnormal individuals.87,90 An earlyonset of periodontal disease is seen in Down syndrome patients in that pocket formation is evident in 36% of children less than 6 years old.91 Several cross-sectional studies have reported increased prevalence and severity of periodontal disease in children of older age groups.86-88 Longitudinal studies indicate that the progression of periodontal disease is very rapid.92 Authors of a 1-year follow-up study calculated a mean annual incidence which predicted that the whole dentition would be lost 9 years after onset of periodontal disease.92 The most frequent sites of periodontal destruction are around the incisor and molar teeth.86,93 The roots of the lower incisors are characteristically short91 which, in combination with the loss of bone in this area, predisposes to the premature loss of these teeth.87 Chronic Granulomatous Disease This is a rare disease with at least 2 genetic forms, autosomal recessive and X-linked recessive. The defect in this disease is in the ability of phagocytic cells, both PMN and monocytes, to perform killing by the oxidative pathway after ingestion. Kinane94 described a family with the X-linked recessive form of chronic granulomatous disease. Female carriers suffered from photosensitivity dermatoses and had very much reduced nitroblue tetrazolium reducing ability within their phagocytes. All of the female carriers in this series were examined for oral and periodontal lesions and although erythema of the gingiva and oral mucosa with occasional ulceration were seen, no periodontal manifestations were attributable to this condition. Leukocyte Adhesion Deciency Syndrome Molecular biology research has underlined the important role of several cell-cell adhesion receptors on the neutrophil surface and emphasized that defects in numbers of these receptors may lead to increased susceptibility to infectious disease including periodontitis

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in conditions such as leukocyte adhesion deciency syndrome (LAD).95 Several studies have described severe inflammatory periodontal disease in young patients with leukocyte adhesion deficiency syndrome96-99 which is a rare autosomal recessive disease. This disease is commonly fatal and although children with deciencies in expression of the LFA family of adhesins have been reported as suffering from severe periodontal infections,95 data relating adult periodontitis to this condition are not available. Nevertheless, the importance of the adhesion molecules to the function of the immune and inflammatory systems is fundamental and even small variations or deciencies could contribute to a depressed host response and an increased risk of periodontitis. Hypophosphatasia Patients with this condition have a decreased serum alkaline phosphatase and severe loss of alveolar bone and premature loss of the deciduous teeth,100-103 particularly anteriorly.102 Papillon-Lefvre Syndrome Papillon-Lefvre syndrome (PLS) is a disease with autosomal recessive inheritance,104 characterized by the presence of hyperkeratotic skin lesions. Individuals with this disease exhibit diffuse palmar-plantar keratosis associated with a severe generalized periodontitis, which occurs commonly before puberty with early loss of deciduous and permanent teeth.105-110 A frequency of 1 in 4 million in the general population is reported,107 with 25% having an increased susceptibility to infection, and a history of consanguinity is noted in 33%.106 Teeth are generally lost in the order of eruption106 and as yet there is no general agreement on the success of dental therapy. Another related disease with palmoplantar hyperkeratosis (PPK) is Haim Munk syndrome which is also characterized by severe early-onset periodontitis. Preliminary genetic studies have been performed on these 2 diseases exhibiting palmoplantar keratosis and early-onset periodontitis which suggest that the gene defect in Haim Munk syndrome is not genetically linked to the other more common forms of palmoplantar keratosis.111 This work has been questioned however, and it appears that there is a high degree of consanguinity in these families and that they are probably part of the same syndrome.112 Chediak-Higashi Syndrome Chediak-Higashi syndrome is inherited as an autosomal recessive trait associated with severe periodontitis.113-117 Neutrophil chemotaxis and bactericidal functions are abnormal in these patients. Ehlers-Danlos Syndrome (EDS) The Ehlers-Danlos syndrome covers a group of connective tissue disorders that are characterized by defec-

tive collagen synthesis. The disorders are autosomal dominant and are classied into 10 types on the basis of inheritance and clinical symptoms and they mainly affect the joints and skin. Types IV and VIII have an increased susceptibility to periodontitis.118 Type VIII Ehlers-Danlos syndrome in particular is associated with fragile oral mucosa and blood vessels and severe generalized periodontitis with the clinical appearance of generalized early-onset periodontitis.119 EDS type VIII was rst recognized by McKusick104 in a family with skin fragility, abnormal scarring, early tooth loss, and severe periodontitis. A further family with EDS type VIII had joint laxity, skin fragility, and extensive periodontal destruction.120 In EDS type VIII it appears that there is considerable interfamilial variability but the distinguishing nding is periodontitis, resembling clinically the early-onset form, leading to premature loss of permanent teeth.121 Other Rare Genetic Disorders Glycogen storage disease 1b is an autosomal recessive condition in which there is faulty carbohydrate metabolism and an association with low neutrophil numbers, impaired neutrophil function and periodontal disease.115,122 Infantile genetic agranulocytosis is a very rare autosomal recessive disorder, which features severe neutropenia and has been associated with periodontitis resembling the early-onset form.123,124 Cohens syndrome (autosomal recessive) is characterized by non-progressive mental and motor retardation, obesity, dysmorphia, and neutropenia.125 Individuals with Cohens syndrome show more frequent and extensive alveolar bone loss than matched mentally retarded controls.122 SUMMARY Microbial dental plaque initiates periodontal disease but the form of disease and its progression is dependent on the host defenses to this challenge. Systemic disorders and environmental exposures may modify the normal defenses and inuence the resultant forms of periodontal disease. A reduction in number or function of polymorphonuclear leukocytes (PMNs) generally results in increased rate and severity of periodontal destruction. Many drugs such as phenytoin, nifedipine, and cyclosporin predispose to gingival overgrowth in response to plaque and thus may have an effect in modifying preexisting periodontitis. Changes in circulating hormone levels may result in an increased severity of plaqueinduced gingival inammation but not typically in any increased susceptibility to periodontal attachment or bone loss. Hormonal changes as seen following menopause have been associated with osteoporosis but studies are lacking to link this disease or an estrogen-deficient state to a higher susceptibility to peri59

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odontal disease. Immunosuppressive drug therapy and any disease resulting in suppression of the normal inammatory and immune processes, such as HIV infection, may predispose the individual to periodontal destruction. It is difcult, however, to be sure of the precise causative agent in these conditions and it is particularly complex when immunosuppressive drugs are prescribed together with antibiotics for variable periods of time. The evidence for smoking having a deleterious inuence on periodontal health is convincing. Nutritional deciencies in animals have been shown to affect the periodontal tissues but epidemiological data do not support the suggestion that such deciencies play an important role in chronic periodontal disease. Gingival bleeding is the most consistent oral feature of vitamin C deciency or scurvy but there is also some evidence to suggest that avitaminosis-C may aggravate established chronic periodontitis.126,127 Stress and other psychosomatic conditions which may have direct anti-immune effects or indirect behavior-mediated effects on the bodys defenses may prove to be important in the etiology of periodontitis and necrotizing ulcerative gingivitis and periodontitis. The role or relative importance of these mechanisms have yet to be fully elucidated but the evidence that stress and depression can inuence the immune system is mounting. Many of the genetic disorders have numerous possible etiological factors which may render the individual susceptible to periodontal disease. Many of the genetic conditions, however, predominantly inuence the periodontium during childhood and the periodontal manifestations of this disease may resemble the early-onset forms of periodontitis, but that is not to say that the inuence of such diseases will not carry on into adulthood. The periodontal features of the histiocytoses group of diseases may present as necrotizing ulcerative periodontitis. Furthermore, although systemic diseases such as diabetes will aggravate all forms of periodontitis, chronic periodontitis is the most prevalent and thus will be the most common form presenting with diabetes-induced modifications. Currently numerous genetic polymorphisms relevant to inammatory and immune processes have been suggested and are being investigated for their modifying effects on periodontal disease. The literature on how periodontitis is modied by systemic factors, with the exception of the link with diabetes, HIV infection and smoking, is as yet sparse and clearly, well-controlled cross-sectional and longitudinal studies are needed to fully elucidate the relationship between systemic modiers and periodontitis. REFERENCES
1. Le H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 1993;16(Suppl. 1):329334. 2. Kinane DF, Chestnutt IG. Relationship of diabetes to 60

periodontitis. Current Opinion Dent 1997:4;29-34. 3. Rees TD. The diabetic dental patient. Dent Clin N Am 1994;38:447-463. 4. Oliver RC, Tervonen T. Diabetes - a risk factor for periodontitis in adults? J Periodontol 1994;65:530-538. 5. Grossi SG, Zambon JJ, Ho AW, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994;65:260-267. 6. Soskolne WA. Epidemiological and clinical aspects of periodontal diseases in diabetics. Ann Periodontol 1998;3:3-12. 7. Tervonen T, Oliver RC. Long-term control of diabetes mellitus and periodontitis. J Clin Periodontol 1993; 20:431-435. 8. Aldridge JP, Lester V, Watts TLP, Collins A, Viberti G, Wilson RF. Single-blind studies of the effects of improved periodontal health on metabolic control in type 1 diabetes mellitus. J Clin Periodontol 1995;22:271-275. 9. Thorstensson H, Hugoson A. Periodontal disease experience in adult long-duration insulin-dependent diabetics. J Clin Periodontol 1993;20:352-358. 10. Westfelt E, Rylander H, Blohm G, Jonasson P, Lindhe J .The effect of periodontal therapy in diabetics. Results after 5 years. J Clin Periodontol 1996;23:92-100. 11. Thorstensson H. Periodontal disease in adult insulindependent diabetics. Swed Dent J 1995;Suppl. 107: 1-68. 12. Ellis JS, Seymour RA, Steele JG, Robertson P, Butler TJ, Thomason JM. Prevalence of gingival overgrowth induced by calcium channel blockers: A communitybased study. J Periodontol 1999;70:63-67. 13. Klar LA. Gingival hyperplasia during dilantin therapy: A survey of 312 patients. J Public Health Dent 1973; 33:180-185. 14. Aas E. Hyperplasia gingivae diphenylhydantoinea. A clinical, histological, and biochemical study. Acta Odontol Scand 1963;21(Suppl. 34):5-142. 15. Kapur RN, Girgis S, Little TM, Masotti RE. Diphenylhydantoin-induced gingival hyperplasia: its relationship to dose and serum level. Developmental Med Child Neurol 1973;15:483-487. 16. Dummett CO. Oral tissue reactions from dilantin medication in the control of epileptic seizures. J Periodontol 1954;25:112-122. 17. Hassell T, ODonnell J, Pearlman J, Tesini D, Murphy T, Best H. Phenytoin induced gingival overgrowth in institutionalized epileptics. J Clin Periodontol 1984; 11:242-253. 18. Anderson HH, Rapley JW, Williams DR. Gingival overgrowth with valproic acid: A case report. J Dent Child 1997;64:294-297. 19. Katz J, Givol N, Chaushu G, Taicher S, Shemer J. Vigabatrin-induced gingival overgrowth. J Clin Periodontol 1997;24:180-182. 20. Bullon P, Machuca G, Martinez-Sahuquillo A, et al. Clinical assessment of gingival size among patients treated with diltiazem. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:300-304. 21. Bird AG, Britton S. A new approach to the study of human B lymphocyte function using an indirect plaque assay and a direct B cell activator. Immunolog Rev 1979;45:41-67. 22. Bennett JA, Christian JM. Cyclosporine-induced gingival hyperplasia; case report and literature review. J Am Dent Assoc 1985;111:272-273. 23. Rostock MH, Fry HR, Turner JE. Severe gingival overgrowth associated with cyclosporine therapy. J Peri-

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