non-surgical periodontal therapy improves serum levels of c-reactive protein and edematous states in...

Non-Surgical Periodontal TherapyImproves Serum Levels of C-ReactiveProtein and Edematous States inFemale Patients With Idiopathic EdemaRosamma Joseph,* Vivek Narayan,* Rajaratnam Krishnan,† and Sreelatha Melemadathil†

Background: The relationship between periodontal diseaseand systemic disease is revealing new and exciting associa-tions. Idiopathic edema presents a clinical syndrome withobscure pathophysiology. The present study investigateswhether non-surgical periodontal therapy is beneficial in pa-tients who are not responding to conventional treatment ofidiopathic edema.

Methods: Thirty patients with idiopathic edema were al-located to intervention and control groups. All the subjectswere assessed for systemic (body weight, body mass index,visual scale of edema, serum C-reactive protein, and serumalbumin) and periodontal (plaque index, calculus index,and gingival index) parameters. Non-surgical periodontaltherapy, including oral hygiene instructions, scaling and rootplaning, and systemic antibiotic therapy, was provided in theintervention group. Both groups were reevaluated after 4weeks.

Results: Both groups were comparable at baseline. Allparameters, except serum albumin, showed significant im-provement after periodontal therapy. The control groupshowed further worsening of these parameters.

Conclusions: This study shows that sources for systemicinflammation, such as periodontal disease, could affect thepathogenesis of idiopathic edema. Successful elimination ofsuch covert sources of inflammation leads to a clinical benefitin patients who are distressed by this condition. J Periodontol2011;82:201-209.

KEY WORDS

C-reactive protein; dental prophylaxis; edema; focalinfection, dental; nephrology; periodontal disease.

Idiopathic edema isa clinical syndromeoccurring exclusively in females andcharacterized by irregular intermit-

tent bouts of generalized swelling.1 It ismost evident in the feet or abdomenafter prolonged standing or sitting andin the fingers and eyelids after recum-bence overnight.2 The prevalence of thiscondition has been reported to rangefrom 28% to 33%.3

The pathophysiology of idiopathicedema is obscure. Most investigatorsagree that the condition is precipitatedby an upright posture coupled with in-creased sodium-water retention.4-6 Theprobable causes for sodium-water re-tention in these patients include alteredrenin-angiotensin-aldosterone levels, en-docrinologicabnormalities, and prolongeduse of diuretics.1 Idiopathic edema hasalso been attributed to the presence ofincreased capillary abnormality resultingin the extravasation of water and electro-lytes to extravascular tissues.3,7,8

This condition has been addressed us-ingphysical therapy,psychotherapy,andpharmacotherapy. Many drugs, such asangiotensin-converting enzyme (ACE)inhibitors and angiotensin II (Ang II) re-ceptor blockers, have been used.1,7,9

However, patients may not respond fa-vorably to routine medical managementand this may lead to resentment andfrustration to the patient and doctoralike.1

* Department of Periodontics, Government Dental College, Calicut, Kerala, India.† Department of Nephrology and Hypertension, Government Medical College, Calicut,

Kerala, India.

doi: 10.1902/jop.2010.100258

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Numerous clinical and laboratory data are nowavailable supporting the hypothesis of the renin-angiotensin system as one of the essential links inthe pathophysiology of vascular disease.10,11 Histor-ically, Ang II was only seen as a hormone that re-gulates blood pressure, aldosterone release, andsodium reabsorption. Recently, this view has beenenlarged with a novel concept. Ang II acts as a proin-flammatory mediator that modifies several steps ofinflammatory response, such as increase of vascularpermeability and leukocyte infiltration.12 Therefore,it is probable that vascular inflammatory processesplay an important role in the pathogenesis of idio-pathic edema.

Periodontal diseases involve chronic inflamma-tory processes resulting from interaction of selectedGram-negative bacterial species with the host re-sponse in disease-susceptible individuals. The ulcer-ated gingival tissues provide a portal of entry for thesesubgingival organisms, such as Porphyromonasgingivalis, and their by-products into the systemiccirculation. The host responds to the microbial-lipopolysaccharide challenge with an abnormallyhigh inflammatory response with increased levelsof cytokines, such as interleukin (IL)-1, IL-6, andtumor necrosis factor (TNF)-a.13 These mediatorspromote activation of the acute-phase reactantsresulting in elevated serum levels of C-reactiveprotein (CRP), a1-acid glycoprotein, ceruloplasmin,and serum amyloid A.14

Bacteria, such as P. gingivalis, possess an arrayof cysteine proteinases, collectively termed ‘‘gingi-pains,’’15,16 which are potent factors of vascularpermeability enhancement. This activity is mediatedthrough plasma prekallikrein activation and subse-quent bradykinin release resulting in increased gin-gival crevicular fluid production and edema formationat sites infected with P. gingivalis.17,18 Therefore, thesystemic dissemination of P. gingivalis and its viru-lence factors could influence the development ofclinical symptoms as seen in idiopathic edema.

Chronic systemic inflammation, as that which oc-curs in periodontal disease, has been implicated asa major factor underlying several serious chronic dis-eases and conditions, such as atherosclerosis,19,20

low-birth-weight preterm infants,21 diabetes melli-tus,22 and renal diseases.23,24 Treatment of periodon-tal disease has resulted in reduction in serum CRPlevels,25,26 improved glycemic control,27 and im-proved endothelial function.28,29 The relationshipbetween periodontal disease and systemic diseaseis revealing new and exciting associations.

Therefore, we hypothesized that periodontal in-flammation could be involved in the pathogenesis ofidiopathic edema in patients who did not respondfavorably to conventional treatment. The primary

aim of this study is to know whether non-surgical peri-odontal therapy results in reduction of systemicinflammation and thereby would be beneficial in im-provement of edematous states in patients with idio-pathic edema and periodontal disease.

MATERIALS AND METHODS

Study SettingThis open-labeled clinical trial was conducted underthe joint efforts of the Department of Nephrologyand Hypertension, Government Medical College,Calicut, India, and the Department of Periodontics,Government Dental College, Calicut, India, from Jan-uary to November 2009. The study protocol wasapproved by the Institutional Ethics Committee, Gov-ernment Dental College, and a written informed con-sent was obtained from all subjects.

Study SubjectsThirty subjects were recruited from the Departmentof Nephrology and Hypertension, Government Medi-cal College. The study involved six visits: V0: screen-ing visit at the Department of Nephrology andHypertension; V1: inclusion and baseline visit atthe Department of Nephrology and Hypertension;V2: inclusion and baseline visit at the Department ofPeriodontics; V3: extraction of teeth with hopelessprognosis; V4: non-surgical periodontal therapy;and V5: reevaluation visit at the Department ofNephrology and Hypertension and the Departmentof Periodontics.

Eligibility CriteriaEligibility criteria were assessed in the Departmentof Nephrology and Hypertension (V0, V1) and theDepartment of Periodontics (V2).

Screening Visit at the Department of Nephrologyand Hypertension (V0)The diagnosis of idiopathic edema was made using thefollowingcriteria: female patients >14 years ofage, pre-senting with edema. Other causes for edema, such ascardiac, endocrinologic, renal, hepatic, nutritional, al-lergic, hypoproteinemic, obstructive venous, or lym-phatic disease, were ruled out using appropriateclinical examination and laboratory investigations.

Conventional Therapy for Idiopathic EdemaAll patients diagnosed with idiopathic edema wereprescribed oral dosage of ACE inhibitors and Ang IIreceptor blockers and were asked to restrict fluidand salt intake. Patients were strictly advised notto take oral diuretics because it would worsen thecondition. The patients were reassured that the clin-ical symptoms are not caused by any serious renaldisorders. The patients were reviewed after 12 weeks(V1).

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Inclusion and Baseline Visit at the Department ofNephrology and Hypertension (V1)The patients were reevaluated and were consideredfor inclusion in the trial using the following criteria:1) patients not responding to conventional treatmentas assessed using changes in body weight, body massindex (BMI), and visual grade of edema in the most in-volved limb by a single trained examiner (SM); and 2)patients willing to provide a written, informed consent.Exclusion criteria were: 1) presence of infectiousdisease, such as HIV or hepatitis; 2) patients underantihypertensive medication or any drugs that maycause sodium retention and oral contraceptives; and3) presence of any other known chronic immunoin-flammatory conditions, such as rheumatoid arthritisor systemic lupus erythematoses. The eligible sub-jects were reviewed at the Department of Periodon-tics at a scheduled appointment within 1 week.

Inclusion and Baseline Visit at the Department ofPeriodontics (V2)The patients were subjected to a dental and periodon-tal examination by a single, trained examiner (RJ).Only subjects with clinical evidence for periodontaldisease were included in the trial. Oral hygiene statusand periodontal disease were assessed using the fol-lowing criteria: Turesky-Gillmore-Glickman modi-fication of Quigley-Hein plaque index values (PI)>1;30 simplified calculus index (CIS) >1;31 modifiedgingival index values (MGI) ‡1;32 and ‡1 site withperiodontal probing depth ‡4 mm and clinical at-tachment level ‡3 mm on ‡4 teeth. Subjects whosatisfied ‡2 of these criteria were recruited for thestudy. Only subjects with ‡10 teeth were includedin the study.

Exclusion criteria were as follows: acute oral infec-tions unrelated to periodontal conditions, subjectswho had received previous periodontal therapy orantibiotic therapy within 6 months, and subjectswith known allergy to such drugs as doxycycline andchlorhexidine.

Eligible subjects were allocated into interventionand control groups using a simple lottery method afterrecording baseline measurements. The subjects inthe intervention group were given a scheduled ap-pointment within 10 days (V3, V4) after giving oralhygiene directions. The subjects in the control groupwere not given oral hygiene directions and werereevaluated after an interval of 4 weeks (V5). Subjectsin both groups were instructed to continue the con-ventional therapy for idiopathic edema.

Intervention ProtocolsPeriodontal treatment provided in the interventiongroup included oral hygiene directions, non-surgicalperiodontal therapy, and extraction of teeth withhopeless prognosis followed by systemic antibiotic

therapy using doxycycline. Subjects in the controlgroup did not receive periodontal treatment betweenbaseline and reevaluation. Periodontal treatment, sim-ilar to that instituted in the intervention group, wasalso initiated in subjects in the control group at V5to meet ethical concerns.

Oral Hygiene DirectionsBefore periodontal treatment, subjects in the inter-vention group received oral hygiene directions. A15-minute oral session included verbal and visual in-formation on proper brushing technique and use ofinterdental cleansing devices. A 10-ml chlorhexidine0.12% mouthwash twice daily was prescribed.

Extraction of Teeth With Hopeless PrognosisTeeth with hopeless prognosis (unrestorable grosslydecayed teeth and periodontally involved teeth withsevere [grade 3] mobility) were extracted in the inter-vention group. This was done in a scheduled appoint-ment (V3) 1 week before periodontal therapy. A totalof four teeth were extracted from three subjects in theintervention group. This included one tooth each intwo subjects, whereas two teeth were extracted fromone subject. A total of three teeth were extracted inthe control group (one tooth each in three subjects)during the period in which treatment was initiated inthis group.

Non-Surgical Periodontal Therapy (V4)The non-surgical debridement in a quadrant-wisemanner in multiple visits was completed within 2weeks by a single operator (VN). It consisted of scal-ing and root planing of all involved tooth surfaces.Adjunctive subgingival irrigation using an antisepticmouth rinse (chlorhexidine 0.12%) was also per-formed.

Adjunctive systemic antibiotic therapy using doxy-cycline, 100 mg, twice daily for 1 day followed by oncedaily for 4 days was prescribed. It was initiated onthe day of completion of mechanical debridement.33

All patients were reevaluated after 4 weeks of peri-odontal maintenance (V5).

Outcome MeasuresSystemic and periodontal outcome measures wererecorded from all subjects included in the trial bysingle, trained examiners at the Department of Ne-phrology (SM) and the Department of Periodontics(RJ) at baseline (V1, V2) and during reevaluation(V5). The primary outcome measures were changesin body weight, BMI, high-sensitivity serum CRP(hsCRP), and serum albumin between the groups.Changes in body weight and BMI were used as indi-rect measures for assessing edema. hsCRP and se-rum albumin were used as markers for systemicinflammation. Visual grading of edema in the mostinvolved limb and patients’ perception of change in

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edema between visits V1 and V5 were also recordedas secondary outcome measures.

Visual Grade of EdemaThe edema state was recorded from the most involvedlower limb by a single trained examiner at the Depart-ment of Nephrology (SM). The edema was recordedas: Grade 0: no edema; Grade 1: involvement offeet alone; Grade 2: involvement of feet and extendingup to the ankle; Grade 3: edema extending onto theleg but not extending to the knee; Grade 4: edemaextending up to the knee and beyond.

Periodontal AssessmentA complete full-mouth examination was performed atV2 and V5. The oral hygiene status and gingival in-flammation were recorded. Although PI30 and MGI32

were recorded for whole dentition, CIS was recordedfor selected teeth as originally described.31 The peri-odontal status was measured using probing depth andclinical attachment level at four sites (buccal, lingual,mesial, and distal) on each tooth using a graduatedperiodontal probe. The periodontal disease statuswas then recorded as gingivitis/mild periodontitis,moderate periodontitis, and severe periodontitisbased on the criteria proposed by the CDC WorkingGroup.34 The changes after periodontal therapy wereassessed using changes in PI, CIS, and MGI from V2to V5 between the groups.

QuestionnaireDemographic information (name, age, sex, and ad-dress) and medical and dental history were collectedat baseline using a questionnaire. Perception ofchange in edema between baseline and reevaluationwas recorded during V5.

Patient Perception of Change in EdemaSubjects in both groups were asked whether they ob-served any change in edema between baseline andreevaluation. The responses were recorded on a scaleof 0 to 2, where 0 was no change, 1 was increased, and2 was decreased.

hsCRP and Serum Albumin AssessmentSerum CRP was assessed by a high-sensitivity quan-titative turbidimetric test.‡ Quantitative determina-tion of serum albumin was made with a diagnostickit using bromocresol green methodology.§

Statistical AnalysisThe data were analyzed using a statistical softwarepackage.i Differences in mean values of quantitativevariables (hsCRP, serum albumin, body weight, andBMI) between the two groups were assessed using un-paired t tests. Mann-Whitney U tests were used to as-sess the difference in mean values of periodontalvariables between the groups. Differences in quanti-tative variables in the intervention and control group

between baseline and reevaluation were assessedusing paired sample t tests. The difference in meanvalues for periodontal variables in the interventionand control group between baseline and reevalua-tion was assessed using Wilcoxon signed-rank test.Intergroup and intragroup analysis of categoricalvalues was done using x2 tests. P value <0.05 wasconsidered significant for all tests.

RESULTS

A total of 56 patients diagnosed with idiopathic edemawas examined. Twenty-six patients were excluded fornot matching eligibility criteria. Thirty patientswho didnot respond favorably to conventional therapy for idi-opathic edema with clinical evidence of periodontaldisease were included in this study. The mean valuesfor periodontal parameters in the study populationare given in Table 1 and the distribution of periodontaldisease in Table 2. The intervention and control groupsshowed no difference in distribution of periodontal dis-ease or mean serum levels of periodontal and systemicparameters at baseline (Tables 1 and 2).

The intervention group (n = 15) showed a signifi-cant decrease in mean values for serum hsCRP, bodyweight, and BMI (P <0.05) between baseline andreevaluation (Table 3), reflecting a decrease insystemic inflammation and edema. All periodontalparameters (Table 3) and visual scores for edema(Table 4) also decreased significantly after periodon-tal therapy in the intervention group (P <0.05).However, serum albumin levels were not altered sig-nificantly (Table 3).

In contrast, the control group (n = 15) showed a sig-nificant increase in mean values for serum hsCRP,body weight, and BMI (P <0.05) between baselineand reevaluation (Table 3), indirectly indicatingan increase in systemic inflammation and edema.Serum albumin levels were not altered significantly(Table 3). Visual scores for edema (Table 4) alsoshowed a trend toward worsening of edema in thesesubjects. However, these changes did not achievestatistical significance.

Although primary outcome measures, such asserum levels of hsCRP, body weight, and BMI, de-creased after intervention, the subjects in the controlgroup showed elevation in these parameters (Table5). The difference in these parameters, except thatof serum albumin, between the groups was statisti-cally significant (P <0.05). The patient perception ofchange in edema between baseline (V2) and reevalua-tion (V5) showed that 60% of subjects in the interven-tion group experienced a decrease in edema (Table6). However, a comparison between the groups failed

‡ Spinreact CRP-Ultra test kit, S.A, Ctra, Santa Coloma, Spain.§ M/s Agappe Diagnostics, Kerala, India.i SPSS 17.0 for Windows, SPSS South Asia (P) Limited, Bangalore, India.


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to attain statistical significance. All these changes in-dicate a beneficial effect of periodontal therapy in re-ducing systemic inflammation and thereby resultingin a decrease in edema in subjects in the interventiongroup, whereas subjects in the control group showedsignificant worsening in these parameters.

DISCUSSION

This clinical trial investigates the hypothesis that peri-odontal inflammation could be involved in the patho-genesis of idiopathic edema by evaluating effects ofnon-surgical periodontal therapy in these patients.Thirty patients with idiopathic edema not respondingto conventional treatment participated in this trial.The distribution of periodontal disease status (Table2) showed that 14 (46.7%) subjects had gingivitis/mild periodontitis, 13 (43.3%) had moderate peri-odontitis, and three (10%) subjects had severe peri-odontitis.

Both groups showed comparable results for peri-odontal and systemic parameters at baseline (Table1). All the outcome measures, except serum albuminin the intervention group, showed significant im-

provement after peri-odontal therapy (Tables3 and 4). The reductionin periodontal parame-ters in the interventiongroup indicates thatperiodontal therapy waseffective and that the re-sults are well maintained.The control subjects, inwhom the periodontal in-flammation was not re-solved, showed furtherworsening of these pa-rameters(Tables3and4).

The changes in themean body weight andBMI from baseline toreevaluation were signif-icantly different in theintervention and controlgroups (Tables 3 and 5).These changes may beconsidered an indirectmeasure of reduction inedema. Previous stud-ies35,36 conducted inpatients with idiopathicedema have also usedsimilar parameters for theassessment of edema.

The mean serumhsCRP level in our study

population was 9.3 mg/L. Ebersole et al.37 reportedthat mean hsCRP levels were elevated among patientswith adult periodontitis. The mean serum level of hsCRPobtained in their study was 9.12 mg/L, which is verymuch consistent with our results. A systematic reviewand meta-analyses on CRP in relation to periodontitisconcluded that serum CRP in periodontitis is elevatedcompared with controls.25 Thus, presence of elevatedserum CRP in patients with idiopathic edema couldbe attributed to the presence of periodontal disease.

Previous studies38,39 have established that there isconsiderable variability in population levels of serumCRP, even in studies using comparable enzyme-linkedimmunosorbent assay methods. Therefore, more em-phasis should be placed on the mean difference in CRPlevels from baseline to reevaluation. The mean valuesfor serum CRP decreased significantly in the interven-tion group (Table 3). It has been established that peri-odontal treatment results in a significant decrease ofthe serum CRP levels.25,26 Therefore, non-surgicalperiodontal therapy seems to have resulted in a signif-icant reduction in systemic inflammation in subjectswith idiopathic edema and periodontal disease.

Table 1.

Demographic and Clinical Parameters (mean – SD) at Baseline

Clinical Parameter

Total Population

(n = 30)

Intervention Group

(n = 15)

Control Group

(n = 15) P Value

Age (years) 37.03 – 9.40 39.93 – 10.15 34.13 – 7.87 0.091

Serum albumin (g/dl) 3.80 – 0.71 3.77 – 0.98 3.82 – 0.32 0.862

Serum hsCRP (mg/L) 9.32 – 13.66 12.53 – 15.87 6.10 – 10.60 0.203

Body weight (kg) 65.23 – 10.99 62.96 – 8.87 67.50 – 12.66 0.266

BMI (kg/m2) 27.17 – 5.19 26.77 – 4.42 27.58 – 5.99 0.676

PI 2.21 – 0.46 2.31 – 0.47 2.12 – 0.45 0.198

CIS 1.86 – 0.46 1.88 – 0.53 1.84 – 0.38 0.933

MGI 2.09 – 0.38 2.19 – 0.34 2.00 – 0.39 0.158

Table 2.

Distribution of Periodontal Disease in Study Population

Periodontal Disease

Total Population

n (%)

Intervention Group

n (%)

Control Group

n (%) P Value

Gingivitis/mild periodontitis 14 (46.7) 5 (33.3) 9 (60)

Moderate periodontitis 13 (43.3) 8 (53.3) 5 (33.3)

Severe periodontitis 3 (10) 2 (13.3) 1 (6.7) 0.338

Total 30 15 15


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The mean serum level of albumin of the studysubjects was within the normal range (Table 1).Macgregor and de Wardener1 have also reportednormal serum albumin levels in patients with idio-pathic edema.

Because edema in these patients is most evident inlower limbs and feet, edema was recorded in the mostinvolved lower limb using an arbitrary visual scalefrom grade 0 to grade 4. The scores for visual gradeof edema in the intervention group (Table 4) also re-flect the reduction in edema between baseline andreevaluation (P <0.05). A subjective assessment ofpatient perception of change in edema also showedpositive results (Table 6). However, these changes didnot achieve statistical significance.

Thus, it seems that periodontal therapy has resultedin a significantly positive experience for patients whoare distressed with idiopathic edema. Unfortunately,patient experience may be regarded as a rather sub-jective measure. Dunnigan et al.3 have also used sim-

ilar subjective outcomes and visual analog scores forassessing patients with idiopathic edema.

Because both groups were similar at baseline, thedifferences observed in the groups could be attributedto the non-surgical periodontal therapy. It is wellestablished that non-surgical periodontal therapy iseffective in reducing the numbers of subgingival mi-croorganisms.33,40 After successful treatment, bacte-rial load is significantly reduced, whereas antibodytiters and avidity to specific pathogens, such as P. gin-givalis, are also improved.41

However, the mechanisms as to how periodontaltherapy may result in these changes are more diffi-cult to explain. As previously stated, the exact etiol-ogy of idiopathic edema is still uncertain. However, itis likely that inflammatory processes, such as acti-vation of the kinin-kallikrein system, and novel path-ways, such as the renin-angiotensin-aldosteronesystem, could be involved in the pathogenesis of thisclinical syndrome.

Table 3.

Changes in Clinical Parameters From Baseline to Reevaluation

Intervention Group Control Group

Baseline Reevaluation Baseline Reevaluation

Parameter Mean – SD P Value Mean – SD P Value

Serum albumin (g/dl) 3.77 – 0.98 3.75 – 0.46 0.919 3.82 – 0.32 3.84 – 0.42 0.818

Serum hsCRP (mg/L) 12.53 – 15.87 3.73 – 7.92 0.026 6.10 – 10.60 8.52 – 11.78 0.045

Body weight (kg) 62.96 – 8.87 61.30 – 8.88 0.002 67.50 – 12.66 68.36 – 12.59 0.004

BMI (kg/m2) 26.77 – 4.42 26.05 – 4.33 0.002 27.58 – 5.99 27.89 – 5.81 0.003

PI 2.31 – 0.47 0.51 – 0.34 0.001 2.12 – 0.45 2.14 – 0.46 0.532

CIS 1.88 – 0.53 0.08 – 0.15 0.001 1.84 – 0.38 1.90 – 0.38 0.173

MGI 2.19 – 0.34 0.52 – 0.32 0.001 2.00 – 0.39 2.11 – 0.54 0.100

Table 4.

Changes in Visual Edema Scale in Both Groups From Baseline to Reevaluation

Intervention Group Control Group

Visual Edema Grade Baseline, n (%) Reevaluation, n (%) P Value Baseline, n (%) Reevaluation, n (%) P Value

Grade 0 0 5 (33.3) 0 0

Grade 1 0 5 (33.3) 0 2 (13.3)

Grade 2 6 (40) 4 (26.7) 0.001 5 (33.3) 2 (13.3) 0.739

Grade 3 4 (26.7) 1 (6.7) 8 (53.3) 7 (46.7)

Grade 4 5 (33.3) 0 2 (13.3) 4 (26.7)


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The chief etiologic agents involved in periodontaldiseases are a group of Gram-negative bacteria, suchas P. gingivalis. Gingipains are involved directly intissue invasion and destruction and in evasion andmodulation of host immune defenses.15 Various stud-ies17,18,42 have established that gingipains are impor-tant vascular permeability enhancement factors. Invitro studies show that gingipains act either by prekal-likrein activation or kininogen cleavage to releasebradykinin and potentially contribute to gingival crev-icular fluid production and edema formation at peri-odontitis sites infected with P. gingivalis.17,18 Onceit enters systemic circulation, it is possible thatthe bacterium also may exhibit similar vascular per-meability enhancement properties at distant sites.The organism possesses the ability to disseminateor invade host tissues, including epithelial cells, con-nective tissue, and endothelial cells, which is attrib-uted to the presence of major fimbriae.43,44 Anin vitro study42 showed that activation of the vasoac-tive kinin system permits dissemination of certainstrains of P. gingivalis. Therefore, vascular perme-

ability enhancement induced byP. gingivalis through activation ofkinin-kallikrein pathway along withits ability to spread to distant sitesmay have led to edematous statesin otherwise healthy individuals asseen in idiopathic edema.

The massive immunoinflamma-tory response mounted in the hostas a result of periodontal diseasecould also have far reaching effects.Periodontal inflammation generatesa significant activation of both theinnate and the adaptive immune re-sponse.13 This results in activationof complement cascade and releaseof proinflammatory mediators, suchas IL-1, IL-6, and TNF-a, which inturn may stimulate many inflamma-tory pathways, such as the acute-phase response resulting in elevated

levels of such molecules as CRP, serum amyloid A,and fibrinogen.14 The complement cascades andthese cytokines are directly involved with increasedvascular permeability,45,46 which could have con-tributed to the development of edema.

Research now indicates that these proinflam-matory mediators, such as IL-6 and bacterialendotoxins, may also enhance the generation ofangiotensinogen in the vascular wall leading to acti-vation of the renin-angiotensin-aldosterone mecha-nism.47 Current evidence10,11 indicates that Ang II isinvolved in inflammatory response in the vascularendothelium. Ang II augments vascular inflamma-tion and induces endothelial dysfunction, therebyenhancing the atherogenic process.

Renin released from the juxtaglomerular cells of thekidney cleaves angiotensinogen to produce the inac-tive Ang I, which is converted to the active Ang II byACE, primarily within the pulmonary circulation. Be-sides the ACE pathway, non-ACE pathways, includ-ing cathepsin G and tissue plasminogen activator,have been suggested as catalyzing the productionof Ang II within tissues. Non-ACE pathways are func-tionally important in human blood vessels. It has beenestimated that ‡40% of the total Ang II is formed bynon-ACE pathways.48 This may have accounted forthe ineffectiveness of ACE inhibitors in the manage-ment of idiopathic edema.

Once stimulated, Ang II may precipitate edemathrough activation of AT1 receptors by increasingvascular permeability12 and aldosterone production,leading to sodium-water retention or stimulationof antidiuretic hormone secretion.49 Thus, the renin-angiotensin-aldosterone pathway represents a proba-ble mechanism as to how proinflammatory mediators

Table 5.

Difference in Changes in Clinical Parameters FromBaseline to Reevaluation Between the Intervention andControl Group

Mean Values of Difference From Baseline to Reevaluation

Parameter Intervention Group Control Group P Value

Serum albumin (g/dl) 0.02 – 0.74 -0.02 – 0.32 0.851

Serum hsCRP (mg/L) 8.80 – 13.70 -2.42 – 4.25 0.005

Body weight (kg) 1.66 – 1.68 -0.86 – 0.97 0.000

BMI (kg/m2) 0.72 – 0.71 -0.31 – 0.34 0.000

PI 1.80 – 0.40 -0.02 – 0.28 0.000

CIS 1.80 – 0.47 -0.06 – 0.18 0.000

MGI 1.67 – 0.31 -0.10 – 0.30 0.000

Table 6.

Patient Perception of Change in EdemaFrom Baseline to Reevaluation

Perception

Intervention Group

n (%)

Control Group

n (%) P Value

No change 4 (26.7) 7 (46.7)

Increased 2 (13.3) 5 (33.3) 0.078

Decreased 9 (60) 3 (20)


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induced in periodontal inflammation could be associ-ated in the pathogenesis of idiopathic edema.

CONCLUSIONS

Within its limitations, this study provides evidencethat a novel pathway, such as systemic inflammation,could play a significant role in the development ofidiopathic edema. Periodontal disease represents amodifiable source for systemic inflammation.Wehavenot come across any study that has investigated therelationship of such chronic inflammatory conditionsas periodontal disease and idiopathic edema. Moreimportantly, this study indicates that non-surgicalperiodontal therapy may be helpful to patients whoare distressed by these conditions. Periodontaltherapy may be effective in reversing clinical symp-toms in these patients by reducing the number ofpathogens colonizing the subgingival biofilm and byaltering the serum levels of proinflammatory media-tors.

A major limitation of this trial involves the smallnumber of subjects in each group. Therefore, the re-sults obtained should be further corroborated usinga larger number of patients. Another important limita-tion is the lack of any serum bacterial quantification.The changes observed were not correlated with thepresence of microorganisms, such as P. gingivalis.More potent alterations could have been elicited ifother mediators, such as proinflammatory cytokines(IL-1, IL-6, and TNF-a), had been assessed. Themechanisms highlighted in this study need furtherinvestigation in animal and clinical models to estab-lish causality.

Even though both groups had comparable param-eters at baseline, the possibility remains that recog-nized and unrecognized confounding factors couldhave accounted for our observations. Therefore, largemulticenter studies with prospective cohort designsare essential to elucidate the exact mechanisms un-derlying the novel association between idiopathicedema and inflammatory conditions, such as chronicperiodontal disease.

ACKNOWLEDGMENT

The authors report no conflicts of interest related tothis study.

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Correspondence: Dr. Rosamma Joseph, Department of Peri-odontics, Government Dental College, Calicut, Kerala, India.Fax: 91-495-2356781; e-mail: [email protected].

Submitted April 30, 2010; accepted for publication July22, 2010.


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non-surgical periodontal therapy improves serum levels of c-reactive protein and edematous states in...

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