Anemia of Chronic Disease and ChronicPeriodontitis: Does Periodontal TherapyHave an Effect on Anemic Status?A. R. Pradeep,* Sharma Anuj,* and Arjun Raju P.†

Background: As the periodontal tissues mount an immuneinflammatory response to bacteria and their products, the sys-temic challenge with these agents also induces a major vascu-lar response. Certain inflammatory cytokines produced duringperiodontal inflammation can depress erythropoietin produc-tion leading to the development of anemia. The aim of thisstudy is to investigate whether patients with chronic peri-odontitis have an anemic status, and subsequently, to analyzethe effect of non-surgical periodontal therapy on the anemicstatus of subjects over a 6-month period.

Methods: A total of 187 patients with chronic periodontitisparticipated in the study. After red blood cell analyses, 60 pa-tients with hemoglobin concentrations below reference rangesentered into the second part of the study in which patients weretreated with non-surgical periodontal therapy. Clinical param-eters and red blood cell analyses were repeated at 3 and 6months.

Results: In the first part of the study, 33.6% of patients hadhemoglobin concentrations below normal reference ranges. Inthe second part of the study, all red blood cell parameters andclinical parameters showed statistical improvements over a6-month period.

Conclusion: The present study strengthens the hypothesisthat chronic periodontitis may lead to anemia and providesevidence that non-surgical periodontal therapy can improvethe anemic status of patients with chronic periodontitis withgreater improvement in females. J Periodontol 2011;82:388-394.

KEY WORDS

Anemia; chronic periodontitis; cytokines.

Periodontitis is an inflammatory dis-ease fundamentally initiated bychronic bacterial infection.1,2 Sub-

stantial scientific data indicate that thelocalized infections characteristic of peri-odontitis can have a significant effecton the systemic health of humans andanimals.3-6 Just as the periodontal tis-sues mount an immune inflammatoryresponse to bacteria and their products,systemic challenges with these agentsalso induce a major vascular response.This host response may offer explana-tory mechanisms for the interactionsbetween periodontal infection and a vari-ety of systemic disorders.7 Infections,malignant cells, and autoimmune dysre-gulation all lead to the activation of theimmune system and production of cyto-kines, most notably tumor necrosis fac-tor-alpha and interleukin (IL)-1 and IL-6.8

Such inflammatory cytokines can de-press erythropoietin production leadingto the development of anemia.9,10

The anemia of chronic disease (ACD)is defined as the anemia that occurs inchronic infections, inflammatory condi-tions, or neoplastic disorders that is notdue to marrow deficiencies or other dis-eases and occurs despite the presenceof adequate iron stores and vitamins.11

Hutter et al.12 proposed that periodontitisalso needs to be considered a chronicdisease that may cause lower numbersof erythrocytes and consequently lowerhemoglobin concentrations (Hb%) in asubstantial number of patients.

* Department of Periodontics, Government Dental College and Research Institute,Bangalore, Karnataka, India.

† Bangalore Medical College and Research Institute, Bangalore, Karnataka, India.

doi: 10.1902/jop.2010.100336

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The purpose of this study is to investigate whetherpatients with chronic periodontitis have an anemicstatus and the effect of non-surgical periodontaltherapy (NSPT) on red blood cell (RBC) analysesof patients with chronic periodontitis over a 6-monthperiod.

MATERIALS AND METHODS

In this 6-month follow-up, longitudinal, interventionalstudy,a total of 187subjects (age range: 30 to 50years)with chronic periodontitis were selected from the out-patient section of the Department of Periodontics,Government Dental College and Research Institute,and screened for RBC analyses. Patients with chronicperiodontitis with anemic status underwent NSPT as

a second part of the study (Fig. 1). The study was con-ducted from January 2009 to July 2009. The researchprotocol was submitted to the Institutional EthicalCommittee and Review Board, Government DentalCollege and Research Institute. After ethical approval,all subjects were verbally informed about the study,and written informed consent was obtained. Pastmedical histories were recorded. Patients who werepregnant; who suffered from any acute or chronic med-ical condition, except chronic periodontitis; who hada history of blood loss; who were smokers; or had un-dergone periodontal therapy or used antibiotics or oralsupplementation in the previous 6 months prior toenrollment were excluded. Subjects had £1 toothmissing per quadrant (excluding third molars).

Figure 1.Study flowchart.

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At the first visit, subjects were examined forchronic periodontitis on the basis of the followingcriteria: probing depths (PDs) ‡5 mm at 30% of sitesand clinical attachment levels (CALs) ‡2 mm at 30%of sites. Other signs of inflammation were recordedusing the gingival index13,14 and plaque index.14,15

After periodontal recording, blood samples were ob-tained from all patients for RBC analyses.

After RBC analyses, patients with values below ref-erence values were classified as anemic. All anemicpatients were further selected for the second part ofthe study. Subjects with chronic periodontitis withoutanemia were excluded after the first part of the study.Those patients were followed and treated as per rou-tine periodontal therapy. After considering the firstvisit periodontal recordings and RBC analyses atbaseline, a full-mouth NSPT, which consisted of scal-ing and root planing, was performed and repeatedafter 8 weeks. Patients were instructed to follow theirroutine diet habits without any modification, includingany iron or vitamin supplementation. Periodontal re-cordings and RBC analyses were repeated after com-pletion of 3 and 6 months.

RBC AnalysesUnder aseptic measures, venous blood samples weredrawn by venipuncture in antecubital fossa between9:00 am and 12:00 pm using a 5-ml syringe, collectedinto EDTA-containing vacuum tubes, and transportedto a clinical laboratory for RBC analyses £3 hoursafter collection.

Hb%, number of erythrocytes (RBC), packed cellvolume(PCV),meancorpuscular volume(MCV),meancorpuscular hemoglobin (MCH) and MCH concentra-tion (MCHC) were measured on a fully automated he-matologic analyzer.‡ The erythrocyte sedimentationrate (ESR) was measured according to Westergrenprocedures.16

Statistical AnalysesStatistical analyses of data were performed with a soft-ware program.§ To determine differences betweenmales and females for all variables, analysis of co-variance (ANCOVA) was used, and the following po-tential confounders were entered in the model withage, sex, and visit as covariates. Means and SDs forthe different parameters were calculated for malesand females separately. P values from all statistical testsare presented, but were considered statistically signifi-cant at P <0.05 to compensate for multiple testing.

RESULTS

For the first part of our study, in which a total of 187subjects (124 males and 63 females) with chronicperiodontitis underwent RBC analyses, 33.6% of pa-tients (n = 63) (29.8% males [n = 37] and 41.3% fe-males [n = 26]) had Hb% below normal reference

ranges (the normal reference range for Hb% is 13 to18 g/dl for males and 11.5 to 16.4 g/dl for females).Hence, a higher prevalence of anemic status wasfound in female than in male patients with chronicperiodontitis.

As a second part of this study, 60 patients (36males and 24 females; mean age: �41 years) partic-ipated while 3 patients were excluded because theyfailed to follow-up. Mean and SD values of PI, GI,CAL, and PD at baseline and 3 and 6 months areshown in Table 1. Differences in clinical parametersat different times for males and females are shown inTable 2. All clinical parameters showed statisticallysignificant differences over time with obvious maxi-mum differences from baseline to 6 months.

The ANCOVA test for all hematologic and periodon-tal clinical parameters with covariates of age, sex, andvisit is shown in Table 3. Overall P values showed sta-tistically significant correlations. The Hb%, RBC, PCV,MCV, MCH, and MCHC were significantly lower in fe-males compared to males (P <0.001). Statistical anal-yses showed that sex was a significant covariate andvisit was not a significant covariate for MCV, andMCHC. Age was never identified as a covariate atthe P <0.05 level. Sex and visit were significant co-variate factors for the plaque and gingival indexes,CAL, and PD.

Mean and SD values of various parameters of RBCanalyses for Hb%, RBC, PCV, ESR, MCV, MCH, andMCHC at baseline and 3 and 6 months for malesand females are shown in Table 4. All parameters of

Table 1.

Means and SDs of the Plaque Index,Gingival Index, CAL, and PD at Baselineand 3 and 6 Months

Clinical Parameters Visit n Mean SD

Plaque index Baseline 60 1.487 0.23993 months 60 1.147 0.19766 months 60 0.799 0.1684

Gingival index Baseline 60 1.561 0.25723 months 60 1.230 0.22066 months 60 0.901 0.1977

CAL (mm) Baseline 60 3.645 0.60383 months 60 3.147 0.58096 months 60 2.503 0.5578

PD (mm) Baseline 60 5.834 0.74383 months 60 5.253 0.72466 months 60 4.522 0.6954

‡ HORIBA ABX Micros 60, HORIBA, Montpellier, France.§ SPSS package version 11.0, IBM, Chicago, IL.

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RBC analyses showed improvement over 6 monthsas shown in Table 5. Hb% and ESR showed statisti-cally significant improvements from baseline to 3and 6 months for both sexes. The improvement inHb% in females (1.40) was greater than in males

(1.05) from baseline to 6 months. RBC counts weresignificantly increased from baseline to 6 months forboth sexes. PCV values significantly increased frombaseline to 3 and 6 months for the male group, butin the female group, there was only a statisticallysignificant increase from baseline to 6 months. MCVand MCHC showed no statistical differences frombaseline to 3 and 6 months in both sexes. MCH showedstatistically significant increase from baseline to 3 and6 months in males, whereas there was no significantincrease in MCH in females.

DISCUSSION

The aim of this study is to investigate the hematologicstatus of patients with chronic periodontitis for ane-mia and to subsequently analyze the effects of NSPTon anemic status.

In the present study, a total of 187 subjects, withchronic periodontitis were enrolled. Both sexes wereconsidered for inclusion because both may becomeanemic.12 Smokers were excluded because smokingis considered a cofactor for the development of peri-odontitis17-19 and anemia.20

Sixty-three (33.6%) subjects had Hb% below nor-mal reference values. A tendency toward anemia inpatients with chronic periodontitis was also previ-ously reported,21-24 whereas a reverse relationshipwas presented in data collected during the ThirdNational Health and Nutrition Examination Survey(NHANES III), which suggested that individualswith anemia may be more likely to have periodontaldisease.25 Anemic status in patients with chronicperiodontitis with no history of systemic disease

Table 2.

Mean Difference in Clinical Parameters at Different Times

Males Females

Clinical Parameters Comparison Among Visits Mean Difference SE P Mean Difference SE P

Plaque index Baseline 3 months 0.3477 0.0490 <0.001* 0.3291 0.0514 <0.001*6 months 0.6891 0.0491 <0.001* 0.6866 0.0514 <0.001*

3 months 6 months 0.3413 0.0491 <0.001* 0.3573 0.0514 <0.001*

Gingival index Baseline 3 months 0.3288 0.0533 <0.001* 0.3337 0.0505 <0.001*6 months 0.6644 0.0533 <0.001* 0.6533 0.0505 <0.001*

3 months 6 months 0.3355 0.0533 <0.001* 0.3195 0.0505 <0.001*

CAL (mm) Baseline 3 months 0.4833 0.1391 <0.001* 0.5208 0.1506 <0.001*6 months 1.1222 0.1391 <0.001* 1.1708 0.1506 <0.001*

3 months 6 months 0.6389 0.1391 <0.001* 0.6500 0.1506 <0.001*

PD (mm) Baseline 3 months 0.6942 0.1349 <0.001* 0.6507 0.1323 <0.001*6 months 1.4231 0.1349 <0.001* 1.2610 0.1323 <0.001*

3 months 6 months 0.8341 0.1349 <0.001* 0.7422 0.1323 <0.001*

* Statistically significant at P <0.001.

Table 3.

ANCOVA Test for All Hematologic andPeriodontal Clinical Parameters With Age,Sex, and Visit as Covariates

P Values for Covariates

Variable Overall P Age Sex Visit

Hb% <0.001* 0.653 <0.001* <0.001*

RBC count <0.001* 0.332 <0.001* <0.001*

PCV <0.001* 0.799 <0.001* <0.001*

ESR <0.001* 0.800 0.028* <0.001*

MCV <0.001* 0.117 <0.001* 0.568

MCH <0.001* 0.205 <0.001* 0.016†

MCHC <0.001* 0.880 <0.001* 0.143

Plaque index <0.001* 0.953 <0.001* <0.001*

Gingival index <0.001* 0.556 <0.001* <0.001*

CAL <0.001* 0.873 <0.001* <0.001*

PD <0.001* 0.924 <0.001* <0.001*

* Statistically significant at P <0.001.† Statistically significant at P <0.05.

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indicates that chronic periodontitis can lead to ane-mia. It can also be hypothesized that chronic peri-odontitis should be considered a chronic diseasethat can lead to ACD.

Thirty-seven (29.8%) males and 26 (41.3%) fe-males had Hb% below normal reference values. Thus,it can be inferred that females with chronic peri-odontitis have a higher tendency toward anemia.PCV values were low, but MCV values were within ref-erence ranges. This could suggest that the anemicstatus cannot be attributed to iron or vitamin defi-ciency because MCV values decrease26 or increase27

in such circumstances, respectively.ESR is considered a valuable parameter for any

inflammatory process. Elevated values of ESR at base-line suggested that chronic periodontitis has an in-flammatory component in it and the improvement inESR over time was due to a reduction of the periodon-tal inflammation and, thus, inflammatory markers.

There is a tendency in this study toward anemia insubjects with severe periodontitis compared to sub-jects with mild to moderate periodontitis, and im-provements in anemic status were greater among

subjects with severe periodontitis because of a re-solution of inflammation. Because of the small sam-ple size, the subjects were not classified into mild,moderate, and severe periodontitis groups.

The anemic status in patients in our study is thoughtto be caused by periodontal tissue inflammation upre-gulating the proinflammatory cytokine. It has beenproposed that hepcidin is a primary factor in the path-ogenesis of ACD, which is a cytokine-mediated ane-mia commonly encountered in clinical practice andcharacterized by hypoferremia with adequate reti-culoendothelial iron stores.28 A previous study29 in-dicated that IL-6 mediates hepcidin increases andconsequent hypoferremia during inflammation. Kemnaet al.30 showed the importance of the IL-6–hepcidinaxis in the development of hypoferremia in inflam-mation and highlighted the rapid responsiveness ofthis iron regulatory system.

For the second part of our study, 60 subjects (36males and 24 females) participated. Because sexand visit were found to be significant covariates forall clinical and RBC parameters (except for the ESRfor sex and MCV, and MCHC for visits), all clinical

Table 4.

Means and SDs of Various Parameters of RBC Analyses at Baselineand 3 and 6 Months for Male and Female Patients

Males (n = 36) Females (n = 24)

Parameters Visit Mean SD f Mean SD f

Hb% (g/dl) Baseline 11.92 0.78 18.254* 10.16 0.61 28.900*3 months 12.41 0.72 10.72 0.736 months 12.97 0.70 11.57 0.56

RBC count (1012/l) Baseline 4.46 0.23 7.904* 4.00 0.27 4.103*3 months 4.56 0.22 4.10 0.256 months 4.68 0.23 4.22 0.25

PCV (%) Baseline 38.33 1.29 17.875* 34.13 1.99 5.781*3 months 39.11 1.31 35.02 1.866 months 40.18 1.35 36.05 2.02

ESR (mm/hour) Baseline 14.06 1.89 128.842* 15.08 1.76 171.233*3 months 10.94 1.58 11.08 1.106 months 7.64 1.58 8.04 0.95

MCV (fl) Baseline 89.32 1.32 1.366 84.70 3.79 0.0713 months 89.56 1.33 84.92 3.776 months 89.84 1.32 85.11 3.72

MCH (pg) Baseline 29.36 0.85 3.586* 28.12 1.21 1.1513 months 29.63 0.83 28.39 1.226 months 29.90 0.88 28.66 1.21

MCHC (%) Baseline 32.56 1.64 1.175 31.10 1.32 1.0533 months 32.86 1.64 31.40 1.226 months 33.15 1.64 31.63 1.25

* Statistically significant at P <0.05.

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and RBC analyses were carried out separately for bothsexes. All clinical and RBC parameters showed im-provement from baseline to 6 months for males andfemales. A previous study31 reported improvementin hematologic parameters in male subjects withHb% £15g/dl after NSPT at 6 and 12 months. The pres-ent study is the first study, to our knowledge, designedto analyze and compare improvements in hemato-logic parameters in both sexes with anemia. Improve-ments in Hb%, RBC counts, and ESR at 6 months(mean improvement: 1.05, 0.22, and 6.42, respec-tively, in males) in the present study is greater thanin the previous study31 (values of 0.95, 0.22, and6.23, respectively) at 12 months. This can be ex-plained because of the criteria for patient selection.The present study includes subjects with chronicperiodontitis with Hb% below normal referenceranges (anemic) rather than subjects with chronicperiodontitis with Hb% £15 g/dl (within normal refer-ence ranges).31 Additionally, a meager improvementin MCV, MCH, and MCHC (0.52, 0.54, and 0.59, re-spectively) with significant improvements in Hb%

and PCV after NSPT at 6 months indicated that theanemia was not due to iron or vitamin deficiency.Thus, the present study supports the improvementin hematologic parameters in subjects with anemiaafter NSPT with greater improvement in female sub-jects compared to male subjects. All parametersshowed more improvement from 3 to 6 months com-pared to baseline to 3 months. These results can beexplained on the basis that, as time progresses, fur-ther reductions in periodontal inflammation lead toimprovements in hematologic parameters. The re-solution of periodontal inflammation with improve-ments in RBC parameters provided evidence thatNSPT alone can improve the anemic status of patientswith chronic periodontitis.

CONCLUSION

The present study indicates that chronic periodontitismay tend toward anemia and provides evidence thatNSPT can improve the anemic status of patients withchronic periodontitis, and that improvement in hema-tologic parameters was greater in female subjects.

Table 5.

Mean Differences in Parameters of RBC Analyses at Different Time Pointsfor Male and Female Patients

Males Females

Parameters Comparison Among Visits Mean Difference SE P Mean Difference SE P

Hb% (g/dl) Baseline 3 months -0.4889 0.1739 0.006* -0.5542 0.1861 0.004*6 months -1.0500 0.1739 <0.001† -1.4042 0.1861 <0.001†

3 months 6 months -0.5611 0.1739 0.002* -0.8500 0.1861 <0.001†

RBC count (1012/l) Baseline 3 months -0.1000 0.0545 0.070 -0.1029 0.0755 0.1776 months -0.2166 0.0545 <0.001† -0.21625 0.0755 0.006*

3 months 6 months -0.1166 0.0545 0.035* -0.1133 0.0755 0.138

PCV (%) Baseline 3 months -0.7833 0.3121 0.014* -0.8875 0.5667 0.1226 months -1.8583 0.3121 <0.001† -1.9250 0.5667 0.001†

3 months 6 months -1.0750 0.3121 0.001* -1.0375 0.5667 0.071

ESR (mm/hour) Baseline 3 months 3.111 0.400 <0.001† 4.001 0.382 <0.001†

6 months 6.417 0.400 <0.001† 7.042 0.382 <0.001†

3 months 6 months 3.306 0.400 <0.001† 3.042 0.382 <0.001†

MCV (fl) Baseline 3 months -0.2417 0.3128 0.441 -0.2167 1.0874 0.8436 months -0.5167 0.3128 0.102 -0.4083 1.0874 0.708

3 months 6 months -0.2750 0.3128 0.381 -0.1917 1.0874 0.861

MCH (pg) Baseline 3 months -0.2694 0.2022 0.186 -0.2667 0.3516 0.4516 months -0.5417 0.2022 0.009* -0.5333 0.3516 0.134

3 months 6 months -0.2722 0.2022 0.181 -0.2667 0.3516 0.451

MCHC (%) Baseline 3 months -0.3056 0.3878 0.433 -0.2958 0.3655 0.4216 months -0.5944 0.3878 0.128 -0.5292 0.3655 0.152

3 months 6 months -0.2889 0.3878 0.458 -0.2333 0.3655 0.525

* Statistically significant at P <0.05.† Statistically significant at P <0.001.

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ACKNOWLEDGMENTS

The authors thank Mr. P. S. Jagannatha, statisticianin Rajajinagar, Bangalore, India, for carrying outall required statistics. The authors report no conflictsof interest related to this study.

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Correspondence: Dr. A.R. Pradeep, Department of Peri-odontics, Government Dental College and Research In-stitute, Fort Bangalore-560002, Karnataka, India. E-mail:periodontics_gdc@rediffmail.com.

Submitted June 2, 2010; accepted for publication August26, 2010.

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