B-TYPE NATRIURETIC PEPTIDE IN LYMPHEDEMA

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ABSTRACT

Lymphedema often responds tocompression therapy which can also causeundesirable cardiac overload if heart failurecoexists. We hypothesized that the biomarkerB-type natriuretic peptide (BNP) can be usedto screen lymphedema patients for undetectedcardiac dysfunction. We studied unselectedconsecutive patients with lymphedema todetermine their BNP status and comparedthese data with those obtained from healthysubjects without known cardiovasculardiseases. Out of a total of 305 subjects withlymphedema screened, 102 (33%) consented totake part in this study. The majority (87%)were female with a mean age of 60.5 ± 13.2(SD) years, and 47% had just lower limbswelling. The groups were equally dividedbetween cancer and non-cancer relatedcauses. There were 45 females and 4 malesunder 60 years old, and 44 female and 9 malepatients over 60 years old. Median (IQR) BNP(ng/L) were as follows: <60 years females =17.9 (15.2) (median [RR: 3 - 64] and males =12.4 (14.7) [RR: 0.2 - 44], >60 years females =35.8 (57.9) [RR: 2 -247)] and males = 47.2(44.1) [RR: 2 - 238]. For this population, theBNP concentration 100 ng/L was adopted asthe value to exclude heart failure. Using thisdefinition, 7 lymphedema subjects had BNPconcentrations of 120 (19.8) ng/L, and all werefound to have cardiac abnormalities onechocardiography. This study demonstratedthat 93% of unselected subjects with

Lymphology 44 (2011) 29-34

B-TYPE NATRIURETIC PEPTIDE IN LYMPHEDEMA

J. Todd, T. Austwick, D. Berridge, L.B. Tan, J.H. Barth

Departments of Lymphoedema (JT), Clinical Biochemistry (TA,JHB), Vascular Surgery (DB), andCardiology (LBT), Leeds Teaching Hospitals NHS Trust, Leeds

lymphedema had BNP concentrations thatexclude a diagnosis of heart failure. Thosesubjects with elevated BNP were found onsubsequent echocardiography to have cardiacabnormalities. The use of a BNP assay is ofpotential value in screening patients who aremore likely to have cardiac failure. Indicativefactors include bilateral leg swelling, over theage of 50 years, breathlessness, where there isno known cause for the swelling. A BNP assayusing a BNP concentration threshold of 100ng/L (29 pmol/L) will identify those patientswho require more detailed investigations.

Keywords: Lymphedema, B-type natriureticpeptide (BNP), cardiac edema

Lymphedema is a form of chronic edemathat is the result of lymphatic dysfunction. It is a chronic and progressive condition thatis usually treated using non-invasive physicaltherapies, and long-term improvement can be achieved using a combination of physicaltherapies which are undertaken on a dailybasis as part of a self-treatment program with compression therapy in the form ofbandages or garments enhancing the pum-ping force of skeletal muscle and preventingre-accumulation of lymph. In cases of chronicheart failure, compression may have adetrimental effect by forcing extravascularfluid into the intravascular compartmentsand increasing the risks of raised cardiacpreload and afterload. Therefore, preliminaryscreening is recommended to exclude a

Permission granted for single print for individual use. Reproductiom not permitted without permission of Journal LYMPHOLOGY.

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diagnosis of chronic heart failure prior to the commencement of treatment. However,conventional cardiological investigations suchas echocardiography would be too costly touse as a general screening tool.

There is a growing body of evidence tosupport the utilization of the biomarker, B-type Natriuretic Peptides (BNP), both as aprognostic and diagnostic indicator of chronicheart failure (1). This biomarker has beenincorporated in a recent British nationalguidance, which recommends the use of BNP to aid the diagnosis of heart failure (2).Elevated concentrations of BNP (and NT-proBNP) have also been shown to beproportional to the extent of cardiacdysfunction (3,4).

To date, there is no literature on theeffect of chronic lymphedema on thecirculating concentrations of BNP. Moreover,lower limb swelling may make a clinicaldiagnosis of congestive heart failure moredifficult. One set of guidelines on lymphe-dema has recommended the use of BNP inbreathless subjects (5). A systematic review of heart failure management has exposedweaknesses of utilizing clinical features todiagnose heart failure and shown the benefitof BNP over other diagnostic investigationssuch as electrocardiography and chestradiography (6).

We studied a group of unselectedsubjects with lymphedema to determine theirBNP status. The objective was to provideevidence to clarify the potential diagnosticvalue of BNP in individuals with lymphe-dema. We tested the hypothesis that BNP isuseful to screen lymphedema patients forundetected cardiac dysfunction.

METHODS

Consecutive patients with lymphedemawere recruited from a Hospital Trust basedspecialist lymphedema clinic. Inclusioncriteria included age between 18 and 90 yearswith visible limb swelling, and establishedlymphedema defined by one or more of the

following criteria: unilateral limb swelling,>10% excess volume, digit swelling, positiveStemmers sign, shape distortion as measuredby a distal proximal ratio >1.0, or enhancedskin folds. Exclusion criteria were chronicrespiratory disease, liver cirrhosis withascites, acute infection and/or cellulitis orsuspected advanced cancer.

Control data were obtained by collectingredundant blood samples [EDTA samples;n=300 (males 150, females 150)] in a routinelaboratory from subjects with no apparentsuggestion of cardiovascular disease. Detailsof age, gender, clinical details and locationwere used to ensure a comparable group fromwhich to establish a reference range. Plasmasamples were anonymized after collection ofdemographics (age & gender) prior toanalysis (7).

Protocol for Lymphedema Patients

All eligible patients received informationand an invitation to participate with theirfirst appointment letter. Recruitmentoccurred between February 16, 2006, andNovember 10, 2007. All who consentedunderwent a BNP assay and agreed tosubsequent echocardiography in the case ofan elevated BNP, and blood samples wereobtained. Ethical approval was obtained fromthe Leeds West Research Ethics Committee,and signed consent was obtained from alllymphedema participants.

Laboratory Analysis

Blood samples were collected in EDTAcontaining tubes. Plasma was separated andstored at -20°C prior to analysis in a singlebatch. BNP was measured with an immuno-metric assay on Advia Centaur using Centaurreagents according to the manufacturer’sprotocols (Siemens Healthcare Diagnostics,Strawberry Hill, Newbury, UK). The withinbatch coefficient of variation was <2.4% at44, 459, and 1652 ng/L.


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Statistics

Descriptive statistics were used to analysethe range of values within and between bothgroups using the Analyse-it add-in package(version 2.10) for Microsoft Excel (Analyse-it,Leeds, UK. www.analyse-it.com).

RESULTS

A total of 305 subjects with lymphedemawere approached, and 102 (33%) agreed andgave informed consent to participate. Therewere 89 (87.25%) females and 13 (12.75%)males. The mean age was 60.5 ± 13.2 (SD)years with a range of 29 to 89 years.

Of the 102 subjects, 83 (81%) had asecondary lymphedema. 48 had lower limbedema which in 23 patients was a bilateralswelling. 54 had upper limb lymphedema andnone had combined upper and lower limblymphedema. The numbers with a cancer andnon-cancer related swelling were relativelyequal. The mean duration of swelling prior toreferral to the service was 7 years (medianduration 19 years, range 3 months to 39 years).

The control data have been divided intofour groups by gender and age using a cut-offat 60 years. There were 75 subjects in each ofthe four groups. Data on BNP measurementin lymphedema subjects and controls areshown in Table 1.

Seven lymphedema subjects had elevatedBNP concentrations (>100 ng/L, median 120

(19.8) ng/L (see Table 2). Of this number, twohad breast cancer related lymphedema, threehad unilateral leg swelling, and two hadbilateral leg swelling. In both the leg swellingcategories, one of the participants developedswelling following cancer treatment, and theother was a non-cancer referral. A thirdparticipant with unilateral leg swelling hadprimary lymphedema.

Echocardiography was performed onthese subjects, and all of them showed cardiacabnormalities as summarized in Table 2.

DISCUSSION

We have shown that 93% patients with uncomplicated chronic lymphedemahave normal and low BNP concentrationsthat exclude heart failure (7). A subgroup of subjects (7%) had marginally elevatedconcentrations and were referred forechocardiography to clarify cardiac statusand diagnose heart failure. These patients did not have heart failure, but were all notedto have cardiac abnormalities. The presenceof these cardiac abnormalities was sufficientto account for the elevated BNP concen-trations. It is uncertain how these relate tothe BNP status as we did not performechocardiography on the subjects withnormal BNP. Since the biomarker is not anindicator specifically for heart failure, raisedBNP concentrations are not necessarilyindicative of heart failure per se although

TABLE 1BNP Test Results in Lymphedema Patients Compared with Control Subjects


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the risk of heart failure does increase withincreasing BNP concentrations (3,4,8).Further studies might be performed toinvestigate the relationship between totalbody water and BNP in these patients todetermine the intravascular volume. Our data would confirm that BNP can be used as an initial assessment of individuals withlymphedema to screen for concomitantcardiac abnormalities. Patients with bilateralleg swelling are the group that are moreusually associated with an increased

likelihood of heart failure; however, only two with elevated BNP concentrations hadlymphedema in both lower limbs. It was notpossible to predict which group of patientswould be more likely to have elevated BNPbased on the nature and site of swelling inour study. The numbers of participantsinvolved in this study may be too small todemonstrate any tendencies among thepatient groups, and a larger sample sizewould help to identify these relationships.

TABLE 2Echocardiographic Findings in Lymphedema Subjects with Elevated BNP


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Diagnostic tests are used to predictwhether a subject has a disorder. Theiraccuracy will depend on the incidence offalse-positive and false-negative results andthe prevalence of the disease in the groupexamined (9). In the case of BNP, a clinicaldecision threshold is used to stratify patientsinto groups who would benefit from echo-cardiography. Reference intervals are notused in view of the poor specificity of thisapproach as is illustrated by our evaluation of reference intervals. We have therefore usedaccepted cut-off values (10) which can beused to exclude heart failure. These datasuggest that lymphedema treatment includingcompression therapy can be introduced inthose patients with specificity of >95% usingBNP concentration threshold of 100 ng/L (29 pmol/L) using the Centaur BNP assay (9).It should be noted that other analyticalmethods would use different values; forexample, a recent primary care studyproposed a value of 40 ng/L (11.6 pmol/L)using the Biosite Triage assay (11).

The differential diagnosis of leg edema isbased on its duration, painfulness, medicationand presence of systemic disease, knownmalignancy, or sleep apnea. It is likely thatvenous insufficiency will be present in someadults over 50 years with leg swelling.However, if the underlying cause is unclear inthis age group after physical examination, itmay be of use to rule out systemic diseasewith laboratory and/or radiologicalinvestigations. Over recent years, BNP hasbeen widely recognized as a valuable tool toexclude heart failure and is recommended inbreathless patients suspected of having heartfailure (12).

Compression therapies in the form ofgarments or bandages are regularly used inthe treatment of lymphedema to enhance theeffect of skeletal muscle activity and controlcapillary filtration. The use of a multi-layeredbandaging system (known as multi-layerlymphedema bandaging) is a key componentof intensive therapy programs and can resultin large edema volume reductions (13). On

completion of intensive treatment, bandagesare replaced with compression hose which are applied as part of a maintenance or self-management program (14). The type andlevel of compression is determined by anumber of factors including the severity ofthe lymphedema, medical history anddexterity of the patient. Compression levelsrange from 14 mm to >49mmHg (5). Theeffect is to reduce local fluid volume andredistributing blood towards central parts ofthe body (15). These potential fluid shifts canlead to an increase in the preload of the heartand affect cardiac output by up to 5% (16). In addition, the compressive forces also affectthe systemic arterial system, and these canalso unduly raise the cardiac afterload (17)which can be detrimental in heart failure aswell (2). Before instituting compressivetherapy, for lymphedema, it is consideredgood clinical practice to first exclude thepresence of undetected heart failure or occultcardiac dysfunction. The deployment of aBNP measurement is recommended as ascreening method in the following cases:

• in patients over 50 years who are breathless

• in bilateral leg swelling where the cause of the chronic edema is unclear

• if heart failure is suspected

The BNP screening method will identifythose patients who require more detailedcardiac investigations such as echocardio-graphy. BNP concentrations in excess of 100 ng/L (29 pmol/L) should be referred forfurther detailed investigation. Such anapproach would allow a rational and efficientutilization of cardiac investigations.

ACKNOWLEDGMENT

We are grateful to the BritishLymphology Society Caroline BadgerResearch Fund for financial support.

REFERENCES


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1. Daniels, LB, AS Maisel: Natriureticpeptides. J. Am. Coll. Cardiol. 50 (2007),2357-2368.

2. NICE chronic heart failure guideline:The management of adults with chronicheart failure in primary and secondarycare (partial Update). In: NationalClinical Guideline for Chronic HeartFailure. Draft for prepublication check.London: the Royal College of Physicians,June 2010. http://www.nice.org.uk/nicemedia/live/12058/49090/49090.pdf

3. Williams, SG, LL Ng, R O’Brien, et al: Is plasma N-BNP a good indicator of thefunctional REServe of failing hearts? The FRESH-BNP study. Eur. J. HeartFailure 6 (2004), 7, 891-900.

4. Williams, SG, LL Ng, R O’Brien, et al:Comparison of the plasma N-brain natri-uretic peptide, peak oxygen consumption,and left ventricular ejection fraction forseverity of chronic heart failure. Am. J.Cardiol. 93, (2004), 1560-1561.

5. Lymphoedema Framework. Best Practicefor the Management of Lymphoedema.International Consensus. London: MEPLtd, 2006. http://www.activahealthcare.co.uk/lymph/pdfs/lf_best_practice .pdf

6. Mant, J, J Doust, A Raolfe, et al:Systematic review and individual patientdata meta-analysis of diagnosis of heartfailure, with modeling of implications ofdifferent diagnostic strategies in primarycare. Health Technol. Assess. 13 (2009),32.

7. Maisel, A: B-type natriuretic peptidelevels. Diagnostic and prognostic incongestive heart failure: What’s next?Circulation. 105 (2002), 20, 2328-31.

8. Steinhart, B, KE Thorpe, AM Bayoumi,et al: Improving the diagnosis of acuteheart failure using a validated predictionmodel. J. Am. Coll. Cardiol. 54 (2009),1515-1521.

9. Galen RS, SR Gambino: BeyondNormality: The Predictive Value andEfficiency of Medical Diagnoses. JohnWiley & Sons, London. 1975.

10. Wu, AH, M Packer, A Smith, et al:Analytical and clinical evaluation of theBayer ADVIA Centaur automated B-type natriuretic peptide assay in patients

with heart failure: A multisite study.Clin. Chem. 50 (2004), 867-873.

11. Fuat, A, JJ Murphy, APS Hungin, et al:The diagnostic accuracy and utility of aB-type natriuretic peptide test in acommunity population of patients withsuspected heart failure. Br. J. Gen. Pract.56 (2006), 327-333.

12. Ely, JW, JA Osheroff, ML Chambliss, et al: Approach to leg edema of unclearetiology. J. Am. Board Fam. Med. 19(2006), 148-160.

13. Lawenda, BD, TE Mondry, PAJohnstone: Lymphedema: A primer onthe identification and management of achronic condition in oncologic treatment.CA Cancer J. Clin. 59 (2009), 8-24.

14. Partsch, H, M Jünger: Evidence for theuse of compression hosiery in lymphoe-dema. In: Lymphoedema Framework.Template for Practice: CompressionHosiery in Lymphoedema. London, MEPLtd, 2006, 5-9.

15. Christopoulos, DC, AN Nicolaides, G Belcaro, et al: Venous hypertensivemicroangiopathy in relation to clinicalseverity and effect of elastic compression.J. Dermatol. Surg. Oncol. 17 (1991), 809-813.

16. Mostbeck, A, H Partsch, L Peschl:Alteration of blood volume distributionthroughout the body resulting fromphysical and pharmacologicalinterventions. VASA 6 (1977), 137-141.

17. Wilkins MR, Gammage MD, Lewis HM,et al: The effect of lower-body positive-pressure on blood pressure, plasma ANPconcentration and sodium and waterexcretion in healthy volunteers andcardiac transplant recipients. Cardiovasc.Res. 22 (1988), 231-235.

Dr. Jacquelyne ToddLymphoedema DepartmentWharfedale HospitalNewall Carr RoadOtley, West Yorkshire LS21 2LY, UKTel: 00 44 (0) 113 3921807Fax: 00 44 (0) 113 3921806 E-mail: [email protected]


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B-TYPE NATRIURETIC PEPTIDE IN LYMPHEDEMA