cardiac amyloidosis – an easy, but usually delayed diagnosis7)_no1/2009_vol4(… · mædica a...

Mædica A Journal of Clinical Medicine, Volume 4 No.1 200946

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Cardiac amyloidosis – an easy,but usually delayed diagnosisR. SILISTE, MDa; I. CALANGEA, MDa; F. VOINEA, MDa; I. SAVULESCU-FIEDLER, MD, PhDa;M. GHERGHICEANU, MD, PhDb; D. ISACOFF, MD, PhDa

aInternal Medicine and Cardiology Department, “Coltea” Clinical Hospital,Bucharest, RomaniabINCD “Victor Babes”, Bucharest, Romania

ABSTRACTAmyloidosis is a group of rare diseases in which a specific protein is deposited as aggregated interstitial

fibrils that can compromise organ function and lead to death. More than 20 proteins form clinicallyrelevant amyloid deposit. Primary amyloidosis consists in deposition of immunoglobulin light chains(AL). Secondary amyloidosis is due to excess of nonimunoglobulinic proteic material deposits (AA). Thecommon clinical presentation form is the association between nephrotic syndrome, hepatomegaly, peripheralneuropathy, gastrointestinal tract involvement and heart failure.

Cardiac involvement appears frequently in the end stage and it’s very seldom as the only manifestationof the disease. The cardiac amyloidosis has a very poor prognosis.

We present the case of a 54 year old patient admitted to our clinic for exertional dyspnoea, massiveedemas and repetitive syncope. Although the patient was extensively investigated (including diagnosticlaparoscopy), the key of diagnosis was the association between nephrotic syndrome, the ECG aspect andechocardiographical changes suggestive of an infiltrative cardiomyopathy, besides neuropathy andgastrointestinal tract disorders.

The purpose of our presentation is to stress the importance of the correlation between ECG changes andthe ultrasonography in order to diagnose an infiltrative cardiopathy. These findings, besides the extracardiacbiopsies, are an important tool in the diagnosis of the cardiac amyloidosis. The biopsy of subcutaneous fattytissue is a new, highly sensitive method with sensitivity 73% and specificity 90%, so that it can be used asa screening test in patients without any clinical symptom or organ dysfunction. Although the classicalhistological diagnosis is made by Congo red stains, the sensitivity of the diagnosis is higher by usingnegatively stained electron microscopy.

Key words: cardiac amyloidosis, delayed diagnosis

CCCCCASEASEASEASEASE REPORTSREPORTSREPORTSREPORTSREPORTS

Mædica - a Journal of Clinical Medicine

Address for correspondence:Roxana Nicoleta Siliste, MD, „Coltea“ Clinical Hospital, 1 IC Bratianu Blvd., District 3, Bucharest, Romaniaemail address: [email protected]

Mædica A Journal of Clinical Medicine, Volume 4 No.1 2009 47

CCCCCARDIAC AAAAAMYLOIDOSIS – AAAAAN EEEEEASY, BUT UUUUUSUALLY DDDDDELAYED D D D D DIAGNOSIS

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BACKGROUND

The AL form of systemic primary amyloido-sis is caused by excessive production of im-

munoglobulin light chains and their depositionin different tissues, as muscles, connective tis-sue, vessels and peripheral nerves. Depositiongenerally leads to organ failure and death, witha median survival of 20 months. The commonclinical presentation form is an association be-tween nephrotic syndrome, infiltrative cardi-omyopathy, hepatosplenomegaly, gastrointes-tinal and peripheral nerves involvement.

If the ECG and echocardiography findingssuggest the presence of an infiltrative cardiomy-opathy the diagnosis of amyloidosis may beconfirmed by subcutaneous fat sampling. Thistechnique requires no additional invasive pro-cedure and confers no extra risk for the pa-tient. Confirmation of amyloidosis providesimportant prognostic information and may al-low specific treatment. The most useful tool inthe positive diagnosis of amyloid fibrils is thenegatively stained electron microscopy exam.Although the classical histological diagnosis ismade by staining with Congo red and exami-nation under polarized light, the sensitivity ofthe diagnosis is higher by using negatively stainedelectron microscopy.

The rarity of the disease and the variableinvolvement of different organs and tissues areoften responsible for missed or delayed diag-nosis, and amyloidosis remains a considerableclinical challenge.

CASE REPORT

A 54 year old male patient was admitted forexertional dyspnoea, massive edemas and

repetitive syncope. He had multiple hospitalpresentation within the last 6 months for im-portant weight loss, progressive asthenia, gas-trointestinal (dyspepsia, bowel motility distur-bances) and neurological complains. Superiordigestive endoscopy, abdominal computed to-mography and laparoscopy were performedand the diagnosis was perivisceritis with func-tional duodenal stenosis. Because he describedduring this time neurological disturbances,namely peripheral sensitive neuropathy andsevere orthostatic hypotension, a neurologicalexam with MRI and EMG was performed. Alumbar neuroforamen stenosis was diagnosedat that time.

Physical examination on admission showedpallor, massive hypoproteinemic edemas, bi-lateral pleural effusion, blood pressure.: 100/60 mmHg with orthostatic hypotension (70/40mmHg), heart rate: 75/min, mitral and tricus-pid regurgitation murmur, hepatosplenomegaly.

Anaemia, hypoalbuminemia and nephroticproteinuria was revealed by lab tests. Serumprotein electrophoresis showed a monoclonalimmunoglobulin component.

An ECG showed low voltage, first degree AVblock, left axis deviation and QS in V1-V3, DII,DIII, aVF and poor R progression in V4-V6 (FIG-URE 1).

The 24 hours ECG Holter monitoring re-corded nonsustained ventricular tachycardiaduring an episode of syncope (FIGURE 2).

An echocardiogram showed typical featuresof restrictive cardiomyopathy: thickening of theleft ventricular walls (interventricular septum 1.5cm and posterior wall 1.4 cm thick), biatrialenlargement with mitral and tricuspid regurgi-tation, normal ventricular diameter and restric-tive pattern of transmitral flow (FIGURE 3). Weperformed abdominal fat biopsies and thenegatively stained electron microscopy examcertified amyloid fibrils (FIGURE 4,5).

Additional haematological tests (immuno-electrophoresis, bone marrow biopsy specimenand flow citometry) excluded multiple mielomaand confirmed lambda chains Ig M monoclonalgammopathy. The patient started standard im-munosuppressive therapy (intravenousmelphalan and dexametasone, 9 cycles) with aregression of the nephrotic syndrome and a cer-tain improvement in clinical status. For the lifethreatening arrhythmia he received therapywith amiodarone. The patient survived 10month after diagnosis.

DISCUSSION

Amyloidosis is a group of rare diseases inwhich a specific protein is deposited as aggre-gated interstitial fibrils that can compromise or-gan function and lead to death. More than 20proteins form clinically relevant amyloid deposit.Primary amyloidosis consists in deposition ofimmunoglobulin light chains (AL). This disor-der occurrs at an incidence of 9 per million peryear which is about 1/5 common as multiplemyeloma. Secondary amyloidosis is due to ex-cess of nonimunoglobulinic proteic materialdeposits (AA). (1-3) The common clinical



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FIGURE 1. ECG on admission: low QRS voltage, pseudoinfarction pattern in anterior and inferior region

presentation form is the association betweennephrotic syndrome, hepatomegaly, peripheralneuropathy, gastrointestinal tract involvementand heart failure.

Cardiac amyloid is always a manifestationof systemic amyloidosis, and the significance andprognosis depend greatly on the amyloid fibriltype (4). Monoclonal immunoglobulin lightchain amyloidosis is the most serious and fre-quently diagnosed form of cardiac amyloid, butcardiac amyloid derived from wild-type trans-thyretin,(nonimunoglobulinic protein) whichoften causes no symptoms, occurs in about onequarter of very elderly people (5).

When cardiac amyloid is present and symp-tomatic, mean survival is less then 8 months.The cardiac manifestations of primary amyloi-dosis are thought to be largely due to interstitialdeposition within the ventricles, which, in turn,may cause restrictive hemodynamics as well as

conduction disturbances (6). Our patient had alsoventricular arrhythmia and this add an additionalrisk for sudden cardiac death in this case.

The key of the diagnosis in this case was thecorrelation of the echocardiography that revealsnormal contractions of the ventricular walls withthe ECG findings compatible with a pseudo-infarction pattern (7). On the other hand, wenoticed the discrepancy between the relativelow voltage of the QRS complex and the hy-pertrophy showed by ultrasonography. Thediagnosis is strongly supported by the associa-tion of a restrictive cardiomyopathy pattern withnephrotic syndrome and neurological and gas-trointestinal involvement.

It is rarely necessary to perform endo-myocardial biopsy, and histology is usually ob-tained from an abdominal fat biopsy – the char-acteristic apple green birefringence seen whenthe tissue is stained with congo red and viewed



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FIGURE 2. ECG Holter monitoring: Nonsustained ventricular tachycardia



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FIGURE 3. Transtoracic parasternal long axis: walls hipertrophy, with a granularappearance

FIGURE 4, 5. Abdominal fat biopsy: Electron microscopy: A: small amyloid fibrils E: Epidermal layer,SMC: Smooth muscle cells

under polarised light is diagnostic for systemicamyloidosis. Congo red staining for amyloid is nota very sensitive test and requires an adequateamount of amyloid, sufficiently thick tissue sec-tions, technically correct staining and visualizationprocedures, and adequate observer experience.In this case the congo red staining was negative,but the fibrils were easily observed in negativelystained electron microscopy, a more sensitive toolsused in the diagnosis of amyloidosis (amyloid fibrilsare usually about 10 nm diameter, straight, rigid,nonbranching, of indeterminate length, and com-posed of twisted protofibrils) (8,9).

After a positive tissue biopsy is obtained andif there is no family history of amyloidosis, ALamyloidosis is considered first as it is the mostcommon type. A search for a clonal plasma celldyscrasia is the first step. Monoclonal immuno-globulins or light chains are detected in 90% ofAL patients by means of immunofixation elec-trophoresis of serum and urine, a more sensi-tive technique than simple protein electrophore-sis. When there is no evidence of a plasma celldyscrasia, consideration should be given to an-other form of amyloidosis (10-12).



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3. Mark B – Pesys Amyloidosis Annu RevMed 2006; 57:223-241

4. Spyrou N, Foale R – Restrictivecardiomyopathies. Curr Opin Cardiol1994; 9:344

5. Pepys MB, Hawkins PN – Amyloi-dosis. In Oxford Textbook ofMedicine, ed.DA Warrell,TMCox, JDFirth, EJ Benz, Jr., 2003; pp.162-73,Oxford, UK: Oxford Univ. Press.

6. Murtagh B, Hammill SC, Gertz MA,et al – Electrocardiographic findingsin primary systemic amyloidosis andbiopsy-proven cardiac involvement.Am J Cardiol 2005 Feb 15; 95(4):535-7

7. Batrani M, Marwah S, Buxi G, et al– Infiltrative cardiomyopathy due toAL amyloidosis. Indian J PatholMicrobiol 2008 Oct-Dec; 51(4):566-568

8. Cohen AS, Calkins E – Electronmicroscopic observations on a fibrouscomponent in amyloid of diverseorigins. Nature 1959 Apr 25;183(4669):1202-1203

9. Puchtler H, Sweat F, Levine M – Onthe binding of Congo red by amyloid.J Histochem Cytochem 1962; 10:355-364

10. Bradwell AR, Carr-Smith HD, MeadGP, et al – Highly sensitive, auto-mated immunoassay for immunoglo-bulin free lightchains in serum andurine. Clin Chem 2001; 47:673-680

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