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BMJ Case Rep. 2010; 2010: bcr0220102767.
Published online 2010 October 8. doi:  10.1136/bcr.02.2010.2767
PMCID: PMC3027836
Rare disease

Amyloid disease and the danger of late diagnosis

Abstract

An 84-year-old man was admitted with a 1-year history of recurrent falls, diarrhoea and haemoptysis. He described a poor appetite for a number of years and over the last 9 months had experienced dysphagia with worsening anorexia and significant weight loss of 25 kg over the last 6 months. His deteriorating condition was compounded by ongoing type II diabetes mellitus and a past history of treated pulmonary tuberculosis, 40 pack-years of cigarette use and prostate cancer treated with radiotherapy. Ten days later he developed complete heart block and required a temporary pacemaker. The patient had a cardiac arrest due to electromechanical dissociation and died within 14 days of this admission.

The diagnosis of amyloidosis was only established after an autopsy provided tissue for histochemical analysis. Amyloidosis is frequently diagnosed late in the disease course, with catastrophic consequences, particularly in the case of amyloid cardiomyopathy.

Background

Amyloidosis is caused by the extracellular deposition of misfolded and largely insoluble aggregated proteins. Because light chain (AL) amyloid can accumulate in virtually all organs, it may present to any specialist with very non-specific symptoms. When diagnosed late, the outcome is extremely poor. Many patients will often not survive long enough to receive an adequate dose of chemotherapy or have sufficient reserves to undergo ‘curative’ bone marrow transplantation. Cardiac involvement is of particular concern, being associated with the worst prognosis.

Case presentation

An 84-year-old man was admitted with a 1-year history of recurrent falls, diarrhoea and haemoptysis. He also had significant weight loss of 25 kg over 6 months associated with anorexia. His past medical history included type II diabetes mellitus and pulmonary tuberculosis. On examination he appeared frail with multiple bruises on the arms and head. A macular rash on the upper chest and peri-orbital bruising were noted. The pulse was 80 beats per minute and regular. A marked postural drop in blood pressure (126/73 mm Hg to 76/43 mm Hg) was documented. The jugular venous pressure was elevated and there was bilateral pitting oedema to the shins.

Over the following 3 days, several episodes of marked bradycardia occurred which included 3–4 s pauses. The electrocardiogram (ECG) showed new first degree heart block. Elective permanent pacing was delayed due to a temperature and C reactive protein (CRP) rise. On the third day, complete heart block developed with an inadequate ventricular escape rate.

Investigations

Blood tests revealed a normocytic anaemia and a mild rise in ALP (152 U/l; normal range 32–120). Stool samples were negative on culture. An electrocardiogram (ECG) showed sinus rhythm with extreme low voltage (<0.5 mV) in all the limb leads (figure 1). Q-waves were evident in the inferior and anterior leads, although there was no record of prior myocardial infarction. Thoracic and upper abdomen computer tomography showed bibasal effusions and no obvious malignancy. Bronchoscopy, colonoscopy and oesophogastroduodenoscopy were performed, to explore the cause of haemoptysis and change in bowel habit, respectively, and were all normal. Computer tomography of the brain was unremarkable. Echocardiography noted concentric left ventricular ‘hypertrophy’ (mean wall thickness 15 mm; normal range 6–12 mm), moderate bi-ventricular impairment (left ventricular ejection fraction of 45%) and a restrictive filling pattern on the mitral valve inflow Doppler (E:A ratio of 4). Both atria were significantly dilated (figure 2). The pulmonary artery systolic pressure, assessed by Doppler, was elevated at 38 mm Hg, plus the jugular venous pressure (10 mm Hg).

Figure 1
Electrocardiogram showing sinus rhythm with marked first degree atrioventricular (AV) block, extreme low voltage (mean 0.2 mV) in the limb leads and Q-waves in both the inferior and anterior leads (a pseudo-infarction pattern). T-waves are also flattened ...
Figure 2
Subcostal four-chamber echocardiographic view showing thickening of the interventricular septum and papillary muscles, the right ventricular free wall and dilatation of the left atrium. The ventricular cavities are not dilated. The double headed arrows ...

Treatment

With the development of complete heart block, immediate external pacing was commenced and a temporary transvenous pacing wire was positioned. Permanent pacing was arranged but while being stabilised, electromechanical dissociation developed.

Outcome and follow-up

Despite resuscitation the patient died.

A limited thoracic postmortem examination revealed concentric bi-ventricular wall thickening, bi-atrial dilatation and premortem thrombus in the right atrial appendage. The temporary pacing wire was well positioned. The right-dominant coronary artery was severely atheromatous with only mild non-stenosing atheroma in the remainder of the coronary artery tree. Extensive myocardial vascular and interstitial amyloid deposition was confirmed on Congo red straining with red-green birefringence on cross-polarisation (figure 3). Small deposits of amyloid were also noted in epicardial coronary arteries. There was also extensive deposition of amyloid in smaller pulmonary veins and arteries. Immunohistochemistry supported immunoglobulin light chains of the λ-subtype, confirming the diagnosis of AL amyloid.

Figure 3
Cardiac amyloid deposition. (A) There is pink smudging of the walls of the intramyocardial arteries and interstitial amyloid surrounding and compressing individual myocytes (haematoxylin-eosin×100). (B) Congo Red staining viewed under cross-polarised ...

Discussion

This is a case of AL amyloid where the aggregating protein is an immunoglobulin light chain produced by a clonal population of plasma cells in the bone marrow. It can be associated with multiple myeloma. Half of all AL amyloid patients will have cardiac involvement of whom many develop heart failure.1

Low voltage (QRS voltage amplitude ≤0.5 mV in all the limb leads) is a common feature in cardiac amyloid. It reflects the fact that increasing myocardial thickness is due to an inert substance (amyloid) rather than viable myocardium. Typically, there is also a ‘pseudo-infarction’ pattern with Q-waves. Echocardiography provides a non-invasive assessment of cardiac involvement. Early deposition causes impaired cardiac relaxation, or ‘diastolic impairment’ with normal or only mildly reduced systolic function. Disease progression leads to thickened walls with poor compliance and restrictive physiology on echo Doppler studies. Characteristically, the ventricles retain normal dimensions but there is bi-atrial dilatation. With further protein accumulation, myocytes are lost, leading to additional systolic dysfunction. It is the combination of low voltage on the ECG and thick walls on echocardiography (a reduction in voltage:mass ratio) that provides the earliest clue that the heart is involved with amyloid deposition.

Atrial amyloid deposition can cause mechanical standstill with significant risks of atrial fibrillation and thrombus formation as occurred in our patient. Pulmonary involvement causes pulmonary hypertension and cor pulmonale leading to a very poor prognosis.

Alongside such cardiac investigations, serum and urine electrophoresis will aid the diagnosis with bone marrow biopsy required to identify the plasma cell clone.

The conduction system of the heart is also affected. Electrophysiological assessment in AL cardiomyopathy has shown abnormal prolongation of infra-His conduction times, predictive of death.2 This abnormality was present even when the QRS duration on the surface ECG was normal and this likely reflects extensive amyloid infiltration of the distal conduction system as well as fibrosis. Such subjects had a propensity for complete heart block and bradycardic death, often resulting in electromechanical dissociation.2

Other authors have described complete heart block and consequent asystole despite well placed pacing leads.3 Thus, while pacing improves symptoms, it does not appear to improve survival.4 The clinical value of biventricular pacemakers or implantable cardiac defibrillators is also questionable.5

Cardiac amyloid is a progressive disorder and is usually treated with conventional heart failure therapies with a focus on salt restriction and diuretics.6 Caution is required with digoxin because it binds avidly to the amyloid fibrils leading to toxicity. Ace inhibitors and angiotensin-receptor blockers have limited benefit in diastolic heart failure and may be poorly tolerated due to profound hypotension. Early diagnosis is key, with the aim of targeting the plasma cell responsible for the proliferation of light chains. Chemotherapy with prednisolone and melphalan is used, followed by autologous stem cell transplantation.6 7 A multidisciplinary approach is essential in the management of this aggressive systemic disease.

The profound postural hypotension and intermittent bradycardia would account for the falls experienced by our patient. This case highlights the features of late presentation cardiac AL amyloid and demonstrates the very poor prognosis associated with significant cardiac involvement.

When diagnosed late in the course of their disease, the patient will not be clinically eligible to undertake the required intensive chemotherapy necessary to cure this aggressive disease.

Learning points

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Amyloid disease may prove difficult to diagnose due to the multiple ways in which it can present and its relative rarity.
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An early diagnosis is paramount, to allow time to institute ‘curative’ therapies.
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In a patient with congestive heart failure and particularly right heart failure in whom systolic function appears adequate, the echo should be carefully examined for diastolic dysfunction and in the case of amyloid cardiomyopathy, a restrictive physiology.
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The combination of low voltage on the ECG and thick walls on echocardiography should alert the physician to the possibility of amyloid heart disease.
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The presence of Q-waves on the ECG, in the absence of any history of myocardial infarction, should raise suspicion as to the presence of amyloid infiltration.

Footnotes

Competing interests None.

Patient consent Obtained.

References

1. Desai HV, Aronow WS, Peterson SJ, et al. Cardiac amyloidosis: approaches to diagnosis and management. Cardiol Rev 2010;18:1–11. [PubMed]
2. Reisinger J, Dubrey SW, Lavalley M, et al. Electrophysiologic abnormalities in AL (primary) amyloidosis with cardiac involvement. J Am Coll Cardiol 1997;30:1046–51. [PubMed]
3. Ogano M, Takano H, Fukuma N, et al. Sudden death in a case of cardiac amyloidosis immediately after pacemaker implantation for complete atrioventricular block. J Nippon Med Sch 2005;72:285–9. [PubMed]
4. Mathew V, Olson LJ, Gertz MA, et al. Symptomatic conduction system disease in cardiac amyloidosis. Am J Cardiol 1997;80:1491–2. [PubMed]
5. Wright BL, Grace AA, Goodman HJ. Implantation of a cardioverter-defibrillator in a patient with cardiac amyloidosis. Nat Clin Pract Cardiovasc Med 2006;3:110–4; quiz 115. [PubMed]
6. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112:2047–60. [PubMed]
7. Dispenzieri A, Lacy MQ, Kyle RA, et al. Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. J Clin Oncol 2001;19:3350–6. [PubMed]

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