Amyloidosis is due to pathogenic processes in which normal or mutated proteins are transformed and deposited in various organs and tissue as extracellular, insoluble fibrils (1) – (3). These cause characteristic histological changes that can be detected in tissue samples with the aid of light microscopy of special stained sections (1) – (3). There are 27 different proteins in humans that can be transformed to amyloids (3). The type of amyloid precursor protein largely determines which tissues or organs are primarily affected (1) – (3). The two most common causes of amyloid deposition in the heart are overproduction of monoclonal light chain immunoglobulins (AL amyloidosis) and transthyretin-related disease (familial and senile type), but rare variants of fibrinogen and apolipoproteins A-I and A-II have also been described as potential causes of the disease (2). Family transthyretin cardiac amyloidosis is due to transthyretin mutations and believed to be very rare in Norway. Senile cardiac amyloidosis is due to deposition of normal transthyretin proteins (1). In unselected autopsy material from persons aged at least 80, 25 % of the individuals displayed amyloid deposition of normal transthyretin in the heart (4), but in the majority this deposition will not be sufficient to affect the heart function. However, cardiac amyloidosis should be especially suspected in elderly men with biventricular heart failure and thickened myocardium without other cause, and the condition is suspected to be considerably underdiagnosed (2, 5).
Amyloid deposition in the heart is conducive to restrictive cardiomyopathy with the development of heart failure. Electrocardiography is a key early examination for determining both the causes and the degree of heart failure. Characteristic findings in connection with cardiac amyloidosis are biventricular thickened walls with a good ejection fraction (5, 6). The left ventricular cavity has normal or reduced dimensions, and where cavity dimensions are reduced (secondary to wall hypertrophy) the ventricle tends to be hypercontractile radially. Conversely, the longitudinal contractility of the ventricle is reduced already at an early stage of the disease. The ventricular ejection fraction only decreases at a late stage. Progressive diastolic dysfunction is a general finding (7). Other common findings with cardiac amyloidosis are enlarged atria, mild to moderate pericardial fluid accumulation, myocardium with a pronounced granular expression, thickened atrial septum and thickened papillary muscles and valve leaflets (6). The echocardiographic findings in connection with advanced cardiac amyloidosis clearly indicate the presence of the disease and help to distinguish it from possible differential diagnoses such as Fabry disease, hypertrophic cardiomyopathy and secondary hypertrophy in connection with hypertension (6, 8). A correct diagnosis is important for the prognosis and choice of therapy.
Various ECG changes will tend to occur with cardiac amyloidosis. The QRS complexes often show a distinctly reduced amplitude (low voltage) in the extremity leads (6). The combination of ventricular hypertrophy as indicated by echocardiography and a small QRS amplitude strengthens suspicion of this disease (9). However, this ECG finding is not a sine qua non for this condition, and in a large study of 127 patients with biopsy-confirmed cardiac amyloidosis, a small QRS amplitude was found in only 47 % of the patients, whereas an assessment of the patients’ QRS complexes revealed hypertrophy criteria in 16 % (10). Particularly when the causes are transthyretin-related, the reduced QRS amplitude feature may be absent (5). Other common ECG findings with the condition are abnormal right or left deviation of the heart axis, pseudoinfarction changes, conduction disturbances and atrial fibrillation (2, 6, 10). However, no ECG changes are pathognomonic for this condition. Our patient’s ECG did not show a low QRS amplitude, but did show incipient conduction disturbances in the AV node and pseudoinfarction changes in the anterior and lateral walls (Fig. 1). There is reason to believe that the patient’s sick sinus node and increasing AV node blockages were related to the cardiac amyloidosis.
Different indicators have been used for scintigraphic detection of amyloidosis in different organs (2, 11). A recent study showed that scintigraphy with 99mTc-DPD identified transthyretin cardiac amyloidosis with very high sensitivity and specificity (11) (Fig. 3). With various kinds of cardiac amyloidosis, magnetic resonance imaging will typically show diffusely enhanced late uptake of gadolinium in the myocardium, most pronounced subendocardially (12, 13). Cardiac amyloidosis can be histologically confirmed by means of a cardiac biopsy, and findings of amyloid deposits in biopsies from other organs such as the rectum will indirectly confirm the diagnosis (2). However, biopsies from extracardiac organs have a low sensitivity for detection of transthyretin cardiac amyloidosis (14). Further tests (immunohistochemical analyses of the amyloid, DNA analyses etc.) may show which type of amyloidosis is present (2).
The heart is the predilection site for amyloid deposition in senile transthyretin-related amyloidosis. In this type of amyloidosis, deposition may also occur among others in the lungs, gastrointestinal tract and liver (2, 14). However, deposition of amyloid in the kidneys is indicated as being unusual in senile cardiac amyloidosis, but impaired renal function will often occur when the heart’s pumping function has been significantly impaired (2). The extracardiac amyloid deposits may result in carpal tunnel syndrome, orthostatism and intestinal dysmotility disorders (2, 14). Our patient did not suffer from these. The cause of the renal failure was not studied further, and we suspect it to be largely secondary to the impaired heart function.
With cardiac amyloidosis, the transthyretin-related forms have a better prognosis than AL amyloidosis (5, 14). However, once heart failure has developed, the prognosis is poor irrespective of the type of amyloidosis (15). Heart failure is treated according to the usual guidelines, with the emphasis on diuretics and fluid restriction (6, 8). Caution is recommended in the use of ACE inhibitors and angiotensin 2-receptor blockers because these patients easily develop hypotension when using these types of drugs, particularly patients with AL amyloidosis (6, 8). Digitalis drugs bind easily to amyloid fibrils with subsequent danger of intoxication, and these drugs are therefore not recommended for this condition (16). Liver transplantation possibly combined with heart transplantation may be one possibility for familial transthyretin-related amyloidosis, and heart transplantation may be considered with AL amyloidosis after aggressive treatment of the primary disorder (8).
Revealing the causes of heart failure is important for the choice of treatment and assessment of the prognosis. In our patient, arterial hypertension was probably not the causal factor behind progressive heart failure, as was initially believed. On the contrary, the echocardiogram showed changes that are distinctive for cardiac amyloidosis (Fig. 2). Further tests yielded no evidence of AL amyloidosis, while the 99mTc-DPD scintigram showed myocardial changes consistent with transthyretin-related cardiac amyloidosis (Fig. 3). There was no familial occurrence of heart failure, and the patient probably had the far more common senile form of transthyretin-related disorder. Representative biopsies might have provided further confirmation of the disease. However, extracardiac biopsies have a low sensitivity for transthyretin-related amyloidosis. Referring our patient to a university hospital for a heart biopsy appeared unnecessary since the echocardiogram and scintigram findings made us sure of our diagnosis. Any biopsy findings would hardly have changed our treatment of this sick patient.