Common Signs and Symptoms
Amyloidosis can smolder subclinically for years to over a decade. Some amyloidosis manifestations reach clinical significance but often are attributed to other causes and are not investigated for amyloidosis. Restrictive cardiomyopathy with diastolic heart failure and dilated cardiomyopathy with systolic heart failure are some of the final amyloidosis manifestations in the disease cascade. The progression of symptoms and involved organs varies by the subtype of amyloidosis. Generally, AL symptoms are more varied and are specific to the organ systems involved. ATTRwt tends to have primarily musculoskeletal and cardiac involvement. In ATTRv, the phenotype can range from neuropathy predominant, cardiac predominant, or a mixed phenotype.
Skin: Easy bruising can accompany amyloidosis. In AL amyloidosis, periorbital purpura is a pathognomonic sign that should prompt diagnostic testing.
The earliest initial symptoms of amyloidosis are often musculoskeletal. Amyloid deposits can build up in the transverse carpal ligament and impinge on the median nerve, resulting in carpal tunnel syndrome. If these deposits build up in the ligamentum flavum of the spine, patients can present with back pain and radiculopathy from lumbar spinal stenosis. Biceps tendon rupture can also occur with amyloid deposition. A high rate of knee and hip replacements has been noted in amyloidosis.19 ATTR
seems to have high rates of musculoskeletal complaints, and these can present 5 to 15 years prior to cardiac manifestations.
Gastrointestinal: Indigestion, gastroesophageal reflux, gastrointestinal immobility, constipation, and diarrhea can all be related to amyloid deposition. An enlarged tongue can also be present. These symptoms are seen most commonly in patients with AL and some variants of ATTRv (specifically T60A, G89Q). When these symptoms are present, they can be prominent and significantly affect quality of life. Patients often seek gastrointestinal specialty care and undergo endoscopy or colonoscopy, at which time tissue from these procedures can be screened for amyloid deposits.
Renal: The kidneys are frequently affected by systemic amyloidosis. Patients with AL can initially present with nephrotic syndrome with or without renal dysfunction. Amyloidosis frequently is diagnosed after renal biopsy. Other patients with less severe deposition may have an elevated creatinine because of reduced glomerular filtration rate.
Nervous system: In addition to nerve compression from thickened ligaments, patients can develop peripheral and autonomic neuropathy. Often the etiology of peripheral neuropathy is not investigated. Some patients with amyloidosis have been on gabapentin for years, but are not diagnosed with amyloidosis until cardiac symptoms develop. If a patient has underlying diabetes, the degree of neuropathy is often out of proportion and more rapidly progressive than otherwise anticipated. Neuropathy can also manifest as erectile dysfunction and sweating abnormalities. For patients that develop autonomic neuropathy, the most prominent symptom is orthostatic hypotension. The first sign of autonomic neuropathy may be improvement of their baseline hypertension that may no longer require antihypertensive medications. For many amyloidosis patients, neuropathy is the most prominent symptom. Neuropathy is common in AL and certain variants of ATTRv (Val-30Met). Peripheral neuropathy is less common in ATTRwt.
Early progression of amyloid heart disease is subclinical and subtle. Amyloid cardiomyopathy becomes more prominent as the disease progresses. Patients can present with mild dyspnea on exertion, fatigue, and exercise intolerance. These symptoms can be accompanied by angina, likely related to coronary microvascular dysfunction. Almost all patients with cardiac amyloidosis (>95%) had significantly reduced peak stress myocardial blood flow (<1.3 mL/g/min).20
When the conduction system is involved, arrhythmias, bundle branch block, and sinoatrial disease are common. Patients can also present at later stages with heart failure. Most often, patients have heart failure with preserved EF. Yet many patients can present with mildly reduced ejected fraction. In end-stage amyloid cardiomyopathy, severely reduced EF with dilated cardiomyopathy can be seen. Common cardiac tests can reveal signs of amyloidosis and should prompt diagnostic testing. A single normal cardiac test should not stop pursuit of diagnostic testing if clinical suspicion is otherwise present.
In the early stages of the disease, a patient may have no obvious abnormalities on echocardiogram—particularly for AL. Subsequently, the heart develops concentric remodeling or mild left ventricular hypertrophy (Figures 30.1A
). As the disease progresses, the walls become thicker and the patient develops diastolic dysfunction. On longitudinal strain imaging, apical sparing can be present (“cherry red spot”) (Figures 30.2A-C
). Next, the patient develops an infiltrative phenotype with biventricular concentric hypertrophy, valve thickening, interatrial septal thickening, and pericardial effusion. The left ventricle is often described as having a granular sparkling pattern, although this is neither sensitive nor specific for cardiac amyloidosis and is dependent on the imaging technique. Severe diastolic dysfunction with restrictive physiology ensues. Eventually, the patient develops systolic dysfunction with a nondilated left ventricle. Special attention should also be paid to patients with paradoxical low-flow/low-gradient aortic stenosis that is accompanied by a right ventricular thickening.
In early stages of amyloidosis, the ECG
is unremarkable (Figure 30.1B
). Even in patients with amyloid cardiomyopathy, the ECG
can be unremarkable, particularly in those with ATTRwt. When they do occur, the initial changes can be a mild first-degree atrioventricular block. As the left ventricle thickens, there is no commensurate increase in voltage on ECG
; the voltage remains normal. A pseudo-infarct pattern of Q waves unrelated to prior myocardial infarction is common. Only in late stages of the disease is the classic sign of low QRS voltages in the limb leads sometimes present (Figure 30.3
). Atrial fibrillation is common in amyloid cardiomyopathy and can present in early or late stages of the disease. Complete heart block and the need for a pacemaker can also occur at late stages.
FIGURE 30.1 Cardiac tests in early amyloid cardiomyopathy. A: Transthoracic echocardiogram showing concentric remodeling on the parasternal long axis view. B: Normal electrocardiogram in a patient with biopsy proven amyloid cardiomyopathy with no evidence of low voltages, a classic amyloidosis red flag.
FIGURE 30.2 Transthoracic echocardiogram red flags in late amyloid cardiomyopathy. A: Parasternal long axis view demonstrating thick right ventricular walls, thick left ventricular walls (1.5 cm), and granular sparkling appearance of the myocardium. B: Four chamber view demonstrating thick mitral and tricuspid valves and thick interatrial septum. Pericardial effusion, another red flag, is not seen in this example.
FIGURE 30.2 (continued) C: Global longitudinal strain demonstrating apical sparing, also known as “cherry on top” sign.
FIGURE 30.3 Electrocardiogram red flags in late amyloid cardiomyopathy. Electrocardiogram demonstrating low voltage in limb leads and normal voltage in the lateral leads despite known left ventricular hypertrophy.
Cardiac magnetic resonance imaging (CMR):
, amyloidosis in the heart is seen as diffuse subendocardial or transmural late gadolinium enhancement. The extracellular volume is increased (typically >0.4). The native T1 can be elevated greater than 1100 ms with difficulty, nulling the myocardium (Figure 30.4A-C
Troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP
) are useful biomarkers in amyloid cardiomyopathy.
In early stages, both tests are normal. As diastolic dysfunction develops, the NT-proBNP
elevates commensurate with heart failure with preserved EF. In later stages of the disease, the troponin can be persistently, mildly elevated with little change on repeat testing.
red flags in late amyloid cardiomyopathy. A:
Native T1 is >1100 ms. B:
Diffuse late gadolinium enhancement.
FIGURE 30.4 (continued) C: Extracellular volume >27% in the short axis view. LV, left ventricle.