Approaches for Early Diagnosis of Amyloidosis

The heterogeneity of amyloidosis presentation makes diagnosis challenging. Each type of amyloidosis has a different spectrum of clinical manifestations, diagnostic approaches, therapies, and prognosis. Current disease-modifying therapies reduce the deposition of amyloid but do not deplete preexisting amyloid deposition. Thus, early diagnosis is critical.

Researchers at the University College London, England, recently outlined approaches to diagnosis to assist in the timely identification of amyloid disease and amyloid type, with emphasis on cardiac amyloidosis (CA).

The most common types of amyloidosis are light chain (AL), transthyretin (ATTR), and serum amyloid A (AA). Patients with clonal disorders have a higher risk for AL, whereas patients with chronic inflammatory disorders are at a higher risk for AA.

CA caused by AL should be considered when patients present with rapid-onset heart failure, weight loss and fatigue, symptoms from multiple organs, or clonal disorders. In contrast, ATTR cardiomyopathy more frequently presents as indolent heart failure. ATTR cardiomyopathy is also more common in elderly men and individuals of African ancestry. Other red flags for ATTR cardiomyopathy are a history of carpal tunnel syndrome, spinal stenosis, or tendon rupture. Persistent elevations in the serum biomarkers NT-proBNP and troponin can indicate amyloidosis.

Almost all patients with AL will be positive for plasma-cell dyscrasia by laboratory tests for serum-free AL and serum and urine electrophoresis with immunofixation. Some patients with ATTR cardiomyopathy may have incident clonal disease as well, so positive biochemical findings alone cannot be used to diagnose AL.

CA has some characteristic features on imaging modalities that can raise suspicion of amyloidosis. Echocardiography demonstrating left ventricular hypertrophy >12 mm, particularly with small or normal QRS voltages by electrocardiography, may indicate CA.

The researchers stressed that cardiac magnetic resonance imaging (CMR) and radiotracer bone scintigraphy can be especially useful in determining a diagnosis of CA. CMR will typically show an elevated native T1 signal, increased extracellular volume, and late gadolinium enhancement in CA. Almost all cases of ATTR cardiomyopathy will show cardiac uptake of a radiotracer by bone scintigraphy, but so will approximately 30% of AL-CA cases.

ATTR cardiomyopathy can be diagnosed in most cases when patients with heart failure have amyloid features on echocardiogram, CMR, and radiotracer bone scintigraphy, along with the absence of plasma-cell dyscrasia. Otherwise, a biopsy is needed.

Laser capture microdissection and tandem mass spectrometry using biopsy samples can identify the amyloid type more accurately than immunohistochemistry.

AA-CA is diagnosed by histology, and the cause of inflammation needs to be identified and treated. AA protein should be monitored to assess treatment effectiveness cases.

According to the researchers, clinicians need to be highly suspicious of amyloidosis and knowledgeable about these diagnostic features so that the disease can be diagnosed and treated early to slow organ injury and mortality.

Source: Law S, Gillmore JD. When to suspect and how to approach a diagnosis of amyloidosis. Am J Med. January 23, 2022. Epub ahead of print.

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