Diagnosis and Management of Transthyretin Amyloidosis

Transthyretin amyloidosis (ATTR) may present with neuropathic symptoms or cardiomyopathy. Patients may inherit TTR gene variants (ATTRv) that promote amyloid deposition or develop amyloidosis from the wild-type protein (ATTRwt). Although it has traditionally been thought that ATTRv caused neurologic amyloidosis and ATTRwt caused cardiac amyloidosis, recent evidence has shown that ATTRv and ATTRwt can have overlapping phenotypes.

A team of neurologists and cardiologists recently wrote a guide on the characteristics, diagnostic procedures, and management of ATTR amyloidosis to update clinicians on recent advances.

Characteristics

Mainly produced by the liver, ATTR is a stable tetramer that dissociates to form monomers. Misfolded monomers aggregate into amyloid fibrils and deposit in tissues. The most common TTR gene mutation appears to be Val122Ile (V122I), which causes cardiac amyloidosis. In contrast, patients with a Val30Met (V30M) mutation tend to present with somatic and autonomic neuropathies.

Amyloid deposits of ATTRwt can also be found in different tissues. Autopsy studies have found that elderly men often have ATTR deposition in the heart. However, carpal tunnel syndrome in ATTRwt can present much earlier than cardiomyopathy, particularly in elderly patients. Patients with ATTRwt may also present with spinal canal stenosis and biceps tendon rupture.

Diagnosis

One of the main features of amyloid neuropathy is sensorimotor polyneuropathy with autonomic symptoms, whereas the main feature of amyloid cardiomyopathy is heart failure with preserved ejection fraction.

Neurologists should consider ATTR in patients presenting with bilateral carpal tunnel syndrome, sensorimotor polyneuropathy, dysuria, unexplained weight loss, or ocular symptoms.

Cardiologists should consider ATTR in patients presenting with heart failure with preserved ejection fraction with other signs such as polyneuropathy, carpal tunnel syndrome, low voltage in limb leads or pseudoinfarction pattern on electrocardiogram, or thickened left ventricular wall on echocardiogram.

Further testing will be needed to confirm amyloidosis. A biopsy may be done on affected tissues to view amyloid deposits, followed by immunohistochemistry or mass spectrometry to identify the amyloid type.

In some cases, biopsy may be avoided by using other imaging techniques. For example, reduced left ventricular strain with apical sparing on speckle-tracking echocardiography is typical in cardiac amyloidosis, whether caused by light-chain amyloid or ATTR. Cardiac magnetic resonance imaging can also detect amyloidosis. T1 mapping may be more sensitive than late gadolinium enhancement for ATTRv cardiac amyloidosis. Finally, radiotracer bone scintigraphy has high sensitivity and specificity for ATTR cardiac amyloidosis. When cardiac uptake is equal to or greater than that of bone and no light-chain amyloid is detected in serum and urine, the diagnosis will be ATTR.

Management

Small molecules that stabilize tetramers and liver transplantation are demonstrated in disease-modifying therapies for ATTR. Gene silencing agents are demonstrated in disease-modifying therapies for ATTRv and are in clinical trials for ATTR cardiac amyloidosis.

Patients may have multiple symptoms that require multidisciplinary care, typically from neurology, cardiology, and urology specialists. Of note, ATTRv is also produced in the retinal pigment epithelium and patients who are successfully treated with disease-modifying therapies for ATTRv may still develop visual impairments because of the blood–ocular barrier.

Source: Koike H, Okumura T, Murohara T, Katsuno M. Multidisciplinary approaches for transthyretin amyloidosis. Cardiol Ther. 2021;10:289-311.

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