Raising the Suspicion of ATTR Through Distinguishing Features

Transthyretin amyloidosis (ATTR) is often overlooked or misdiagnosed in patients due to nonspecific symptoms arising from the multisystem disease. Symptoms and clinical manifestations of ATTR commonly mimic those of more common diseases, making diagnosis particularly complex. Early suspicion of ATTR is key to early diagnosis and treatment, and recognizing differentiating symptoms can raise the suspicion of amyloidosis earlier in the disease course.

Despite patients with ATTR sometimes presenting with predominantly symptoms of cardiomyopathy or polyneuropathy, there can be substantial overlap, with many patients presenting with a combination of both, in addition to other abnormalities, such as orthostatic hypotension, erectile dysfunction, gastrointestinal abnormalities, and unexplained weight loss.

Signs and symptoms that should raise the suspicion of ATTR with cardiomyopathy (ATTR-CM) include right-sided heart failure (HF); HF with preserved ejection fraction; intolerance to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin-receptor neprilysin inhibitors, or beta-blockers; atrial arrhythmias; conduction system disease; and the need for a pacemaker. HF in patients with ATTR also progressively worsens over time, with patients experiencing worsening of diastolic function, decreased left ventricular ejection fraction, increased restrictive filling, and decline in functional capacity. Troponin levels or N-terminal pro‒B-type natriuretic peptide levels are also elevated in these patients and continually increase over time, indicating clinical progression of HF. Carpal tunnel syndrome, the most common noncardiac manifestation in ATTR-CM, often presents years before diagnosis. Other unique manifestations of ATTR-CM include trigger finger, lumbar spinal stenosis, and biceps tendon rupture (also known as Popeye sign). These unique manifestations should raise the suspicion for ATTR.

Early symptoms of ATTR with polyneuropathy (ATTR-PN) include burning pain, numbness, and loss of pain and temperature sensation. As ATTR-PN progresses, muscle weakness increases, especially in the lower limbs; patients often suffer from progressive lower limb numbness and weakness, in addition to imbalance. Key features for distinguishing ATTR-PN from more common diabetic polyneuropathy include its progressive nature and frequently encountered distal limb weakness.

Cardiologists should screen for ATTR in patients with signs and symptoms suggesting multisystem involvement. Given the multisystem nature of ATTR, a multidisciplinary approach is recommended by guidelines. Awareness of the distinguishing features of ATTR may raise the suspicion of disease and prompt referrals to specialized centers. Widespread recognition of these signs and symptoms may allow for earlier recognition and diagnosis of ATTR, in addition to earlier treatment initiation.


Nativi-Nicolau JN, Karam C, Khella S, Maurer MS. Screening for ATTR amyloidosis in the clinic: overlapping disorders, misdiagnosis, and multiorgan awareness. Heart Fail Rev. 2022;27(3):785-793.

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