Fast Five Quiz: ATTR-CM Presentation and Diagnosis

Medscape

17-06-2025

Transthyretin amyloid cardiomyopathy (ATTR-CM) presents with a diverse range of symptoms involving the cardiovascular and peripheral systems. The clinical manifestations of ATR-CM are typically related to the location of amyloid fibrils in various tissues. In individuals with hereditary transthyretin amyloid, the type of TTR mutation also influences the presentation.
Owing to the heterogeneity of presentation, diagnosis might be delayed for several years after symptom onset. In addition, the true prevalence of the disease is unknown because many cases go undiagnosed and patients are also often misdiagnosed with more common conditions.
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ATTR-CM can affect several organ systems outside of the heart and periphery, disrupting gastrointestinal, genitourinary, auditory, and vision functions. Ocular manifestations (usually caused by vitreous deposits) include conjunctivitis, dry eye, floaters, reduced visual acuity, and eye pain. Regarding other extracardiac manifestations, neuropathic pain, a consequence of deposits in the peripheral nerves, can result in weakness and impaired sensation, as well as autonomic dysfunction that manifests as sexual or urinary dysfunction.
Cardiac manifestations of ATTR-CM can include symptoms associated with chronic heart failure, such as dyspnea on exertion and peripheral edema, and arrythmias (such as syncope).
Learn more about the clinical presentation of ATTR-CM.
Echocardiography can reveal signs of amyloid deposition within the heart. Characteristic imaging findings can include increased ventricular wall thickness, increased septal thickness, valvular thickening, valvular insufficiency, and atrial enlargement. The myocardium might also appear to have a granular "sparkling" appearance, as indicated by bright spots in the image. Although this sign alone is not sufficient to confirm a diagnosis, it is suggestive of ATTR-CM and can help with diagnosis.
Thinning of the valvular walls and reduced septal thickness are usually not indicative of cardiac amyloid deposition. Though increased diastolic volume might be seen in patients with cardiac amyloid deposition, this factor alone is not definitive. Specifically, a common presentation of cardiac amyloidosis is ' rapidly progressive diastolic dysfunction in a nondilated ventricle.'
Learn more about cardiac imaging in AT TR-CM.
Patients who exhibit possible signs of cardiac amyloidosis should be screened using electrophysiology and imaging to detect any abnormalities due to amyloid deposits. If those results are suggestive of cardiac amyloidosis, additional tests must be ordered to determine the amyloidosis type.
The first step in the differential diagnostic pathway includes testing for the presence of monoclonal proteins. A serum/kappa lambda free light chain ratio of < 0.26 or > 1.65 or an abnormal serum/urine immunofixation electrophoresis can indicate amyloid light chain amyloidosis, but alone these factors are usually not definitive for ATTR-CM diagnosis. However, absence of monoclonal proteins and grade 2/3 uptake of 99mTc-pyrophosphate highly indicate AT TR-CM; these factors can be used for diagnosis. TTR mutation does not need to be present for ATTR-CM diagnosis and alone does not strongly indicate this disease; rather, genetic testing for TTR mutations should be conducted to distinguish between hereditary and wild-type ATTR-CM following diagnosis.
Learn more about conducting a workup for ATTR-CM.
Many neurologic symptoms associated with ATTR-CM overlap with those of other conditions, including Charcot-Marie-Tooth disease. Peripheral neuropathy is a common neurologic symptom of ATTR-CM. Other neurologic symptoms can include autonomic dysfunction, gastroparesis, orthostatic hypotension, erectile dysfunction, and urinary incontinence. As such, ATTR-CM might also be misdiagnosed as other hereditary motor and sensory neuropathies, such as Refsum disease. Therefore, these conditions should be included in a differential diagnosis in patients presenting with neurologic symptoms.
Though some with ATTR-CM might experience seizures (usually in cases of patients with leptomeningeal amyloidosis), they are not common. Muscle weakness usually occurs distally in patients with ATTR-CM. Sudden onset of sensory impairment is less common in patients with ATTR-CM and is more characteristic of transthyretin amyloid polyneuropathy.
Learn more about performing a differential diagnosis of ATTR-CM.
Subcutaneous fat aspiration, which is most commonly used for tissue biopsy, can be sufficient for amyloid detection. While biopsy of samples from organs directly involved in ATTR-CM can be advantageous because sensitivity is reportedly higher, subcutaneous fat aspiration is a less invasive method that can be helpful in diagnosis. However, if tissue biopsy is negative in a patient with a high clinical suspicion of ATTR-CM, or if cardiac scintigraphy is unavailable or negative, endomyocardial biopsy should be performed. It is often used to confirm ATTR-CM diagnosis, along with other forms of cardiac amyloidosis.
Learn more about approach considerations for ATTR-CM evaluation.