When trying to understand a disease, it’s sometimes beneficial to rule out what it isn’t in order to determine what it truly is. Generally, symptoms of hATTR amyloidosis are progressive and may include sensory and motor impairment, autonomic and GI symptoms, or cardiac involvement. When polyneuropathy is present, it is a progressive sensorimotor and autonomic polyneuropathy. Polyneuropathy in hATTR amyloidosis may mimic neuropathy observed in other neuropathic conditions, potentially resulting in multiple misdiagnoses prior to identification of the causative condition. If untreated, patients with hATTR amyloidosis experience progressive symptoms until death occurs, typically 3 to 15 years after clinical presentation.
Disease heterogeneity and its rarity make a diagnosis of hATTR amyloidosis challenging. However, making a correct diagnosis is vital to determining prognosis, treatment, and appropriate patient and family counseling. Timely diagnosis is also important because it allows patients the opportunity to receive appropriate care as early as possible in the disease course.
Diagnosis can be confirmed via biopsy of the affected tissue or organ followed by staining with Congo red to confirm the presence of amyloid.5,15 Diagnosis can be established less invasively through biopsy of the salivary gland, endoscopic biopsy of the gastric mucosa, or subcutaneous fat aspiration. Western blot analysis, immunohistochemical staining, laser microdissection, proteomics, and mass spectrometry are subsequently used to characterize amyloid type. Limitations of biopsy are due to the often patchy distribution of amyloid deposits, sometimes necessitating multiple biopsies to confirm or exclude the diagnosis.5 Additionally, biopsy sensitivity depends on multiple factors, such as pathologist experience and protocol for Congo red staining.
In patients with a family history of disease and/or evaluation of symptomatic burden (ie, polyneuropathy), genetic testing is a crucial component to confirm a hATTR amyloidosis diagnosis as it identifies the specific TTR mutation present.5 Presymptomatic testing is now widely available and may be performed at the request of the patient with appropriate genetic counseling and follow-up.
The most sensitive test used for diagnosing cardiac involvement in hATTR amyloidosis is endomyocardial biopsy.However, it is not widely available.13 Therefore, other diagnostic tests are used for identifying cardiac involvement in hATTR amyloidosis, including electrocardiography (ECG), echocardiography, and cardiac magnetic resonance imaging (cMRI).
References: Hanna M. Novel drugs targeting transthyretin amyloidosis. Curr Heart Fail Rep. 2014;11(1):50-57. doi: 10.1007/s11897-013-0182-4. – Berk JL, Suhr OB, Obici L, et al; Diflunisal Trial Consortium. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658-2667. doi: 10.1001/jama.2013.283815. – Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-638. doi: 10.3109/07853890.2015.1068949. – Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. doi: 10.1136/jnnp-2014-308724. – Rapezzi C, Longhi S, Milandri A, et al. Cardiac involvement in hereditary-transthyretin related amyloidosis. Amyloid. 2012;19(suppl 1):16-21. doi: 10.3109/13506129.2012.673185.
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