ATTR-CM | Suspect & Detect | Mechanism of Disease

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ATTR amyloidosis is due to the misfolding of TTR protein¹

TTR is a transport protein for a thyroid hormone (thyroxine [T4]) and is a retinol-binding protein²

Produced mainly in the liver, but there is also some production in the choroid plexus (brain) and retinal epithelium (eye)²
TTR protein plays an important role in the body. The long-term impact of TTR reduction in humans is unknown^2,3
The complete absence of TTR in humans has not been reported²

The physiologic role of TTR is not fully defined, but the growing body of evidence suggests TTR has additional important functions.²

Biological functions of TTR from mouse and human studies²*

Human and mouse TTR share 80% similarity at the amino acid level, so it may be expected that insights into the physiologic function of human TTR could be gained through the generation of TTR knockout mice.²

Other important functions of TTR that are independent of protein transport:

Neuroprotective effects have been shown in both the peripheral nervous system (PNS) and the central nervous system (CNS) in animal and clinical studies²

Protection against neurodegeneration and Alzheimer disease in a mouse model²

The pathogenesis of ATTR amyloidosis is caused by the destabilisation, not production, of TTR protein tetramers²

In ATTR-CM, a TTR gene mutation or age-related changes destabilise the protein tetramers, which separate into monomers and then misfold and aggregate into amyloid fibrils that deposit in the heart and other organs over time.^2,4

Fibrils can deposit is multiple areas⁵

Because amyloid fibrils can deposit in different parts of the body, including the heart and nerves, some patients may present with a mixed phenotype, namely, symptoms of both cardiomyopathy and polyneuropathy.^2,5

Suspicion of cardiac involvement should prompt immediate cardiac evaluation to assess for ATTR-CM.⁶

Wild-Type ATTR-CM >

References:

Coelho T, Ericzon B, Falk R, et al. A Guide to Transthyretin Amyloidosis. Clarkston, MI: Amyloidosis Foundation; 2016. http://www.amyloidosis.org/wp-content/uploads/2017/05/2017-ATTR-guide.pdf. Accessed October 28, 2019.

Liz MA, Coelho T, Bellotti V, Fernandez-Arias MI, Mallaina P, Obici L. A narrative review of the role of transthyretin in health and disease. Neurol Ther. 2020;9(2):395-402. doi:10.1007/s40120-020-00217-0

Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122. doi:10.1007/s00415-019-09688-0

Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286-1300. doi:10.1161/CIRCULATIONAHA.111.078915

Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail. 2019;12(9):e006075. doi:10.1161/CIRCHEARTFAILURE.119.006075

Garcia-Pavia P, Rapezzi C, Adler Y, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021;42(16):1554-1568. doi:10.1093/eurheartj/ehab072

Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2—evidence base and standardized methods of imaging. J Nucl Cardiol. 2019;26(6):2065-2123. doi:10.1007/s12350-019-01760-6. Addendum: J Nucl Cardiol. Published online July 1, 2021. doi:10.1007/s12350-020-02455-z

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