Determinants of circulating transthyretin levels across the clinical spectrum of transthyretin amyloidosis

Background Serum TTR is increasingly measured in ATTR, yet its clinical interpretation remains uncertain. Purpose To identify clinical factors associated with circulating transthyretin (TTR) across the spectrum of transthyretin amyloidosis (ATTR). Methods We analyzed 347 longitudinal serum samples from 139 patients with ATTR. Clinical variables included age, ATTR subtype, albumin, estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), brain natriuretic peptide (BNP), troponin-T, and use of TTR tetramer stabilizers or small-interfering RNA (siRNA) therapy. Associations with TTR were assessed using linear mixed-effects models. Results Lower TTR was independently associated with greater inflammation (log₁₀[CRP+0.1]: β −4.90; 95% CI −6.46 to −3.35; p<0.001) and more severe heart failure (log₁₀BNP: β −4.73; 95% CI −6.16 to −3.31; p<0.001). Higher albumin and younger age correlated with higher TTR (β +3.56; 95% CI 1.88–5.23, and −0.23 per year; 95% CI −0.32 to −0.13; both p<0.001). Lower eGFR was associated with slightly higher TTR (β +0.09 per mL/min/1.73 m²; 95% CI 0.05–0.13; p<0.001). Stabilizer therapy increased TTR (β +7.55; 95% CI 6.46–8.65; p<0.001), whereas siRNA therapy markedly reduced it (β −12.3; 95% CI −17.5 to −7.0; p<0.001). Wild-type ATTR had higher TTR than variant disease (β +7.02; 95% CI 2.84–11.2; p=0.001). Troponin-T was not independently associated with TTR. Conclusions Serum TTR primarily reflects systemic physiology—including inflammation, heart failure, renal function, nutritional status, and therapeutic modulation—rather than ATTR disease status alone. These findings provide important context for interpreting TTR concentrations in clinical practice.