To determine whether cutaneous amyloid deposition and small fiber densities predict long-term outcomes in hereditary transthyretin amyloidosis (ATTRv) and to assess disease progression following tafamidis discontinuation.

ATTRv is a progressive multisystem disorder caused by pathogenic TTR variants. With disease-modifying therapies available, prognostic biomarkers are needed to guide treatment decisions. Skin biopsy enables evaluation of amyloid deposition and somatic and autonomic innervation, but its prognostic value remains uncertain.

We evaluated 40 ATTRv patients originally enrolled in a four-year tafamidis trial (30 treated, 10 untreated). Survival analyses included all 40 patients, while long-term progression and nutritional outcomes were evaluated in the 21 with extended follow-up (median 8 years, range 7–11; all previously tafamidis-treated). Baseline distal leg and thigh skin biopsies were analyzed for amyloid deposition [Amyloid Deposition Index (ADI)] and intraepidermal (IENFD), sweat gland (SGNFD), and pilomotor (PMNFD) nerve fiber density. Associations with disease progression and survival were tested.

At baseline, 70% had a polyneuropathy disease (PND) score of 0, and 27% of I. Among the 21 patients with long-term follow-up, 33% remained stage 0, while 48% progressed to stage I and 19% to stage IIIa–IV. Nutritional status declined after tafamidis withdrawal (modified body mass index, p=0.00028). In the full 40-patient cohort, higher ADI predicted mortality (total ADI odds ratio [OR] 1.03, 95% confidence interval 1.003-1.05, p=0.030; thigh ADI OR 1.05, 1.003-1.10, p=0.037), with consistent trends after age adjustment. Greater SGNFD (OR 0.84, 0.73-0.97, p=0.016) and PMNFD (OR 0.90, 0.83-0.97, p=0.006) were associated with reduced mortality; after adjustment, thigh PMNFD independently predicted survival (age-adjusted OR 0.90, 0.83–0.98, p=0.012).

Patients experienced progressive decline following tafamidis discontinuation. ADI was associated with mortality, underscoring the prognostic relevance of amyloid deposition, though its effect weakened after age adjustment. Pilomotor innervation independently predicted survival, reinforcing the prognostic value of skin biopsy in ATTRv.