Cardio-renal-neural phenotype shapes survival after liver transplant in ATTR amyloidosis

Background: From surgical standard to selective therapy

Hereditary transthyretin amyloidosis (ATTRv) is a multisystem disorder driven by misfolded transthyretin protein, leading to progressive neuropathy, cardiomyopathy and organ dysfunction. Liver transplantation (LTx), which removes the primary source of mutant transthyretin, was historically the standard of care. However, the emergence of TTR-stabilising and gene-silencing therapies has shifted treatment paradigms, leaving LTx reserved for selected patients. In this context, understanding which patients benefit most from transplantation remains clinically important.

Study design: 30 years of global registry data

This retrospective study analysed data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), including 1,762 patients who underwent isolated liver transplantation between 1990 and 2012 across 82 centres in 21 countries.

Patients were stratified into four phenotypes based on organ involvement prior to transplantation: (1) Polyneuropathy only (PN); (2) Cardiac + polyneuropathy (C-PN); (3) Renal + polyneuropathy (R-PN); (4) Cardiorenal + polyneuropathy (CR-PN).

The study evaluated long-term survival and post-transplant disease progression across these groups.

Key finding 1: Phenotype is a major determinant of survival

Overall survival after LTx was substantial, with:

• Median survival: 20.4 years
• 25-year survival rate: 32.4%

However, outcomes differed markedly by phenotype:

• Cardiac phenotype (C-PN): 15.2 years
• Cardiorenal phenotype (CR-PN): 20.8 years
• Polyneuropathy only (PN): 22.7 years

Cardiac involvement emerged as the strongest adverse prognostic factor, doubling mortality risk in univariable analysis and remaining significant after adjustment.

Key finding 2: Clinical and nutritional factors influence outcomes

Several additional predictors of survival were identified:

• Older age at transplantation increased mortality risk
• Longer disease duration worsened outcomes
• Adverse nutritional status (mBMI) predicted poorer survival
• Non-V30M variants were associated with worse prognosis

Notably, each year increase in age at transplantation raised mortality risk by ~6%, while better nutritional status independently improved survival. These findings reinforce the importance of early referral and optimisation before transplantation.

Key finding 3: Autonomic neuropathy signals early disease progression

Post-transplant disease evolution revealed a distinct pattern:

• Autonomic neuropathy deteriorated earlier than peripheral neuropathy or organ involvement
• This effect was particularly pronounced in patients with polyneuropathy-only phenotype

This suggests that worsening autonomic symptoms may serve as an early clinical marker of disease progression, potentially guiding the introduction of adjunct pharmacotherapy after transplantation.

Clinical implications: Refining patient selection in the modern era

Although LTx is no longer first-line therapy, the study provides several clinically relevant insights: (1) Cardiac involvement should weigh heavily in decision-making, given its strong association with poorer survival; (2) Renal involvement alone is not a contraindication to transplantation; (3) Early intervention and good nutritional status remain critical for optimal outcomes; (4) Post-transplant monitoring should prioritise autonomic symptoms as early warning signs. Importantly, these long-term data offer a benchmark for comparing emerging therapies, including RNA-silencing drugs and gene-editing approaches.

Looking ahead: Role of transplantation in the era of gene therapy

With the advent of therapies targeting TTR production—including RNA interference and CRISPR-based gene editing—LTx is now reserved for highly selected cases. Nevertheless, this study highlights that transplantation can still deliver decades-long survival benefit, particularly in carefully chosen patients without significant cardiac involvement.

See the article: 

Wilczek HE, Tranäng M, Coelho T, et al. Amyloidogenic phenotypical variation affects post-transplant outcome of hereditary transthyretin amyloidosis: a retrospective study. eGastroenterology 2026;4:e100243. doi:10.1136/egastro-2025-100243

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