Autonomic Dysfunction in Patients with Transthyretin Amyloidosis
Autonomic nervous system disorders are a common complication of transthyretin amyloidosis. Their frequency, nature, and impact on patients' quality of life were examined in the longitudinal THAOS study.
Transthyretin Amyloidosis and Its Neurological Symptoms
Transthyretin amyloidosis (ATTR) is a rare systemic and fatal disease caused by the deposition of transthyretin (TTR) monomers in the extracellular space of organs and tissues. Amyloidogenic TTR can occur in either a nonmutated form (ATTRwt; in the acquired form of the disease) or as a variant protein (ATTRv; in the hereditary form).
The deposition of amyloid fibrils and circulating TTR oligomers causes damage and loss of unmyelinated nerve fibers and small-diameter myelinated fibers, leading to autonomic dysfunction affecting the cardiovascular, gastrointestinal, or urogenital systems. Symptoms of autonomic dysfunction often occur in the early stages of ATTRv amyloidosis, even before the onset of sensory and motor nerve damage, and significantly negatively impact patient quality of life and survival. Autonomic neuropathy in ATTRwt is less common.
Although autonomic dysfunction is a well-known symptom of ATTR, its progression is not yet fully understood and requires further characterization.
THAOS Study Methodology
The longitudinal observational THAOS study (Transthyretin Amyloidosis Outcome Survey) includes patients with ATTR amyloidosis and asymptomatic TTR mutation carriers. The presented analysis included data from 2922 patients (1943 with ATTRv, 979 with ATTRwt) with ≥ 1 symptom definitively related to the disease as assessed by the investigator at study entry. Patients who had undergone liver transplantation, participated in clinical studies, or received disease-modifying therapy were excluded.
Demographic and clinical characteristics and quality of life scores (according to the Norfolk Quality of Life Questionnaire – Diabetic Neuropathy) at study entry were compared between patients with and without autonomic dysfunction. Patients with autonomic dysfunction were those with orthostatic hypotension or ≥ 1 of the following symptoms: early satiety, nausea, vomiting, constipation, diarrhea, alternating constipation and diarrhea, urinary retention, fecal or urinary incontinence, erectile dysfunction, dry eye syndrome, sweating disorders, dizziness.
Results
Autonomic dysfunction was present in 40% of the observed cohort, more frequently in patients with hereditary amyloidosis (93.7%) than in those with the acquired form (6.3%). The time from disease onset to the first occurrence of autonomic dysfunction symptoms was shorter in patients with ATTRv (average 3.4 years; standard deviation [SD] 5.7 years) than in those with ATTRwt (9.7 years; SD 10.4).
Quality of life in patients with ATTRv and autonomic dysfunction was significantly worse than in those without autonomic dysfunction symptoms (mean score 47.3 [SD 33.2] vs. 16.1 [SD 18.1]). Patients with ATTRwt reported similar quality of life regardless of autonomic dysfunction symptoms (23.0 [SD 18.2] vs. 19.9 [SD 20.5]).
Conclusion
Autonomic dysfunction occurred more frequently and appeared earlier in symptomatic patients with the hereditary form of ATTR compared to those with the acquired form. Autonomic dysfunction significantly increased the disease burden in patients with ATTRv.
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Source: Barroso F. A., Coelho T., Dispenzieri A. et al.; THAOS investigators. Characteristics of patients with autonomic dysfunction in the Transthyretin Amyloidosis Outcomes Survey (THAOS). Amyloid 2022; Apr 22: 1−9, doi: 10.1080/13506129.2022.2043270 [Epub ahead of print].
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