Orthostatic hypotension in hereditary transthyretin amyloidosis: epidemiology, diagnosis and management

Jose-Alberto Palma,Alejandra Gonzalez-Duarte,Horacio Kaufmann

doi:10.1007/s10286-019-00623-x

Abstract

PurposeNeurogenic orthostatic hypotension is a prominent and disabling manifestation of autonomic dysfunction in patients with hereditary transthyretin (TTR) amyloidosis affecting an estimated 40–60% of patients, and reducing their quality of life. We reviewed the epidemiology and pathophysiology of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis, summarize non-pharmacologic and pharmacological treatment strategies and discuss the impact of novel disease-modifying treatments such as transthyretin stabilizers (diflunisal, tafamidis) and RNA interference agents (patisiran, inotersen).MethodsLiterature review.ResultsOrthostatic hypotension in patients with hereditary transthyretin amyloidosis can be a consequence of heart failure due to amyloid cardiomyopathy or volume depletion due to diarrhea or drug effects. When none of these circumstances are apparent, orthostatic hypotension is usually neurogenic, i.e., caused by impaired norepinephrine release from sympathetic postganglionic neurons, because of neuronal amyloid fibril deposition.ConclusionsWhen recognized, neurogenic orthostatic hypotension can be treated. Discontinuation of potentially aggravating medications, patient education and non-pharmacologic approaches should be applied first. Droxidopa (Northera®), a synthetic norepinephrine precursor, has shown efficacy in controlled trials of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis and is now approved in the US and Asia. Although they may be useful to ameliorate autonomic dysfunction in hereditary TTR amyloidosis, the impact of disease-modifying treatments on neurogenic orthostatic hypotension is still uninvestigated.

Highlights

Hereditary transthyretin amyloidosis is a rare, autosomal dominant disease caused by mutations in the TTRgene encoding transthyretin, a T4-thyroid hormone and retinol transport protein [107]
Mutations in the TTRgene destabilize the tetramer structure of transthyretin, turning it into monomers and fibrils that deposit as amyloid predominantly in the peripheral motor, sensory and autonomic nerves, gastrointestinal tract and heart resulting in progressive polyneuropathy and cardiomyopathy [107]
Studies in Japan showed that droxidopa increased norepinephrine levels and blood pressure when standing and improved orthostatic tolerance in patients with nOH caused by hereditary transthyretin amyloidosis [7, 129,130,131]

Summary

Introduction

Hereditary transthyretin amyloidosis is a rare, autosomal dominant disease caused by mutations in the TTRgene encoding transthyretin, a T4-thyroid hormone and retinol transport protein [107]. OH in patients with hereditary transthyretin amyloidosis who do not have heart failure, volume depletion (frequently caused by diarrhea) or drug effects is usually neurogenic, i.e., caused by impaired norepinephrine release from sympathetic postganglionic neurons, because of neuronal amyloid fibril deposition. Studies in Japan showed that droxidopa increased norepinephrine levels and blood pressure when standing and improved orthostatic tolerance in patients with nOH caused by hereditary transthyretin amyloidosis [7, 129,130,131]. Two phase-3 clinical trials with patisiran and inotersen, newly developed RNA-based antisense therapies approved by the US FDA and the European Medicines Agency in 2018, showed that blocking the production of transthyretin improves the polyneuropathy and quality of life of patients with hereditary transthyretin amyloidosis [1, 16] Both trials used the modified NIS + 7 (mNIS + 7) as primary outcome measure. A specific study on whether RNA interference agents abate the orthostatic drop in BP and improve symptoms of nOH in patients with hereditary transthyretin amyloidosis is warranted

Conclusion

Findings

Compliance with ethical standards