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

PURPOSE: Neurogenic 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). METHODS: Literature review. RESULTS: Orthostatic 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. CONCLUSIONS: When 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.