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

Abstract

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.

Keywords: Amyloid; Autonomic dysfunction; Autonomic failure; Droxidopa; Orthostatic hypotension; Peripheral neuropathy; Transthyretin.

Fig. 1

Cardiovascular autonomic testing and gastrointestinal biopsy in a patient with acquired amyloid polyneuropathy after domino liver transplant. a–d Representative test results of a 76-year-old female who, as a result of autoimmune liver failure, had a liver transplant at age 55 years. She suffered a liver transplant rejection and required a second liver transplant at age 69. The liver she received was from a donor with hereditary transthyretin amyloidosis (Val71Ala mutation), who had recently died after several years of severe sensory and autonomic neuropathy (i.e., domino liver transplant). Approximately 1 year after receiving the second liver transplant, the patient developed severe diarrhea, exercise intolerance and painful tingling in the feet. Two years after the liver transplant her tingling had worsened significantly and she developed dry mouth and neurogenic bladder. At age 75 she developed severe weight loss (15–20 lb), recurrent orthostatic dizziness and lightheadedness and suffered frequent episodes of loss of consciousness upon standing. She became wheelchair bound at age 76. a Cardiovascular autonomic testing showing absent blood pressure overshoot after release of the Valsalva strain (dashed arrow), indicating impaired baroreflex-mediated sympathetic activation. b Tilt-table test showing a supine blood pressure of 133/70 mmHg with a heart rate of 79 bpm. After 15 min of head-up tilt, her blood pressure had fallen to 76/40 mmHg and her heart rate was 88 bpm, consistent with severe neurogenic orthostatic hypotension. To confirm that her sensory and autonomic neuropathy was caused by amyloid, she underwent a upper gastrointestinal endoscopy and biopsies from the stomach and duodenum were obtained. c and d Congo red stain in upper gastrointestinal tissue showing abundant amyloid deposition in the muscularis mucosae (arrows)