How is transthyretin amyloidosis diagnosed and treated?

Updated: May 09, 2019
  • Author: Robert O Holmes, Jr, DO; Chief Editor: Herbert S Diamond, MD  more...
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The precursor protein is the normal- or mutant-sequence transport protein transthyretin (TTR), a transport protein synthesized in the liver and choroid plexus. TTR is a tetramer of 4 identical subunits of 127 amino acids each. Normal-sequence TTR forms amyloid deposits in the cardiac ventricles of elderly people (ie, >70 y); this disease was also termed senile cardiac amyloidosis. The prevalence of TTR cardiac amyloidosis increases progressively with age, affecting 25% or more of the population older than 90 years. Normal-sequence TTR amyloidosis (ATTR) can be an incidental autopsy finding, or it can cause clinical symptoms (eg, heart failure, arrhythmias). [44]

Point mutations in TTR increase the tendency of TTR to form amyloid. Amyloidogenic TTR mutations are inherited as an autosomal dominant disease with variable penetrance. More than 100 amyloidogenic TTR mutations are known, but many remain unknown. [45] The most prevalent TTR mutations are TTR Val30Met (common in Portugal, Japan, and Sweden), and TTR Val122Ile (carried by 3.9% of African Americans).

Amyloidogenic TTR mutations cause deposits primarily in the peripheral nerves, heart, gastrointestinal tract, and vitreous. The presentation of ATTR is fairly nonspecific, but signs and symptoms typical of chronic heart failure, polyneuropathy, and carpal tunnel syndrome occur commonly.45  Autonomic nerves are often affected before motor nerves. [46]

Treatment for mutant-sequence amyloidogenic ATTR is liver transplantation or supportive care. Liver transplantation should be performed in Val30Met patients as early as possible as it removes the main source of mutant TTR and dramatically reduces the progression of neuropathy (up to 70%) and can double the median survival. The US Food and Drug Administration (FDA) has not approved any pharmacological treatments for ATTR, but tafamidis, diflunisal, patisiran, revusiran, and tolcapone have demonstrated some benefit. For normal-sequence amyloidogenic ATTR, the treatment is supportive care. For details, see Transthyretin-Related Amyloidosis.

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