Overview

Amyloidosis is a disorder in which misfolded proteins aggregate into insoluble beta-pleated sheet fibrils and deposit extracellularly in tissues, leading to progressive organ dysfunction. It may be systemic or localized. 

In current practice, the most clinically important systemic forms are AL (light-chain), AA (serum amyloid A), and ATTR (transthyretin; hereditary or wild-type). The phenotype depends on the precursor protein and the organs involved, with the heart, kidneys, peripheral/autonomic nerves, liver, and soft tissues commonly affected.

The major forms of systemic amyloidosis are classified according to the precursor protein that misfolds and deposits in tissues:

• AL amyloidosis is due to a monoclonal plasma-cell disorder producing amyloidogenic immunoglobulin light chains.
• AA amyloidosis is a reactive/inflammatory amyloidosis caused by persistent elevation of serum amyloid A (SAA) in chronic inflammatory or infectious states.
• ATTR amyloidosis results from deposition of transthyretin and is divided into:
  • ATTRv: hereditary, due to a TTR pathogenic variant
  • ATTRwt: wild-type, age-related deposition of normal TTR, classically in older adults, especially men.

Typical red flags include unexplained nephrotic proteinuria, restrictive/infiltrative cardiomyopathy, heart failure with increased wall thickness, peripheral/autonomic neuropathy, hepatomegaly, macroglossia, bilateral carpal tunnel syndrome, and unexplained multisystem disease.

Definitive diagnosis requires demonstration of amyloid in tissue and accurate amyloid typing; organ-specific treatment depends on the subtype.

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Classification