For Providers: A brief overview of amyloidosis
What is Amyloid?
Rudolph Virchow first characterized amyloid in humans in 1854. He described waxy tissue deposits seen on light microscopy which stained in a similar manner to cellulose with Iodine, and was later found to stain with Congo red and show apple–green birefringence with polarized microscopy.
What is Amyloidosis?
Amyloid undergoes conformational change, such as forming antiparallel beta pleated sheets, and become insoluble fibrils which deposit in the extracellular spaces. The distribution of this insoluble deposition causes the heterogenous presentation of amyloidosis.
While there are around 30 types of protein precursors that cause amyloid, there are several major forms of amyloidosis. AL, or primary amyloidosis, is due to deposition of immunoglobulin light chain fragments and is the more common type in the United States. AA amyloidosis, or secondary amyloidosis, are due to fibrils are made of acute phase reactant serum amyloid A protein, and are often seen in patient who also have inflammatory diseases ie: Rheumatoid arthritis, Inflammatory bowel disease. Amyloidosis can also be hereditary, dialysis related, age related, systemic or organ-specific.
Cardiac Amyloidosis:
The majority of cardiac amyloidosis is caused by either AL amyloid deposition or transthyretin (ATTR) amyloidosis. Less frequently it can be caused by AA amyloidosis or Apolipoprotein A-1 deposition.
What is ATTR amyloidosis?
Transthyretin, also known as prealbumin, is synthesized by the liver to transport RetinolA and thyroid hormone. Tranthyretin is normally in a stable tetramer form that doesn’t break down into the monomers and oligomers that form the amyloid fibrils. This instability can be hereditary and can be caused by ~120 known possible genetic mutations or it can be caused by a normal sequence of TTR, with the mechanism of deposition yet to be uncovered.
ATTRwt vs ATTRv ?
ATTRv types:
- pV50M (V30M) ATTR: Northern Portugal and Sweden
- pT80A (T60A): 1% Donegal Ireland, with high phenotypic penetrance
- V142I (V122I): unclear penetrance, increased prevelance in African American population
ATTRwt:
Deposition: Primarily cardiac and soft tissue deposition
Associations: Carpal Tunnel Syndrome, Spinal Stenosis
Age: >60
ATTRv:
Deposition: Cardiac and peripheral nervous system
Associations: peripheral and autonomic neuropathy
Age: depends on variant
How common is it?
Amyloidosis as a cause of heart failure is becoming an increasingly recognized and perhaps a less rare disease than first thought. wATTR accumulation is demonstrable in ~25% of hearts in patients over age 80 years old. It is estimated that around 10-15% of the patient population with HFpEF has cardiac amyloidosis. There is also an increased incidence of findings of cardiac amyloidosis in those with aortic stenosis (~15%) and presumed hypertrophic cardiomyopathy (~5-10%).
What are the suspicious clinical findings?
Cardiac findings are consistent with restrictive cardiomyopathy with low cardiac output as an advanced sign of the disease. Suspicion for cardiac amyloidosis should be raised in patient with new unexplained HF symptoms, unexplained LVH, known amyloidosis, and aortic stenosis with signs of amyloidosis. Some systemic signs of amyloidosis include bilateral carpal tunnel syndrome, spinal stenosis, biceps tendon rupture, macroglossia, and proteinuria.
How to work up suspected ATTR amyloidosis?
- A thorough history
- EKG
- initial laboratory tests:
- Troponin I or T
- BNP or NT-pro-BNP
- pre-albumin
- kappa and lambda serum free light chains
- serum immunofixation electrophoresis
- renal function panel
- referral testing:
- Echocardiogram
- Electromyography/nerve conduction studies
How to diagnose ATTR amyloidosis?
Testing generally involves three components.
- Biopsy to identify amyloid by histology OR non-invasive imaging using nuclear medicine tests
- exclusion of plasma cell disorder ie. AL amyloidosis
- sequencing of the TTR gene to determine presence of variants
Helpful Resources:
Systematic Amyloidosis Recognition, Prognosis, and Therapy: A Systematic Review
Amyloidosis Diagnosis and Treatment App for Healthcare Professionals
Cardiac Amyloidosis Alert Cards: pocket cards which help trigger the clinician to consider further amyloid testing