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Transthyretin Amyloidosis

Transthyretin (TTR) is a plasma protein that is synthesized by the liver and transports thyroxine (thyroid hormone) and retinol (vitamin A). TTR is also known as prealbumin and normally circulates in the plasma as a homotetramer.  When these tetramers dissociate, the monomers can be cleaved by proteolytic enzymes and can subsequently misfold and aggregate into amyloid fibrils. Deposition of these misfolded amyloid fibrils in organs or other body tissues causes amyloidosis. ATTR is the term used to refer to amyloidosis caused by misfolding of the TTR protein.

ATTR can occur in association with TTR that have a normal genetic sequence (wild-type ATTR) or with TTR  possessing variant genetic sequences (variant ATTR). More than 130 different inherited genetic variants in TTR exist. The most common genetic variant is Val122Ile (pV142I) . This allele is believed to have originated in West African countries and is present in 3.4% of African American individuals in the US. The Val30Met variant is the most commonly encountered variant outside the US.

Wild type ATTR accounts for 75% of ATTR amyloidosis presents clinically as cardiomyopathy.  Variant ATTR manifests as cardiomyopathy and/or polyneuropathy. ATTR amyloidosis can cause heart failure, arrhythmia, and death, while ATTR deposition in nerves causes a small-fiber peripheral and/or autonomic poly- neuropathy. ATTR deposition in ligaments can cause carpal tunnel syndrome and cervical or lumbar spinal stenosis.

Approximately 50 000 to 150 000 people in the US have heart failure due to ATTR amyloidosis. Without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximately 5 years. 

Diagnosis can be made by first ruling out light chain amyloidosis (AL amyloidosis) by ordering serum free light chains and immunofixation electrophoresis. AL amyloidosis is a serious, more rapidly progressive type of amyloid disease that arises from a B-cell neoplasms that produce excess monoclonal κ or λ light chains. Excess light chains can misfold and aggregate into amyloid fibrils. The sensitivity of serum free light chain ratio and serum and urine immunofixation electrophoresis in AL amyloidosis is approximately 99%. Approximately 10% to 40% of patients with ATTR cardiomyopathy have elevated light chains suggestive of a monoclonal gammopathy of unknown significance (MGUS) that does not cause AL amyloidosis and is unrelated to ATTR amyloidosis. 

Noninvasive imaging with nuclear scintigraphy has largely replaced biopsy for identification of ATTR cardiomyopathy. Technetium 99m (Tc 99m) pyrophosphate, Tc 99m hydroxymethylene diphosphonate, and Tc 99m-3,3-diphosphono-1, 2-propanodicarboxylic acid can be used as tracers. Radiotracer uptake in the myocardium is compared to uptake in bone. A scan is considered positive for cardiac ATTR amyloidosis If uptake in the myocardium is equal to or greater than uptake in bone.

Direct cardiac biopsy with Congo red staining followed by mass spectrometry should be considered in patients with inconclusive tracer uptake or in patients with a mono- clonal gammopathy for whom AL amyloidosis remains a possibility.

After ATTR cardiomyopathy is diagnosed, TTR genetic testing is necessary to distinguish between hereditary vs wild-type amyloidosis. The genotype determines treatment and also helps to determine if first-degree relatives may have inherited a pathologic variant.

Prealbumin concentration may be low (<20 mg/dL) in patients with genetic variants that induce TTR misfolding. Prealbumin levels may be helpful in assessing treatment efficacy. Compared with baseline, a increased prealbumin concentration of at least 7.5 mg/dL suggests response to treatment. 


Ruberg FL and Maurer MS. Cardiac Amyloidosis Due to Transthyretin Protein: A Review. JAMA 2024;331(9):778-91. doi:10.1001/jama.2024.0442

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