Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
Hereditary transthyretin (hATTR) amyloidosis is a rare condition in which protein misfolding results in the buildup of abnormal amyloid deposits throughout tissues and organs. The accumulation of amyloid damages primarily the heart and the peripheral, autonomic, and central nervous systems. The disease is inherited in an autosomal-dominant fashion.1
In addition to a thorough physical examination and a complete family medical history, the diagnostic workup for hATTR amyloidosis includes genetic testing, biopsy, and amyloid typing. Additional testing may be performed to evaluate the extent of damage in cardiac, neural, and other tissue.2
In patients with a family history or symptoms of hATTR amyloidosis, DNA testing confirms the presence of variations in the transthyretin (TTR) gene. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) testing and real-time PCR (melting curve analysis) testing can detect suspected TTR mutations with high sensitivity and specificity; genetic sequencing and polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis can detect unknown TTR variations, sequencing with high sensitivity and specificity and PCR-SSCP with moderate sensitivity and specificity.2
Genetic testing identifies approximately 90% of TTR variants.3
Biopsy of impaired tissues and organs (eg, the heart, nervous system, and gastrointestinal tract) provides histopathological evidence of amyloid protein deposits, demonstrated by the presence of Congo red binding material in specimens. Aspiration of subcutaneous fat may also provide adequate tissue for a diagnosis of hATTR amyloidosis.4
Biopsies of different tissue sites detect hATTR amyloidosis with varying rates of sensitivity. The rates are relatively high for labial salivary gland (91%) and sural nerve specimens (80%), with a wider range for abdominal subcutaneous adipose tissue specimens (14%-83%).4 Other biopsy sites include the stomach, rectum, and any organs with evidence of involvement.3,4
Once Congo red staining confirms the presence of amyloid proteins in the tissues, the specific type of amyloidosis can be determined by comparing immunostained biopsy samples with control antisera against various amyloid precursors, such as immunoglobulin light chains and amyloid A proteins.4
Once the type of amyloid protein has been identified correctly, an accurate differentiation between hATTR amyloidosis and other types of amyloidosis, such as amyloid light chain (AL) amyloidosis, is possible, enabling more effective treatment. Mass spectroscopy identifies protein subunits to distinguish between immunoglobulin light chain amyloidosis and transthyretin-related amyloidosis.4 TTR immunolabeling of amyloid deposits confirms a diagnosis of TTR amyloidosis.3
Cardiac tissue biopsy may not be necessary to diagnose cardiac hATTR amyloidosis; cardiac imaging may be sufficient.4
Amyloid deposits in cardiac tissue may lead to life-threatening cardiac failure. Imaging studies such as electrocardiography, echocardiography, cardiac magnetic resonance imaging (MRI), and bone scintigraphy with technetium-labeled radioactive tracers can determine the extent of cardiac involvement.2,5
hATTR amyloidosis with cardiac involvement often manifests on electrocardiograms with a low-voltage QRS complex, indicating the replacement of functional cardiac tissue with nonconductive amyloid material.6
Echocardiography detects ventricular hypertrophy, increased septal thickness, valvular thickening and insufficiency, atrial enlargement, and granular tissue, suggestive of amyloid deposits. The cardiac ejection fraction remains unaffected until progression to late-stage disease.5
Bone scintigraphy provides a highly accurate, noninvasive diagnostic measure of cardiac hATTR amyloidosis.5
Additional cardiac testing can include Holter monitoring to detect cardiac arrhythmias and measurement of the levels of circulating B-type natriuretic peptide (BNP) and troponin, which are known biomarkers of cardiac strain and myocardial cellular death.2
Neurological studies detect the severity of peripheral neuropathy and can be used to monitor disease progression.6 Other nerve tests include electromyography with sympathetic skin response (SSR), autonomic testing, measurement of nerve conduction velocity, measurement of sensory and motor action potentials, and quantitative sensory testing.3
Proteinuria, an abnormal creatinine clearance rate, azotemia, a decreased glomerular filtration rate, and albuminuria are evidence of renal dysfunction due to amyloid protein infiltration in the kidneys.3,7
Additional abnormal findings on laboratory tests include normochromic normocytic anemia and electrolyte abnormalities suggestive of malabsorption and cardiac failure.7
hATTR amyloidosis is characterized by length-dependent sensory-motor polyneuropathy; however, this symptom is not exclusive to hATTR amyloidosis. Symptoms overlap with those of other conditions, resulting in misdiagnosis.3
Common misdiagnoses due to polyneuropathy include chronic inflammatory demyelinating polyneuropathy (CIDP), AL amyloidosis, idiopathic axonal polyneuropathy, inherited sensory polyneuropathy, hereditary sensory and autonomic neuropathies, leprous neuropathy, Fabry disease, Charcot-Marie-Tooth neuropathy or motor neuron disease, vitamin B12 deficiency, lumbar spinal stenosis, anxiety, and diabetic neuropathy.3
- Transthyretin amyloidosis. MedlinePlus. Accessed July 9, 2022.
- Roberts JR. Transthyretin-related amyloidosis: approach considerations. Medscape. Updated June 16, 2022. Accessed July 10, 2022.
- Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018;13(1):6. doi:10.1186/s13023-017-0726-x
- Roberts JR. Transthyretin-related amyloidosis workup: biopsy. Medscape. Updated June 16, 2022. Accessed July 10, 2022.
- Roberts JR. Transthyretin-related amyloidosis workup: cardiac Imaging. Medscape. Updated June 16, 2022. Accessed July 10, 2022.
- Roberts JR. Transthyretin-related amyloidosis workup: other tests. Medscape. Updated June 16, 2022. Accessed July 10, 2022.
- Roberts JR. Transthyretin-related amyloidosis workup: laboratory studies. Medscape. Updated June 16, 2022. Accessed July 10, 2022.
Reviewed by Harshi Dhingra, MD, on 7/17/2022.