Transthyretin Amyloidosis (ATTR Amyloidosis): Clinical Features and Diagnosis
In transthyretin amyloidosis (ATTR amyloidosis), the normally soluble transport protein transthyretin (TTR) becomes unstable, misfolds, and aggregates into insoluble amyloid fibrils. These fibrils accumulate in tissues and progressively impair organ function. The heart and peripheral nervous system are particularly important sites of involvement, although tendons, ligaments, the gastrointestinal tract, eyes, and other organs may also be affected. (NCBI)
Two major forms of ATTR amyloidosis are distinguished:
The term ATTRv is increasingly preferred to the older terms hereditary ATTR (hATTR) or familial amyloid polyneuropathy.
Wild-Type ATTR Amyloidosis
Wild-type ATTR amyloidosis (ATTRwt) usually occurs in older adults and is considerably more common in men, although women can also be affected and may be underdiagnosed.
There is no pathogenic TTR mutation. Instead, structurally normal transthyretin becomes unstable and increasingly prone to misfolding and amyloid formation with advancing age. The precise mechanisms responsible for this age-related destabilization remain incompletely understood.
ATTRwt predominantly affects the heart, producing transthyretin amyloid cardiomyopathy (ATTR-CM). Carpal tunnel syndrome, lumbar spinal stenosis, and tendon abnormalities may precede cardiac symptoms by several years. Severe peripheral or autonomic polyneuropathy is much more characteristic of ATTRv than ATTRwt. (NCBI)
Hereditary ATTR Amyloidosis
Hereditary ATTR amyloidosis (ATTRv) is caused by a pathogenic variant in the TTR gene. It is generally inherited in an autosomal dominant manner. A child of a heterozygous carrier therefore has a 50% probability of inheriting the pathogenic variant, although penetrance and age of disease onset vary considerably depending on the particular mutation and other factors. (NCBI)
ATTRv can affect both the peripheral and autonomic nervous systems and the heart. The relative degree of neurological and cardiac involvement depends strongly on the specific TTR variant. Some variants produce predominantly polyneuropathy, others predominantly cardiomyopathy, while many patients develop a mixed phenotype. (NCBI)
Clinical Manifestations of ATTR Amyloidosis
The symptoms of ATTR amyloidosis depend largely on the organs in which transthyretin amyloid accumulates. Clinically, manifestations can be divided into cardiac, peripheral neurological, autonomic, and musculoskeletal features.
Cardiac Involvement: ATTR Cardiomyopathy
Amyloid infiltration progressively increases myocardial wall thickness and stiffness. The ventricles become less compliant and cannot fill normally during diastole, eventually resulting in heart failure, usually with preserved or only mildly reduced ejection fraction in earlier stages.
Typical manifestations include:
Cardiac amyloidosis should particularly be considered when apparently increased left ventricular hypertrophy occurs without an adequate explanation such as severe hypertension or valvular disease. (American College of Cardiology)
Peripheral Polyneuropathy
Peripheral neuropathy is particularly characteristic of ATTRv amyloidosis.
Symptoms often begin symmetrically in the feet and gradually progress proximally. Small sensory nerve fibers may be affected early, followed by larger sensory and motor fibers. (NCBI)
Common manifestations include:
Temperature and pain perception may become impaired relatively early in ATTRv neuropathy. (NCBI)
Autonomic Neuropathy
ATTRv amyloidosis can also damage autonomic nerve fibers that regulate involuntary functions such as blood pressure, gastrointestinal motility, bladder function, sweating, and sexual function.
Clinical manifestations may include:
Importantly, autonomic dysfunction can sometimes precede obvious motor neuropathy. (NCBI)
Musculoskeletal “Red Flags”
Several apparently unrelated orthopedic disorders may precede cardiac ATTR amyloidosis by many years and should therefore be regarded as important diagnostic clues.
Bilateral Carpal Tunnel Syndrome
Carpal tunnel syndrome, particularly when bilateral, is one of the best recognized extracardiac red flags.
Amyloid can accumulate in the tenosynovial tissue surrounding the median nerve. Carpal tunnel syndrome may develop several years before overt cardiomyopathy.
Lumbar Spinal Stenosis
Amyloid deposits within ligaments of the lumbar spine may contribute to thickening of the ligamentum flavum and spinal canal stenosis.
Spontaneous Biceps Tendon Rupture
A spontaneous or disproportionate distal biceps tendon rupture without major trauma is another recognized clue to ATTR amyloidosis.
Other orthopedic clues include repeated joint surgery and tendon or ligament disease. (American College of Cardiology)
No single symptom or test is sufficiently specific. Suspicion should increase when several cardiac and extracardiac red flags occur together.
A practical approach is to consider two major clusters.
Cluster 1: Cardiac Disease Plus Systemic Red Flags
Suspicion of ATTR-CM should increase in an older patient with otherwise unexplained heart failure or increased ventricular wall thickness combined with one or more of the following:
ATTR amyloidosis should also be considered in older patients with severe aortic stenosis, particularly when ventricular wall thickening, low-flow/low-gradient physiology, persistent heart-failure symptoms, or extracardiac ATTR red flags are present. ATTR-CM is found in a clinically relevant proportion of older patients evaluated for transcatheter aortic valve replacement. (Escardio)
Cluster 2: Characteristic Cardiac Findings
Cardiac findings that should raise suspicion include:
A pseudoinfarction pattern usually consists of pathological Q or QS waves suggesting a previous myocardial infarction despite the absence of corresponding coronary infarction. ST-segment elevation is not a typical defining feature of the amyloid pseudoinfarction pattern.
It is also important to note that low ECG voltage is not obligatory. The classic combination of markedly thickened ventricular walls on echocardiography and low ECG voltage is found in only a minority of patients. (American College of Cardiology)
The traditional threshold of ≥12 mm wall thickness is useful as a red flag but should not be regarded as an absolute requirement. Early ATTR-CM, particularly in women, may be present with less pronounced wall thickening. Current ACC guidance emphasizes that this criterion must be interpreted in clinical context. (JACC)
The diagnosis should follow a structured pathway.
Step 1: Cardiac Biomarkers
In patients with suspected cardiac amyloidosis, useful laboratory investigations include:
Persistent elevation, particularly when disproportionate to the apparent clinical severity of heart failure, supports the suspicion of cardiac amyloidosis and also provides prognostic information. (Escardio)
However, biomarkers are not diagnostic on their own. Normal or low values make advanced cardiac involvement less likely but do not reliably exclude early ATTR-CM.
Step 2: Exclude AL Amyloidosis
This is one of the most important steps in the entire diagnostic pathway.
Immunoglobulin light-chain (AL) amyloidosis must be excluded before a positive bone scintigraphy is interpreted as diagnostic of ATTR-CM.
The monoclonal protein screen should include all three of the following:
If all three tests are negative, AL amyloidosis is effectively excluded in the great majority of cases. Standard serum protein electrophoresis alone is not sufficiently sensitive to exclude AL amyloidosis. (American College of Cardiology)
If a monoclonal protein is detected, hematological assessment is required and tissue biopsy with definitive amyloid typing may be necessary. This distinction is critical because AL amyloidosis and ATTR amyloidosis require completely different treatments.
Step 3: Echocardiography
Transthoracic echocardiography is usually the initial cardiac imaging examination.
Findings that may suggest cardiac amyloidosis include:
An unexplained ventricular wall thickness of approximately ≥12 mm is an important red flag but is neither completely sensitive nor specific. (American College of Cardiology)
Step 4: Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (CMR) provides detailed assessment of myocardial structure and tissue characteristics.
Characteristic findings include:
CMR is particularly useful for demonstrating an infiltrative cardiomyopathy and estimating the extent of extracellular expansion. (American College of Cardiology)
However, an important limitation is that CMR cannot reliably distinguish ATTR amyloidosis from AL amyloidosis. It therefore supports the diagnosis of cardiac amyloidosis but does not by itself establish the amyloid subtype.
Step 5: Bone-Tracer Scintigraphy
Bone scintigraphy has fundamentally changed the diagnosis of ATTR-CM because it can allow a non-invasive diagnosis without cardiac biopsy in appropriately selected patients.
Common tracers include:
Strong cardiac uptake is characteristic of ATTR-CM. (Escardio)
The visual uptake is commonly categorized according to the Perugini grade:
Non-Biopsy Diagnosis
A diagnosis of ATTR-CM can generally be established without endomyocardial biopsy when:
SPECT or SPECT/CT imaging is important to confirm that tracer uptake is genuinely located within the myocardium rather than representing residual blood-pool activity.
Grade 1 uptake, discordant tests, or the presence of a monoclonal protein generally requires additional assessment and may require biopsy.
Step 6: Tissue Biopsy
Endomyocardial biopsy allows direct demonstration of cardiac amyloid and remains the definitive diagnostic method when non-invasive testing is inconclusive.
Amyloid is demonstrated histologically using Congo red staining, producing characteristic birefringence under polarized light.
Importantly, detecting amyloid alone is not sufficient. The amyloid protein should be typed, preferably using validated methods such as mass spectrometry, because treatment depends on the amyloid subtype.
Endomyocardial biopsy is invasive and is therefore no longer routinely required when the established non-invasive criteria for ATTR-CM are fulfilled. (Escardio)
Step 7: Genetic Testing
Once ATTR amyloidosis has been diagnosed, TTR genetic testing should be performed to distinguish:
Genetic testing is important even in older patients because hereditary disease cannot be reliably excluded solely on the basis of age or the absence of a known family history.
If a pathogenic TTR variant is identified, genetic counseling and appropriate testing of adult relatives should be considered. ATTRv is generally inherited in an autosomal dominant manner. (NCBI)
Practical Diagnostic Algorithm
For clinical use, the diagnostic pathway can be summarized as:
Clinical suspicion / red flags
↓
ECG + echocardiography + NT-proBNP + hs-troponin
↓
Screen for monoclonal protein
→ serum free light chains
→ serum immunofixation
→ urine immunofixation
↓
No evidence of monoclonal gammopathy
↓
99mTc-DPD/HMDP/PYP scintigraphy + SPECT
↓
Grade 2–3 myocardial uptake
↓
ATTR-CM can usually be diagnosed non-invasively
↓
TTR genetic testing
↓
ATTRwt or ATTRv
If a monoclonal protein is present, or if scintigraphy and imaging findings are inconclusive, tissue biopsy with amyloid typing should generally be pursued rather than assuming ATTR amyloidosis. This is particularly important because delayed recognition of AL amyloidosis can have serious consequences. (American College of Cardiology)