How is cardiac amyloidosis diagnosed in an older patient with unexplained heart failure with preserved ejection fraction, concentric left‑ventricular thickening, low‑voltage electrocardiogram, and systemic signs such as neuropathy, carpal tunnel syndrome, or proteinuria?

Detecting Cardiac Amyloidosis: A Structured Diagnostic Approach

In an older patient with unexplained HFpEF, concentric LV thickening, low-voltage ECG, and systemic signs, you must first screen for monoclonal proteins (serum free light chains, serum and urine immunofixation), then proceed to technetium-99m bone scintigraphy if negative, or endomyocardial biopsy if positive. 1

Initial Clinical Recognition: Red-Flag Features

The following constellation of findings should immediately trigger a cardiac amyloidosis workup:

Cardiac Features

• LV wall thickness >12 mm without alternative explanation (hypertension, aortic stenosis) 1, 2
• Voltage-mass discordance: low QRS voltage on ECG despite increased wall thickness 1, 2
• Heart failure with preserved ejection fraction (≥40%), particularly in men >60 years 1, 2
• Intolerance to ACE inhibitors, ARBs, or beta-blockers with symptomatic hypotension 1, 2
• Low-flow aortic stenosis (mean gradient ≤40 mmHg) with preserved ejection fraction 1, 2

Extracardiac Clues

• Bilateral carpal tunnel syndrome in males without rheumatoid arthritis 1, 2
• Peripheral sensorimotor neuropathy with autonomic dysfunction (orthostasis, erectile dysfunction, gastroparesis) 1, 2
• Lumbar spinal stenosis or spontaneous biceps tendon rupture 1, 2
• Unexplained proteinuria or nephrotic-range proteinuria 1, 2

Mandatory First Step: Monoclonal Protein Screening

Before any imaging, all three assays must be performed simultaneously 1, 2:

1. Serum free light chain (sFLC) assay with κ/λ ratio

   • Normal ratio: 0.26–1.65 (Binding Site) or 0.31–1.56 (Siemens) 1, 2
   • Interpret cautiously in renal dysfunction (upper limit widens to 3.7) 1, 2

2. Serum immunofixation electrophoresis (SIFE) 1, 2

3. Urine immunofixation electrophoresis (UIFE) 1, 2

Critical pitfall: Approximately 5% of individuals >70 years have monoclonal gammopathy of uncertain significance (MGUS), and >10% of patients with monoclonal gammopathy can have ATTR deposits rather than AL amyloidosis 1, 2. Therefore, detecting a monoclonal protein does NOT confirm AL amyloidosis without tissue typing.

Diagnostic Pathway Based on Monoclonal Protein Results

Pathway A: Monoclonal Protein NEGATIVE

Proceed directly to technetium-99m bone scintigraphy (PYP in USA, DPD/HMDP outside USA) 1, 2, 3

Non-Invasive Diagnosis of ATTR Cardiac Amyloidosis

A definitive diagnosis can be made without biopsy when ALL of the following criteria are met 1, 2, 3:

1. Grade 2 or 3 myocardial uptake on visual scoring:

   • Grade 0: No uptake
   • Grade 1: Mild uptake, less than bone
   • Grade 2: Moderate uptake, equal to bone ✓
   • Grade 3: Intense uptake, greater than bone ✓ 2, 3

2. Quantitative confirmation: Heart-to-contralateral lung ratio >1.5 at 1 hour OR >1.3 at 3 hours 3

3. SPECT imaging added to differentiate true myocardial uptake from blood pool activity 3

4. Absence of any monoclonal protein on comprehensive screening 1, 3

5. Typical cardiac imaging features: LV wall thickness >12 mm, apical-sparing strain pattern, grade ≥2 diastolic dysfunction 2

Pathway B: Monoclonal Protein POSITIVE (Including MGUS)

Endomyocardial biopsy is mandatory because bone scintigraphy cannot differentiate AL from ATTR when any monoclonal protein is detected 1, 2, 3. Over 10% of patients with Grade 2–3 PYP uptake have AL amyloidosis despite positive bone scans 1, 2.

A bone scintigraphy scan alone is neither appropriate nor valid for distinguishing ATTR from AL cardiac amyloidosis. 1

Tissue Biopsy Strategy

For Suspected AL Amyloidosis (Monoclonal Protein Present)

Start with less invasive sites first 2:

1. Abdominal fat pad aspiration: 84% sensitivity for AL, but only 15% for wild-type ATTR and 45% for hereditary ATTR 2, 4
2. Bone marrow biopsy: 69% sensitivity for systemic AL 2

If surrogate-site biopsies are negative but clinical suspicion remains high, proceed directly to endomyocardial biopsy 2. Fat pad biopsy has unacceptably low sensitivity for ATTR and should not be used as the sole diagnostic test when ATTR is suspected 2.

Endomyocardial Biopsy Indications

Endomyocardial biopsy is required when 2:

• Monoclonal protein is detected (even MGUS) and cardiac amyloidosis is suspected
• Non-invasive sites are negative but clinical suspicion remains high
• Both AL and ATTR cardiac amyloidosis are suspected to coexist

Endomyocardial biopsy has approximately 100% specificity and sensitivity for detecting cardiac amyloid deposits 2.

Amyloid Typing: Mandatory for All Positive Biopsies

1. Congo red staining demonstrates apple-green birefringence under polarized light, confirming amyloid deposits 2

2. Mass spectrometry (LC-MS/MS) is the gold standard for identifying the precursor protein with 88% sensitivity and 96% specificity 2. If not immediately available, transfer samples to an experienced reference laboratory 2.

3. Immunohistochemistry can be performed in experienced centers but is less reliable than mass spectrometry 2

Subtype-Specific Confirmation

For ATTR Amyloidosis

DNA sequencing of the TTR gene differentiates wild-type (no mutation) from hereditary (mutation-positive) ATTR 1, 2. A negative genetic test confirms wild-type ATTR, not absence of amyloidosis 2.

For AL Amyloidosis

Referral to a hematologist is indicated for further evaluation of the plasma cell disorder and to guide chemotherapy/immunotherapy targeting aberrant plasma cells 1, 2.

Cardiac Assessment: Required in All Patients

Echocardiography (Mandatory) 1, 2

• Mean LV wall thickness >12 mm without other explanation
• Apical-sparing pattern on longitudinal strain imaging (reduced basal strain, preserved apical strain)
• Right ventricular wall thickening, interatrial septal thickening, valve thickening
• Granular "sparkling" myocardial appearance on 2D imaging
• Pericardial effusion may be present

Cardiac Biomarkers

• NT-proBNP ≥332 ng/L provides >99% sensitivity for cardiac involvement in AL amyloidosis 1, 2
• Elevated cardiac troponin (T or I) further supports myocardial involvement 1, 2

Cardiac MRI (When Not Contraindicated)

• Diffuse subendocardial or transmural late gadolinium enhancement is typical 2
• Elevated native T1 mapping values aid in detection 2
• Contraindication: eGFR <30 mL/min/1.73 m² due to nephrogenic systemic fibrosis risk 2

Systemic Organ Assessment

Systematically evaluate all potentially affected organs 1, 2:

• Renal: serum creatinine, eGFR, 24-hour urine protein for amyloid-related nephropathy 2
• Neurologic: peripheral neuropathy, autonomic dysfunction (orthostatic hypotension) 1, 2
• Hepatic: hepatomegaly with mildly elevated alkaline phosphatase 1, 2

Common Diagnostic Pitfalls to Avoid

1. Never interpret a bone scintigraphy scan without concomitant monoclonal protein screening 1, 3. This is the most critical error.

2. Do not assume AL amyloidosis based solely on monoclonal protein presence without tissue typing, as ATTR and AL can coexist 2

3. Do not rely on fat pad biopsy alone for suspected ATTR cardiac amyloidosis due to its poor sensitivity (15% for wild-type) 2

4. Do not use serum/urine protein electrophoresis (SPEP/UPEP) alone due to lower sensitivity compared to immunofixation 2

5. Interpret sFLC ratios cautiously in renal dysfunction, as impaired clearance can falsely elevate the ratio 1, 2

6. Some ATTR variants (p.Phe84Leu, p.Ser97Tyr) may show negative bone scintigraphy, requiring alternative diagnostic approaches 2