How do I diagnostically evaluate an older adult with unexplained heart‑failure symptoms, restrictive physiology, increased ventricular wall thickness on echocardiography, low‑voltage QRS complexes, or a history of carpal tunnel syndrome, peripheral neuropathy, or proteinuria for cardiac amyloidosis?

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Last updated: February 19, 2026 • View editorial policy

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Diagnostic Evaluation for Cardiac Amyloidosis

In an older adult with unexplained heart failure, increased ventricular wall thickness (>12 mm), low-voltage QRS, and red-flag features like carpal tunnel syndrome or neuropathy, immediately perform comprehensive monoclonal protein screening (serum free light chains with κ/λ ratio, serum and urine immunofixation) alongside echocardiography with strain imaging, followed by technetium-99m bone scintigraphy if monoclonal protein is absent, or tissue biopsy with mass spectrometry typing if monoclonal protein is present. 1

Initial Clinical Recognition and Red-Flag Assessment

The presence of specific clinical features should immediately trigger a cardiac amyloidosis workup:

Cardiac Red Flags

  • Heart failure with preserved ejection fraction (≥40%), particularly in men over 60 years 1
  • Left ventricular wall thickness >12 mm without alternative explanation (hypertension, aortic stenosis) 1
  • Low QRS voltage on ECG despite increased wall thickness – this voltage-mass discordance is highly specific 1, 2
  • Intolerance to ACE inhibitors or beta-blockers with symptomatic hypotension 1
  • Low-flow aortic stenosis (mean gradient ≤40 mmHg) with preserved ejection fraction in patients >60 years 1
  • Atrial fibrillation with right ventricular thickening 1

Extracardiac Red Flags

  • Bilateral carpal tunnel syndrome without rheumatoid arthritis or trauma 1
  • Peripheral sensorimotor neuropathy with autonomic dysfunction (orthostatic hypotension, gastroparesis, alternating bowel patterns) 1
  • Unexplained proteinuria or nephrotic-range proteinuria 1, 3
  • Biceps tendon rupture or lumbar spinal stenosis 1
  • Hepatomegaly with ascites and lower extremity edema 1

Step 1: Comprehensive Monoclonal Protein Screening (Mandatory First Step)

All three tests must be performed simultaneously – this is non-negotiable: 1, 3, 4

  1. Serum free light chain (sFLC) assay with kappa/lambda ratio

    • Normal ratio: 0.26-1.65 (Binding Site) or 0.31-1.56 (Siemens) with normal renal function 1
    • Ratio widens to 0.31-3.7 in renal failure (Binding Site) 1

  2. Serum immunofixation electrophoresis (SIFE) 1, 3

  3. Urine immunofixation electrophoresis (UIFE) 1, 3

Critical pitfall: Standard serum/urine protein electrophoresis (SPEP/UPEP) alone misses approximately 50% of AL amyloidosis cases and should never be used as the sole screening test. 3, 4

Step 2: Cardiac Imaging Studies

Echocardiography (Perform in All Patients)

  • Mean LV wall thickness >12 mm without alternative cause 1
  • Longitudinal strain imaging showing apical sparing pattern (reduced strain at base with preserved apical strain) 1
  • Restrictive filling pattern with grade ≥2 diastolic dysfunction 3
  • Right ventricular wall thickening, interatrial septal thickening, valve thickening 1
  • Granular sparkling appearance of myocardium 1
  • Pericardial effusion 1

Cardiac Biomarkers

  • NT-proBNP ≥332 ng/L has >99% sensitivity for cardiac involvement in AL amyloidosis 1, 3
  • Elevated troponin T or I supports cardiac involvement 1, 3

Cardiac MRI (If No Contraindications)

  • Diffuse subendocardial or transmural late gadolinium enhancement (LGE) 1
  • Elevated extracellular volume (ECV) >0.40 3
  • Elevated native T1 mapping 1
  • Contraindication: eGFR <30 mL/min/1.73 m² due to nephrogenic systemic fibrosis risk 1

Step 3: Diagnostic Algorithm Based on Monoclonal Protein Results

Pathway A: Monoclonal Protein ABSENT

Proceed directly to technetium-99m bone scintigraphy (PYP, DPD, or HMDP tracers): 1, 3

  • Grade 2-3 myocardial uptake (heart uptake equal to or greater than bone) with typical cardiac imaging features establishes non-invasive diagnosis of ATTR cardiac amyloidosis without tissue biopsy 1, 3
  • Visual grading scale: 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) 1
  • Heart-to-contralateral ratio can be calculated for quantification 1

If bone scintigraphy is negative or equivocal but clinical suspicion remains high:

  • Proceed to endomyocardial biopsy with Congo red staining and mass spectrometry typing 3
  • Consider that certain ATTR variants (p.Phe84Leu, p.Ser97Tyr) may show negative bone scintigraphy 3

Pathway B: Monoclonal Protein PRESENT (Including MGUS)

Tissue biopsy is mandatory – bone scintigraphy alone cannot distinguish AL from ATTR when monoclonal protein is detected: 1, 3

  1. Start with less invasive biopsy sites:

    • Abdominal fat pad aspiration: 84% sensitivity for AL amyloidosis but only 15% for wild-type ATTR and 45% for hereditary ATTR 3, 4
    • Bone marrow biopsy: 69% sensitivity for systemic AL amyloidosis, demonstrates clonal plasma cells 3, 4

  2. If surrogate-site biopsies are negative:

    • Proceed to endomyocardial biopsy (100% sensitivity and specificity for cardiac amyloid deposits) 3
    • This is the preferred approach when both AL and ATTR cardiac amyloidosis are suspected 3

Critical pitfall: Approximately 10-40% of ATTR cardiac amyloidosis patients have concomitant monoclonal gammopathy of uncertain significance (MGUS). Never assume AL amyloidosis based solely on monoclonal protein presence without tissue typing. 3, 4

Step 4: Amyloid Typing (Mandatory for All Positive Biopsies)

Congo Red Staining

  • Demonstrates characteristic apple-green birefringence under polarized light 1, 3, 5

Mass Spectrometry (Gold Standard)

  • Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has 88% sensitivity and 96% specificity for identifying the precursor protein 3, 4
  • If LC-MS/MS is unavailable, transfer Congo red-positive samples to an experienced reference laboratory 3
  • Immunohistochemistry is less reliable than mass spectrometry and should not be the sole typing method 3

Critical pitfall: Misdiagnosis of amyloid type leads to inappropriate treatment and patient harm. AL amyloidosis requires chemotherapy/immunotherapy targeting plasma cells, while ATTR amyloidosis requires TTR stabilizers or gene silencers – these are completely different therapeutic approaches. 3, 4

Step 5: Subtype-Specific Confirmation

For AL Amyloidosis

  • Bone marrow biopsy to demonstrate clonal proliferation of kappa or lambda-producing plasma cells 3, 4
  • Hematology consultation to exclude multiple myeloma or lymphoproliferative disorders 3, 4
  • Confirm plasma cell dyscrasia with abnormal sFLC ratio and monoclonal protein on immunofixation 3

For ATTR Amyloidosis

  • TTR gene sequencing to differentiate wild-type (no mutation) from hereditary (mutation-positive) ATTR 3, 4
  • A negative genetic test confirms wild-type (senile) ATTR amyloidosis 3, 4
  • Genetic testing is particularly important in African-Americans and patients with peripheral neuropathy 4

Step 6: Comprehensive Organ Assessment

Systematically evaluate all potentially affected organs: 1, 3

  • Renal function and 24-hour urine protein for proteinuria assessment 1, 3
  • Neurologic examination for peripheral neuropathy and autonomic dysfunction 1
  • Hepatic function tests (alkaline phosphatase may be mildly elevated) 3
  • Coagulation studies (acquired factor X deficiency may occur) 3

Common Diagnostic Pitfalls to Avoid

  1. Never rely on fat pad biopsy alone for suspected ATTR cardiac amyloidosis – its sensitivity is unacceptably low (15% for wild-type ATTR). 3, 4

  2. Never skip monoclonal protein screening before bone scintigraphy – the sequence matters. Performing both simultaneously risks missing the coexistence of ATTR-CA and MGUS. 1

  3. Never assume AL amyloidosis in patients with monoclonal gammopathy without tissue typing – over 10% of patients with monoclonal gammopathy have ATTR deposits. 3, 4

  4. Never use standard protein electrophoresis (SPEP/UPEP) alone – always order the complete three-test monoclonal protein screen. 3, 4

  5. In patients with renal dysfunction, interpret free light chain ratios cautiously as they may be misleadingly elevated due to impaired clearance rather than clonal disease. 1

  6. Never delay endomyocardial biopsy when surrogate-site biopsies are negative but clinical suspicion remains high. 3

Specialist Referral

  • Hematologist should serve as primary coordinator for AL amyloidosis, directing plasma cell-directed therapy 4
  • Cardiologist is essential for cardiac imaging interpretation and management of heart failure, which drives prognosis and mortality 4
  • Referral to specialized amyloidosis centers is strongly recommended for multidisciplinary expertise in diagnosis and treatment 4

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

3
Guideline

Diagnosis and Management of Amyloidosis

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

4
Guideline

Diagnostic Approach to Amyloidosis

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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