How should cardiac amyloidosis be diagnosed in a 47‑year‑old woman with bilateral carpal‑tunnel syndrome that failed surgery and recurrent hand and foot paresthesias?

Diagnosis of Cardiac Amyloidosis

In a 47-year-old woman with bilateral carpal tunnel syndrome that failed surgery and recurrent paresthesias, cardiac amyloidosis should be diagnosed using a structured multimodality approach that begins with echocardiography to assess for increased left ventricular wall thickness (>12 mm), followed by 99mTc-PYP/DPD/HMDP nuclear scintigraphy with concurrent monoclonal protein screening, and tissue biopsy when needed for definitive typing. 1

Clinical Context and Red Flags

This patient presents with a critical red flag: unexplained bilateral carpal tunnel syndrome, defined as symptomatic median nerve compression at the wrist without rheumatoid arthritis or known trauma. 1 This is particularly significant because:

• Bilateral CTS precedes cardiac amyloidosis by 5-10 years in most cases, making it an early diagnostic indicator 2, 3
• The prevalence of amyloid deposits in carpal ligament tissue ranges from 10.2% to 12.6% in patients over age 50-60 undergoing CTS surgery 2, 4
• Failed CTS surgery with recurrent symptoms further raises suspicion for underlying systemic amyloidosis 5

Additional red flags to assess include: unexplained peripheral sensorimotor neuropathy (which this patient has with recurrent paresthesias), unexplained heart failure, intolerance to antihypertensive medications, low voltage on ECG despite increased wall thickness, and family history of cardiomyopathy or polyneuropathy. 1

Diagnostic Algorithm

Step 1: Initial Cardiac Imaging

Echocardiography is the appropriate first-line imaging modality: 1

• Assess for mean LV wall thickness >12 mm without alternative cardiac cause 1
• Look for preserved ejection fraction (≥40%), which is typical 1
• Evaluate for additional features: atrial septal thickening, granular sparkling appearance, restrictive diastolic dysfunction, valve thickening, and reduced longitudinal strain with apical sparing 1
• Check for discordance between wall thickness and QRS voltage on ECG 1

Step 2: Concurrent Nuclear Scintigraphy and Monoclonal Protein Screening

The key diagnostic pathway depends on whether you suspect ATTR or AL amyloidosis. The 2021 expert consensus recommends performing both tests together rather than sequentially: 1

99mTc-PYP/DPD/HMDP Bone Scintigraphy: 1

• Grade 2 or 3 myocardial uptake is diagnostic for ATTR cardiac amyloidosis when combined with negative monoclonal protein screen
• This allows non-biopsy diagnosis of ATTR cardiac amyloidosis

Monoclonal Protein Screen (must be done concurrently): 1

• Serum free light chains (kappa and lambda) with ratio assessment
• Serum and urine immunofixation electrophoresis
• Critical caveat: 10-40% of ATTR patients have concomitant monoclonal gammopathy of uncertain significance (MGUS), especially in elderly patients 1
• Abnormal FLC ratio reference ranges: 0.26-1.65 (normal renal function) or 0.31-3.7 (renal failure) using Binding Site assay 1

Step 3: Cardiac Biomarkers

Measure cardiac biomarkers to assess disease severity and support diagnosis: 1

• NT-proBNP (age-adjusted) or BNP
• High-sensitivity troponin T/I
• Abnormal biomarkers with typical imaging features support AL cardiac amyloidosis diagnosis even without biopsy 1

Step 4: Tissue Biopsy and Typing

For ATTR Cardiac Amyloidosis: 1

If Grade 2-3 nuclear uptake AND negative monoclonal protein screen AND typical cardiac imaging features are present, no cardiac biopsy is needed for ATTR diagnosis.

However, given this patient's failed CTS surgery, consider obtaining tissue from any future hand surgery:

• Tenosynovial or transverse carpal ligament biopsy during revision CTS surgery 2, 4
• Congo red staining with apple-green birefringence under polarized light 1
• Typing by mass spectrometry is mandatory (not just immunohistochemistry) as >10% of patients with monoclonal gammopathy can have ATTR deposits 1

For AL Cardiac Amyloidosis: 1

AL amyloidosis requires tissue diagnosis and cannot be diagnosed by imaging alone:

• Extracardiac biopsy (abdominal fat pad aspiration has 84% sensitivity for AL-CM, or bone marrow biopsy with 69% sensitivity) 1
• If surrogate site biopsy is negative but suspicion remains high, proceed to endomyocardial biopsy 1
• Must demonstrate both: (1) amyloid deposits on tissue AND (2) evidence of plasma cell dyscrasia 1

Step 5: Subtype Determination for ATTR

Once ATTR is confirmed, determine if wild-type (ATTRwt) or variant (ATTRv):

• Genetic testing for TTR gene mutations
• Family history assessment for hereditary amyloidosis 1

Cardiac Magnetic Resonance (CMR)

CMR can be used as an alternative or adjunct to echocardiography: 1

• Typical features include subendocardial or transmural late gadolinium enhancement (LGE) and increased extracellular volume (ECV) 1
• Contraindicated if eGFR <30 mL/min/1.73m² due to nephrogenic systemic fibrosis risk 1
• Useful when echocardiography is inconclusive

Critical Pitfalls to Avoid

Do not dismiss an abnormal monoclonal protein screen in the setting of positive nuclear scintigraphy. This requires hematology consultation to distinguish between MGUS, AL amyloidosis, or multiple myeloma, as these can coexist with ATTR. 1

Do not rely on immunohistochemistry alone for amyloid typing. Mass spectrometry is the gold standard and prevents misclassification. 1

Do not overlook renal function when interpreting free light chain ratios. Chronic kidney disease causes polyclonal elevation that can confound interpretation. 1

In this specific patient with bilateral CTS and recurrent symptoms, strongly consider obtaining tissue during any future hand surgery rather than waiting for cardiac symptoms to progress, as this represents an opportunity for early diagnosis when disease-modifying therapies are most effective. 2, 4, 3

Age and Gender Considerations

While this patient is younger (47 years) than the typical ATTRwt population (usually >60 years), the presence of bilateral CTS with failed surgery warrants full evaluation. 1 Consider ATTRv (hereditary) more strongly in younger patients with family history. 1

Recent screening studies show that among patients 5-15 years post-bilateral CTS surgery, 4.8% had undiagnosed cardiac amyloidosis (8.8% in men, 21.2% in men ≥70 years with BMI <30). 6 This patient's age suggests evaluation now rather than waiting, given the temporal relationship between CTS and cardiac involvement.