What is the recommended diagnosis and treatment approach for a patient suspected of having Transthyretin (TTR) amyloidosis, particularly with a family history of the disease and symptoms suggestive of amyloid deposition in organs such as the heart or nerves?

Diagnosis and Treatment of TTR Amyloidosis

Diagnostic Algorithm for Suspected TTR Amyloidosis

In patients with suspected TTR amyloidosis, particularly those with family history and cardiac or neurologic symptoms, immediately perform monoclonal protein screening (serum free light chains, serum and urine immunofixation) alongside cardiac imaging and consider bone scintigraphy, as this non-invasive approach can establish diagnosis without biopsy in most cases. 1, 2

Initial Clinical Recognition: Red Flags

When evaluating for TTR amyloidosis, specifically look for these high-yield clinical patterns:

• Cardiac manifestations: Left ventricular wall thickness ≥12-14 mm with disproportionately low QRS voltage on ECG (voltage-to-mass discordance), heart failure with preserved ejection fraction, or restrictive cardiomyopathy pattern 1, 2
• Neurologic manifestations: Length-dependent sensorimotor polyneuropathy with autonomic dysfunction (orthostatic hypotension, erectile dysfunction, gastrointestinal dysmotility), bilateral carpal tunnel syndrome (especially without rheumatoid arthritis or trauma), or small fiber neuropathy 1, 3, 4
• Systemic clues: Unexplained weight loss, lumbar spinal stenosis, spontaneous biceps tendon rupture, vitreous opacities, or unexplained proteinuria 1, 4
• Family history: Any first-degree relative with amyloidosis, unexplained cardiomyopathy, or polyneuropathy 5, 6

Step 1: Monoclonal Protein Screening (Critical First Step)

Order all three tests simultaneously—delays beyond 6 weeks increase early mortality 2:

• Serum free light chain assay (sFLC) with kappa/lambda ratio
• Serum immunofixation electrophoresis (SIFE)
• Urine immunofixation electrophoresis (UIFE) 1, 7

Critical pitfall: Do not rely on serum/urine protein electrophoresis (SPEP/UPEP) alone, as these have lower sensitivity and will miss cases 7. Approximately 5% of patients over age 70 have monoclonal gammopathy of undetermined significance (MGUS), and over 10% of patients with monoclonal protein can have ATTR deposits rather than AL amyloidosis 7, 2.

Step 2: Divergent Pathways Based on Monoclonal Protein Results

If Monoclonal Protein is ABSENT:

Proceed directly to bone scintigraphy with 99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP tracers 1, 2:

• Grade 2-3 myocardial uptake on bone scintigraphy in the absence of monoclonal protein is diagnostic for ATTR cardiac amyloidosis without need for biopsy 1, 2
• This non-invasive diagnosis is highly specific and should be considered in patients >65 years with bilateral carpal tunnel syndrome, no family history of hypertrophic cardiomyopathy, and features consistent with cardiac amyloidosis on ECG and imaging 1

Important caveat: Some rare ATTR variants (p.Phe84Leu, p.Ser97Tyr) may show negative bone scintigraphy, requiring endomyocardial biopsy if clinical suspicion remains high 7.

If Monoclonal Protein is DETECTED:

You cannot rely on bone scintigraphy alone—endomyocardial biopsy is necessary to definitively distinguish AL from ATTR cardiac amyloidosis, as both can coexist 1, 7, 2:

1. First attempt abdominal fat pad aspiration (84% sensitivity for AL amyloidosis, but only 15% for wild-type ATTR and 45% for hereditary ATTR) 1, 7
2. If fat pad biopsy is negative but clinical suspicion remains high, proceed directly to endomyocardial biopsy 1, 7
3. Perform bone marrow biopsy to demonstrate clonal plasma cells and exclude multiple myeloma 7, 2

Step 3: Tissue Confirmation and Amyloid Typing

When biopsy is required:

• Congo red staining demonstrates apple-green birefringence under polarized microscopy (approximately 100% specificity and sensitivity for cardiac deposits) 1
• Mass spectrometry (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity—this is superior to immunohistochemistry 1, 7
• If mass spectrometry is unavailable, transfer Congo red-positive samples to an experienced reference laboratory 7

Step 4: TTR Gene Sequencing (Mandatory for All ATTR Cases)

Perform TTR gene sequencing in ALL patients with confirmed ATTR amyloidosis, regardless of family history 1, 5:

• This differentiates hereditary (ATTRv/ATTRm) from wild-type (ATTRwt) disease
• Penetrance of ATTRm varies among variants and families—absence of family history does not exclude hereditary disease 1
• V122I (p.V142I) variant occurs in 3-4% of African Americans and is the most common pathogenic variant identified in genetic testing programs 1, 6
• If a TTR variant is detected, provide genetic counseling and recommend cascade screening of first-degree relatives 1, 5

Cardiac Imaging Protocol

Echocardiography (First-Line)

Perform in all patients with suspected cardiac amyloidosis 1, 7:

• Measure LV wall thickness (≥12 mm is significant), assess for biatrial enlargement, and evaluate for restrictive transmitral Doppler filling pattern 2
• Apical sparing pattern on speckle-tracking strain with apical-to-basal ratio >2.1 is highly specific for cardiac amyloidosis 2

Cardiac MRI (When Echocardiography is Equivocal)

Consider when echocardiographic windows are inadequate or findings are suggestive but not definitive 1, 2:

• Diffuse subendocardial or transmural late gadolinium enhancement (LGE) is characteristic 1
• Elevated native T1 values (>1020-1044 ms) support the diagnosis 2
• CMR with LGE should be considered specifically when cardiac amyloidosis is suspected 1

Biomarker Assessment

• NT-proBNP: Disproportionately elevated relative to degree of heart failure (93% sensitivity, 90% specificity for cardiac involvement) 1, 2
• Cardiac troponin (T, I, or high-sensitivity): Often elevated in cardiac amyloidosis 1, 2
• These biomarkers are used for prognostic staging: Stage 1 (neither NT-proBNP >3000 pg/mL nor eGFR <45 mL/min), Stage 2 (one threshold met), Stage 3 (both thresholds met) 1

Treatment Approach

For ATTR Cardiac Amyloidosis (Wild-Type or Hereditary)

Tafamidis is the FDA-approved disease-modifying therapy for ATTR-CM in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization 8:

• Dosing: Tafamidis 80 mg once daily (or tafamidis meglumine 61 mg once daily equivalent) 8
• The pivotal trial demonstrated 30% relative reduction in all-cause mortality (HR 0.70,95% CI 0.51-0.96, p=0.026) and significant reduction in cardiovascular hospitalizations over 30 months 8
• Treatment is most effective when initiated earlier in the disease course 1

For Hereditary ATTR with Polyneuropathy

Gene silencing therapies are approved for polyneuropathy stages 1 and 2 (Coutinho classification) 9:

• Patisiran (RNA interference agent) or inotersen (antisense oligonucleotide) significantly reduce TTR protein levels and slow neuropathy progression 9
• Both agents improve quality of life in ATTRv patients 9

Supportive Cardiac Management

• Diuretics are the mainstay of heart failure therapy in cardiac amyloidosis 7
• Standard heart failure medications (ACE inhibitors, beta-blockers) may be ineffective or harmful due to the restrictive physiology 7
• Avoid digoxin and calcium channel blockers, as amyloid fibrils can bind these agents, increasing toxicity risk 7

Family Screening Protocol

All first-degree relatives of patients with confirmed hereditary ATTR should undergo genetic screening with TTR gene sequencing 5:

• Begin surveillance approximately 10 years before the age of disease onset in affected family members 5
• Annual assessments should include ECG, echocardiogram with strain imaging, cardiac biomarkers, and targeted neurologic examination 5
• In-depth assessments every 3-5 years should include bone scintigraphy, cardiac MRI with LGE, and neurologic assessments if symptoms develop 5

Critical Pitfalls to Avoid

1. Do not assume AL amyloidosis based solely on monoclonal protein presence—ATTR and AL can coexist, requiring tissue typing for definitive diagnosis 7, 2
2. Do not use fat pad biopsy as the sole diagnostic test for suspected ATTR cardiac amyloidosis—its sensitivity is unacceptably low (15% for wild-type, 45% for hereditary) 1, 7
3. Do not skip TTR gene sequencing even with negative family history—penetrance varies and wild-type disease must be distinguished from hereditary forms for family counseling and prognosis 1, 5
4. Do not delay diagnosis—delays beyond 6 weeks are associated with increased early mortality, and treatment efficacy is greatest when initiated early 1, 2