What is the appropriate workup for a 28-year-old man with suspected amyloidosis?

Workup for Amyloidosis in a 28-Year-Old Man

Immediate First-Line Testing

Order all three monoclonal protein screening tests simultaneously: serum immunofixation electrophoresis (SIFE), urine immunofixation electrophoresis (UIFE), and serum free light chain assay (sFLC) with kappa/lambda ratio. 1, 2 This triple testing is essential because delays beyond 6 weeks are associated with increased early mortality. 1

Additional Initial Laboratory Tests

• NT-proBNP (or BNP if NT-proBNP unavailable) - disproportionately elevated relative to degree of heart failure with 93% sensitivity and 90% specificity for cardiac involvement 1
• Troponin (T, I, or high-sensitivity) - often elevated in cardiac amyloidosis 1
• Complete blood count with differential 3
• Serum albumin and alkaline phosphatase - hepatomegaly with elevated alkaline phosphatase suggests hepatic involvement 3, 1
• Urinalysis with quantification of proteinuria - unexplained proteinuria is a red flag 1, 2

Initial Cardiac Evaluation

• 12-lead ECG - look for low QRS voltage despite increased wall thickness (voltage-to-mass discordance), pseudoinfarct pattern 1, 4
• Transthoracic echocardiography - first-line cardiac imaging to assess for LV wall thickness ≥12 mm, biatrial enlargement, restrictive filling pattern, and apical sparing pattern on longitudinal strain (apical-to-basal ratio >2.1) 1, 4

Divergent Diagnostic Pathways Based on Monoclonal Protein Results

If Monoclonal Protein IS Detected → Suspect AL Amyloidosis

Proceed with tissue confirmation via abdominal fat pad aspiration as the first-line biopsy site (84% sensitivity for AL cardiac amyloidosis). 1, 2 Request Congo red staining specifically, as standard histology alone may miss the diagnosis. 3

• Bone marrow biopsy is required to demonstrate clonal lambda or kappa-producing plasma cells and exclude multiple myeloma or B-cell lymphoproliferative disorders 1, 2
• If fat pad biopsy is negative but clinical suspicion remains high, proceed directly to endomyocardial biopsy (approximately 100% sensitivity and specificity for cardiac amyloid deposits) 2
• Mass spectrometry (LC-MS/MS) of the biopsy specimen is the gold standard for amyloid typing with 88% sensitivity and 96% specificity 2, 5

If Monoclonal Protein IS NOT Detected → Suspect ATTR Amyloidosis

Proceed with bone scintigraphy using 99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP tracers. 1, 2 Grade 2-3 myocardial uptake in the absence of monoclonal protein is diagnostic for ATTR cardiac amyloidosis without need for biopsy. 1, 2

• DNA mutational analysis (TTR gene sequencing) to differentiate hereditary (variant) ATTR from wild-type (senile) ATTR 2
• If bone scintigraphy is negative but clinical suspicion remains high, consider endomyocardial biopsy 2

Critical Clinical Red Flags in a 28-Year-Old

Given the patient's young age, certain findings should heighten suspicion:

• Bilateral carpal tunnel syndrome without rheumatoid arthritis or trauma 1, 2, 4
• Unexplained peripheral neuropathy with autonomic dysfunction (orthostatic hypotension, erectile dysfunction, gastroparesis) 1, 2
• Heart failure with preserved ejection fraction (HFpEF) with unexplained LV hypertrophy 1, 2
• Macroglossia or periorbital purpura - highly specific for AL amyloidosis 1, 6
• Spontaneous biceps tendon rupture or lumbar spinal stenosis 1, 2, 4
• Unexplained hepatomegaly without imaging abnormalities 2, 7

Advanced Cardiac Imaging (If Echocardiography Is Equivocal)

Cardiac MRI should be reserved for cases where echocardiography shows suggestive but not definitive findings. 1, 4 Key diagnostic features include:

• Diffuse subendocardial or transmural late gadolinium enhancement (LGE) - 88% sensitivity and 100% specificity for AL amyloidosis 4
• Elevated native T1 values (>1020-1044 ms) 1, 4
• Myocardial nulling before blood pool nulling on inversion recovery sequences 4
• Elevated extracellular volume (ECV >0.40) 4

Comprehensive Organ Assessment

Once amyloidosis is confirmed, systematically evaluate all potentially affected organs:

• Gastrointestinal involvement: If symptomatic (bloating, nausea, vomiting, diarrhea, constipation), consider endoscopy and colonoscopy with random biopsies using Congo red staining 3
• Renal function: Assess creatinine, eGFR, and 24-hour urine protein 2
• Hepatic involvement: Hepatomegaly with elevated alkaline phosphatase suggests involvement 3
• Neurologic assessment: Evaluate for peripheral and autonomic neuropathy 1, 2

Common Pitfalls to Avoid

• Do not assume AL amyloidosis based solely on monoclonal protein presence without tissue typing - over 10% of patients with monoclonal gammopathy have ATTR deposits, and both types can coexist 2
• Do not use fat pad biopsy as the sole diagnostic test for suspected ATTR amyloidosis - it has only 15% sensitivity for wild-type ATTR and 45% for hereditary ATTR 2
• Do not rely solely on serum/urine protein electrophoresis (SPEP/UPEP) - immunofixation has higher sensitivity, especially in AL amyloidosis with typically low levels of monoclonal protein 2
• If any monoclonal protein is detected, endomyocardial biopsy is necessary to definitively distinguish AL from ATTR cardiac amyloidosis when cardiac involvement is suspected, as bone scintigraphy alone is insufficient 2

Multidisciplinary Collaboration

• Hematology consultation is essential for AL amyloidosis to guide chemotherapy/immunotherapy targeting aberrant plasma cells 2, 8
• Cardiology consultation for monitoring cardiac decompensation and managing heart failure 2
• Consider referral to specialized amyloidosis centers whenever possible, as the workup requires adequate technology and expertise 8