What is the appropriate diagnostic workup and treatment approach for a patient suspected of having amyloidosis?

Amyloid Workup: Diagnostic Algorithm

Initial Clinical Suspicion and Red Flags

When you suspect amyloidosis, immediately obtain serum and urine immunofixation electrophoresis, serum free light chain assay with kappa/lambda ratio, NT-proBNP, troponin, and complete metabolic panel—these tests should be ordered simultaneously to avoid diagnostic delay. 1, 2, 3

Key clinical presentations that should trigger immediate workup include:

• Cardiac: Heart failure with preserved ejection fraction with LV wall thickness ≥12-14 mm plus low QRS voltage on ECG (this paradoxical finding is highly suggestive) 1, 2, 4
• Renal: Nephrotic range proteinuria (>3g/24hr) without diabetes 1
• Neurologic: Bilateral carpal tunnel syndrome without rheumatoid arthritis or trauma, peripheral neuropathy with autonomic features 1, 2
• Gastrointestinal: Unexplained weight loss, early satiety, hepatomegaly with elevated alkaline phosphatase 1, 2
• Musculoskeletal: Spontaneous biceps tendon rupture, lumbar spinal stenosis, macroglossia 1

Mandatory Tissue Diagnosis and Typing

Tissue biopsy with Congo red staining demonstrating apple-green birefringence under polarized light is absolutely required for diagnosis—imaging alone is never sufficient. 1, 2

Biopsy Site Selection Algorithm:

1. First-line surrogate sites (less invasive, perform first):

   • Abdominal fat pad aspiration: 84% sensitivity for AL amyloidosis, 15% for ATTRwt 1, 3
   • Bone marrow biopsy: 69% sensitivity for systemic AL, >90% positivity rate, also evaluates plasma cell burden 1, 3

2. If surrogate sites are negative but clinical suspicion remains high:

   • Proceed directly to biopsy of the clinically affected organ (endomyocardial biopsy for cardiac involvement, renal biopsy for nephrotic syndrome, duodenal biopsy for GI symptoms) 1, 2

3. Amyloid typing is mandatory after positive Congo red staining:

   • Mass spectrometry (LC-MS/MS) is the gold standard: 88% sensitivity, 96% specificity 1, 2, 3
   • This step is critical because AL amyloidosis requires chemotherapy while ATTR amyloidosis requires targeted therapy like tafamidis 1, 5

Critical pitfall: Always request Congo red staining specifically when submitting biopsies, as amyloidosis may be missed on routine histology alone 1, 2

Distinguishing AL from ATTR Amyloidosis

After confirming amyloid deposits, immediately determine the type:

For AL Amyloidosis:

• Serum and urine immunofixation electrophoresis (not just SPEP/UPEP—these have lower sensitivity) 1
• Serum free light chain assay with kappa/lambda ratio 1, 3
• Bone marrow biopsy showing clonal plasma cells producing lambda or kappa light chains 1
• Exclude multiple myeloma or B-cell lymphoma 1

For ATTR Amyloidosis:

• If no monoclonal protein is detected and cardiac imaging shows typical features, nuclear scintigraphy (Tc-99m PYP, DPD, or HMDP) can diagnose ATTR cardiac amyloidosis without endomyocardial biopsy 1
• TTR gene sequencing is mandatory even without family history to differentiate hereditary (ATTRv) from wild-type (ATTRwt), as penetrance varies 1

Critical distinction: In patients with monoclonal gammopathy AND positive nuclear scintigraphy, endomyocardial biopsy with mass spectrometry is required to definitively establish whether cardiac deposits are AL or ATTR 1

Comprehensive Organ Involvement Assessment

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

Cardiac Evaluation (perform in all patients):

• Echocardiography (first-line): Look for LV wall thickness ≥12 mm, biatrial enlargement, restrictive filling pattern, apical sparing on longitudinal strain 1, 2, 3
• NT-proBNP: >332 ng/L has >99% sensitivity for cardiac involvement; >8500 ng/L indicates very high-risk disease 1, 3
• Cardiac MRI: Diffuse subendocardial or transmural late gadolinium enhancement is highly suggestive 1, 2, 3
• ECG: Low QRS voltage despite LV hypertrophy is a key diagnostic clue 1, 4

Renal Assessment:

• 24-hour urine protein collection and urine immunofixation 1, 3
• Serum creatinine and eGFR 3
• Consider renal biopsy if significant proteinuria or renal insufficiency present 1

Hepatic Assessment:

• Hepatomegaly with elevated alkaline phosphatase suggests hepatic involvement 1
• Abdominal ultrasound or CT if alkaline phosphatase elevated 1

Neurologic Assessment:

• Neurology consultation for peripheral neuropathy characterization 3
• Evaluate for bilateral carpal tunnel syndrome 1, 2, 3

Nutritional Status:

• Calculate modified BMI (mBMI = serum albumin × BMI): <600 kg/m²·g/L indicates poor nutritional status and poor prognosis 1, 2, 3

Gastrointestinal (if symptomatic):

• Endoscopy and colonoscopy with random biopsies (duodenum has highest yield) 1, 2
• Specifically request Congo red staining 1

Risk Stratification for AL Amyloidosis

Use the Mayo 2004 staging system (or European 2015 modification) based on cardiac biomarkers 1, 3:

• Stage I: Troponin T <0.035 mcg/L AND NT-proBNP <332 ng/L
• Stage II: One biomarker elevated
• Stage III: Both biomarkers elevated
• Stage IIIB (very high risk): NT-proBNP >8500 ng/L 1, 3

Troponin T >0.06 ng/mL or NT-proBNP >5000 ng/L indicates high transplant-related mortality and affects eligibility for autologous stem cell transplant 1

Treatment Approach Based on Type

AL Amyloidosis:

• Transplant-eligible patients: High-dose melphalan with autologous stem cell transplant achieves 40% complete hematologic response and prolonged survival 1
• Non-transplant candidates: Bortezomib-based chemotherapy (VCD regimen shows up to 90% hematologic response) or melphalan/dexamethasone 1
• Treatment must begin before irreversible organ damage occurs 1

ATTR Amyloidosis:

• ATTR cardiac amyloidosis: Tafamidis (VYNDAQEL/VYNDAMAX) is FDA-approved to reduce cardiovascular mortality and hospitalization in adults with ATTR-CM 5
• Hereditary ATTR with polyneuropathy: Patisiran (ONPATTRO) is FDA-approved for polyneuropathy of hereditary transthyretin-mediated amyloidosis 6

The cornerstone of management is early recognition and treatment initiation before irreversible organ damage occurs—median survival in AL amyloidosis is only 4 months once heart failure develops. 1