What is the recommended diagnostic workup and treatment for a patient suspected of having amyloidosis, presenting with symptoms such as weight loss, fatigue, and neuropathy, and possibly a family history of the condition?

Diagnostic Workup for Suspected Amyloidosis

For a patient presenting with weight loss, fatigue, and neuropathy with possible family history, immediately obtain serum and urine immunofixation electrophoresis, serum free light chain assay with kappa/lambda ratio, NT-proBNP, troponin, and proceed directly to tissue biopsy with Congo red staining followed by mandatory mass spectrometry typing—treatment depends entirely on distinguishing AL from ATTR amyloidosis. 1, 2

Initial Laboratory Screening

Obtain these tests simultaneously to avoid diagnostic delay:

• Serum and urine immunofixation electrophoresis (not just SPEP alone, which misses monoclonal protein in ~50% of AL cases) 1
• Serum free light chain (FLC) assay with kappa/lambda ratio (reference range 0.26-1.65 for normal renal function; lambda chains more common than kappa in amyloidosis) 1, 3, 4
• NT-proBNP (>332 ng/L has >99% sensitivity for cardiac involvement; >8500 ng/L indicates very high-risk disease) 1, 3
• Troponin T (>0.035 mcg/L indicates cardiac involvement) 1
• Complete metabolic panel including albumin, liver enzymes, and creatinine 1
• 24-hour urine protein and eGFR for renal assessment 3

Critical point: In AL amyloidosis, only 12% have no detectable monoclonal protein when both serum and urine are analyzed properly, so negative SPEP alone does not exclude the diagnosis. 1, 4

Tissue Biopsy and Typing (Mandatory)

The diagnosis requires histologic confirmation—imaging alone is never sufficient. 2, 3

Biopsy Site Selection:

• Abdominal fat pad aspiration (least invasive, positive in ~84% of systemic cases) 1, 3
• Bone marrow biopsy (positive in >90%, also evaluates plasma cell burden) 1
• Rectal biopsy (positive in 84% of cases) 4
• Involved organ biopsy (kidney, liver, or endomyocardial biopsy if other sites negative; >90% positive) 1, 4
• Duodenal biopsy (highest GI yield if GI symptoms present) 2

Histologic Confirmation:

• Congo red staining showing apple-green birefringence under polarized light microscopy is pathognomonic and mandatory 2, 3, 5
• Eosinophilic (pink) hyaline material on routine H&E staining should prompt Congo red staining 3

Amyloid Typing (Absolutely Required):

Never initiate treatment without typing—AL requires chemotherapy while ATTR requires targeted therapy like tafamidis or patisiran. 1, 2, 3

• Mass spectrometry is the gold standard (88% sensitivity, 96% specificity) 3, 5
• Alternative methods: immunohistochemistry, immunofluorescence, or immunogold electron microscopy 1, 3
• Genetic testing (TTR gene sequencing) is mandatory if ATTR is suspected, especially in African-Americans and patients with peripheral neuropathy or family history 1, 6

Cardiac Evaluation

Given the patient's fatigue (potential cardiac symptom), assess cardiac involvement immediately:

• Echocardiography (first-line): Look for LV wall thickness ≥12 mm with small cavity, biatrial enlargement, restrictive transmitral Doppler pattern, and apical sparing on longitudinal strain 2, 3
• ECG: Low QRS voltage despite increased wall thickness on echo is a red flag 2
• Cardiac MRI with gadolinium: Diffuse subendocardial or transmural late gadolinium enhancement is highly suggestive 2, 3

Neurologic Assessment

The patient's neuropathy requires detailed characterization:

• Neurologist consultation with expertise in peripheral neuropathy 1
• Distinguish between:
  • Length-dependent small-fiber polyneuropathy with autonomic dysfunction (typical of ATTR) 6, 7
  • Distal sensory symptoms (numbness, paresthesias, dysesthesias) 8
  • Autonomic dysfunction: orthostatic hypotension, GI dysmotility, urinary retention 1, 7
• Evaluate for carpal tunnel syndrome (bilateral CTS without trauma/rheumatoid arthritis is a red flag) 2, 4
• Modified body mass index (mBMI): Calculate as serum albumin × BMI; <600 kg/m²·g/L indicates malnutrition and poor prognosis 1, 2

Additional Organ System Assessment

• Hepatic: Palpate for hepatomegaly (present in ~50% at diagnosis); check alkaline phosphatase 1, 4, 8
• Renal: Proteinuria present in >90% of cases with renal involvement 4
• Ophthalmologic exam: Look for vitreous opacities (suggests ATTR) 6

Risk Stratification After Diagnosis

Use Mayo 2004 staging for AL amyloidosis:

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

Critical Diagnostic Pitfalls

Avoid these common errors that delay diagnosis and worsen outcomes:

• Never rely on SPEP alone—always order immunofixation of both serum and urine 1
• Never skip amyloid typing—treatment for AL (chemotherapy/transplant) versus ATTR (tafamidis, patisiran, inotersen) is completely different 1, 2, 3, 9, 10
• Request Congo red staining specifically—diagnosis is missed on routine histology 2, 3
• Don't assume negative family history excludes hereditary ATTR—family history is not always known and penetrance varies 6
• Recognize that symptoms may mimic CIDP, diabetic neuropathy, or idiopathic axonal polyneuropathy—maintain high suspicion 6, 7

Timeline for Action

By the time symptoms of weight loss, fatigue, and neuropathy appear, organ damage has already occurred—diagnostic delay directly worsens mortality. 1 In AL amyloidosis, 25% of patients die within 6 months of diagnosis, and in ATTR amyloidosis, 25% die within 24 months. 8 Complete the diagnostic workup within 2-4 weeks to enable early treatment initiation before irreversible end-organ damage progresses.