Diagnostic Workup and Treatment for Suspected Amyloidosis
For patients with suspected amyloidosis, the diagnostic workup should begin with screening for serum and urine monoclonal light chains, followed by appropriate imaging studies based on clinical presentation, with treatment directed at the specific type of amyloidosis identified. 1
Initial Diagnostic Approach
Step 1: Clinical Suspicion and Initial Screening
- Clinical red flags that should prompt amyloidosis workup:
- Left ventricular wall thickness ≥14 mm with fatigue, dyspnea, or edema
- Discordance between wall thickness on echocardiogram and QRS voltage on ECG
- History of carpal tunnel syndrome, spinal stenosis, or peripheral neuropathy
- Unexplained proteinuria or renal dysfunction
- Orthostatic hypotension or autonomic dysfunction
- Skin bruising or periorbital purpura
- Macroglossia (highly specific for AL amyloidosis)
- Aortic stenosis in patients ≥65 years
Step 2: Initial Laboratory Testing
- Serum and urine immunofixation electrophoresis
- Serum free light chain assay
- Complete blood count with differential
- Comprehensive metabolic panel including renal function
- BNP or NT-proBNP and cardiac troponins (sensitive markers for cardiac involvement)
Step 3: Tissue Diagnosis
- Tissue biopsy is required for definitive diagnosis
- Preferred initial biopsy sites:
- Abdominal subcutaneous fat aspiration (least invasive)
- Involved organ if clinically indicated
- Bone marrow biopsy (especially if monoclonal gammopathy is present)
- Congo red staining with apple-green birefringence under polarized light confirms amyloid
Amyloid Typing
If Monoclonal Protein Present:
- Hematology-oncology consultation
- Consider heart or other organ biopsy if clinically indicated
- If amyloid confirmed → AL amyloidosis diagnosis
If No Monoclonal Protein Present:
- Perform bone scintigraphy (Tc-99m-PYP scan)
- Positive scan without monoclonal protein → ATTR amyloidosis
- Perform TTR gene sequencing to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt) 1
Treatment Approach
For AL Amyloidosis:
- Treatment by hematologist-oncologist
- Options include:
- High-dose melphalan with autologous stem cell transplantation (for eligible patients)
- Oral melphalan and dexamethasone (for transplant-ineligible patients)
- Bortezomib-based regimens
- Lenalidomide and dexamethasone
- Daratumumab-based regimens 1
For ATTR Amyloidosis:
- Tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg once daily) is indicated for ATTR cardiomyopathy to reduce cardiovascular mortality and hospitalization 2
- For ATTRv:
- Genetic counseling
- Consider screening family members
- TTR silencer therapy if neuropathy is present
For Cardiac Amyloidosis with Atrial Fibrillation:
- Anticoagulation is reasonable regardless of CHA₂DS₂-VASc score 1
Monitoring Response to Treatment
- For AL amyloidosis:
- Monitor serum and urine monoclonal protein
- For light chain only disease, monitor serum free light chains
- Assess organ response (particularly cardiac and renal)
- For ATTR amyloidosis:
- Monitor cardiac function with echocardiography
- Follow BNP/NT-proBNP levels
- Assess functional capacity
Important Caveats and Pitfalls
Misdiagnosis risk: Symptoms of amyloidosis are often nonspecific, leading to delayed diagnosis. Maintain high index of suspicion in patients with multisystem disease.
Cardiac involvement: Cardiac amyloidosis is the major determinant of survival. Early detection is critical for better outcomes.
Typing errors: Some patients may have two potential amyloid-forming proteins. Direct tissue typing through mass spectrometry may be necessary in ambiguous cases.
Treatment toxicity: Patients with cardiac amyloidosis are particularly sensitive to fluid shifts and medication side effects. Careful monitoring is essential.
Renal response: In AL amyloidosis, renal response (≥50% reduction in proteinuria) after treatment is associated with improved survival and is an independent marker of treatment success.
By following this systematic approach to diagnosis and treatment, clinicians can improve outcomes for patients with this complex and often challenging disease.