TTR Amyloidosis and Splenomegaly
Splenomegaly is not a recognized manifestation of TTR amyloidosis, and its presence should prompt investigation for alternative diagnoses, particularly AL amyloidosis or other hematologic conditions. 1
Key Distinction: TTR vs. AL Amyloidosis
TTR amyloidosis does not typically cause splenomegaly. The organ involvement pattern differs fundamentally from AL amyloidosis:
Typical TTR Amyloidosis Manifestations
- Cardiac involvement: Restrictive cardiomyopathy is the hallmark of ATTR-CM 1
- Neurologic involvement: Peripheral and autonomic neuropathy, particularly in ATTRv 2
- Gastrointestinal involvement: Hepatomegaly (not splenomegaly) with elevated alkaline phosphatase may occur, but is uncommon and typically indicates widespread systemic distribution rather than dominant organ involvement 1
AL Amyloidosis Pattern
- Hepatic involvement: Hepatomegaly with elevated alkaline phosphatase occurs in approximately 15-20% of AL amyloidosis patients 1
- Splenomegaly: More characteristic of AL amyloidosis when present
- Hematologic disease: Light chain production from plasma cell dyscrasia 1
Diagnostic Approach When Splenomegaly is Present
If a patient presents with suspected amyloidosis and splenomegaly, you must exclude AL amyloidosis first:
- Screen for monoclonal light chains (serum free light chains, serum and urine immunofixation) to exclude AL amyloidosis 3
- Tc-99m-PYP bone scintigraphy will be positive in ATTR but negative in AL amyloidosis 3
- Tissue biopsy with Congo red staining and mass spectrometry-based proteomic analysis to definitively identify the amyloid protein type 4
Management Implications
If TTR Amyloidosis is Confirmed Despite Splenomegaly
The management focuses on the primary manifestations (cardiac and/or neurologic):
Disease-Modifying Therapy:
- Tafamidis for ATTR-CM (both wild-type and variant) 1, 5
- TTR silencers (patisiran, inotersen, vutrisiran) only for ATTRv polyneuropathy, not for ATTRwt or cardiac-only disease 5
Supportive Management:
- Cardiac symptoms: Judicious diuresis with loop diuretics (torsemide or bumetanide preferred over oral furosemide due to better bioavailability) 1, 3
- GI symptoms: Dietary modifications, antiemetics, prokinetics as needed 1
- Avoid: Digoxin and calcium channel blockers due to binding to amyloid fibrils causing toxicity and exaggerated hypotensive responses 5
If AL Amyloidosis is Diagnosed
- Plasma cell-directed therapy is the cornerstone (bortezomib-based regimens, daratumumab) 4
- TTR-specific therapies have no role in AL amyloidosis 3
Critical Pitfalls to Avoid
- Do not assume TTR amyloidosis explains splenomegaly - this is not a typical manifestation and warrants investigation for other causes 1
- Do not initiate TTR-specific therapy without confirming the amyloid protein type through proper diagnostic workup 3, 4
- Do not use TTR silencers for ATTRwt disease - they are only approved and effective for ATTRv polyneuropathy 5