Do both AL (Amyloid Light-chain) and ATTR (Amyloid Transthyretin) amyloidosis have pathognomonic cutaneous manifestations?

Cutaneous Manifestations in AL vs ATTR Amyloidosis

Only AL amyloidosis has pathognomonic cutaneous manifestations, while ATTR amyloidosis does not have characteristic skin findings. 1, 2

AL Amyloidosis: Pathognomonic Cutaneous Features

AL amyloidosis presents with several distinctive cutaneous manifestations that are highly specific for this subtype:

Periorbital Purpura

• Periorbital purpura (periorbital ecchymoses) is the most characteristic and pathognomonic dermatologic finding in AL amyloidosis and should trigger immediate evaluation for this disease. 1, 2
• This finding frequently precedes cardiac diagnosis and warrants urgent referral for comprehensive amyloidosis workup. 2
• The purpura results from amyloid infiltration of blood vessel walls and acquired factor X deficiency. 1

Macroglossia and Soft Tissue Involvement

• Macroglossia and submandibular gland enlargement from soft tissue amyloid infiltration are pathognomonic when present in AL amyloidosis. 1, 2
• These findings result from direct amyloid deposition in soft tissues and are not seen in ATTR amyloidosis. 1

Additional Cutaneous Manifestations

• Easy bruising and coagulopathy manifestations occur due to acquired factor X deficiency in AL amyloidosis. 1, 2
• Skin involvement is specifically listed as an extracardiac manifestation of AL amyloidosis but NOT of ATTR amyloidosis. 2
• Mucocutaneous manifestations occur in approximately 34.7% of systemic amyloidosis cases, predominantly in AL type (50.0% vs 20.0% in other types, P = 0.01). 3
• Purpuric macules are the most common morphology (44.1%), with head and neck being the most frequently affected site (38.2%). 3

ATTR Amyloidosis: Absence of Cutaneous Manifestations

ATTR amyloidosis does not have pathognomonic cutaneous manifestations. 1, 2

Distinguishing Musculoskeletal Features (Not Cutaneous)

• Instead of skin findings, ATTR amyloidosis presents with characteristic musculoskeletal manifestations including:
  • Biceps tendon rupture 1, 2
  • Spinal stenosis 1, 2
  • History of carpal tunnel syndrome 4

These musculoskeletal findings help distinguish ATTR from AL amyloidosis but are not cutaneous manifestations. 1, 4

Clinical Significance and Diagnostic Implications

Why This Distinction Matters

• The presence or absence of cutaneous findings helps distinguish between amyloid types, which is crucial because treatments are completely different. 2
• AL amyloidosis requires chemotherapy targeting the plasma cell clone (daratumumab-based regimens), while ATTR requires TTR stabilizers like tafamidis. 1, 5, 6
• Median survival in AL amyloidosis with heart failure is only 4 months without treatment, making early recognition through cutaneous findings critical. 2

Diagnostic Workup When Cutaneous Findings Present

• When periorbital purpura or macroglossia is identified, immediately order comprehensive monoclonal protein screening including serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) simultaneously. 5, 2
• Skin biopsy from affected areas can demonstrate Congo red-positive amyloid deposits, with mass spectrometry (LC-MS/MS) typing having 88% sensitivity and 96% specificity. 2
• Abdominal fat pad aspiration has 84% sensitivity for AL cardiac amyloidosis and may be considered as an alternative biopsy site. 2

Common Pitfalls

• Do not confuse type I collagen autofluorescence with amyloid positivity when assessing skin biopsies stained with Congo red, as collagen can appear similar to amyloid under fluorescence. 7
• In the absence of specific cutaneous manifestations of amyloidosis, it is unlikely that amyloidogenic light chain deposition would be found incidentally in skin biopsies. 7
• Clinically occult AL amyloid deposition may occur in up to 31% of patients with multiple myeloma, but routine skin biopsies without specific cutaneous lesions are not useful for screening. 7