AL Amyloidosis

Pathophysiology & epidemiology

• Pathogenesis: Clonal plasma cell dyscrasia (often subtle/low burden compared to myeloma) secretes unstable monoclonal light chains.
  • Light chain type: Lambda (λ) light chains are more amyloidogenic than Kappa (κ) (ratio ~3:1).
  • Fibrils deposit in tissues → disruption of tissue architecture and direct cellular toxicity.
• Epidemiology:
  • Most common form of systemic amyloidosis.
  • Age: > 50 years (peak 60–70).
  • Association: 10–15% of patients with multiple myeloma develop AL amyloidosis.

Clinical features (exam high-yields)

• General: Fatigue, weight loss.
• "Aunt Minnie" signs:
  • Macroglossia: Pathognomonic (seen in 10–20%).
  • Periorbital purpura: "Raccoon eyes" (capillary fragility).
• Renal: Nephrotic range proteinuria (most common presentation).
• Cardiac: Restrictive cardiomyopathy (major determinant of prognosis).
• Neurological: Peripheral neuropathy, autonomic dysfunction.

Imaging findings

Cardiac (high yield)

Cardiac involvement carries the worst prognosis.

• Echocardiography:
  • Concentric LV hypertrophy (with granular sparkling appearance of myocardium).
  • Bi-atrial enlargement (restrictive physiology).
  • Pericardial effusion.
  • Reduced longitudinal strain with "apical sparing" (cherry-on-top pattern).
• Cardiac MRI (Gold Standard for tissue characterisation):
  • Morphology: Thickened LV/RV walls, thickened interatrial septum.
  • LGE (Late Gadolinium Enhancement):
    • Global subendocardial LGE: Classic pattern (non-coronary distribution).
    • Can progress to transmural patchiness.
    • Abnormal gadolinium kinetics: Difficulty achieving myocardial nulling; the myocardium may null before or simultaneously with the blood pool (due to rapid washout from blood and retention in expanded ECV).
  • T1 Mapping: Markedly elevated native T1 values (diagnostic utility independent of LGE).
  • ECV (Extracellular Volume): Markedly increased.

Thoracic

• Tracheobronchial:
  • Diffuse submucosal thickening (irregular/nodular).
  • Can calcify (differentiate from Tracheobronchopathia osteochondroplastica – TBO spares the posterior membranous wall; amyloidosis is circumferential).
• Parenchymal:
  • Nodular: Solitary or multiple pulmonary nodules (Amyloidomas). Can cavitate or calcify.
  • Diffuse: Septal thickening (reticulonodular pattern), mimicking lymphangitis carcinomatosis or interstitial oedema.
• Pleural: Recurrent pleural effusions.
• Lymphadenopathy: Hilar/mediastinal calcified nodes (rare but possible).

Abdominal

• Hepatosplenomegaly:
  • Liver: Hepatomegaly with heterogeneous decreased attenuation on CT (infiltration).
  • Spleen: Splenomegaly; can have calcifications.
• Renal:
  • Kidneys often enlarged or normal in size (despite chronic dysfunction).
  • Cortical thinning occurs only in late stages.
• Gastrointestinal:
  • Diffusely thickened folds (stomach/small bowel/colon).
  • Loss of haustra (mimicking chronic ulcerative colitis 'lead pipe' appearance).

Musculoskeletal

• Amyloid Arthropathy: Bilateral symmetrical polyarthritis (mimics Rheumatoid arthritis but lacks erosions).
• Dialysis-related (Beta-2 microglobulin): Note distinct entity, but overlap in appearance (cystic bone lesions, destructive spondyloarthropathy).
• Soft Tissue: Carpal tunnel syndrome (bilateral).

Diagnosis

• Histopathology (Gold standard):
  • Congo Red Stain: Apple-green birefringence under polarised light.
  • Biopsy sites: Abdominal fat pad (sens. ~70–80%), bone marrow, or affected organ.
• Serum Studies: Serum free light chain (FLC) assay, serum/urine immunofixation.
• Scintigraphy:
  • Bone Scintigraphy (Tc-99m DPD/PYP):
    • AL Amyloid: Usually shows low or no uptake (Grade 0 or 1).
    • ATTR Amyloid: Shows high uptake (Grade 2 or 3).
    • Exam Tip: This differentiates AL from ATTR (Transthyretin) amyloidosis.

Differential diagnosis

1. ATTR Amyloidosis (Transthyretin):
   • Wild-type (Senile) or Hereditary.
   • Differentiation: Strong cardiac uptake on bone scintigraphy (DPD scan).
2. Hypertrophic Cardiomyopathy (HCM):
   • Usually asymmetric septal hypertrophy; LGE occurs at RV insertion points, not diffuse subendocardial.
3. Sarcoidosis:
   • Patchy LGE, often involves septum/lateral wall; nodal calcification different pattern.
4. Lymphoma:
   • For nodular lung/GI disease.

Management & guidelines

• Goal: Suppression of plasma cell clone to reduce light chain production.
• Treatment:
  • Chemotherapy (Bortezomib/Cyclophosphamide/Dexamethasone - CyBorD).
  • Autologous Stem Cell Transplantation (ASCT) for eligible candidates.
• Prognosis:
  • Depends heavily on cardiac involvement (Mayo Staging uses Troponin T and NT-proBNP).
  • Median survival without treatment: < 1 year.