What are the signs and symptoms of amyloid disease?

Signs and Symptoms of Amyloidosis

Amyloidosis presents with a wide range of signs and symptoms affecting multiple organ systems, with cardiac, neurologic, gastrointestinal, and soft tissue manifestations being the most common clinical presentations. 1, 2

Cardiac Manifestations

• Heart failure with preserved ejection fraction (HFpEF)
• Restrictive cardiomyopathy
• ECG abnormalities with low QRS voltage despite ventricular wall thickening
• "Grainy" appearance of myocardium on echocardiography
• Atrial fibrillation

Neurologic Manifestations

• Peripheral neuropathy:

  • Small-fiber neuropathy with sensory loss and pain in toes and feet (initial presentation)
  • Symptoms worse at end of day or nighttime
  • Numbness, paresthesia, pain beginning symmetrically in feet, later progressing to fingertips
  • Rapidly progressive (15-20× faster than diabetic neuropathy) 1
  • Distal muscle weakness (toe extensors, ankle dorsiflexors)
  • Reduced or absent reflexes
  • Wide-based unsteady gait

• Autonomic neuropathy:

  • Orthostatic hypotension
  • Alternating diarrhea and constipation (particularly night diarrhea)
  • Urinary retention
  • Sexual dysfunction

• Other neurologic manifestations:

  • Carpal tunnel syndrome
  • Lumbar stenosis
  • Lumbosacral radiculopathy

Gastrointestinal Manifestations

• Nausea and early satiety
• Diarrhea (including night diarrhea)
• Constipation
• Alternating diarrhea and constipation
• Malabsorption
• Weight loss
• GI bleeding
• Hepatomegaly with mildly abnormal liver tests 2

Soft Tissue and Other Manifestations

• Macroglossia (enlarged tongue) - highly specific for AL amyloidosis 3
• Periorbital purpura - highly specific for AL amyloidosis 3
• Submandibular gland enlargement
• Coagulopathy
• Biceps tendon rupture
• Spinal stenosis
• Proteinuria and nephrotic syndrome 2, 4
• Fatigue and lethargy 5
• Peripheral edema 5
• Pleural effusions 5, 6

Type-Specific Manifestations

AL (Light Chain) Amyloidosis

• Most common type (12 cases per million persons per year) 4
• Cardiac involvement in up to 50% of cases 2
• Macroglossia and periorbital purpura (specific but insensitive signs) 3
• Nephrotic syndrome
• Peripheral neuropathy in 17-35% of patients 1

ATTR (Transthyretin) Amyloidosis

• ATTRv (variant/hereditary):

  • Peripheral neuropathy (varies by genetic variant)
  • Val30Met variant: >80% develop peripheral neuropathy by age 50 1
  • Val122Ile variant: ~10% develop polyneuropathy 1

• ATTRwt (wild-type/senile):

  • Predominantly cardiac manifestations
  • Milder neuropathy with less prominent autonomic dysfunction 1
  • Approximately 30% may have polyneuropathy 1

Key Diagnostic Considerations

• The combination of proteinuria, cardiomyopathy, hepatomegaly, peripheral/autonomic neuropathy, weight loss, and GI symptoms without clear etiology should prompt consideration of amyloidosis 2
• Gold standard diagnosis: tissue biopsy with Congo red staining showing apple-green birefringence under polarized microscopy 2, 6
• Early diagnosis is crucial before irreversible organ damage occurs 2

High-Risk Populations for Screening

• Patients with unexplained heart failure with preserved ejection fraction
• Patients with unexplained proteinuria
• Patients with peripheral neuropathy of unknown origin
• All MGUS (monoclonal gammopathy of undetermined significance) patients 3

Prognostic Implications

• Cardiac involvement is the main determinant of survival 2
• 25% of patients with AL amyloidosis die within 6 months of diagnosis 4
• 25% of patients with ATTR amyloidosis die within 24 months of diagnosis 4

Early recognition of these signs and symptoms is critical as effective treatments exist but become less effective once end-organ damage is severe 4.