Main Clinical Findings of Amyloidosis
Amyloidosis presents with a constellation of clinical findings affecting multiple organ systems, with cardiac, neurologic, renal, gastrointestinal, and soft tissue manifestations being the most common presentations. 1
Key Organ System Manifestations
Cardiac Manifestations
- Restrictive cardiomyopathy 2, 1
- Heart failure with preserved ejection fraction 1
- Electrocardiographic abnormalities (low QRS voltage despite ventricular wall thickening) 1
- Cardiac involvement is present in up to 50% of AL amyloidosis cases 1
- Cardiac involvement is the most important prognostic factor in AL amyloidosis, influencing survival regardless of other organ involvement 2
Renal Manifestations
Neurologic Manifestations
- Peripheral neuropathy (17-35% of patients) 1
- Small-fiber neuropathy with sensory loss and pain in extremities
- Symptoms worse at end of day or nighttime
- Rapidly progressive (15-20× faster than diabetic neuropathy)
- Autonomic neuropathy 1
- Bilateral carpal tunnel syndrome 2, 1
Gastrointestinal Manifestations
- Hepatomegaly with mildly elevated liver enzymes (particularly alkaline phosphatase) 1, 4
- Diarrhea, steatorrhea, or constipation 4
- Pseudo-obstruction (carries particularly poor prognosis) 4
- Macroglossia (pathognomonic for AL amyloidosis) 2, 1
Soft Tissue and Other Manifestations
- Periorbital purpura/ecchymoses (highly specific for AL amyloidosis) 2, 1
- Submandibular gland enlargement 1
- Acquired factor X deficiency with coagulopathy 2
- Musculoskeletal: biceps tendon rupture and spinal stenosis 1
- Weight loss 4
Diagnostic Clues by Amyloidosis Type
AL (Primary) Amyloidosis
- Most common type of systemic amyloidosis 1
- Cardiac involvement in up to 50% of cases 1
- Median survival of 13 months (only 4 months if heart failure present) 1
- Distinctive features: macroglossia and periorbital purpura 5
- Associated with monoclonal gammopathy or multiple myeloma 2
ATTR (Transthyretin) Amyloidosis
- Hereditary variant (ATTRv): median survival of 70 months 1
- Wild-type (ATTRwt): median survival of 75 months 1
AA (Secondary) Amyloidosis
- Associated with inflammatory, infectious, and neoplastic diseases 4
- Cardiac involvement in <10% of cases 1
- Median survival of 25 months 1
Clinical Patterns Suggesting Amyloidosis
A combination of the following should prompt consideration of amyloidosis 1, 4:
- Proteinuria
- Restrictive cardiomyopathy
- Hepatomegaly with mildly abnormal liver tests
- Peripheral/autonomic neuropathy
- Weight loss
- GI symptoms without clear etiology
Prognostic Factors
- Age (patients <65 years have better survival than those ≥65 years) 2
- Number and type of organs involved (significant decrease in survival as number increases) 2
- Cardiac involvement (most important prognostic factor in AL amyloidosis) 2
- Cytogenetic abnormalities (hyperdiploidy is a poor prognostic factor) 2
Important Diagnostic Considerations
- Gold standard for diagnosis: tissue biopsy with Congo red staining showing apple-green birefringence under polarized microscopy 1
- Abdominal fat aspiration has 84% sensitivity for AL amyloidosis 2
- Mass spectrometry is the gold standard for typing amyloid deposits (sensitivity 88%, specificity 96%) 2
- Early diagnosis is crucial before irreversible organ damage occurs 1
- 25% of patients with AL amyloidosis die within 6 months of diagnosis 3
Amyloidosis should be considered in patients with unexplained heart failure with preserved ejection fraction, unexplained proteinuria, peripheral neuropathy of unknown origin, or any patient with MGUS presenting with atypical clinical features 1, 3.