When should amyloidosis be considered in a patient?

When to Consider Amyloidosis

Amyloidosis should be considered in patients presenting with a seemingly disparate constellation of symptoms including unexplained proteinuria, restrictive cardiomyopathy, peripheral neuropathy with autonomic features, bilateral carpal tunnel syndrome, hepatomegaly, or acquired factor X deficiency with coagulopathy. 1

Clinical Presentations That Should Trigger Suspicion

AL Amyloidosis

• Cardiac manifestations:

  • Heart failure with preserved ejection fraction (HFpEF)
  • Restrictive cardiomyopathy
  • Unexplained thickening of ventricular walls

• Renal manifestations:

  • Nephrotic syndrome
  • Unexplained proteinuria

• Distinctive physical findings:

  • Macroglossia (enlarged tongue)
  • Periorbital ecchymoses ("raccoon eyes")
  • Submandibular gland enlargement
  • Acquired coagulopathy (factor X deficiency)

• Other organ involvement:

  • Hepatomegaly without imaging abnormalities
  • Peripheral neuropathy with autonomic features
  • GI tract involvement with malabsorption or motility disorders 1

ATTR Amyloidosis

• Musculoskeletal presentations:

  • Biceps tendon rupture
  • Spinal stenosis
  • Bilateral carpal tunnel syndrome

• Cardiac manifestations:

  • Heart failure with preserved ejection fraction
  • Conduction abnormalities

• Neurologic manifestations:

  • Peripheral neuropathy
  • Autonomic dysfunction 1

High-Risk Populations for Screening

Certain patient populations should undergo regular screening for early detection of amyloidosis:

• Patients with monoclonal gammopathy of undetermined significance (MGUS) should have regular follow-up with markers such as:

  • N-terminal pro-brain natriuretic peptide (NT-proBNP)
  • Albuminuria monitoring 1

• Patients with multiple myeloma should be evaluated for AL amyloidosis, as approximately 10-15% of multiple myeloma patients also have AL amyloidosis 1

• Patients over 70 years old with unexplained heart failure should be evaluated for wild-type ATTR amyloidosis

Diagnostic Approach

When amyloidosis is suspected, the diagnostic algorithm should proceed as follows:

1. Initial screening:

   • Serum and urine immunofixation
   • Serum free light chain assay
   • NT-proBNP and troponin T (cardiac biomarkers)

2. Tissue diagnosis:

   • For AL amyloidosis: Requires both demonstration of tissue amyloid deposits AND evidence of plasma cell dyscrasia
   • Biopsy options include:
     • Abdominal fat aspiration (sensitivity: 84% for AL-CM, 45% for ATTRv-CM, 15% for ATTRwt-CM)
     • Bone marrow biopsy (sensitivity: 69% for AL amyloidosis)
     • Affected organ biopsy if surrogate site biopsies are negative 1

3. Amyloid typing:

   • Mass spectrometry (gold standard)
   • Immunohistochemistry
   • Immunofluorescence 1

Common Pitfalls in Diagnosis

1. Delayed diagnosis due to nonspecific symptoms - maintain high index of suspicion for patients with multisystem involvement

2. Misinterpreting monoclonal protein in ATTR patients - 10-40% of ATTR-CM patients may have evidence of plasma cell dyscrasia without AL amyloidosis, representing concomitant MGUS 1

3. Failure to recognize cardiac involvement - cardiac involvement is the most important prognostic factor and should be assessed in all suspected cases 2

4. Missing the diagnosis in patients with multiple myeloma - approximately 10-15% of multiple myeloma patients also have AL amyloidosis 1

5. Overlooking amyloidosis in elderly patients with HFpEF - wild-type ATTR amyloidosis is increasingly recognized as a cause of HFpEF in the elderly 3

Importance of Early Diagnosis

Early diagnosis is critical as:

• 25% of patients with AL amyloidosis die within 6 months of diagnosis
• 25% of patients with ATTR amyloidosis die within 24 months of diagnosis
• Effective therapies exist but are ineffective if end-organ damage is severe 3

The main hallmark of management remains early recognition and initiation of treatment before the occurrence of irreversible organ damage 1.