Amyloidosis

KEY FEATURES

• Congo red positive amyloid protein on tissue biopsy

• Primary amyloid protein is kappa or lambda immunoglobulin light chain

• In primary amyloidosis, there is usually a serum or urine (or both) light chain paraprotein

General Considerations

• A rare condition whereby

  • A protein abnormally deposits in tissue

  • Results in organ dysfunction

• There are six main categories, classified according to the type of amyloid protein deposited

  • Primary (immunoglobulin light chain [AL])

  • Secondary

    • Serum protein A

    • Produced in chronic inflammatory conditions [AA]

  • Hereditary (mutated transthyretin [TTR])

  • Senile

    • Wild-type TTR

    • Atrial natriuretic peptide

  • Dialysis-related

    • β₂-microglobulin

    • Not filtered out by dialysis membranes [Aβ₂M]

  • LECT2 (associated with Latina/Latino patients)

• Amyloidosis is further classified as

  • Localized (amyloid deposits only in a single tissue type or organ)

  • Systemic (widespread amyloid deposition)

CLINICAL FINDINGS

Symptoms and Signs

• Localized amyloidosis: symptoms and signs are related to the affected single organ, such as

  • Hoarseness (vocal folds)

  • Proptosis and visual disturbance (orbits)

• Systemic amyloidosis: symptoms and signs of unexplained medical syndromes, including

  • Heart failure (infiltrative/restrictive cardiomyopathy)

  • Nephrotic syndrome

  • Malabsorption and weight loss

  • Hepatic dysfunction

  • Autonomic insufficiency

  • Carpal tunnel syndrome (often bilateral)

  • Sensorimotor peripheral neuropathy

• Additional signs and symptoms include

  • Enlarged tongue

  • Waxy, rough plaques on skin

  • Contusions (including the periorbital areas)

  • Cough or dyspnea

  • Disturbed deglutition

Differential Diagnosis

• Plasma cell myeloma

• Monoclonal gammopathy of unknown significance (MGUS)

• Other malignant lymphoproliferative disorders with a paraprotein

DIAGNOSIS

Laboratory Tests

• In primary AL amyloidosis

  • Serum and urine will reveal

    • Kappa or lambda light chain paraprotein by protein electrophoresis (PEP), immunofixation electrophoresis (IFE), or free light chain assay (90% of patients)

  • Mass spectroscopy demonstrates light chain in the tissue biopsy in remainder of patients

• Albuminuria is present with renal amyloid; can be in the nephrotic range

Diagnostic Procedures

• Cardiac amyloidosis

  • Echocardiogram

    • Infiltrative cardiomyopathy with thick ventricular walls

    • Specific speckling pattern may be seen

  • ECG: low QRS voltages

  • Cardiac MRI

    • Has a distinctive delayed enhancement of gadolinium

    • Virtually diagnostic

• Blind aspiration of the abdominal fat pad

  • Reveals systemic amyloid two-thirds of the time

  • If unrevealing, then the affected organ needs biopsy

• Tissue biopsy

  • Required to diagnose amyloid protein

  • Demonstrates deposition of a pink interstitial substance in the tissue with the hematoxylin and eosin stain

  • Protein stains red with Congo red

  • Becomes an apple-green color when the light is polarized

• Electron microscopy

  • Amyloid fibrils form beta-pleated sheets

  • Amyloid protein is either the kappa or lambda immunoglobulin light chain

• Bone marrow examination

  • In primary amyloidosis, most have a small excess of kappa- or lambda-restricted plasma cells (but < 10%)

  • May or may not demonstrate interstitial amyloid deposition or amyloid in the blood vessels