Amyloidosis

KEY FEATURES

Essentials of Diagnosis

• 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 resulting 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) or, most common, 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 cords) or 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

• 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

• Hemochromatosis

• Sarcoidosis

• Waldenström macroglobulinemia

• Metastatic cancer

• Other causes of nephrotic syndrome, eg, lupus nephritis

DIAGNOSIS

Laboratory Tests

• Analysis of the serum and urine will reveal a kappa or lambda light chain paraprotein by protein electrophoresis (PEP), immunofixation electrophoresis (IFE), or free light chain assay

• Mass spectroscopy demonstrates light chain in the tissue biopsy

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

Diagnostic Procedures

• 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 that is virtually diagnostic

• Blind aspiration of the abdominal fat pad

  • Reveals amyloid two-thirds of the time

  • If unrevealing, then the affected organ needs biopsy

• Tissue biopsy

  • Demonstrates deposition of a pink interstitial substance in the tissue with the H&E 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

TREATMENT

Medications

• Active agents for AL amyloid include melphalan, cyclophosphamide, dexamethasone, lenalidomide, and bortezomib

• Daratumumab

  • An anti-CD38 monoclonal antibody

  • Added to ...