What is amyloidosis?

What is Amyloidosis?

Amyloidosis is a disorder in which abnormal proteins, known as amyloid fibrils, build up and deposit in tissues and organs, ultimately leading to organ dysfunction and potentially death. 1

Basic Disease Mechanism

• Amyloidosis results from the extracellular deposition of misfolded proteins that aggregate in tissues throughout the body 2, 3
• These deposits are recognizable by their affinity for Congo red stain and their characteristic apple-green birefringence when viewed under polarized light 4, 2
• The accumulation of these insoluble proteins causes progressive organ damage by disrupting normal tissue architecture and function 5

Major Types of Amyloidosis

The classification is based on the specific protein type that forms the amyloid deposits, which is critical because treatment differs dramatically between types 1, 4:

AL Amyloidosis (Light Chain Amyloidosis)

• Previously known as primary amyloidosis, this is the most common type in developed countries, affecting approximately 10 people per million per year 4, 2
• Caused by increased production of light chain portions of antibodies by abnormal plasma cells in the bone marrow that misfold and form amyloid deposits 1, 6
• Lambda light chains account for 75-80% of cases, with kappa light chains comprising the remainder 6
• Can be associated with multiple myeloma or Waldenström's macroglobulinemia (10-15% of multiple myeloma patients have AL amyloidosis) 1, 6
• Primarily affects the heart and kidneys, causing restrictive cardiomyopathy and proteinuria 6
• Cardiac involvement occurs in up to 50% of cases and is the main driver of mortality, with median survival of only 13 months when cardiac involvement is present (4 months if heart failure develops) 4, 7

ATTR Amyloidosis (Transthyretin Amyloidosis)

• Caused by amyloid deposits made up of transthyretin (TTR) protein 1, 6
• Exists in two distinct forms 1, 6:
  • Hereditary ATTR: Caused by mutations in the TTR gene, resulting in abnormal "variant" TTR protein that is heritable 1, 6. Can manifest as familial amyloid polyneuropathy (primarily affecting nerves) or familial amyloid cardiomyopathy (primarily affecting the heart) 1
  • Wild-type ATTR: Previously known as senile amyloidosis, occurs when normal "wild-type" TTR protein misfolds to form amyloid deposits, usually due to aging 1, 6
• More commonly affects the heart, peripheral nerves, and musculoskeletal system rather than the lungs 7

AA Amyloidosis (Reactive Amyloidosis)

• Previously known as secondary amyloidosis 1
• Results from chronic infectious or inflammatory diseases such as rheumatoid arthritis, Crohn's disease, or ulcerative colitis 1, 4
• Caused by deposition of amyloid type A protein in organs 1
• Rarely involves the lungs (less than 10% of cases show pulmonary involvement) 7

Other Types

• Hemodialysis-associated amyloidosis (derived from β2 microglobulin) 1, 2
• Organ-specific amyloidosis such as familial visceral amyloidosis and familial corneal amyloidosis 1
• To date, 36 proteins have been identified as amyloidogenic in humans 2

Clinical Presentation

Key features that should raise suspicion for amyloidosis include: 6

• Unexplained proteinuria
• Peripheral or autonomic neuropathy
• Multisystem disorders involving heart, kidney, liver, or nervous system 4
• Macroglossia (enlarged tongue) and periorbital purpura (bruising around the eyes) strongly suggest AL amyloidosis specifically 7

Diagnostic Approach

Accurate diagnosis requires both confirmation of amyloid deposits AND identification of the specific protein type: 4, 2

• Tissue biopsy with Congo red staining showing characteristic apple-green birefringence under polarized light 4, 2
• Typing of amyloid protein using mass spectrometry (gold standard with 88% sensitivity and 96% specificity), immunohistochemistry, or immunofluorescence 4, 7
• For AL amyloidosis specifically: Serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 4, 6
• Cardiac imaging including echocardiography, cardiac MRI, and nuclear scintigraphy 6

Treatment Principles

Treatment is entirely type-specific, making accurate diagnosis absolutely critical before initiating therapy: 2, 8

• AL amyloidosis: Targets the underlying plasma cell clone with chemotherapy regimens such as daratumumab-CyBorD (daratumumab, cyclophosphamide, bortezomib, dexamethasone) or high-dose melphalan followed by autologous stem cell transplantation 4, 6, 7
• ATTR amyloidosis: Tafamidis (VYNDAQEL/VYNDAMAX) is FDA-approved to treat the cardiomyopathy of wild-type or hereditary ATTR amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization 9
• Early treatment initiation before irreversible organ damage occurs is critical for improving outcomes 6

Critical Clinical Considerations

• Differentiation between AL and ATTR amyloidosis is essential as management differs significantly 4, 6
• Cardiac involvement is the main driver of disease prognosis and mortality across all types 4
• Multidisciplinary management involving cardiologists, hematologists, neurologists, and other specialists is crucial 6
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma alone 4
• Inappropriate treatment based on incorrect typing can cause harm, making accurate protein identification imperative 2, 8