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, leading to organ dysfunction and potentially death. 1

Fundamental Disease Mechanism

• Amyloidosis results from the misfolding of proteins that aggregate into insoluble amyloid fibrils with an abnormal cross-β-sheet conformation, which then deposit extracellularly in tissues. 2, 3
• These deposits are recognizable by their affinity for Congo red staining and their characteristic apple-green birefringence under polarized light microscopy. 4, 2
• The deposited amyloid fibrils generate toxic masses that cause direct cell damage and progressive impairment of organ function. 3

Major Types of Amyloidosis

The American College of Cardiology identifies several clinically important types, with classification based on the specific amyloid protein involved: 1

AL Amyloidosis (Light Chain Amyloidosis)

• AL amyloidosis is the most common type in developed countries, affecting approximately 10 people per million per year. 4, 2
• It occurs from increased production of immunoglobulin light chain portions of antibodies by plasma cells in the bone marrow, which come together to form amyloid deposits. 1, 5
• Lambda isotype occurs in 75-80% of cases, with kappa isotype in the remaining cases. 5
• AL amyloidosis can be associated with multiple myeloma or Waldenström's macroglobulinemia, with cardiac involvement occurring in up to 50% of cases. 1, 5
• It primarily affects the heart (causing restrictive cardiomyopathy) and kidneys (causing nephrotic-range proteinuria). 5

ATTR Amyloidosis (Transthyretin Amyloidosis)

• ATTR amyloidosis is caused by amyloid deposits made up of transthyretin (TTR) protein and exists in two distinct forms. 1, 5

Hereditary ATTR amyloidosis:

• Caused by a mutation in the TTR gene, which is heritable, resulting in abnormal "variant" TTR protein. 1, 5
• Can manifest as familial amyloid polyneuropathy when disease mainly affects the nerves or familial amyloid cardiomyopathy when disease mainly affects the heart. 1

Acquired (wild-type) ATTR amyloidosis:

• Involves normal "wild-type" TTR protein that misfolds due to aging. 5
• Typically affects older adults and is emerging as an underdiagnosed cause of heart failure. 2, 6
• Wild-type ATTR is now recognized as the most common type of amyloidosis due to increased identification of age-related cases. 6

AA Amyloidosis (Reactive Amyloidosis)

• AA amyloidosis results from chronic inflammatory or infectious diseases such as rheumatoid arthritis, Crohn's disease, or ulcerative colitis. 1
• It is caused by deposition of amyloid type A protein in organs. 1

Other Types

• Other forms include hemodialysis-associated amyloidosis, isolated atrial amyloidosis, and organ-specific amyloidosis such as familial visceral or corneal amyloidosis. 1
• To date, 36 proteins have been identified as being amyloidogenic in humans. 2

Clinical Significance and Organ Involvement

• Systemic amyloidosis affects multiple organs simultaneously, particularly the heart, kidneys, liver, and nervous system, whereas localized amyloidosis affects a single organ or tissue. 7
• Cardiac involvement is the main driver of disease prognosis and mortality across all types of amyloidosis. 4
• The number and type of organs involved significantly impact survival, with median survival dropping from 13 months to just 4 months when heart failure symptoms develop in AL amyloidosis. 7

Critical Diagnostic Considerations

• Accurate differentiation between amyloidosis types is essential because management differs significantly between AL and ATTR amyloidosis. 4, 5
• Clinical suspicion should be raised with unexplained proteinuria, peripheral/autonomic neuropathy, restrictive cardiomyopathy, and characteristic multisystem involvement patterns. 5
• Diagnosis requires tissue biopsy with Congo red staining, followed by typing of the amyloid protein using mass spectrometry (gold standard), immunohistochemistry, or immunofluorescence. 4, 8
• All suspected cases require serum free light chain assay, serum and urine immunofixation electrophoresis to exclude systemic AL amyloidosis. 4, 7

Treatment Principles

• Early treatment initiation before irreversible organ damage occurs is critical for improving outcomes in both AL and ATTR amyloidosis. 5
• AL amyloidosis requires chemotherapy targeting the underlying plasma cell clone, with daratumumab-CyBorD as first-line therapy for transplant-eligible patients. 4, 5
• ATTR amyloidosis requires targeted therapies like tafamidis to stabilize or reduce TTR protein. 5
• Management requires multidisciplinary collaboration between hematologists, cardiologists, nephrologists, and neurologists. 4, 5

Key Clinical Pitfalls

• Delays in diagnosis remain the greatest challenge, as amyloidosis can present with nonspecific symptoms that mimic more common conditions. 6
• Even when amyloidosis appears confined to one organ, subclinical involvement of other organs may be present but not yet detectable, necessitating extensive workup. 7
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma alone, requiring close monitoring for cardiac decompensation during therapy. 4