Amyloidosis and Fibril Proteins

• Amyloidosis involves pathologic proteinaceous substances depositing in the extracellular space of various tissues and organs in a wide range of clinical settings.

Composition of Amyloid Material

• Fibril proteins account for 95% of amyloid material.
• P component and other glycoproteins make up the remaining 5% of amyloid material, with serum amyloid P protein contributing to amyloid deposition.

Fibril Proteins

• More than 20 distinct forms of amyloid proteins exist, with three being most common.
• AL (amyloid light chain) is derived from Ig light chains produced in plasma cells.
• AA (amyloid-associated) is derived from non-Ig protein synthesized by the liver.
• Aβ (β amyloid) is produced from the β amyloid precursor protein and found in the cerebral lesions associated with Alzheimer's disease.
• Two other important fibril proteins are Transthyretin (TTR) which affects the heart of aged individuals in senile systemic amyloidosis, and β2-microglobulin, Aẞ2m accumulation causes amyloidosis in patients on long-term hemodialysis.

Pathogenesis of Amyloidosis

• Misfolded proteins are formed normally or pathologically and are usually degraded intracellularly by proteasomes or extracellularly by macrophages.
• In amyloidosis, the degradation mechanisms fail, and misfolded proteins deposit as fibrils in extracellular tissues, disrupting normal function.

Classification of Amyloidosis

• Amyloidosis can be classified into systemic (generalized) amyloidosis, hereditary amyloidosis, systemic senile amyloidosis, and localized amyloidosis.

Systemic Amyloidosis

• Primary amyloidosis is usually systemic and classified as AL type, affecting 5% to 15% of individuals with multiple myeloma.
• Malignant B cells synthesize single specific Ig / whole Ig molecules, as well as only the light chains known as Bence-Jones protein of either κ or λ variety, and the amyloid deposits contain the same light chain (κ or λ variety) protein.
• Reactive systemic amyloidosis is usually systemic and involves the AA protein, secondary to an inflammatory condition, also known as secondary amyloidosis.
• Reactive systemic amyloidosis is commonly associated with rheumatoid arthritis (the most common reason), ankylosing spondylitis, and inflammatory bowel diseases, such as Crohn disease and ulcerative colitis.
• Heroin abusers and individuals with renal cell carcinoma and Hodgkin lymphoma are also commonly affected.
• Hemodialysis-associated amyloidosis pathogenesis occurs with long-term hemodialysis (more than 20 years).
• β2-microglobulin cannot be filtered through dialysis membranes, which leads to its deposition.
• Common deposition sites in hemodialysis-associated amyloidosis include the synovium, joints, and tendon sheaths, which can lead to carpal tunnel syndrome due to amyloid deposition in the wrist, compressing the median nerve.

Common sites of deposition in Systemic Amyloidosis

• Kidneys
• Liver
• Spleen
• Heart
• Pituitary gland
• Lymph nodes
• Adrenals
• Thyroid gland
• Gastrointestinal tract

Amyloidosis of the Kidney

• Amyloidosis of the kidney is the most common and most serious manifestation.
• Kidneys are generally normal in size and color, but in advanced cases, are shrunken due to ischemia caused by vascular narrowing by the deposition of amyloid within arterial and arteriolar walls.
• Microscopic features of renal amyloidosis include amyloid deposition in the glomeruli, interstitial peritubular tissue, arteries, and arterioles.

Amyloidosis of Spleen

• Gross pathological features include moderate to marked splenomegaly that can weigh up to 800 g.
• Sago spleen involves deposits of amyloid around white pulp arterioles, producing tapioca-like granules.
• Lardaceous spleen involves deposits of amyloid in between the white pulp arterioles.
• Fusion of the deposits gives rise to large, map-like areas of amyloidosis.

Clinical Manifestations of Amyloidosis

• Clinical manifestations may be asymptomatic or present with specific findings related to renal, cardiac, and gastrointestinal involvement.
• Renal involvement leads to proteinuria, nephrotic syndrome, uremia, and renal failure.
• The most common cause of death in systemic amyloidosis is renal failure.

Investigations for Amyloidosis

• Diagnosis involves biopsy and histologic demonstration of amyloid deposits in tissues.
• Common sites for biopsy include abdominal fat aspirates (quite specific), kidney, rectal tissue, and gingival tissue.
• Congo red stain is the most commonly used staining technique.
• Light microscopy reveals pink or red coloration of amyloid deposits.
• Polarizing microscopy reveals apple-green birefringence in amyloid.
• Electron microscopy is used for confirmation.

Prognosis

• Prognosis is generally poor in systemic amyloidosis.
• Prognosis is significantly better in reactive systemic amyloidosis.

Amyloidosis is characterized by abnormal protein deposits in tissues. Fibril proteins, including AL, AA, and Aβ, constitute 95% of amyloid material. These proteins are associated with conditions like plasma cell disorders, liver issues, and Alzheimer's disease.