Understanding Amyloidosis: Causes, Symptoms & Diagnosis

Amyloidosis Definition

• Amyloidosis is caused by pathologic proteinaceous substance
• Proteins deposit in extracellular space in various tissues, and organs
• Protein deposits occur in a wide variety of clinical settings

Composition of Amyloid Material

• Fibril proteins make up 95% of amyloid material
• P component and other glycoproteins comprise 5% of amyloid material
• Serum amyloid P protein contributes to amyloid deposition

Fibril Proteins

• More than 20 distinct forms of amyloid proteins exist
• The three most common forms are AL, AA and Aβ

AL (Amyloid Light Chain) Fibril Proteins

• AL proteins are derived from Ig light chains
• Ig light chains produced in plasma cells in the body

AA (Amyloid-Associated) Fibril Proteins

• AA proteins derive from non-Ig proteins synthesized by the liver

Αβ (β Amyloid) Fibril Proteins

• Αβ proteins are produced from β amyloid precursor protein and found in cerebral lesions from Alzheimer's disease

Other Fibril Proteins

• Transthyretin (TTR) affects heart of aged individuals, causing senile systemic amyloidosis
• β2-microglobulin, or Aẞ2m, impacts patients on long-term hemodialysis

Pathogenesis of Amyloidosis

• Misfolded proteins are formed normally or pathologically
• These proteins degrade intracellularly in proteasomes or extracellularly by macrophages
• In amyloidosis, these mechanisms fail, leading to deposition of misfolded proteins as fibrils
• Misfolded protein deposits in extracellular tissues disrupting normal function

Classification of Amyloidosis

• Systemic amyloidosis is a generalized form of the disease including primary, reactive systemic, and hemodialysis-associated amyloidosis
• Other classifications include hereditary, systemic senile, and localized amyloidosis

Primary Amyloidosis

• Is usually systemic with AL type proteins
• Occurs in 5% to 15% of individuals with multiple myeloma

Primary Amyloidosis Pathogenesis

• Malignant B cells synthesize single specific Ig, whole Ig molecules, or only the light chains called Bence-Jones protein of either κ or λ variety
• Amyloid deposits contain the same light chain protein (κ or λ variety)

Reactive Systemic Amyloidosis

• Usually systemic with AA protein
• Secondary to an inflammatory condition

Common Associations with Reactive Systemic Amyloidosis

• Rheumatoid arthritis is the most common cause/reason
• Ankylosing spondylitis
• Inflammatory Bowel Diseases, including Crohn's and Ulcerative Colitis
• Heroin abusers
• Renal cell carcinoma and Hodgkin lymphoma are the two most common tumors

Hemodialysis-Associated Amyloidosis

• Pathogenesis occurs through long-term hemodialysis (over 20 years)
• β2-microglobulin proteins cannot be filtered through dialysis membrane leading to deposition

Common Sites of Deposition

• Synovium,
• Joints
• Tendon sheaths

Related Complications

• Carpal tunnel syndrome caused by amyloid deposition in wrist leading to compression of median nerve

Systemic (Generalized) Amyloidosis

• Common sites are kidneys, liver, spleen, heart, pituitary gland, lymph nodes, adrenals, or thyroid gland, and the gastrointestinal tract

Amyloidosis of Kidney

• Most common and most serious site
• Normal size and color, but in advanced cases the kidneys will shrink
• Ischemia is caused by vascular narrowing by the deposition of amyloid within arterial and arteriolar walls

Microscopic Features of Amyloidosis of Kidney

• In glomeruli
• Interstitial peritubular tissue
• Arteries and arterioles

Amyloidosis of Spleen

• Moderate to marked splenomegaly (up to 800 gm)
• Sago spleen occurs through deposits of proteins around white pulp arterioles, producing tapioca-like granules
• Lardaceous spleen is caused by deposits of proteins in between the white pulp arterioles
• Fusion of the deposits leads to large, map-like areas of amyloidosis

Clinical Manifestations

• Asymptomatic
• Can include Specific findings related to renal, cardiac, and gastrointestinal involvement

Renal Involvement

• Proteinuria
• Nephrotic syndrome.
• Uremia
• Renal failure.

Investigations

• Biopsy and histologic demonstration of amyloid deposits
• Common sites for biopsy include abdominal fat aspirates, kidney, rectal or gingival tissue

Common Staining Technique

• Congo red stain is the most commonly used staining technique
• Light microscopy: specimens display a pink or red color when amyloid deposits present
• Polarizing microscopy: amyloid shows an apple green birefringence

Prognosis

• Poor in systemic amyloidosis
• Better prognosis in reactive systemic amyloidosis
• Renal failure causes the most common cause of death in systemic amyloidosis

Explore the causes, complications, and characteristics of amyloidosis, including hemodialysis-associated amyloidosis and systemic forms. Learn about amyloid deposition, diagnostic techniques, and common complications affecting organs. This information is crucial for medical students and healthcare professionals.