Extracellular Deposition and Amyloidosis

Extracellular Deposition

  • Definition: An abnormal element deposited around cells.

  • Main Types:

    • Hyalinosis

    • Calcium

    • Amyloid

    • Mucin

    • Uric acid

Hyaline Degeneration (Hyalinosis)

  • Definition: An alteration within cells or in extracellular spaces that gives a homogeneous acellular glassy pink appearance in H&E stained sections.

  • Usage: A descriptive histologic term rather than a specific marker for cell injury.

  • Characteristics:

    • Produced by various alterations and does not represent a specific pattern of accumulation.

Types of Hyalinosis

  • Intracellular Hyalinosis:

    • Examples:

    • Plasma cell (Russel bodies)

    • Hepatocytes (Mallory bodies)

    • Renal tubule cell

  • Extracellular Hyalinosis:

    • Examples:

    • Old scar

    • Uterine fibroid

    • Blood vessels of systemic hypertension (HT)

Pathological Calcification

  • Definition: A common process in diverse disease states, resulting from abnormal deposition of calcium salts, along with smaller amounts of iron, magnesium, and other minerals.

Classification of Pathological Calcification

  • Types:

    • Dystrophic Calcification:

    • Features: Normal calcium metabolism but deposits in injured or dead tissue, such as areas of necrosis.

    • Initiation: Extracellular deposition of crystalline calcium phosphate.

    • Metastatic Calcification:

    • Features: Associated with hypercalcemia and can occur in normal tissues, often due to parathyroid hormone excess.

    • Commonly Affected Tissues: Blood vessels, kidneys, lungs, gastric mucosa.

Additional Conditions Related to Calcification

  • Calcinosis:

    • A disorder of unknown cause characterized by calcification of skin and subcutaneous tissues; may be localized or generalized.

    • Often involves tendons, fascia, muscles, and nerves.

  • Pathologic (Heterotropic, Extraosseous, Soft Tissue) Ossification:

    • Characterized by the formation of bone tissue away from bones; an example is myositis ossificans after a suprachondylar bone fracture.

Amyloidosis

  • Definition: A disorder characterized by extracellular deposition of various fibrillary proteins in organs, leading to tissue damage and functional compromise.

  • Association: Linked with several inherited and inflammatory disorders.

  • Cause of Name: The term comes from 'amylose' because of the starch-like appearance.

Nature of Amyloid

  • Composition:

    • 90% is fibril protein.

    • 10% is a glycoprotein called P component.

  • Role of Macrophages: Important in amyloidosis through proteolytic cleavage of precursor proteins into amyloid fibrils.

  • Types of Amyloid Fibril Proteins: Various types exist.

Pathogenesis of Amyloidosis

  • Causes of Protein Deposition:

    • Excessive production of proteins prone to aggregation.

    • Mutations result in improperly folded proteins that aggregate.

    • Defective or incomplete proteolytic degradation of extracellular proteins.

  • Mechanism:

    1. Excessive production of amyloidogenic proteins.

    2. Mutant proteins lead to aggregation due to inability to fold correctly.

    3. Monoclonal B-lymphocyte proliferation and macrophage activation contribute through cytokines such as Interleukins 1 and 6.

  • Fibril Formation: Monomers assemble to form $\beta$-sheet structures, leading to significant amyloid formation.

Chemical Composition of Amyloid

  • Diversity: Biochemically heterogeneous with at least 30 different proteins.

  • Common Forms:

    • AL (Amyloid Light Chain): Comprised of complete immunoglobulin light chains.

    • AA (Amyloid-Associated): Derived from SAA (Serum Amyloid Associated) protein synthesized in the liver.

    • β-Amyloid Protein (Aβ): Comes from proteolysis of the amyloid precursor protein.

Characteristic Stains of Amyloid

  • Staining Reactions:

    • Iodine: Brown color when added to fresh tissue containing amyloid.

    • H&E Stain: Amyloid stains red.

    • Methyl Violet: Shows metachromasia and appears pink.

    • Congo Red Stain: Appears orange-red with apple-green birefringence under polarized light.

  • Electron Microscopy (EM): Amyloid appears as non-branching fibrils, 7.5-10 nm wide.

  • X-ray Diffraction: Exhibits $\beta$-pleated sheet structure.

Classification of Amyloidosis

  • Categories:

    • Systemic (Generalized) Amyloidosis:

    • Plasma cell proliferations (Primary Amyloidosis)

    • Reactive systemic amyloidosis (Secondary Amyloidosis)

    • Hemodialysis-associated amyloidosis

    • Hereditary Amyloidosis (e.g., Familial Mediterranean fever)

    • Other hereditary types (familial amyloidotic neuropathies, systemic senile amyloidosis).

    • Localized Amyloidosis:

    • Affects specific organs such as the brain (senile cerebral), endocrine organs (medullary carcinoma of thyroid, islets of Langerhans).

Primary Amyloidosis

  • Overview: Most common form of amyloidosis.

  • Causes: Clonal proliferation of plasma cells.

  • Prevalence: Occurs in 5% to 15% of multiple myeloma cases.

  • Light Chain Distribution: λ light chains are approximately six times more likely to form amyloid than κ light chains.

Reactive Systemic Amyloidosis

  • Distribution: Systemic; composed of AA protein.

  • Common Causes: Rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and certain cancers (e.g., renal cell carcinoma).

  • Infectious Causes: Tuberculosis, chronic osteomyelitis.

Heredofamilial Amyloidosis

  • Examples: Familial Mediterranean fever; characterized by excessive IL-1 production.

  • Protein Involvement: Deposition of amyloid derived from mutant transthyretin (TTR).

Hemodialysis-Associated Amyloidosis

  • Risk Factor: Long-term hemodialysis for renal failure can lead to amyloid deposits derived from β2 microglobulin.

Localized Amyloidosis

  • Definition: Limited to a single organ or tissue; often affects lung, larynx, skin, urinary bladder, and tongue.

  • Composition: Typically consists of AL protein.

Endocrine Amyloid

  • Examples: In endocrine tumors (e.g., medullary carcinoma of the thyroid), amyloid protein is procalcitonin produced by tumor cells.

  • Aging Related: Amyloid derived from normal TTR in older individuals leading to restrictive cardiomyopathy and arrhythmias.

  • Alzheimer's Disease: Involves β2-amyloid protein (Aβ).

Morphology in Amyloidosis

  • Affected Organs:

    • Kidneys: The most common and serious involvement.

    • Gross: Enlarged kidney with possible ischemic changes.

    • Cut Section: Pale gray waxy amyloid spots with sharp borders.

    • Microscopy: Amyloid deposits in glomeruli and tubules, pink and refractile in H&E, with orange-red birefringence in Congo red.

    • Liver:

    • Gross: Enlarged and firm with pale gray amyloid streaks.

    • Microscopy: Deposits in walls of arterioles and venules, leading to pressure atrophy of liver cells.

    • Spleen: Characterized by two patterns:

    • Sago Spleen: Amyloid deposits in walls of central arterioles, moderate splenomegaly with mottled cut surface.

    • Diffuse Amyloid Spleen: Amyloid in walls of sinusoids, marked splenomegaly with uniformly pale gray cut surface.

    • Heart:

    • Patterns: Localized or part of generalized amyloidosis.

    • Gross: Moderate cardiac enlargement, subendocardial amyloid deposits.

    • Complications: Potential heart failure due to amyloid causing pressure atrophy of myocardial fibers.

Clinical Features of Amyloidosis

  • Initial Symptoms: Nonspecific, such as weakness, weight loss, lightheadedness, or syncope.

  • Later Symptoms: Related to renal, cardiac, and gastrointestinal involvement, leading to:

    • Progressive obliteration of glomeruli causing renal failure and uremia.

    • Cardiac amyloidosis leading to conduction disturbances and potentially fatal arrhythmias.

    • Gastrointestinal symptoms possibly leading to malabsorption and diarrhea.

  • Tongue Involvement: Can hamper speech and swallowing due to inelasticity.

  • Vascular Amyloidosis: Causes fragility and may lead to bleeding.

Diagnostic Procedures

  • Common Biopsies: Kidney, rectal, or gingival tissues when systemic amyloidosis is suspected.

  • Testing: Serum and urine protein electrophoresis and immunoelectrophoresis for cases of AL amyloidosis.

Prognosis

  • Generalized Amyloidosis: Generally poor outlook.

  • Reactive Systemic Amyloidosis: Better prognosis depending on control of underlying conditions; rare occurrence of amyloid resorption after treatment.

  • Affect on Tissues: Amyloid deposits cause tissue injury and dysfunction by exerting pressure on cells without causing an inflammatory response.

References

  1. Robbins, Cotran & Kumar Pathologic Basis of Disease, 11th Edition.

  2. Anderson’s Pathology, 10th Edition.

  3. Boyd’s Pathology, 10th Edition.