Secondary amyloidosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In systemic amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera, blood vessel walls, and in the different connective tissues. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).

Pathophysiology

• AA amyloid is an abnormal insoluble extracellular protein derived from the spontaneous aggregation of fibrils composed of misfolded proteins, called amyloid precursors.
• In secondary amyloidosis, the amyloid precursor is SAA, an acute phase reactant, encoded by SAA 1&2 genes.
• Normally, SAA increased during the inflammatory process and then taken up by macrophages and degraded within lysosomal compartments.
• In patients with secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments.
• These protofilaments with other protein materials accumulate within extracellular space and form the insoluble amyloid deposits.
• Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.

Associated Conditions

• Conditions associated with AA amyloidosis include:
  • Monogenic periodic fever syndromes, such as:
    • FMF
    • TNF Receptor associated periodic syndrome (TRAPS)
    • Cryopyrin-associated periodic fever syndrome
    • Mevalonate kinase deficiency
  • Tuberculosis
  • Leprosy
  • Whipple Disease
  • Osteomyelitis
  • Chronic pyelonephritis
  • Subacute bacterial endocarditis
  • Chronic cutaneous ulcers
  • Conditions Predisposing to chronic infections including:
    • Cystic fibrosis
    • Bronchiectasis
    • Kartagener syndrome
    • Epidermolysis bullosa
    • Injected drug abuse
    • Jejuno-ileal bypass
    • Paraplegia
    • Sickle cell anemia
    • Immunodeficiency
    • Common variable immunodeficiency
    • Cyclic neutropenia
    • Hyperimmunoglobulin M syndrome
    • Hypogammaglobulinemia
    • Sex-linked agammaglobulinemia
    • Human immunodeficiency virus/AIDS
  • Neoplasia
  • Adenocarcinoma
  • Basal cell carcinoma
  • Carcinoid tumor
  • Castleman disease
  • Gastrointestinal stromal tumor
  • Hairy cell leukemia
  • Hepatic adenoma
  • Hodgkin disease
  • Mesothelioma
  • Renal cell carcinoma
  • Sarcoma
  • Inflammatory Arthritis
  • Adult-onset Still disease
  • Ankylosing spondylitis
  • Juvenile idiopathic arthritis
  • Psoriatic arthropathy
  • Reiter syndrome
  • Rheumatoid arthritis
  • Gout
  • Systemic Vasculitis
  • Antineutrophil cytoplasmic antibody-associated vasculitis
  • Behcet disease
  • Giant cell arteritis
  • Polyarteritis nodosa
  • Polymyalgia rheumatica
  • Systemic lupus erythematosus
  • Takayasu arteritis
  • Inflammatory Bowel Disease
  • Ulcerative colitis
  • Crohn disease
• Others include:
  • Atrial myxoma
  • Inflammatory abdominal aortic aneurism
  • Retroperitoneal fibrosis
  • SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome
  • Sarcoidosis
  • Sinus histiocytosis with massive lymphadenopathy

Gross Pathology

On gross pathology, the organs affected by amyloidosis can be characterized by the following features:

• Porcelain like or waxy appearance
• Enlargement

Images

Nodular deposits of amyloid on the pleural surfaces.

Cut section of an inguinal lymph node showing firm and waxy consistency.

A slice of the affected node (left) has turned black after treatment with Lugol's solution. A piece of normal myometrium (right) treated similarly with no reaction is also shown.

Microscopic Pathology

On microscopic histopathological analysis, amyloidosis is characterized by:

• Green birefringence under polarized light after Congo red staining (appears red under normal light)
• Linear non-branching fibrils (indefinite length with an approximately same diameter)
• Distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril

Images

Small bowel duodenum with amyloid deposition Congo red.

Amyloidosis (black arrows) in a lymph node after staining with Congo Red.

Green birefringence under polarized light.