Secondary amyloidosis pathophysiology

Secondary amyloidosis Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]Shaghayegh Habibi, M.D. Sabawoon Mirwais, M.B.B.S, M.D.

Overview

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. In secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments that accumulate within extracellular space and form the insoluble amyloid deposits. 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:

Associated Conditions
Conditions	Examples
Chronic infections	Tuberculosis Leprosy Whipple Disease Osteomyelitis Chronic pyelonephritis Subacute bacterial endocarditis Chronic cutaneous ulcers
Monogenic periodic fever syndromes	TNF Receptor associated periodic syndrome (TRAPS) Cryopyrin-associated periodic fever syndrome Mevalonate kinase deficiency Familial mediterranean fever
Conditions predisposing to recurrent infections	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	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, aa 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

On electron microscopy, amyloid fibrils have the following characteristics:

• 10 to 15 nm diameter
• Straight, rigid, and nonbranching
• Composed of twisted protofilaments

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.