From the Guidelines
AA amyloidosis is a systemic disorder characterized by the extracellular deposition of amyloid A protein in various tissues and organs, triggered by persistent inflammation that leads to excessive production of serum amyloid A (SAA). The pathophysiology of AA amyloidosis begins with chronic inflammation, which stimulates the liver to synthesize SAA, an acute phase reactant, in response to pro-inflammatory cytokines like IL-1, IL-6, and TNF-α 1. During chronic inflammation, SAA levels can increase significantly, leading to abnormal processing of this protein and the formation of amyloid A fragments that are resistant to degradation. These fragments misfold into β-pleated sheet structures and aggregate to form amyloid fibrils that deposit in tissues, with proteoglycans and serum amyloid P component stabilizing these deposits and making them resistant to proteolysis. Key points about the pathophysiology of AA amyloidosis include:
- Persistent inflammation triggers excessive SAA production
- SAA is synthesized primarily by the liver in response to pro-inflammatory cytokines
- Chronic elevation of SAA leads to the formation of amyloid A fragments and fibrils
- Amyloid deposits can interfere with normal tissue architecture and function, leading to organ dysfunction
- The kidneys, liver, spleen, adrenal glands, and gastrointestinal tract are commonly affected organs. As noted in the study by Bozkurt et al 1, anti-inflammatory therapies, such as anti-tumor necrosis factor used for the treatment of rheumatoid arthritis, have been shown to suppress serum amyloid A production, highlighting the importance of treating the underlying inflammatory condition to prevent progression of amyloidosis.
From the Research
Pathophysiology of Amyloid A (AA) Amyloidosis
The pathophysiology of Amyloid A (AA) amyloidosis involves the extracellular deposition of insoluble amyloid fibrils composed of amyloid A (AA) protein, an amino (N)-terminal fragment of serum amyloid A (SAA) 2, 3. This deposition disrupts tissue structure and compromises organ function, with the kidney being the most commonly affected organ 2, 3, 4.
Key Events in the Pathogenetic Cascade
- The deposition of AA amyloid is preceded by a longstanding overproduction of SAA, which is induced by chronic inflammation 2, 5.
- The time before amyloid deposition is determined by the circulating SAA concentration, with high levels of SAA expression inducing amyloidosis after a short delay 2.
- Post-translational modifications (PTM) of AA protein, including carbamylation, acetylation, and oxidation, may play a role in fibrillogenesis 3.
- The amyloid deposits can regress with restoration of normal SAA production, but reinduction of SAA overproduction can lead to rapid glomerular amyloid deposition and renal failure 2.
Organ Involvement
- Renal involvement is the most common manifestation of AA amyloidosis, with almost all patients showing some degree of renal involvement 4.
- Other organs, such as the heart, can also be affected, although this is less common 2.
- The extent of organ involvement can vary widely between patients, and the disease can be systemic in nature 4.
Underlying Diseases and Inflammatory Markers
- AA amyloidosis is typically associated with chronic inflammatory conditions, such as rheumatoid arthritis or Crohn's disease 4.
- However, some patients may have idiopathic AA amyloidosis, with no known underlying inflammatory disease 4.
- Inflammatory markers, such as interleukin-6, can be elevated in patients with AA amyloidosis, and may represent a therapeutic target 4.