Classification and Nature of the Disease
Systemic (generalized) amyloidosis is a group of conditions in which a pathological protein is deposited throughout the body. The disease is divided into three main groups based on the underlying etiology:
- Primary: arises in the setting of immunocyte dyscrasia.
- Secondary: develops as a severe complication of prolonged chronic inflammation or processes accompanied by massive tissue destruction.
- Hereditary (familial): represents a distinct heterogeneous group of genetically determined disorders with specific regional clustering.
Additionally, the classification includes a specific form of amyloidosis closely associated with long-term artificial kidney support (hemodialysis).
Primary Amyloidosis (AL Type)
This is the most common form of the pathology, accounting for about 75% of all diagnosed cases of systemic amyloidosis. The pathogenesis is driven by plasma cell dyscrasia. The disease is very frequently associated with multiple myeloma, whose clinical presentation typically features osteolytic skeletal lesions.
The substrate for amyloid fibril formation is an excess of immunoglobulin (Ig) light chains. A mandatory condition for disease initiation is the presence of Bence Jones protein (which consists exclusively of Ig light chains). It is important to understand that this is a necessary but not sufficient condition.
The mechanism of amyloid formation is directly linked to impaired proteolysis: defective degradation generates light chain fragments. These fragments become resistant to complete further cleavage and precipitate in tissues as AL amyloid.
Secondary Reactive Amyloidosis (AA Type)
This develops in the setting of chronic inflammation with tissue destruction. Historically, the primary etiologic factors were severe infections (tuberculosis, chronic osteomyelitis, bronchiectasis), but these are now less common due to modern antimicrobial therapy. Today, the leading causes are autoimmune pathologies and connective tissue diseases (ankylosing spondylitis, as well as rheumatoid arthritis, which complicates ~3% of patients with amyloidosis). Inflammatory bowel diseases (ulcerative colitis, regional enteritis, or Crohn disease) can also act as triggers.
The pathogenesis of AA amyloidosis involves the following steps:
- Prolonged tissue destruction acts as a trigger, prompting the release of inflammatory mediators—cytokines (IL-1 and IL-6).
- These cytokines actively stimulate the liver to synthesize the acute-phase precursor protein SAA (serum amyloid A).
- Normally, monocyte enzymes successfully cleave SAA into soluble products.
- In pathology, this process fails. Scenario A: monocyte enzyme defects lead to incomplete SAA degradation. Scenario B: genetic abnormalities in the structure of SAA itself render it resistant to monocyte enzymes. In both cases, the insoluble AA molecule is formed.
Dialysis-Associated and Familial Amyloidosis
Amyloidosis is detected in approximately 70% of patients with renal failure undergoing long-term hemodialysis. The main cause is the gradual accumulation of β2-microglobulin. Because this protein cannot pass through standard dialysis membranes, it accumulates in the blood serum. Deposits of this amyloid localize predominantly in synovial membranes, tendons, and joints.
Hereditary (familial) forms are rare disorders strongly linked to specific ethnicities and geographic regions:
- Autosomal recessive variant (Familial Mediterranean Fever). Found predominantly among Arabs, Armenians, and Sephardic Jews. Clinically manifested by recurrent fever and pronounced serositis (pleuritis, peritonitis, synovitis). The resulting amyloid type is the AA variant.
- Autosomal dominant variant (Familial amyloid polyneuropathy). Characteristic of populations in the US, Sweden, Japan, and Portugal. It predominantly affects peripheral nerves. The substrate is the protein transthyretin (ATTR). An important pathogenetic feature is that the disease does not stem from transthyretin overproduction, but rather from genetic mutations causing structural instability of the protein molecule.