Systemic amyloidosis

Classification and Nature of the Disease

Systemic (generalized) amyloidosis represents a group of conditions in which a pathological protein is deposited throughout the body. The disease is divided into three main groups depending on the cause of origin:

• Primary: occurs against the background of immunocyte dyscrasia.
• Secondary: develops as a severe complication of prolonged chronic inflammation or processes accompanied by massive tissue destruction.
• Congenital (familial): represents a separate heterogeneous group of genetically determined pathologies linked to specific regions.

Separately, the classification distinguishes a specific form of amyloidosis closely associated with a patient's prolonged stay on artificial kidney (hemodialysis) support.

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 based on plasma cell dyscrasia. The disease is very often associated with multiple myeloma, the clinical picture of which is typified by osteolytic skeletal lesions.

The substrate for the formation of amyloid fibrils is an excess of immunoglobulin light chains (Ig). A mandatory condition for the onset of the disease 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 insufficient condition.

The mechanism of amyloid formation is directly related to impaired proteolysis processes: due to defective degradation, fragments of light chains are formed. They become resistant to further complete cleavage and precipitate into tissues as AL amyloid.

Secondary Reactive Amyloidosis (AA Type)

Develops against the background of chronic inflammation with tissue destruction. Previously, the main etiological factors were severe infections (tuberculosis, chronic osteomyelitis, bronchiectasis), but thanks to modern antimicrobial therapy, they are less common. Today, the primary place is occupied by autoimmune pathologies and connective tissue diseases (ankylosing spondylitis, as well as rheumatoid arthritis, in which amyloidosis develops in ~3% of patients). Inflammatory bowel diseases (ulcerative colitis, regional enteritis, or Crohn's disease) can also be the cause.

The pathogenesis of AA amyloidosis includes the following stages:

1. Prolonged tissue destruction acts as a trigger initiating the production of inflammatory mediators — cytokines (IL-1 and IL-6).
2. Cytokines actively stimulate the liver to synthesize the serum precursor — the acute-phase protein SAA.
3. Normally, monocyte enzymes successfully cleave SAA into soluble products.
4. In pathology, a failure occurs. Option one: a defect in monocyte enzymes leads to incomplete degradation of SAA. Option two: genetic anomalies in the structure of SAA itself make it resistant to monocyte enzymes. In both cases, an insoluble AA molecule is formed.

Dialysis and Familial Amyloidosis

In patients with renal failure undergoing long-term hemodialysis, amyloidosis is detected in approximately 70% of cases. The main cause is the gradual accumulation of β2-microglobulin. This protein is physically incapable of filtering through dialysis membranes, so it accumulates in blood serum. Deposits of this amyloid are localized predominantly in synovial membranes, tendons, and joints.

Congenital (familial) forms are rare diseases clearly linked to certain ethnicities and geographical zones:

• Autosomal recessive variant (Familial Mediterranean Fever or Periodic Disease). Found predominantly among Arabs, Armenians, and Sephardic Jews. Clinically manifested by fever attacks and pronounced inflammation of serous membranes (pleuritis, peritonitis, synovitis develop). The type of amyloid formed is the AA variant.
• Autosomal dominant variant (Familial Amyloid Polyneuropathy). Characteristic of residents of the USA, Sweden, Japan, and Portugal. Predominantly affects peripheral nerves. The substrate is the transthyretin protein (ATTR). An important feature of the pathogenesis: the disease arises not due to transthyretin hyperproduction, but as a consequence of genetic mutations that cause structural instability of the protein molecule.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• The connection between multiple myeloma and osteolytic skeletal lesions.
• The role of IL-1 and IL-6 cytokines in stimulating the synthesis of acute-phase proteins in the liver.
• Mechanisms of monocyte enzymatic deficiency during the degradation of the SAA protein.
• The clinical picture of serous membrane inflammation in Familial Mediterranean Fever.
• Features of the structure of Bence Jones protein and methods for its detection.

Other topics in the section «Immunopathological processes»

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