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Amyloidosis

Q: How do organs appear macroscopically in advanced amyloidosis?

The macroscopic appearance depends on the affected organ: Kidneys — firm, with a waxy, greasy sheen on cross-section; ultimately leading to a small, contracted amyloid kidney.Spleen — amyloid may deposit along the follicles ("sago spleen") or diffusely throughout the pulp ("lardaceous spleen"). Organ appearance may also reflect the underlying primary disease responsible for the deposition.

For medical students2 min readUpdated 2026-10-10

Amyloidosis is a broad group of disorders characterized by the extracellular deposition of an abnormal fibrillar protein that aggregates with other components to form a complex substance known as amyloid. Amyloid is deposited exclusively in the extracellular space—within the interstitium and vessel walls. The progressive accumulation of these deposits leads to compression of surrounding structures and their progressive atrophy.

DiagnosisExclusively via biopsy (Congo red stain)

StructureF-component (95%) and P-component (5%)

LocalizationInterstitium and walls of blood vessels

Cellular OutcomeCompression by deposits causes cellular atrophy

Morphology and Diagnostic Methods

Vital identification of the pathology is possible exclusively through the examination of biopsy specimens. Historically, this condition was classified among stromal-vascular protein dystrophies.

Light microscopy: With traditional stains, deposits appear as an amorphous, eosinophilic, hyaline-like extracellular substance.
Histochemical methods: To differentiate amyloid from fibrin and collagen, Congo red staining is used.
Polarization microscopy: Stained structures exhibit double refraction (birefringence) and a characteristic apple-green birefringence under polarized light.

Physicochemical Nature of Amyloid

Despite biochemical heterogeneity, the physical structure is uniform across all types of the disease. It is studied using electron microscopy, crystallography, and infrared spectroscopy.

The substance consists of two fractions:

F-component (fibrillar): Comprises approximately 95% of the mass. It is represented by non-branching fibrils 7.5–10 nm in width. The fibril shell has a characteristic pleated sheet conformation, which accounts for the birefringence property.
P-component (glycoprotein): Comprises about 5%. It has a pentagonal structure, structural homology with C-reactive protein (CRP), high affinity for fibrils, and is critical for the formation of tissue deposits.

Major Biochemical Types

Around 15 biochemical variants are known, but two major types predominate:

AL amyloid (Amyloid Light chain). Synthesized by plasma cells (immunocytes) during monoclonal B-cell proliferation. It consists of immunoglobulin light chains (most commonly type VI $\lambda$ chains, less frequently $\kappa$ chains), specifically their $\text{NH}_2$-terminal fragments.
AA amyloid (Amyloid Associated). A unique non-immunoglobulin protein (molecular weight ~8,500, consisting of 76 amino acid residues) formed in secondary amyloidosis. Its precursor is SAA (serum amyloid A), which is synthesized in the liver and circulates in the blood bound to the $\text{HDL}_3$ lipoprotein subclass.

Specific Forms and Pathogenesis

In addition to AL and AA, other specific precursor proteins occur:

Transthyretin (TTR): A serum protein that normally transports thyroxine and retinol. With genetic mutations (a single amino acid substitution), it undergoes abnormal aggregation and proteolysis, forming ATTR amyloid. This leads to familial amyloid polyneuropathy.
$\beta$-amyloid: Forms the core of cerebral plaques in Alzheimer disease. It is derived from a large transmembrane glycoprotein, APP (Amyloid Precursor Protein).
Other precursors: Keratin, hormones (e.g., procalcitonin).

The actual conversion of precursor proteins into fibrils occurs with the participation of effector cells. Although the mechanism is not fully understood, macrophages are considered the primary candidates for this role. Based on the distribution of the process, classification distinguishes between systemic (generalized, affecting multiple systems) and localized (deposits in a single organ) amyloidosis.

Mnemonic

The term amyloid derives from the Latin amylum — starch (historically called "animal starch"). To differentiate it from collagen, Congo red staining is used. Under polarized light, it yields apple-green birefringence and dichroism.

Frequently asked questions

How do organs appear macroscopically in advanced amyloidosis?

The macroscopic appearance depends on the affected organ:

Kidneys — firm, with a waxy, greasy sheen on cross-section; ultimately leading to a small, contracted amyloid kidney.
Spleen — amyloid may deposit along the follicles ("sago spleen") or diffusely throughout the pulp ("lardaceous spleen").

Organ appearance may also reflect the underlying primary disease responsible for the deposition.

Which chronic conditions most frequently lead to secondary AA amyloidosis?

Secondary AA amyloidosis (reactive systemic) most frequently develops in the setting of chronic inflammatory states with tissue destruction:

Autoimmune disorders — rheumatoid arthritis (the most common cause), ankylosing spondylitis.
Chronic infections — tuberculosis, leprosy.
Suppurative processes — chronic osteomyelitis, bronchiectasis, lung abscesses, infective endocarditis.
Inflammatory bowel disease — ulcerative colitis, Crohn disease.
Neoplastic processes — certain types of tumors.

What is the complete clinical classification of amyloidosis?

Clinical classification is based on distribution, etiopathogenesis, and clinical syndromes.

By distribution:

Systemic amyloidosis — involvement of multiple organ systems.
Localized amyloidosis — deposits found in a single organ (including localized tumor-like masses).

By etiology and pathogenesis, systemic amyloidosis is divided into:

Primary amyloidosis (idiopathic, associated with immunocyte dyscrasia).
Secondary amyloidosis (acquired, complication of chronic inflammation).
Hereditary (familial) amyloidosis.
Senile amyloidosis.
Amyloidosis associated with plasma cell dyscrasias (e.g., multiple myeloma, Waldenström macroglobulinemia).

Where exactly is amyloid deposited in tissues?

Deposits form exclusively outside cells: in the interstitial tissue and within the walls of blood vessels.

What is the precursor protein in secondary amyloidosis?

It is SAA (serum amyloid A), synthesized in the liver and circulating with lipoproteins, which gives rise to AA amyloid.

Which cells synthesize AL amyloid?

It is produced by plasma cells (immunocytes) during monoclonal proliferation of B-lymphocytes and consists of immunoglobulin light chains.

What is the significance of the P-component of amyloid?

It accounts for only 5% of the mass, has a pentagonal structure, and is structurally similar to C-reactive protein (CRP). Tissue deposition cannot occur without it.

Go deeper

Role of macrophages in converting precursor proteins into fibrils
Association of SAA protein with the HDL3 lipoprotein subclass
Transthyretin (TTR) mutations and the pathogenesis of familial amyloid polyneuropathy
Mechanisms of $\beta$-amyloid generation from APP in Alzheimer disease
Clinical syndromes in systemic versus localized amyloidosis