Amyloidosis is the name for protein-folding diseases characterized by extracellular deposition of a specific soluble precursor protein that aggregates in the form of insoluble fibrils. The classification of amyloidosis is based on the chemical characterization of the precursor protein. Deposition of amyloid is localized or systemic. The 4 main types of systemic amyloidosis are AL, AA, ATTR, and Aβ 2 M type. A schematic approach is proposed for the clinical management of systemic amyloidosis. The importance of typing amyloid with confidence, the usefulness of imaging techniques, the principles of treatment, and the need for well-planned treatment monitoring during follow-up are discussed.
Key points
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Amyloidosis is the name for some diseases caused by protein misfolding; 30 different soluble precursor proteins can aggregate and be deposited as insoluble amyloid fibrils.
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Amyloid deposition is localized or systemic; the 4 main types of systemic amyloidosis are AL (light chain), AA (inflammation), ATTR (hereditary and old age), and Aβ 2 M (dialysis).
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Clinical management comprises proof of amyloid, systemic evidence, reliable typing, precursor assessment, severity of organ disease, choice of treatment, and planned follow-up.
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The precursor-product concept is the current basis of treatment, thereby aiming to decrease the levels of precursor proteins in serum to normal or undetectable values. Future clinical research will be directed at stopping amyloid deposition and increasing amyloid clearance.
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Protein misfolding is not only a characteristic of amyloidosis; it is also involved in many other disabling cardiac and neurologic degenerative diseases that interfere with healthy aging.
Introduction
The description of the autopsy of a young man in 1639 by Nicolaes Fonteyn, a Dutch physician and poet who lived in Amsterdam, was probably the first report of a patient with systemic amyloidosis. Since then, lardaceous changes in enlarged organs, such as the liver, spleen, heart, and kidneys, have drawn the attention of pathologists such as Rokitansky. In 1854, Rudolph Virchow was one of the first to use the term amyloid for this amorphous and hyaline change in tissue because of an iodine-staining reaction similar to that of starch (amylon; Greek for origin). Although it is now known that amyloid has nothing to do with starch, the term amyloid is still in use today. Bennhold introduced Congo Red staining in 1922 as a useful method to identify amyloid in tissue specimens. In 1927, Divry and Florkin described the characteristic green birefringence when Congo Red-stained amyloid was viewed under polarized light. In 1959, Cohen and Calkins detected the fibril nature of amyloid when viewed under the electron microscope.
Amyloidosis is the name for 30 protein-folding diseases ( Table 1 ), all characterized by extracellular deposition of a specific soluble precursor protein that aggregates in the form of insoluble fibrils. These rigid and unbranching fibrils, approximately 10 nm in diameter, are characterized by a molecular β-pleated sheet structure that is usually composed of peptides arranged in an antiparallel configuration. This structure of the fibrils is responsible for its insolubility, resistance to proteolysis, and binding affinity for Congo Red dye that shows a characteristic green birefringence when viewed under polarized light ( Fig. 1 ).
| Fibril Protein | Precursor Protein | Systemic or Localized | Acquired or Hereditary | Target Organs |
|---|---|---|---|---|
| AL | Immunoglobulin light chain | S, L | A | All organs except CNS |
| AH | Immunoglobulin heavy chain | S, L | A | All organs except CNS |
| Aβ2M | β2-microglobulin, wild type | S | A | Musculoskeletal system |
| β2-microglobulin, variant | S | H | ANS | |
| ATTR | Transthyretin, wild type | S, L | A | Heart mainly in men, tenosynovium |
| Transthyretin, variants | S | H | PNS, ANS, heart, eye, leptomeninges | |
| AA | (Apo) serum amyloid A | S | A | All organs except CNS |
| AApoAI | Apolipoprotein A I, variants | S | H | Heart, liver, kidney, PNS, testis, larynx (C-terminal variants), skin (C-terminal variants) |
| AApoAII | Apolipoprotein A II, variants | S | H | Kidney |
| AApoAIV | Apolipoprotein A IV, wild type | S | A | Kidney medulla and systemic |
| AGel | Gelsolin, variants | S | H | PNS, cornea |
| ALys | Lysozyme, variants | S | H | Kidney |
| ALect2 | Leukocyte chemotactic factor-2 | S | A | Kidney, primarily |
| AFib | Fibrinogen α, variants | S | H | Kidney, primarily |
| ACys | Cystatin C, variants | S | H | PNS, skin |
| ABri | ABriPP, variants | S | H | CNS |
| ADan a | ADanPP, variants | L | H | CNS |
| Aβ | Aβ protein precursor, wild type | L | A | CNS |
| Aβ protein precursor, variant | L | H | CNS | |
| APrP | Prion protein, wild type | L | A | CJD, fatal insomnia |
| Prion protein, variants | L | H | CJD, GSS syndrome, fatal insomnia | |
| ACal | (Pro)calcitonin | L | A | C-cell thyroid tumors |
| AIAPP | Islet amyloid polypeptide b | L | A | Islets of Langerhans, insulinomas |
| AANF | Atrial natriuretic factor | L | A | Cardiac atria |
| APro | Prolactin | L | A | Pituitary prolactinomas, aging pituitary |
| AIns | Insulin | L | A | Iatrogenic, local injection |
| ASPC | Lung surfactant protein | L | A | Lung |
| AGal7 | Galectin 7 | L | A | Skin |
| ACor | Corneodesmin | L | A | Cornified epithelia, hair follicles |
| AMed | Lactadherin | L | A | Senile aortic, media |
| AKer | Kerato-epithelin | L | A | Cornea, hereditary |
| ALac | Lactoferrin | L | A | Cornea |
| AOaap | Odontogenic ameloblast-associated protein | L | A | Odontogenic tumors |
| ASem1 | Semenogelin 1 | L | A | Vesicula seminalis |
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