Amyloidosis is a rare condition characterized by the accumulation of abnormal proteins, known as amyloid, within various organs and tissues. These misfolded protein deposits interfere with normal organ function, leading to a range of symptoms and potential complications. The disease manifests in different forms, each linked to a specific type of protein that misfolds and aggregates into insoluble, fibrous amyloid fibrils. These fibrils are resistant to the body’s normal breakdown processes and can progressively impair organ function, potentially leading to organ failure if left untreated.
Major Systemic Amyloidosis Types
Systemic amyloidosis affects multiple organs throughout the body. The most common and clinically significant types include AL, AA, and ATTR amyloidosis.
AL Amyloidosis (Light Chain Amyloidosis)
AL amyloidosis is the most frequently diagnosed form. It originates from abnormal plasma cells in the bone marrow, which produce excessive amounts of misfolded immunoglobulin light chain proteins. These light chain proteins then aggregate and deposit as amyloid fibrils. AL amyloidosis commonly affects the heart, kidneys, liver, nerves, and digestive tract.
AA Amyloidosis (Secondary Amyloidosis)
AA amyloidosis develops in association with chronic inflammatory diseases. Conditions like rheumatoid arthritis, inflammatory bowel disease, or chronic infections can cause sustained high levels of serum amyloid A (SAA) protein. Prolonged overproduction of SAA can lead to fragments of this protein, called AA protein, depositing as amyloid. The kidneys are the most commonly affected organs in AA amyloidosis, with liver and spleen involvement also observed.
ATTR Amyloidosis (Transthyretin Amyloidosis)
ATTR amyloidosis involves the transthyretin (TTR) protein, primarily produced by the liver. This type has two main forms: hereditary and wild-type. Hereditary ATTR amyloidosis is caused by a genetic mutation in the TTR gene, leading to an unstable, abnormal TTR protein that readily misfolds and forms amyloid deposits. This inherited form commonly affects the nerves, causing neuropathy, and the heart, leading to cardiomyopathy. Wild-type ATTR amyloidosis occurs when the normal TTR protein becomes unstable and misfolds with age. This form primarily affects the heart, often leading to heart failure.
Other Types of Amyloidosis
Beyond the major systemic forms, several other types of amyloidosis exist. Some are less common or localized to specific tissues.
Less common systemic types include Aβ2M amyloidosis, associated with long-term dialysis in patients with chronic kidney disease. Here, beta-2 microglobulin (Aβ2M) protein accumulates, primarily affecting the musculoskeletal system. ALECT2 amyloidosis, caused by the LECT2 protein, commonly affects the kidneys and liver. ApoA1 amyloidosis is a hereditary form resulting from mutations in the APOA1 gene, which can lead to amyloid deposits in various organs, including the kidneys, liver, and heart.
Localized amyloidosis differs from systemic forms as the amyloid deposits are confined to a single organ or tissue and do not spread throughout the body. Examples include localized cutaneous amyloidosis, where deposits affect the skin, or localized bladder amyloidosis. Cerebral amyloid angiopathy, characterized by amyloid deposits in the brain’s blood vessels, is often linked to Alzheimer’s disease.
Distinguishing Features Among Types
Distinguishing between different types of amyloidosis involves identifying the specific protein that forms the amyloid deposits. For instance, AL amyloidosis is characterized by light chain proteins, AA amyloidosis by serum amyloid A protein, and ATTR amyloidosis by transthyretin protein. This protein identification is crucial for accurate diagnosis and guiding appropriate treatment strategies. The patterns of organ involvement also provide important clues for differentiation.
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