Causes of Amyloidosis
Amyloidosis occurs due to abnormal protein production and misfolding, leading to the formation of amyloid deposits in different organs and tissues. The specific causes vary depending on the type of amyloidosis, but common factors include genetic mutations, chronic inflammatory diseases, blood cell disorders, and long-term dialysis.
1. Genetic Mutations (Hereditary Amyloidosis)
Some types of amyloidosis are inherited due to mutations in specific genes responsible for producing amyloid-forming proteins. A well-known example is hereditary ATTR amyloidosis, which is caused by mutations in the transthyretin (TTR) gene. These mutations result in the production of an unstable transthyretin protein, which misfolds and forms amyloid deposits, primarily affecting the heart and nervous system. This condition is passed down through families, and individuals with a family history of amyloidosis have a higher risk of developing the disease. Symptoms may include peripheral neuropathy (nerve damage), heart failure, and autonomic dysfunction (issues with blood pressure, digestion, and sweating).
2. Chronic Inflammatory Diseases
Long-term inflammatory conditions can also contribute to amyloidosis. In AA amyloidosis, the liver produces serum amyloid A (SAA) protein as a response to chronic inflammation. Over time, this protein misfolds and accumulates, particularly in the kidneys, liver, and spleen, leading to organ dysfunction. This form of amyloidosis is commonly associated with chronic infections, such as tuberculosis and osteomyelitis (bone infection), as well as autoimmune diseases, including rheumatoid arthritis, Crohn’s disease, and lupus. Since persistent inflammation triggers excess SAA protein production, controlling the underlying disease is the key to preventing or slowing the progression of AA amyloidosis.
3. Blood Cell Disorders (Plasma Cell Dyscrasias)
In AL amyloidosis (primary amyloidosis), abnormal plasma cells in the bone marrow produce defective light chain proteins that misfold and accumulate as amyloid deposits in different organs. This condition is closely linked to multiple myeloma, a type of blood cancer that causes excessive production of these light chains. The most commonly affected organs in AL amyloidosis are the heart, kidneys, nervous system, and liver, leading to symptoms such as heart failure, kidney dysfunction, nerve pain, and liver enlargement. Because plasma cell disorders play a central role in this type of amyloidosis, treatment often involves chemotherapy or stem cell transplantation to target the underlying blood disease.
4. Long-Term Dialysis (Dialysis-Related Amyloidosis)
Patients who have been on kidney dialysis for more than 10 years are at a higher risk of developing dialysis-related amyloidosis (DRA). This occurs because a protein called β2-microglobulin (β2M), which is normally filtered out by healthy kidneys, builds up in the bloodstream of patients with kidney failure. Over time, β2M forms amyloid deposits in bones, joints, and tendons, leading to symptoms such as joint pain, stiffness, carpal tunnel syndrome, and bone fractures. Since dialysis cannot completely remove β2-microglobulin, the best way to prevent or manage DRA is through a kidney transplant, which restores normal kidney function and reduces amyloid accumulation