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What Causes Amyloidosis?

Posted on April 01, 2021
Medically reviewed by
Todd Gersten, M.D.
Article written by
Maureen McNulty

The cause of amyloidosis is not well understood. People with this rare condition have abnormal proteins, known as amyloids, that build up in different organs, leading to a variety of symptoms. Many types of proteins can contribute to amyloidosis, leading to several types of the disease. Both genetic and environmental risk factors can play a role in the development of amyloidosis.

How Proteins Become Amyloids

Every cell in the body contains proteins, each of which has a different role in helping the cell grow, divide, or function. The cell is constantly making new proteins by creating long chains of amino acids that are then folded into a specific three-dimensional shape.

When proteins fold incorrectly, they can begin to clump together. These clusters are called amyloid fibrils, or amyloid deposits. It is hard for the body to break down and remove amyloid proteins. They can bundle together in certain tissues and organs, eventually causing damage, sometimes resulting in organ failure.

There are several types of amyloidosis, and each is caused by a different abnormally folded protein.

  • Amyloid light-chain (AL) amyloidosis develops when plasma cells — white blood cells in the bone marrow — produce too much of an antibody protein called immunoglobulin light chain.
  • AA amyloidosis occurs when inflammation in the body causes overproduction of the serum amyloid A (SAA) protein.
  • Hereditary, or familial amyloidosis, is caused by genetic mutations that lead to various abnormal proteins.
  • Wild-type ATTR amyloidosis forms when normal transthyretin (TTR) protein becomes misfolded, although it is not clear why this happens.
  • Dialysis-related amyloidosis occurs when the kidneys are damaged and can’t filter out abnormal beta-2 microglobulin proteins.

Read more about types of amyloidosis.

Risk Factors for Amyloidosis

It is important to note that while science is good at finding correlations — or apparent relationships — between factors and disease, correlation does not prove the factor causes the disease. Many risk factors for amyloidosis have been identified and are being studied for their role in disease development.

Genetic Factors

Only one form of amyloidosis, the hereditary or familial type, is caused directly by gene changes. Within this type, there are many subtypes. One of these, hereditary ATTR amyloidosis, is caused by a mutation in the TTR gene. Non-TTR subtypes are caused by other genes, such as:

  • Apolipoprotein A1
  • Apolipoprotein A2
  • Fibrinogen A alpha chain
  • Cystatin C
  • LECT2
  • Gelsolin

These genes are often passed down within families, although not everyone with the gene develops symptoms of amyloidosis. If you have a family history of the disease — that is, if you have parents, grandparents, or siblings with hereditary amyloidosis — you may have an increased chance of developing amyloidosis as well. Genetic testing can help you learn whether you have these gene mutations.

If your doctor gives you a diagnosis of hereditary amyloidosis, you also may need to get your genes tested. Tests like urinalyses or biopsies help with diagnosing the overall condition, but they won’t tell you exactly which gene mutations you may have. To sequence your genes, your doctor will need to take a blood sample, which a laboratory can use to “read” the TTR gene or other genes.

If you have a gene mutation connected to amyloidosis, it is possible to pass this gene down to your children. Each of your children will have a 50 percent chance of getting the gene that causes hereditary amyloidosis if you have it, although they may never develop symptoms.

Age

Amyloidosis risk usually increases with age.

Sex

Men are more likely to be affected by this disease than women. About 70 percent of people with AL amyloidosis are men. Men also get the wild-type subtype at higher rates. However, both men and women have an equal chance of getting hereditary types.

Race and Geography

Hereditary amyloidosis is more prevalent in people of certain races or those living in specific areas. In the U.S., this disease is more common in African Americans. Rates of amyloidosis are also higher in Spain, Portugal, Ireland, France, Germany, Sweden, Finland, Greece, and Japan.

Other Health Conditions

Other diseases can sometimes increase a person’s risk of amyloidosis. AA amyloidosis — also called secondary amyloidosis — is always connected to an underlying condition that increases inflammation in the body. For example, rheumatoid arthritis, inflammatory bowel disease (IBD) such as Crohn’s disease or ulcerative colitis, familial Mediterranean fever, and chronic infections can increase the risk of developing AA amyloidosis.

Kidney problems can also lead to amyloidosis. Your kidneys are responsible for filtering out waste that your body doesn’t need. If your kidneys aren’t working properly, they may not be able to eliminate harmful amyloid proteins. Some people with kidney disease also use dialysis treatments to help get rid of waste and toxins. However, dialysis may also be ineffective at removing amyloid deposits. If you have severe kidney problems, you have a greater chance of developing dialysis-related amyloidosis.

Some people with other health conditions also develop amyloidosis. For example, up to 15 percent of people who have multiple myeloma are diagnosed with AL amyloidosis. Other conditions that can occur along with amyloidosis include Hodgkin lymphoma, cancer of the thyroid, and Whipple disease. However, it’s not always clear whether these other diseases actually cause amyloidosis.

Can Amyloidosis Be Prevented?

Scientists still don’t understand exactly what causes this disease or why certain proteins can become misfolded. Therefore, there’s nothing specific you can do to prevent amyloidosis. While it’s clear that hereditary forms of amyloidosis are linked to specific gene mutations, you can’t change the genes you are born with.

When some people are diagnosed with amyloidosis, they may worry that certain lifestyle choices caused the disease. However, amyloidosis is not known to be linked to any lifestyle factors. Your risk of amyloidosis is not affected by:

  • The things you eat, including how much protein you eat
  • How stressed you feel
  • What you do for a living

It’s not possible to completely prevent AA amyloidosis, but it is possible to lower your risk. This subtype is caused by inflammation, so treating any underlying inflammatory condition may decrease your chances of being diagnosed with AA amyloidosis. If you have an inflammatory condition, it is important to work with your health care team to find treatment options that can keep inflammation under control.

Amyloidosis Condition Guide

All updates must be accompanied by text or a picture.
Todd Gersten, M.D. is a hematologist-oncologist at the Florida Cancer Specialists & Research Institute in Wellington, Florida. Review provided by VeriMed Healthcare Network. Learn more about him here.
Maureen McNulty studied molecular genetics and English at Ohio State University. Learn more about her here.

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