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Amyloidosis — The Path To Diagnosis

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

In amyloidosis, early diagnosis can be key to better outcomes and improved quality of life. Unfortunately, amyloidosis can be difficult to diagnose, and delayed diagnosis is common. Amyloidosis is also thought to be underdiagnosed.

Amyloidosis is a rare condition in which the body makes abnormally folded protein called amyloid. Amyloid accumulates in tissues and organs and can affect many parts of the body. Since amyloidosis can cause a wide variety of symptoms, many of which are very general, it can be difficult to distinguish from other diseases. For this reason, a range of tests may be used to diagnose amyloidosis. Tests may serve to confirm a diagnosis of amyloidosis, determine the specific type of amyloidosis, or help rule out other conditions.

Physical Exam

Your doctor may perform an examination to look for some of the common signs of amyloidosis. This exam may include:

  • Asking you about your personal and family health history
  • Checking your joints to see if they are stiff or swollen
  • Examining your muscles to see if you have any unexpected weakness
  • Looking at your skin to see if you have any rashes
  • Assessing your tongue to see if it’s swollen

During this exam, your doctor may also collect blood or urine samples to run laboratory tests. If you have a form of amyloidosis that is systemic — that is, it affects your entire body — then amyloid proteins may be present in the blood or urine.

Biopsy

While many other tests can help indicate whether amyloidosis is a possibility, a biopsy is necessary to confirm a diagnosis. During a biopsy, your doctor will remove a small piece of tissue to examine it for amyloid proteins. If your doctor thinks you may have a form of systemic amyloidosis, they may take a tissue sample from your bone marrow, abdominal fat (sometimes called your “fat pad”), inner lip, or skin. However, if you have localized disease, which only affects one organ, the doctor may take a sample directly from that organ.

After the doctor performs a biopsy, they will send the sample to a laboratory. There, the biopsy sample will be mixed with a dye called Congo red stain. A specialist, called a pathologist, will examine the sample under a special microscope. If amyloid proteins are present, the Congo red stain will make the sample appear green.

Bone Marrow Biopsy

The most common type of amyloidosis — known as AL amyloidosis, amyloid light-chain amyloidosis, or primary amyloidosis — is a disease of the bone marrow. Bone marrow is tissue, found inside certain bones, that makes new blood cells. AL amyloidosis develops due to a dyscrasia, or abnormality, of the plasma cells found in bone marrow. Plasma cells are white blood cells that protect the body from germs. When there are problems with these cells, they can make too much of a protein called immunoglobulin light chain, which is normally used to make infection-fighting antibodies. For this reason, this type of amyloidosis is also called immunoglobulin light-chain amyloidosis.

If there is a chance you may have AL amyloidosis, your doctor may want to look more closely at your bone marrow to see whether you have abnormal plasma cells or amyloid deposits. A bone marrow test usually involves two parts:

  • During a bone marrow aspiration, a doctor removes some of the fluid of the bone marrow.
  • During a bone marrow biopsy, a doctor removes part of the solid bone marrow tissue.

Other types of amyloidosis may start in different organs, but can later spread to the bone marrow. For this reason, you may also need a bone marrow aspiration or biopsy if your doctor suspects you have another form of amyloidosis.

Biopsies of Other Organs

If there is a chance that some of your other organs are affected by amyloid deposits, your doctor may want to biopsy tissue at those locations as well. For example, a type of amyloidosis known as AA amyloidosis can lead to kidney damage. If your doctor suspects you may have AA amyloidosis, they may want to take a biopsy of the kidney. Other areas that may need to be biopsied include the liver, heart, nerves, or organs of the digestive system.

Some people with amyloidosis also have skin symptoms. These can include purpura (small red or purple spots), blood blisters, brittle nails, or hair loss. Diagnosing these problems often requires a skin biopsy.

Imaging Tests

Your health care team can use imaging tests to visualize any abnormalities and get a closer look at how your organs are working. One test your doctor may use is an ultrasound, which takes pictures of your organs using sound waves. Another possible imaging test is magnetic resonance imaging (MRI). During this procedure, radio waves and magnetic fields create a precise picture of your internal organs. MRI can help your doctor evaluate organ health.

Nuclear imaging tests can also provide pictures of organs. Nuclear imaging uses a small amount of radioactive material to highlight different tissues. Doctors can use this information to get an idea of which type of amyloidosis you may have, so they can determine which treatment options may be most likely to help.

Some people with amyloidosis will also get X-rays or computed tomography (CT) scans. These imaging tests can help your doctor see if there are amyloid proteins in your joints, ligaments, tendons, or bones. This can be helpful for diagnosing dialysis-related amyloidosis and other types of the condition that affect the joints.

Organ Tests

If your doctor finds clumps of amyloid (known as amyloid fibrils) within certain organs, they may perform further tests to see if the organs are working correctly. Basic blood and urine tests can provide a clue as to whether amyloidosis is causing damage in organs.

  • Kidneys — If you have a lot of protein in your urine, it may be a sign of kidney damage.
  • Liver — High levels of alkaline phosphatase in your blood may indicate liver problems.
  • Heart — Blood tests that measure markers like troponin or brain natriuretic peptide can provide information about your heart health.

If you have wild-type ATTR or hereditary ATTR amyloidosis, your doctor may also test your cardiac function in more depth. Heart tests may include an electrocardiogram (EKG) or an echocardiogram. These tests can check the structure and function of the heart and identify problems like cardiomyopathy, in which your heart has problems pumping blood correctly. Some people with heart-related amyloidosis end up having heart failure, so it is important to regularly test the function of your heart.

People with gastrointestinal or digestive symptoms may also need other tests. One possible diagnostic test is an endoscopy, in which a tube with a camera is inserted down the throat and into the esophagus, stomach, and small intestines. In another test called a colonoscopy, the tube is inserted into the rectum and large intestine. These tests can help doctors visualize possible digestive system damage, take biopsy samples, and treat symptoms such as bleeding.

Determining the Type of Amyloidosis

After you have a diagnosis of amyloidosis, you will need to know which type of amyloidosis you have. If your health care team identifies amyloid fibrils during a biopsy of the bone marrow, kidney, or another organ, a pathologist may also test that same biopsy sample to determine exactly which abnormal proteins are causing the amyloid deposits.

If your doctor thinks you have AL amyloidosis, further testing can help your health care team determine whether there are problems with your plasma cells or abnormal light-chain proteins. These tests may include:

  • Bone marrow biopsy to look more closely at plasma cells
  • Serum free light-chain assay, a test that analyzes levels of light-chain proteins in the blood
  • Immunofixation electrophoresis, a test that measures light-chain proteins in the blood or urine

AA amyloidosis occurs in conjunction with an underlying disease, such as rheumatoid arthritis or an inflammatory bowel disease like Crohn’s disease or ulcerative colitis. If you know you have one of these conditions, your doctor may want you to undergo diagnostic tests if you develop a symptom of amyloidosis. This often includes looking at protein levels in the urine or taking a kidney biopsy. Some people are diagnosed with AA amyloidosis without realizing that they have an underlying condition. If this is the case for you, you may also have other diagnostic tests to figure out which other inflammatory disease you have.

Hereditary amyloidosis is caused by genetic mutations. However, there are hundreds of different genetic changes that may be responsible for this disease. To figure out which one you have, your doctor can take a blood sample and use genetic testing to read the sequence of genes like transthyretin (TTR).

Some people with kidney disease develop dialysis-related amyloidosis. This subtype often causes amyloid deposits to collect in the bones or joints, leading to bone cysts, joint pain, and swelling. Diagnosis of this subtype often includes imaging tests, such as X-rays, to look for these symptoms.

Amyloidosis Condition Guide

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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