Testing and Diagnosis of ATTR Amyloidosis

ATTR amyloidosis is a serious condition. It happens when a protein called transthyretin (TTR) misfolds. The misfolded proteins build up as amyloid deposits in the body. These deposits most often harm the heart, nerves, as well as some other organs. This can cause ATTR cardiomyopathy (heart problems) or polyneuropathy (nerve damage).¹

Diagnosing ATTR amyloidosis can be difficult. The symptoms often look like other, more common signs of aging. This can cause delays in getting the right diagnosis. Finding the disease early is very important because new treatments may help slow the disease.^1,2

Medical history and physical exam

The first step is a meeting with your doctor. They will ask about your health and your family’s medical history. This is because ATTR amyloidosis can be hereditary (passed down in families). They will also perform a physical exam.^1-4

During this health history and physical exam process, your doctor will listen for "red flags." These are symptoms or other conditions that are common in people with ATTR amyloidosis.^1,3,4

Heart-related red flags may include:^1,3,4

• Symptoms of heart failure. This includes shortness of breath, fatigue, and swelling in the legs (edema).
• Thickened heart walls found on an ultrasound (echocardiogram)
• Irregular heartbeat (arrhythmias)
• Narrowing of a heart valve (aortic stenosis)

Non-heart-related red flags may include:^1,3,4

• Carpal tunnel syndrome – This is numbness, tingling, and pain in 1 wrist or both.
• Lumbar spinal stenosis – This is a narrowing of the spine in the lower
• Peripheral neuropathy – This is numbness, weakness, or pain, often in the hands and feet.
• Tendon ruptures – Amyloid protein deposits can make tendons (the bands that connect muscle to bone) weak and stiff. A weakened tendon is much more likely to tear or break, which is a rupture. This can happen with little or no real injury.

Laboratory tests

Lab tests are a key part of diagnosis. These tests check your blood and urine. Doctors must first rule out a different type of amyloidosis called AL amyloidosis. The treatment for AL amyloidosis is very different. These tests look for something called a monoclonal protein.^3-5

The main tests are:^3,5

• Serum free light chain assay – This blood test measures levels of light chain proteins.
• Protein electrophoresis with immunofixation – These tests check both blood and urine for abnormal proteins.

If these tests are negative, it means AL amyloidosis is unlikely. The doctor will then focus on testing for ATTR amyloidosis.^3-5

Genetic testing

If ATTR amyloidosis is diagnosed, genetic testing is recommended for all patients. This test usually uses a blood sample. It checks the TTR gene for any mutations.^1-4

This test shows which type of ATTR amyloidosis you have:^1-3

• Hereditary ATTR (hATTR) – This means you have a mutation in the TTR gene. This type can be passed down to family members.
• Wild-type ATTR (ATTRwt) – This means your TTR gene is normal. This type is not inherited. It is related to aging.

Knowing the type is very important. It helps guide treatment choices. It also lets family members know if they should be screened.^1,3,4

Imaging tests

Imaging tests take pictures of the inside of your body. They help doctors see the effects of amyloid deposits. These are non-invasive diagnostic tests, as opposed to more invasive methods like a tissue biopsy.^3-5

Echocardiogram

An echocardiogram (echo) uses sound waves to create a picture of your heart. Doctors look for a thickened left ventricle (heart wall). They may also see a pattern called "apical sparing." This pattern is a strong clue for cardiac amyloidosis.^3-5

Cardiac magnetic resonance imaging (CMR)

A CMR uses powerful magnets and radio waves. It creates very detailed pictures of the heart. A CMR can show thickening of the heart muscle. It can also spot amyloid deposits using a contrast dye. This often shows a specific pattern called late gadolinium enhancement (LGE).^3-6

Bone scan (scintigraphy)

This test is the most important imaging test for diagnosing ATTR. It is a type of nuclear medicine scan. A small amount of a radioactive tracer is injected into your vein. These tracers were designed for bone scans but are very good at sticking to ATTR amyloid deposits in the heart.^3-6

A special camera scans your body. If the tracer collects in your heart, it shows up brightly on the scan. Doctors grade what is known as the uptake. A Grade 2 or 3 uptake is a very strong sign of ATTR cardiac amyloidosis.^3,5,6

Tissue biopsy

A biopsy is still needed in some cases. This happens if the lab tests or scan results are unclear. A biopsy involves taking a very small piece of tissue to be checked in a lab.^3,5

This sample might come from the heart (endomyocardial biopsy). Sometimes, doctors can take a sample from a nerve or a fat pad under the skin.^3,5

The lab treats the tissue with a special red dye. If amyloid is present, they use a method called mass spectrometry. This can identify the exact protein type, confirming it is TTR.^3,5

A multi-step process

Diagnosing ATTR amyloidosis is a multi-step process. It starts with your doctor reviewing your medical history and "red flags" like carpal tunnel syndrome. It then involves lab tests to rule out AL amyloidosis.^1,3

For many people, the diagnosis is confirmed with imaging. A positive bone scan combined with negative lab tests can confirm ATTR cardiac amyloidosis without a biopsy. A tissue biopsy may be used if results are not clear.^3-5

Finally, genetic testing is vital. It confirms if the disease is hereditary (hATTR) or wild-type (ATTRwt). This information helps you and your healthcare team build the best treatment plan. If you have symptoms, talk to your doctor about this diagnostic process.