Amyloidosis: ATTR (transthyretin)
What is amyloidosis?
Amyloidosis (am-uh-loy-doh-sis) is a protein disorder. In this disease, proteins change shape (misfold), then bind together and form amyloid fibrils which deposit in organs. As amyloid fibrils build up, the tissues and organs may not work as well as they should.
Our bodies make several proteins that can cause amyloidosis. To choose the right treatment, it is very important to know the exact protein that is causing the disease. The two most common types are light chain (AL) and transthyretin (ATTR) amyloidosis.
What is ATTR (transthyretin) amyloidosis?
Transthyretin (trans-thigh-re-tin), also called TTR, is a protein made by the liver that helps carry thyroid hormone and vitamin A in the blood. Normally, TTR is made up of four identical parts. However, in ATTR amyloidosis, the protein becomes unstable, breaks apart, and deposits in the heart and/or the nerves.
There are two types of ATTR Amyloidosis:
Hereditary (familial) ATTR amyloidosis. In this form, there is a change (mutation) in the DNA that is inherited and can be passed from one generation to the next. This makes the TTR protein more unstable and more likely to form amyloid fibrils. Different mutations lead to different symptoms — some may affect the nerves; some may affect the heart; and some may affect both.
Wild-type ATTR amyloidosis. Unlike hereditary ATTR amyloidosis, wild-type does not involve abnormal DNA and cannot be passed on to family members. Instead, as you get older, the normal TTR protein becomes unstable, misfolds and forms amyloid fibrils.
These ATTR amyloid fibrils usually deposit in:
- The wrist, in a narrow pathway called the carpal tunnel. This can cause carpal tunnel syndrome, which causes your hand and arm to become numb and tingle.
- The spinal canal, which can cause narrowing of the spinal column (spinal stenosis).
- The heart, which can cause heart failure and/or an irregular heart rhythm called atrial fibrillation.
- Carpal tunnel syndrome and spinal stenosis can develop several years before heart failure.
Symptoms and Causes
What are the signs and symptoms of ATTR amyloidosis?
ATTR amyloidosis can affect many organs. Symptoms depend on the organs that are involved.
Symptoms indicating the arms are affected include:
- Carpal tunnel syndrome.
- Numbness, burning and/or tingling (peripheral neuropathy).
- Biceps tendon rupture.
Symptoms indicating the back is affected include:
- Lumbar spinal stenosis.
Symptoms indicating the legs are affected include:
- Swelling of the feet or legs.
- Numbness, burning and/or tingling (peripheral neuropathy).
- Leg weakness.
Symptoms indicating the head and neck are affected include:
- Eye floaters (vitreous opacities).
- Lightheadedness upon standing.
Symptoms indicating the heart and lungs are affected include:
- Shortness of breath.
- Chest pain.
Symptoms indicating the stomach or intestines are affected include:
- Poor appetite.
- Bloating or excessive gas.
- Diarrhea or constipation.
Diagnosis and Tests
How is ATTR amyloidosis diagnosed?
Many tests can help diagnose amyloidosis. A biopsy (the removal of a small piece of tissue) of the affected organ is the most useful test. To take a biopsy from the heart, a small, thin, hollow tube (catheter) is placed into a vein in your neck and then guided into the right side of your heart. A few small pieces of the heart muscle are removed.
A pathologist will examine the tissue with a microscope and perform special tests to identify the exact protein causing the amyloidosis.
A bone scan called a technetium pyrophosphate (TcPYP) scan can detect ATTR in the heart (see video). A positive TcPYP scan, along with blood and urine tests to rule out other forms of amyloidosis, can confirm the diagnosis without the need for a heart biopsy. When ATTR amyloidosis is confirmed, a blood test is used to find out if the ATTR is hereditary or wild-type.
Several other tests may be used to check organ function:
- Blood samples to check the kidneys, heart, and liver.
- An electrocardiogram (EKG) and echocardiogram (ultrasound of the heart) to check the heart.
- An MRI of the heart may also be done.
Family members of someone with hereditary ATTR amyloidosis have a higher risk of also having the condition. Close family members, such as parents, siblings and children have a 50% chance of having the mutation. If you have hereditary ATTR amyloidosis, you should talk to a genetic counselor to learn more about the risk of the condition among other family members and genetic testing.
Management and Treatment
What treatments are available for patients with ATTR amyloidosis?
Several medications have been approved by the Food and Drug Administration (FDA) for treating patients with ATTR amyloidosis. Other medications continue to be investigated.
- ATTR silencers. These medications act on the liver to decrease the production of TTR. Two ATTR silencers approved by the FDA to treat patients with the hereditary type of ATTR who also have neuropathy.
- Patisiran (Onpattro®) is an infusion that is given every three weeks.
- Inotersen (Tegsedi®) is an injection given once a week and requires weekly lab work.
- ATTR stabilizers. These medications stabilize the TTR protein, which in turn prevents it from breaking apart and forming amyloid fibrils.
- Tafamidis (Vyndamax®, Vyndaqel®) is approved by the FDA for patients with hereditary or wild-type ATTR that has affected their heart.
- AG10 is a medication currently being tested in a clinical trial.
- Diflunsial (Dolobid®) is a nonsteroidal anti-inflammatory drug (NSAID) that has been shown to also stabilize the TTR protein. However, this medication has not been fully studied in patients with ATTR that has affected the heart and also may not be tolerated due to side effects.
- Fibril disruptors. These medications may help break up and clear ATTR amyloid fibrils. Doxycycline (antibiotic) and green tea extract (over-the-counter supplement)have only been tested in small studies and there is limited evidence that these medications would be helpful in treating amyloidosis.
An antibody that removes TTR amylod fibrils, called PRX-004, is being tested in clinical trials.
Because TTR is made in the liver, a liver transplant is also a possible treatment for patients with some hereditary forms of ATTR amyloidosis, but not for those with wild-type form.
Your treatment team will likely include:
- Cardiologist: A doctor that specializes in the heart.
- Gastroenterologist: A doctor who specializes in the gastrointestinal tract.
- Genetic Counselor: A healthcare worker who helps patients and family members understand the risk of inheriting certain medical conditions.
- Hematologist: A doctor that specializes in blood problems.
- Nephrologist: A doctor that specializes in the kidneys.
- Neurologist: A doctor that specializes in the nerves.
Outlook / Prognosis
What is the outlook (prognosis) for persons with ATTR amyloidosis?
Amyloidosis is a long term (chronic) disease. The severity of the disease depends on which organs are affected.
Early diagnosis is the key to managing the disease before it becomes advanced.
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Glossary of Terms
Amyloid Fibril: A rigid stack of amyloid proteins that build up in the organs.
Amyloidosis: A disease caused by a buildup of abnormally shaped proteins (amyloid proteins) in organs.
Atrial Fibrillation: An irregular heart rhythm.
Biopsy: A small piece of tissue that is removed and examined under a microscope.
Cardiac magnetic resonance imaging (MRI): A scan that creates detailed pictures of the heart and shows how well it is working.
Echocardiogram: An ultrasound of the heart to show how well it is working.
Electrocardiography (EKG): A recording of the heart’s electrical activity.
Proteins: Large molecules that control the structure and function of the body’s tissues and organs.
Technetium Pyrophosphate Scan (TcPYP): A bone scan that can tell if there is ATTR in the heart.
Transthyretin: A protein produced by the liver.