Transthyretin Amyloidosis (ATTR)

Transthyretin amyloidosis (ATTR) happens when clumps of irregular proteins build up in tissues like your heart and nerves. It can affect other parts of your body, too, like your kidneys and eyes. These buildups damage the tissue, leading to a range of health problems.

“Amyloidosis” is a general term for when abnormal proteins build up in organs. ATTR is just one type. Transthyretin (TTR) is a protein your liver makes. It travels through your blood. This protein carries vitamin A (retinol) and a thyroid hormone to different parts of your body.

ATTR is a progressive disease, which means it gets worse over time. It can be life-threatening. The good news is that recent therapies have improved outcomes for people with ATTR.

Types

There are two main types of ATTR based on how you develop it:

• Hereditary (hATTR): You inherit this type from one or both of your biological parents. Over 120 gene variants, or changes, are linked to hATTR. They often have an autosomal dominant inheritance pattern. This means only one parent needs to have the gene change for you to get it.
• Wild-type (wtATTR): This happens when TTR begins misfolding on its own without any genetic changes. It’s associated with aging-related changes. It typically affects people over 65.

Healthcare providers also classify forms of transthyretin amyloidosis based on the body system it affects:

• ATTR-cardiomyopathy (ATTR-CM): This form affects your heart. It can lead to issues like an irregular heartbeat and heart muscle problems (cardiomyopathy).
• ATTR-polyneuropathy: This form mainly affects your peripheral and autonomic nervous systems. It leads to issues like peripheral neuropathy and dysautonomia.
• Mixed ATTR: Many people have this type, where both your heart and nerves are affected. The mix of symptoms can vary a lot from person to person.

Symptoms of ATTR

The symptoms of transthyretin amyloidosis vary based on which parts of your body ATTR affects. It most commonly affects your heart and peripheral nerves.

Some people with wtATTR also have a history of:

• Lumbar spinal stenosis
• Carpal tunnel syndrome
• Tendon ruptures or other musculoskeletal conditions

ATTR heart-related symptoms

When ATTR affects your heart, symptoms can include:

• Irregular heartbeat (arrhythmia)
• Cardiomyopathy
• Heart failure symptoms, like shortness of breath and leg swelling

ATTR nerve-related symptoms

When ATTR affects your nerves, symptoms can include:

• Peripheral neuropathy (tingling and numbness in your toes and feet)
• Carpal tunnel syndrome and spinal stenosis
• Diarrhea or constipation
• Difficulty peeing
• Dry eyes
• Increased pressure in your eyes, which can lead to glaucoma
• Pupils with an irregular or “scalloped” appearance
• Sexual dysfunction
• A sharp drop in blood pressure upon standing (orthostatic hypotension)

Transthyretin amyloidosis causes

ATTR can develop due to inherited genetic changes or aging-related changes. Regardless of the underlying cause, faulty TTR proteins develop in your body. These abnormal proteins break apart and fold up on themselves (misfold).

Proteins need the right shape to work properly. With ATTR, some proteins fold into the wrong shape. Your body can’t get rid of them. These misshapen proteins stick together and form clumps. Your blood carries these clumps to different parts of your body, where they build up over time. This buildup can damage your heart, nerves and other organs.

Risk factors

People at increased risk for hereditary ATTR include:

• Those who have a biological family member with ATTR
• Males
• Those of African descent — about 3% to 4% of Black Americans carry a gene change (called Val122Ile) that can cause ATTR
• Those who have ancestors from certain parts of the world, including Portugal, Sweden, Japan or Ireland, where specific gene changes are more common

Wild-type ATTR mostly affects men over 65. In the past, healthcare providers thought it was rare in women. But now, they’re finding it more often in women, too. It was likely missed before.

Complications of this condition

ATTR can affect many parts of your body. But the most serious problem is when it damages your heart. This is called ATTR-cardiomyopathy (ATTR-CM), which means your heart muscle gets weak and stiff. This often leads to heart failure.

Wild-type ATTR almost always affects your heart — fewer than 1 in 10 people with this type also have nerve problems. With hereditary ATTR, some people develop heart problems, nerve problems or both. It depends on which gene change you have.

Over time, ATTR causes a decline in your physical health. This can make everyday tasks difficult. Living with the condition can also affect your mental health.

How doctors diagnose this condition

ATTR can be difficult to diagnose because the symptoms have many other more common causes.

You may get many tests before you get an accurate diagnosis, like:

• Blood tests
• Electrocardiogram (EKG)
• Imaging tests, especially heart imaging (like echocardiograms or cardiac MRIs)
• Nuclear medicine imaging tests to check for amyloid deposits in your bones
• Nerve conduction studies
• Biopsies

Genetic testing can provide a definitive diagnosis for hATTR.

How is it treated?

There isn’t a cure for ATTR. But medications can directly target faulty proteins to slow down the progression of the condition. These medications have the most benefit if you’re able to start them early in the development of the condition. You’ll also need treatment to manage any complications.

In the past, a liver transplant was the main treatment for hATTR. As your liver makes the abnormal protein, getting a new liver can stop it from being made. But today, newer medicines have mostly replaced liver transplants as the first-line treatment.

Medications

Certain medicines stabilize the protein (TTR stabilizers). These keep the TTR protein from breaking apart and clumping. They include:

• Tafamidis (Vyndamax®) and acoramidis (Attruby®): These are U.S. Food and Drug Administration (FDA)-approved for ATTR-cardiomyopathy in both wtATTR and hATTR.
• Diflunisal (Dolobid®): This is an older pain medicine that can also stabilize the protein. It’s not FDA-approved for ATTR. But providers sometimes prescribe it when other options aren’t available. It requires careful monitoring of your kidneys and blood.

Certain medicines reduce protein production (TTR silencers). These tell your liver to make less of the problem protein. They include:

• Vutrisiran (Amvuttra®): You get this shot every three months. It’s FDA-approved for hATTR-polyneuropathy and ATTR-cardiomyopathy (both types).
• Patisiran (Onpattro®): You receive an IV infusion of this every three weeks. It’s FDA-approved for hATTR with nerve problems.
• Inotersen (Tegsedi®): This is a weekly shot. It’s FDA-approved for hATTR with nerve problems.
• Eplontersen (Wainua®): This is a monthly shot. It’s FDA-approved for hATTR with nerve problems.

If you take a TTR silencer, you’ll also need to take vitamin A supplements. This is because TTR silencers lower the protein that carries vitamin A in your blood.

Researchers are currently studying other medications that remove amyloid clumps that have already built up in your body. They’re called “TTR depleters.” You may want to ask your healthcare provider if you can join a clinical trial.

When should I see my healthcare provider?

You’ll need to see your healthcare team regularly to make sure your treatment is working. It may help to ask your provider the following questions:

• What type of ATTR do I have?
• What treatments do you suggest?
• What are the benefits and risks of my treatment options?
• Should I look out for signs of complications?
• Should my family members be tested for the condition?

What can I expect if I have ATTR?

ATTR is a progressive disease that eventually causes serious complications. Early diagnosis and treatment are key to a better outlook (prognosis). Living with ATTR is easier than it used to be thanks to advancements in diagnostic tests and medications.

The life expectancy for someone with ATTR can vary based on many factors, such as:

• The type of ATTR
• Your age when symptoms started
• The severity of your symptoms
• How early in the condition’s course you got a diagnosis
• How early you started treatment and the type of treatment

Your healthcare team can give you a better idea of what to expect based on your unique situation.