ATTR Amyloidosis

AL Amyloidosis

AA Amyloidosis

AApoA1 Amyloidosis

AGel Amyloidosis

ALys Amyloidosis

AFib Amyloidosis

About ATTR Amyloidosis

The precursor protein in ATTR amyloidosis is transthyretin, abbreviated to TTR, and is produced mainly in the liver. TTR is what is known as a transport protein, and is named for its function – it transports thyroxine and retinol in the blood. Thyroxin is a hormone made by the thyroid gland, and plays an important role in growth and development; retinol is a form of vitamin A and is important for vision.

There are two types of ATTR amyloidosis — they are caused by different mechanisms, but share many similarities. Hereditary ATTR amyloidosis results from a change in the gene that makes TTR, and this change (also called a variant or mutation) results in the liver making an abnormal form of TTR which then makes amyloid. Wild-type ATTR amyloidosis develops when TTR proteins made in the liver start out normal but then change over time, becoming abnormal and forming amyloid. We’ll go into a bit more detail on each of the two types.

Wild-type ATTR amyloidosis

Wild-type ATTR (ATTRwt) amyloidosis develops when the unchanged (not mutated, ‘normal’) TTR protein becomes abnormal with increasing age and starts to misfolded and form amyloid.

The scientific word for the unchanged or normal form of the protein is the ‘wild-type’ protein, hence the name of the condition. ATTRwt is not passed on in families, and although historically it was thought to be a disease exclusive to white men over the age of 75, it is increasingly being found in women and men from different ethnic backgrounds, and as early as 50 years of age.

Hereditary ATTR amyloidosis

Also known as hATTR or ATTRv amyloidosis, this type is considered a rare form of the disease when compared to the wild-type. ATTRv is passed down in families through the variant or mutated gene. There are over 130 variants that are known to cause ATTRv amyloidosis, and each variant may have particular manifestations, such as the age at which symptoms start developing and which organs are affected. Also, there are links between certain variants, ethnicity and geography. In the UK the most common variants causing ATTRv amyloidosis are V122I and T60A, but there are many others too.

Historically these two variants were thought to mainly affect the heart, but it is now known that both variants can affect other organs and cause a range of symptoms. It’s important to note that while this form of ATTR amyloidosis is hereditary (meaning that people are born with the variant gene), the disease process seems to start in adulthood with symptoms usually appearing after the age of 50, although it can be earlier in some people.

ATTR Amyloidosis Symptoms

A wide range of symptoms may be caused by ATTR amyloidosis; below is a list of the most common ones that can be experienced by people with both types of ATTR amyloidosis.

Gradual swelling of your ankles, moving up to your legs
Periods of feeling like your heart is racing or skipping a beat
Fatigue and weakness despite adequate sleep or rest
Shortness of breath even when doing light exercise or tasks
Trouble walking uphill or up stairs
Numbness, tingling or pain in your hands and/or feet
Problems with sex and libido
Diarrhoea, often alternating with constipation
Dizziness, especially when standing up suddenly
Significant, unintended weight loss

Diagnosing ATTR Amyloidosis

Historically ATTR amyloidosis could only be diagnosed by biopsy and for some people this was fine but for many, especially those whose hearts were affected (cardiac amyloidosis), a biopsy of the heart would be too risky. Additionally, waiting for a slot to have the biopsy, the subsequent lab analysis, and another doctor’s appointment to get the results, could add many months to the wait for a confirmed diagnosis and treatment.

However, a few years ago a group of HCPs and scientists from different countries, led by the team at the UK National Amyloidosis Centre (NAC) developed a way of accurately diagnosing cardiac ATTR amyloidosis using a series of easily available and less invasive tests (scans and blood and urine tests), thereby eliminating the need for a heart biopsy in most cases.

This has made it quicker and easier to diagnose cardiac ATTR amyloidosis, and at times help differentiate between AL and ATTR cardiac amyloidosis – an important distinction as the two types are treated very differently.

Treating ATTR Amyloidosis

Until 2018 there were no medicinal treatments for ATTR amyloidosis available in the UK outside of clinical trials. Some patients with ATTRv were able to have a liver transplant; this would remove the main source of the abnormal TTR protein and replace it with a donated liver from someone without the gene mutation hence, a liver that makes normal TTR. Having an organ transplant is not a viable option for most people as it’s an invasive and high-risk procedure, and you would have to be in fairly good health to be eligible to have this. Furthermore, although the vast majority of TTR is made in the liver some is made in the brain, and this source of variant TTR will continue and amyloid deposits will keep developing, albeit at a slower rate.

In some countries liver transplant is still offered to ATTRv patients who are diagnosed at a very early stage and therefore have only mild symptoms, but in the UK there are now medicines available to effectively treat both ATTRv and ATTRwt. These medicines fall into two main classes:

Tetramer stabilisers (Stabilisers)

These are small molecule medicines that help keep the TTR protein from breaking apart. The TTR protein is made up of four units or pieces joined together. In the abnormal or diseased form the protein is unstable and prone to breaking apart into its four units.

The individual units misfold and form amyloidosis. Stabilisers like tafamidis (Vyndaqel® and Vyndamax®) and acoramidis (AG10) bind to the TTR protein, for a period of time stopping it from breaking up, thereby reducing or slowing down the formation of amyloid deposits.

Gene silencers (Silencers)

These are a whole new class of medicines that have been developed in recent years. These drugs work at the source of the disease, by stopping the TTR gene from making the abnormal protein (i.e. silencing the gene).

There are currently two treatments in this category, vutrisiran (Amvuttra®) and eplontersen (Wainzua®) – they work in slightly different ways but have the same effect of significantly reducing the amount of abnormal TTR in the body, thereby stopping or slowing down the build up of amyloid.

Resources for ATTR Amyloidosis

The hATTR Bridge

World Heart Federation videos

Resources for All types of Amyloidosis...

Amyloidosis Alliance

Amyloidosis Research Consortium (ARC)

Cardiomyopathy UK

NHS Amyloidosis Information

One Amyloidosis Voice

Symptom tracker app (STAR)