FAQ

ATTR amyloidosis

What is ATTR amyloidosis?

Amyloidosis is a rare disease caused by abnormal deposition and accumulation of proteins in the tissues of the body.  Amyloid deposits are primarily made up of protein fibres known as amyloid fibrils.  These amyloid fibrils are formed when normally soluble body proteins aggregate (clump together) and then remain in the tissues instead of safely going away.  About 30 different proteins are known to form amyloid deposits in humans.  These amyloid forming (‘amyloidogenic’) proteins are known as ‘precursor proteins.’  Amyloid deposits cause disease by gradually accumulating within organs and thereby disrupting the structure and damaging the function of the affected tissues.

Different types of amyloidosis are named according to the precursor proteins which form the amyloid fibrils.  All names have the initial “A” denoting amyloidosis and letter(s) identifying the particular precursor protein which forms amyloid fibrils within the amyloid deposits.

In ATTR amyloidosis, a blood protein called transthyretin (TTR) is the amyloid precursor protein that forms the amyloid deposits. TTR is a normal blood protein, present in everybody. In healthy people, normal, so‑called ‘wild-type’ TTR functions as a transporter of thyroid hormone and vitamin A (retinol) within the bloodstream, hence the name: ‘trans-thy-retin’. Most TTR in the body is made in the liver and a small amount is made in the eye and the brain. In ATTR amyloidosis, TTR is the amyloid precursor protein that forms the amyloid deposits

What are the different types of ATTR amyloidosis?

ATTR amyloidosis is a form of systemic amyloidosis that can be either hereditary or acquired (non-hereditary).
Hereditary ATTR amyloidosis is caused by a mutation in the gene for a protein called TTR, inherited from one or other parent. The disease therefore runs in families, though the timing, development and severity of the disease can vary greatly.
In acquired ATTR amyloidosis, the amyloid is formed by the normal, so‑called ‘wild-type’ protein. This disease is not hereditary.  It is known as wild-type ATTR (ATTRwt) amyloidosis (formerly called senile systemic amyloidosis (SSA)).
The clinical presentation and effects of ATTR amyloidosis vary widely depending on which organs are mostly affected.

Hereditary ATTR amyloidosis

How common is hereditary ATTR amyloidosis?

Hereditary ATTR amyloidosis is a very rare disease. The most common type, associated with the Val30Met mutation, is thought to affect about 10,000 people in the whole world.  It has hitherto clearly been by far the most commonly recognised form of hereditary systemic amyloidosis.

In recent years it has been found that the Val122Ile mutation is very widespread amongst people of Afro-Caribbean and African American ancestry. This mutation may be associated with hereditary ATTR amyloidosis mainly affect the heart and often also cause carpal tunnel syndrome in men aged over 60. The mutation has been detected in almost 4% of African Americans, meaning that about 1.3 million people in the US are potentially at risk of developing hereditary ATTR amyloidosis.  There are less precise data available for the UK population but it is believed that this mutation is probably also common in people of Afro-Caribbean and African ancestry in the UK. Most people carrying this mutation do not ever develop disease, but in these population groups, hereditary ATTR amyloidosis is probably an under-diagnosed cause of heart failure.

Who gets hereditary ATTR amyloidosis?

Hereditary ATTR amyloidosis runs in families.  It may be inherited either from the patient’s mother or from the patient’s father.  People with hereditary ATTR amyloidosis are born with a mutation (alteration) in the TTR gene that causes the condition, although they usually only begin to experience symptoms in middle age.  People with a mutation in the TTR gene may pass the condition on to their children.  Some people with TTR gene mutations may never experience symptoms at all.

Hereditary ATTR amyloidosis, mainly affecting the nerves, was first described in 1952 in a number of families in Portugal, associated with the Val30Met mutation. This is still the most commonly detected TTR gene mutation worldwide.

Since then hereditary ATTR amyloidosis has been diagnosed in families from Japan, Sweden and County Donegal in North-West Ireland.  Worldwide, most people with hereditary ATTR amyloidosis have ancestors originating in one of these regions.  It may also be common, but under-diagnosed, in several other regions including Spain, France, Brazil, Argentina, Cyprus, Bulgaria. The Val122Ile mutation, mainly causing heart disease and carpal tunnel syndrome in men aged over 60, has been found to be quite common in people of Afro-Caribbean and African American heritage. Many people carrying this mutation do not ever develop disease.

In the UK, hereditary ATTR amyloidosis is most common in people with Irish ancestry.  It is estimated that 1% of the people in County Donegal have a TTR gene mutation.

What causes hereditary ATTR amyloidosis?

The symptoms of hereditary ATTR amyloidosis are caused by ATTR amyloid deposits inside body tissues, mainly in the nerves, heart, kidneys and eyes.  People with mutations (alterations) in the TTR gene produce abnormal, ‘variant’ TTR protein, throughout their lives.  The variant TTR is amyloidogenic.  This means that it has a tendency to misfold and form ATTR amyloid deposits which build up slowly and damage the affected organs.

When do hereditary ATTR amyloidosis symptoms appear?

Symptoms of hereditary ATTR amyloidosis may appear as early as age 20, or as late as age 80.  Age of onset is usually quite consistent within families.

The TTR gene mutation that most commonly causes hereditary ATTR amyloidosis in the UK results in production of the Thr60Ala (T60A) variant TTR protein.  Thr60Ala associated ATTR amyloidosis is often seen in people with Irish ancestry.  Symptoms tend to start relatively late, between ages 45 to 78, most often after age 60.

The TTR gene mutation that most commonly causes hereditary ATTR amyloidosis worldwide results in production of the Val30Met (V30M) variant TTR protein.  There are three main geographic foci of this type of FAP, in northern Portugal, northern Sweden and specific parts of Japan.  In Portugal and Japan most patients with Val30Met FAP first experience symptoms in their 30s; in Sweden it often starts later in life.

The Val122Ile mutation, which is found most commonly in people of Afro-Caribbean or African American ancestry usually starts to cause symptoms in men aged over 60.

What are the symptoms of hereditary ATTR amyloidosis?

Symptoms may include:

  • Peripheral neuropathy: limb weakness and pain, loss of sensation.
  • Autonomic neuropathy: disturbances of bowel, bladder and blood pressure and sexual dysfunction.
  • Heart failure - symptoms result from stiffening of the heart due to amyloid deposits (restrictive cardiomyopathy). They may include:
    • shortness of breath, sometimes just after mild exertion
    • palpitations and abnormal heart rhythms, most frequently atrial fibrillation or atrial flutter
    • ankle swelling (oedema)
    • fatigue
    • dizziness and collapse (syncope or fainting), which may occur after exertion, or after eating
    • angina (chest pain)
    • weight loss
    • nausea
    • disrupted sleep
  • disease due to amyloid deposits in the :
    • eye
    • kidneys
    • thyroid gland
    • adrenal glands
    • blood vessels

 

Do people carrying a TTR mutation always develop disease?

No. Patients carrying a mutation in the TTR gene do not always develop disease.
Some cases have been reported where people over age 60 have no disease despite having two copies (one inherited from each parent) of the TTR mutation which results in production of the Val30Met TTR protein variant.

Most people carrying the mutation resulting in production of the Val122Ile TTR protein variant do not ever develop disease.

Do different mutations cause different disease patterns?

More than 150 different mutations in the TTR gene have been reported.  Different mutations may cause a wide variety of different clinical symptoms.  But there is often little correlation between the underlying mutation and the clinical disease features.  Within families the pattern is usually quite consistent for:

  • age of onset
  • rate of disease progression
  • involvement of different body systems

In some families all affected members have mainly neuropathy, while in other families all affected members have both neuropathy and cardiac disease.  In a few cases certain mutations have been associated with either particularly severe disease or with relatively limited disease.

The most common TTR gene mutation in the UK leads to production of the Thr60Ala (T60A) TTR protein variant.  People carrying this mutation often have Irish ancestry.  People with this mutation often start to experience symptoms between age 45- 78, most often after age 60.  The heart is almost always affected and about 2/3 of patients also have neuropathy.  Autonomic neuropathy symptoms such as diarrhoea and/or constipation are more common than peripheral neuropathy.

The most common TTR mutation worldwide leads to production of the Val30Met (V30M) TTR protein variant.  People with this mutation often start to experience symptoms in their 30s.  Peripheral and autonomic neuropathy are the main symptoms and heart problems are rare.

The TTR mutation leading to production of the Val122Ile TTR protein variant has been found in 1 in 25 African Americans and is associated with late onset (over age 60) hereditary ATTR amyloidosis mainly affecting the heart and often also causing carpal tunnel syndrome. This condition has only been recognised in the past few years. Although it is believed to be probably widely underdiagnosed, it is believed to have low penetrance, meaning that most people carrying this mutation do not ever develop disease.

No-one else in my family had amyloidosis. Does that mean I’m unlikely to have hereditary ATTR amyloidosis?

Sometimes people diagnosed with hereditary ATTR amyloidosis are not aware of anyone else in the family with the condition.  This may be because the mutation first arose in that person, or because other family members were not diagnosed, or did not develop the disease despite having the mutation.

In a recent NAC study of 60 patients with FAP Thr60Ala, less than 40% had a definite family history of amyloidosis.

How is hereditary ATTR amyloidosis diagnosed?

The ‘gold standard’ test (the best available method) for diagnosing hereditary ATTR amyloidosis is a combination of detection of ATTR amyloid on heart, gastrointestinal tract or nerve biopsy together with genetic testing showing a TTR gene mutation.

What does genetic testing involve?

A blood sample is taken from the patient’s vein in a standard blood test.  Specialised laboratory techniques are then used to examine the DNA from the blood cells to identify amyloidogenic mutations (abnormalities) in the TTR gene.

Where does genetic testing take place?

Genetic testing for all the known types of hereditary amyloidosis is available at the NAC.  The results are usually available after about 4 weeks.

When is genetic testing used?

Genetic testing can be useful for confirming a diagnosis of hereditary ATTR amyloidosis when there are characteristic symptoms of nerve and heart disease and ATTR amyloid is detected in tissue biopsy.

There are over 150 known mutations in the TTR gene, and different mutations lead to different types of disease.  The precise mutation identified may provide information about the likely clinical course.

If there is predominantly amyloid heart disease, with or without carpal tunnel syndrome, and ATTR is detected in tissue biopsy, then genetic testing can distinguish between hereditary and wild type ATTR amyloidosis (senile systemic amyloidosis).  If a TTR gene mutation is detected then the diagnosis is hereditary ATTR amyloidosis.  If there is no TTR gene mutation then the diagnosis is wild type ATTR amyloidosis (senile systemic amyloidosis).

Genetic testing in a healthy person without symptoms can provide information on whether the mutation is present, but cannot predict whether the person will go on to develop amyloidosis.

My family member has hereditary ATTR amyloidosis. Should I have genetic testing?

Genetic testing in a healthy person without symptoms can provide information on whether a mutation is present, but cannot predict whether the person will go on to develop amyloidosis.

The mutations that cause hereditary amyloidosis are variably penetrant.  This means that they do not always cause disease.

People who are at risk of having inherited a potentially amyloid-causing mutation may choose to undergo genetic testing after counselling with a physician at the NAC.  For enquiries please contact Dr Julian Gillmore at the National Amyloidosis Centre j.gillmore@ucl.ac.uk

If you are of Afro-Caribbean or African ancestry and you or your family member have heart disease which is suspected to be amyloidosis, please contact Dr Julian Gillmore at the National Amyloidosis Centre (see above) to discuss the possibility of genetic testing. Your involvement is critical to help doctors to learn more about hereditary ATTR amyloidosis in the UK, so that they may be better able to treat patients.

Tips for patients living with hereditary ATTR amyloidosis

Treatment of hereditary ATTR amyloidosis is discussed in the section below .

Here are some tips for dealing with common symptoms , from a patient who has suffered from this condition for many years:

Dealing with postural hypotension
1. After sitting down for more than 1/2 hour always stand for about 30 seconds before moving off.
2. If feeling light headed or you have ringing in your ears when walking, stand still for a few moments until it passes. Sometimes you can walk through it after some practice!
3. If it gets really bad always ask for help or sit down. I find it, in some cases good to hold onto my wife’s arm when walking distances.
4. I find that when I get a cold or virus the postural hypotension can get worse. I find it helps by taking the standard doses of paracetamol.
5. When getting up from bed in the morning I always sit on the side for a few moments before walking off.
6. Never run and always pace yourself.
7. Always allow more time than you think you need!

Dealing with painful neuropathy symptoms

1. I find doing weekly muscle build-up and light exercise at the gym helps a lot.
2. I find having a regular leg and feet massage eases my leg pains and stiffness.
3. Keep your legs and feet always moisturised.
4. Carry out daily hand exercise to keep them working.

Diet
Over the last 6 years since having my liver transplant I have found that by adjusting my diet my bowel problems have reduced:
1. By reducing the amount of wheat has helped a lot. I very rarely eat sandwiches, cakes and eat very little pastry.
2. I try not to have processed foods and have cooked food at lunchtime and in the evenings.
3. I have cut out sugar as much as I can. (Chocolate seems to still be good!!!)
4. I have cut out all beer and lager and tend to drink water, wine and some spirits.
5. I restrict to only having mild curries.

Wild-type ATTR amyloidosis (senile systemic amyloidosis or SSA)

What is wild-type ATTR amyloidosis?

In wild type ATTR amyloidosis, ATTR amyloid deposits in the heart cause thickening and stiffening without nervous system disease.  There is often carpal tunnel syndrome (pain and tingling in the hands and wrists), sometimes occurring several years before symptoms of heart disease.

This condition is not hereditary.  The amyloid deposits are made up of normal, ‘wild type’ TTR fibrils and there are no mutations in the TTR gene.

What should this condition be called?

Until 2014 this condition was known as senile systemic amyloidosis or cardiac TTR amyloidosis.  It was decided at the XIV International Symposium on Amyloidosis in 2014 that this condition should in future be referred to as wild-type transthyretin amyloidosis or wild-type ATTR amyloidosis.

What causes wild-type ATTR amyloidosis (SSA)?

The cause is unknown –we do not know why ‘wild-type’ TTR, which is a normal blood protein, forms amyloid deposits in some people and not in others although advancing age is undoubtedly a risk factor.  People with this condition do not have a mutation in the TTR gene, and the condition is not hereditary.

How common is wild-type ATTR amyloidosis (SSA)?

We do not know how common this condition really is.  It has been known for some time that small amyloid deposits consisting of ‘wild-type’ TTR are very common in the elderly.  In autopsy studies they have been found in the hearts and blood vessels of one in four people over age 80.  Until recently it was believed that this type of amyloid deposit was hardly ever extensive enough to cause symptomatic heart disease.  New imaging techniques in recent years have shown that in fact, disease caused by ‘wild type’ ATTR deposits may be far commoner than anyone thought.

Who gets wild-type ATTR amyloidosis (SSA)?

This condition is not hereditary and it may affect people from any ethnic background.  Symptoms usually start over age 65 and the disease usually progresses slowly.  The condition is far more common in men than in women.  In a recent study of patients diagnosed with senile systemic amyloidosis at the National Amyloidosis Centre, nearly 90% were men.

When do wild-type ATTR amyloidosis (SSA) symptoms appear?

Symptoms of wild-type ATTR amyloidosis (SSA) usually appear after age 65.

What are the symptoms of wild-type ATTR amyloidosis (SSA)?

The symptoms result from stiffening of the heart due to amyloid deposits (restrictive cardiomyopathy).  They may include:

  • shortness of breath, sometimes just after mild exertion
  • palpitations and abnormal heart rhythms, most frequently atrial fibrillation/ flutter
  • ankle swelling (oedema)
  • fatigue
  • dizziness or fainting, which may occur after exertion, or after eating
  • angina (chest pain)
  • weight loss
  • nausea
  • disrupted sleep

The symptoms of heart disease are often preceded by carpal tunnel syndrome (pain and tingling in the hands and wrists), sometimes occurring several years earlier.

How is wild-type ATTR amyloidosis (SSA) diagnosed?

The ‘gold standard’ test (the best available method) for diagnosis is a combination of detection of ATTR amyloid on heart biopsy together with genetic testing showing that there is no TTR gene mutation.

Biopsies from other parts of the body, such as abdominal fat or the rectum are often used to diagnose other types of amyloidosis.  In wild-type ATTR amyloidosis (SSA), these tests can be useful if they do show amyloid.  But in many patients with this condition these tests are negative despite the presence of amyloid in the heart.

When is genetic testing used?

If there is amyloid heart disease, with or without carpal tunnel syndrome, and ATTR is detected in tissue biopsy, then genetic testing can distinguish between hereditary and wild type ATTR amyloidosis (senile systemic amyloidosis).  If a TTR gene mutation is detected then the diagnosis is hereditary ATTR amyloidosis.  If there is no TTR gene mutation then the diagnosis is wild type ATTR amyloidosis (senile systemic amyloidosis, a non-hereditary condition).

Symptoms and treatment are the same for these two conditions, but genetic testing can help us to learn more about the disease so that we may be better able to treat patients.

My family member has wild-type ATTR amyloidosis (SSA). Should I have genetic testing?

No.  This condition is not hereditary so there is no need for family members to be tested.

Treatment of ATTR amyloidosis

How is ATTR amyloidosis treated?

Treatment of all types of amyloidosis is currently based on the following principles:

  • Reducing the supply of amyloid forming precursor proteins.
  • Supporting the function of organs containing amyloid

SAP scans in thousands of patients with various forms of amyloidosis have shown that when amyloid precursor protein supply is controlled:

  • existing amyloid deposits often regress (become smaller)
  • new amyloid deposits stop appearing
  • organ function is often preserved and may also recover

Liver transplantation as a treatment for hereditary ATTR amyloidosis - reducing the supply of amyloid precursor proteins

Liver transplantation may be helpful for some patients with hereditary ATTR amyloidosis, mainly for patients with disease associated with the Val30Met mutation.

All the TTR in the blood, which forms the amyloid deposits everywhere except in the eye and the blood vessels around the brain, is made in the liver. Liver transplantation is therefore a treatment option for some patients with hereditary ATTR amyloidosis. The liver which forms the abnormal, 'variant' TTR is removed and replaced by a donor liver making normal, 'wild type' TTR. The aim is to prevent the formation of further amyloid deposits by reducing the supply of the amyloidogenic precursor TTR.

Liver transplantation has been performed in hundreds of patients with hereditary ATTR amyloidosis around the world. In many cases this has been successful, leading to stabilisation of disease. Success is greatest when transplantation is performed:

  • early in the course of disease before there has been too much damage to the nerves or the heart
  • in younger patients
  • in patients with the TTR Val30Met mutation

Unfortunately, in some patients amyloid deposits in the heart have continued to progress even after transplantation. It seems that the abnormal TTR fibrils which formed amyloid deposits before the liver transplantation act as a template encouraging deposition of normal TTR as amyloid. Thus the normal TTR protein (wild type TTR) produced by the new liver builds up on top of the existing amyloid deposits containing the abnormal TTR. This problem has appeared most often in older patients with mutations other than Val30Met.

Liver transplantation is not a treatment for senile systemic amyloidosis (wild type ATTR amyloidosis) or for hereditary ATTR amyloidosis affecting mainly the heart, because the cardiomyopathy continues to progress due to continued deposition of wild type TTR in the heart.

Supporting amyloidotic organ function

In all types of amyloidosis it is important that treatment should support the function of organs containing amyloid. In ATTR amyloidosis this may include:

Treatment for heart disease

ATTR amyloid deposits in the heart cause the heart to stiffen which can lead to symptoms of heart failure. Patients can benefit from supportive treatment measures for heart failure. However many standard medications used for heart failure are not helpful for patients with cardiac amyloidosis. Careful attention to fluid balance is important, as explained in the question below.

In patients with low blood pressure, drugs such as fludrocortisone or midodrine may help to maintain blood pressure and allow higher diuretic doses.

Some patients may experience light-headedness, fatigue on minimal exertion or fainting due to drops in blood pressure. They may benefit from instruction in how to change position carefully from lying to sitting, sitting to standing and standing to walking.

Heart transplantation

For hereditary ATTR amyloidosis, combined heart and liver transplant has been performed in a few dozen cases around the world. This operation is only an option for a minority of patients, and it carries significant risks.

Most patients with wild-type amyloidosis (SSA) are too elderly to undergo a heart transplant. The risk of complications from this major operation is high with advanced age. But heart transplantation may be an option for younger, otherwise healthy patients with this condition. The 2 patients who presented to the NAC before age 60 with senile systemic amyloidosis survived 10 and 20 years after heart transplantation.

Treatment of peripheral neuropathy symptoms

Medications that may help to alleviate neuropathic pain include gabapentin, pregabalin and duloxetine. Medical staff can give advice regarding appropriate foot care and footwear. This is important in order to prevent painless ulcers at pressure points and to protect areas of the foot that lack sensation.

Treatment of autonomic neuropathy symptoms

If there is orthostatic hypotension (drops in blood pressure and faintness on standing up from sitting or lying positions), elastic stockings may be recommended. Drug treatment with midodrine may also be helpful. Care should be taken to avoid dehydration if there is vomiting and diarrhoea. Intravenous fluids and anti‑nausea drugs may be necessary, but it is important to avoid fluid overload if there is heart disease. There are drugs that can help to control diarrhoea and constipation, and others that can help to combat erectile dysfunction.

The place of new drugs in the treatment of ATTR amyloidosis is discussed separately in other questions in this section.

Here are some tips for dealing with common symptoms from a patient who has suffered from this condition for many years:

Dealing with postural hypotension
1. After sitting down for more than 1/2 hour always stand for about 30 seconds before moving off.
2. If feeling light headed or you have ringing in your ears when walking, stand still for a few moments until it passes. Sometimes you can walk through it after some practice!
3. If it gets really bad always ask for help or sit down. I find it, in some cases good to hold onto my wife’s arm when walking distances.
4. I find that when I get a cold or virus the postural hypotension can get worse. I find it helps by taking the standard doses of paracetamol.
5. When getting up from bed in the morning I always sit on the side for a few moments before walking off.
6. Never run and always pace yourself.
7. Always allow more time than you think you need!

Dealing with painful neuropathy symptoms
1. I find doing weekly muscle build-up and light exercise at the gym helps a lot.
2. I find having a regular leg and feet massage eases my leg pains and stiffness.
3. Keep your legs and feet always moisturised.
4. Carry out daily hand exercise to keep them working.

Diet
Over the last 6 years since having my liver transplant I have found that by adjusting my diet my bowel problems have reduced:
1. By reducing the amount of wheat has helped a lot. I very rarely eat sandwiches, cakes and eat very little pastry.
2. I try not to have processed foods and have cooked food at lunchtime and in the evenings.
3. I have cut out sugar as much as I can. (Chocolate seems to still be good!!!)
4. I have cut out all beer and lager and tend to drink water, wine and some spirits.
5. I restrict to only having mild curries.

How can I avoid fluid balance problems?

Many patients with ATTR cardiac amyloidosis should limit their fluid intake.  This advice is extremely important, but is often overlooked.

The most important principle of treatment for cardiac amyloidosis is strict fluid balance control. Specialist heart failure nurse involvement may help patients to achieve this.

When there is cardiac amyloidosis, the heart may be too stiff to pump the blood efficiently around the body. This can lead to fluid build- up, causing leg swelling (oedema) and breathlessness due to fluid in the lungs. This problem is exacerbated if the patient drinks too much fluid.

Fluid excess can be avoided by careful attention to the 3 Ds:

  1. Diet
  2. Diuretics
  3. Daily weights

 

  1. Diet:

Fluid intake should be steady and should usually not exceed 1.5 litres per day.

Salt intake should be limited.  This includes attention not just to salt deliberately added to the food during cooking or at the table but also to ready prepared foods with high salt content such as processed foods, crisps, bacon, canned meats, sausages, canned soups and smoked fish.  Apart from that, a balanced, healthy diet is always advisable.  It can be very helpful to meet with a dietician for precise and personalised dietary advice.

  1. Diuretics:

Doctors will often prescribe diuretics (water tablets) which increase the amount of urine produced and help the body to lose excess salt and water in the urine.  This can help to reduce ankle swelling and breathlessness.  Diuretics prescribed may include furosemide and spironolactone.  Taking these drugs is not a substitute for avoidance of excessive dietary salt and water.

Patients should follow their doctor’s advice carefully regarding the dose of diuretic and the time of day when the tablet should be taken.

  1. Daily weights:

Some patients benefit from recording their weight regularly, usually daily or weekly.  It is important that weight should be measured consistently - using the same scales, at the same time of day.  This is usually best done first thing in the morning after passing urine, just wearing underclothes.  Several litres of fluid can accumulate in the body without it being very noticeable.  An increase in weight can be an early sign of fluid overload.  The doctor or nurse can then recommend appropriate measures such as increased diuretic dose, before the patient even feels unwell because of the fluid overload.

Should I be taking tafamidis?

Tafamidis was developed as a specific drug for hereditary ATTR amyloidosis mainly affecting the nerves.  It is bound by TTR in the blood.  This binding is thought to stabilise the TTR and makes it less amyloidogenic.  Tafamidis has been studied in a trial involving 91 patients with early neuropathy.  Neuropathy progression was slightly slower in patients who received the drug than in those who did not.  However, the difference was not statistically significant.  Given the major clinical unmet need, tafamidis has recently been approved in Europe, but only for polyneuropathy caused by ATTR amyloid.  Unfortunately the evidence that tafamidis has an effect on polyneuropathy is not strong, and it is not available in the NHS.  It is also not approved in the USA.  The drug has not been tested in cardiac TTR amyloidosis and has not received approval for this indication

Should I be taking diflunisal?

Diflunisal belongs to a class of drugs called “non-steroidal anti-inflammatory drugs” (NSAIDs).  These drugs are in common use as pain killers, for conditions such as arthritis.  Diflunisal is bound by TTR in the blood.  This binding is presumed to make the TTR less amyloidogenic.  Trials are currently underway to assess the effect of diflunisal on the progression of neuropathy and cardiomyopathy in patients with hereditary ATTR amyloidosis.  The first study report was recently published, with an encouraging result, but the numbers of patients involved was small and the extent of benefit was modest.  The trial involved 130 patients hereditary ATTR amyloidosis affecting mainly the nerves, 64 of whom received diflunisal for 2 years while 66 received placebo (dummy pills).  The rate of progression of neuropathy was slower in the patients who received diflunisal than in those who did not. Results of trials of diflunisal in cardiac ATTR amyloidosis are not yet available.  It is important to note that NSAIDs such as diflunisal may have serious side effects, which may be especially dangerous in patients who are already unwell with amyloidosis.  These side effects include:

  • bleeding from the stomach and gut
  • worsening of kidney function
  • worsening of heart failure

Diflunisal use for ATTR amyloidosis is an ‘off-label’ indication, and only amyloidosis specialists should prescribe it.

What new treatments are being developed for ATTR amyloidosis?

A number of new drugs for TTR amyloidosis are in various stages of development, both in our Wolfson Drug Discovery Unit and elsewhere around the world. These drugs are not yet available, but they do offer hope for the future.

Genetic based therapies:

  • small interfering RNA
  • antisense oligonucleotides

These two approaches aim to “switch off” the gene for TTR in the liver cells, so that TTR (both mutant and wild-type) is simply not produced. Recent clinical trials of these drugs in patients with FAP and symptomatic neuropathy had very encouraging results.
A drug called patisiran belongs to the small interfering RNA drug class. The APOLLO trial was a phase 3 study which enrolled 225 patients with hereditary ATTR amyloidosis mainly affecting the nerves and randomised them to receive either patisiran or placebo by intravenous injection every 3 weeks for 18 months. Patients who received patisiran did significantly better than those who received placebo, in terms of neuropathy symptoms, quality of life, daily activities and disability. According to standardised neuropathy scores, neuropathy symptoms actually improved with patisiran. Patisiran was safe and well tolerated.
Another drug called inotersen belongs to the antisense oligonucleotide drug class. The NEURO-TTR trial was a phase 3 study which enrolled 172 patients with hereditary ATTR amyloidosis mainy affecting the nerves and randomised them to receive either inotersen or placebo for 15 months. Patients who received inotersen did significantly better than those who received placebo, in terms of neuropathy symptoms, quality of life, daily activities and disability. A few patients receiving inotersen experienced drops in platelet counts and abnormal kidney functions. Once this was observed, all patients receiving inotersen were monitored with regular blood tests.
Patisiran and inotersen are now undergoing licensing approval by the regulatory authorities.
So far trials have only assessed the impact of these drugs on nerve damage caused by ATTR amyloid. Effects on cardiac ATTR amyloidosis have not been assessed and patients with wild type ATTR amyloidosis were not included in the drug trials.

Antibody mediated amyloid elimination:

Serum amyloid P component (SAP) is a normal blood protein, present in everybody, which is always present in amyloid deposits, in all types of amyloidosis, because it binds strongly to amyloid fibrils of all types. The Wolfson Drug Discovery Unit, directed by Professor Sir Mark Pepys, has developed a drug called miridesap (formerly known as CPHPC), which clears all the SAP from the blood but leaves some SAP bound to the amyloid deposits. After miridesap has been administered, it is therefore safe and feasible to administer dezamizumab (antibodies to SAP) which targets the amyloid.
In experimental models dezamizumab triggers the body’s normally very efficient systems for removal of debris from tissues to act on the amyloid. There were encouraging results in the first, early stage trial of this treatment approach in patients with different types of systemic amyloidosis, but without cardiac amyloidosis, conducted in collaboration with GlaxoSmithKline.
This Phase 2 trial is designed to investigate the efficacy and safety of the treatment in patients with cardiac amyloidosis.
If this treatment proves to be safe and effective in humans, it will be applicable to patients with all types of amyloidosis.

The National Amyloidosis Centre

What is the National Amyloidosis Centre (NAC)?

The NAC is a highly specialised NHS clinical service funded by NHS England to provide a specialist clinical service for amyloidosis patients throughout the UK.  It is the only specialist amyloidosis centre in the country and has been responsible for the entire UK caseload of amyloidosis since 1999.  About 4,000 patients are seen each year at the NAC, including about 50% of all UK patients with systemic amyloidosis.

How do I arrange an evaluation at the NAC?

Patients in the UK require a physician’s referral to the NAC.  Information for referring physicians is available here.

For questions regarding appointments contact:
Mr Ramon Lamarca
Tel:  020 7433 2813
r.lamarca@ucl.ac.uk

Overseas patients

The Royal Free Hospital and the National Amyloidosis Centre welcome overseas patients.  European Union residents may be entitled to an NHS assessment in the UK under EU reciprocal arrangements for medical care that is not available locally (EU S2 form).  Non‑NHS entitled patients are welcome but are usually liable to charges.

Information for referring physicians is available here: .

For inquiries regarding NHS entitlement or charges, contact:
Mr Ramon Lamarca
Tel:  020 7433 2813
r.lamarca@ucl.ac.uk

How long are waiting times for NAC appointments?

The waiting time for an NAC appointment is an average of 2/3 weeks from when the referral letter is received at the NAC, not from the date on the referral letter.

Where is the NAC?

The NAC is part of the University College London (UCL) Division of Medicine and is situated at the Royal Free Hospital in Hampstead, London.

Directions are available here.

What should I expect at the NAC clinical evaluation?

The NAC clinical evaluation usually takes 1 -2 days, and hospital or hotel overnight accommodation can be arranged when necessary.  It is recommended that you bring a family member or friend with you if possible.  There is a lot of information to take in and it will help to have someone with you to support you and help you.  The evaluation includes:

  • blood and urine tests
  • ECG and echocardiogram (ultrasound scan of the heart)
  • whole body SAP scan to establish the distribution and quantity of amyloid deposits
  • additional tests in some patients may include:
    • abdominal fat biopsy
    • bone marrow biopsy
    • DPD scan of the heart
    • cardiac MRI
  • physician evaluation
  • specialist nurse consultation

The physician who evaluates you will explain your diagnosis, and make recommendations regarding a suitable treatment plan.  The specialist nurses explain and discuss practical nursing issues during the initial evaluation and are available afterwards for patients and relatives to contact with any questions that arise.

The NAC approach to each patient with amyloidosis is tailored individually to the type of amyloid and to patients’ particular problems.  Wherever possible, patients are discussed with the referring physician, after which any available tissue biopsies are re-examined.

Treatment is usually administered at patients’ local hospitals or at other regional centres in conjunction with advice from and reviews at the National Amyloidosis Centre.  A small proportion of cases are managed directly by the NAC doctors together with other colleagues at the Royal Free Hospital.

For questions regarding eligibility for assistance with travel expenses, contact:
Mr Ramon Lamarca
Tel:  020 7433 2813
r.lamarca@ucl.ac.uk.

Am I eligible to participate in a clinical trial?

There are several ongoing trials taking place at the NAC.  See here for more information.  If you are interested in participating in a trial, ask your doctor whether you are eligible when you attend your appointment at the NAC.

How can I support amyloidosis research at the NAC?

For information on donations and fundraising for the UCL Amyloidosis Research Fund, see here.