ATTR amyloidosis is a form of systemic amyloidosis caused by amyloid deposits made up of a protein called transthyretin (TTR). ATTR amyloidosis can be either hereditary or acquired (non-hereditary).
TTR is always present in the blood, where it transports thyroid hormone and vitamin A (retinol), hence the name: ‘trans-thy-retin’. All the TTR in the blood is produced by the liver. TTR in the brain and the eye is made separately by a structure called the choroid plexus, which is located within the brain and produces the cerebrospinal fluid that bathes the brain and spinal cord.
Types of ATTR amyloidosis
Hereditary ATTR amyloidosis is caused by a mutation in the gene for TTR, inherited from one parent. The disease therefore runs in families, though the timing, development and severity of the disease can vary greatly.
In acquired (non-hereditary) 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
People with mutations in the TTR gene produce abnormal, amyloidogenic, ‘variant’ TTR throughout their lives. Amyloid deposits start to form and then build up until they cause clinical disease, mainly affecting the nerves and/or heart, and sometimes the kidneys, eyes and synovial tissues (tendons and ligaments). Symptoms may appear at any time from early adult life onwards. This condition runs in families.
Hereditary ATTR amyloidosis was traditionally referred to as familial amyloid polyneuropathy (FAP) when disease mainly affected the nerves or familial amyloid cardiomyopathy (FAC) when disease mainly affected the heart. However it is now understood that in clinical practice there is significant overlap in disease manifestations not only between patients with different mutations but also among those with the same mutation. Most TTR mutations can cause amyloid deposits in both the nerves and the heart. The International Society of Amyloidosis has therefore recommended the use of the term hereditary ATTR amyloidosis to describe disease caused by ATTR amyloid deposits in all patients with TTR gene mutations.
Hereditary ATTR amyloidosis is the most commonly recognised form of hereditary systemic amyloidosis but it is nevertheless a very rare disease. More than 150 amyloidogenic variants (mutations) of TTR have been observed and different mutations may cause different disease manifestations.
Despite being extremely rare in most parts of the world, hereditary ATTR amyloidosis is common in some very localised parts of Portugal, Sweden and Japan. It may also be common, but under-diagnosed in several other regions including Spain, France, Brazil, Argentina, Cyprus, Bulgaria and Ireland.
Hereditary ATTR amyloidosis is sometimes seen in people living in the UK, with ancestors from these regions.
The commonest type of hereditary ATTR amyloidosis, associated with the Val30Met (V30M) mutation, is thought to affect about 10,000 people in the whole world. 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.
Sometimes people carrying a TTR mutation never develop disease. For example, about 1 in 500 people in northern Portugal carry a Val30Met TTR mutation, and 80% of them develop disease. About 1 in 25 people in northern Sweden carry this same mutation but only 11% of them develop disease. The reason for this geographic variation is unclear.
The most common TTR mutations which cause amyloid in the UK are the Thr60Ala (T60A), often seen in people with Irish ancestry, and the Val122Ile (V122I) mutation, found in people with African ancestry. People with the T60A 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. Symptoms of autonomic neuropathy such as erectile dysfunction (in males), diarrhoea and/or constipation, weight loss, and low blood pressure on standing are more common than peripheral neuropathy.
The V122I mutation 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, often also causing carpal tunnel syndrome and sometimes causing peripheral neuropathy. V122I-associated hereditary ATTR amyloidosis has only been recognised in recent years and usually affects people of African ancestry aged over 60. Although the disease is believed to be underdiagnosed, it is thought to have low penetrance, meaning that most people carrying this mutation do not ever develop disease.
Symptoms of hereditary ATTR amyloidosis 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
- leg swelling (oedema)
- weight loss
- dizziness and collapse (syncope or fainting), which may occur after exertion, or after eating
- disrupted sleep
- angina (chest pain)
- disease due to amyloid deposits in the :
- thyroid gland
- adrenal glands
- blood vessels
Symptoms may appear as early as age 20, or as late as age 80. 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 just 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.
Patients carrying a mutation in their genes do not always develop disease. Some cases have been reported where people over age 60 have no disease despite having two copies of the TTR gene mutation which causes production of the Val30Met TTR protein variant.
Diagnosis of hereditary ATTR amyloidosis
Doctors may suspect ATTR amyloidosis on the basis of patients’ symptoms, findings on physical examination and sometimes family history. The diagnosis can be confirmed (or eliminated) by tests including:
- Tissue biopsy
- Genetic testing
- Imaging studies
All patients in the UK with suspected or diagnosed ATTR amyloidosis should be referred to the NAC.
In this procedure, a small sample of tissue is removed from the body with a needle and examined in the laboratory. The tissue sample is often obtained from under the skin in the stomach area (abdominal fat biopsy). Alternatively, when ATTR amyloidosis is suspected, the biopsy sample may be taken from the heart, a nerve in the arm or leg, or the bowel, depending on the clinical features of the patient. In the laboratory, the tissue sample is examined using specific techniques to identify amyloid fibrils, including staining of the tissue with a dye called Congo red. Positive Congo red staining can identify amyloid. Then immunohistochemistry and proteomics testing can identify TTR fibrils and determine which type of ATTR amyloidosis is present, by distinguishing between ‘variant’ ATTR in hereditary ATTR amyloidosis and ‘wild-type’ ATTR in non-heredtiary wild type ATTR amyloidosis.
These techniques are discussed in more detail here.
Genetic testing involves examination of the DNA from the patient’s cells. These tests are performed on blood samples taken from the patient’s vein.
In patients with hereditary ATTR amyloidosis, these techniques can identify amyloidogenic mutations (abnormalities) in the TTR gene. There are over 100 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. For example, the most common mutation worldwide, the Val30Met mutation often leads to amyloid deposits just in the nerves, not in the heart. In contrast, the Val122lle mutation usually leads to amyloid deposits predominantly in the heart, and only occasionally affects the nerves.
In wild-type ATTR amyloidosis, amyloid fibril analysis detects ‘wild-type’ ATTR protein and genetic testing will not detect any abnormalities in the TTR gene.
Imaging studies of the heart including ECG, echocardiogram, DPD scanning and in some cases cardiac MR scanning may give helpful information. These tests are discussed here.
DPD scanning is exquisitely sensitive for detecting ATTR amyloid deposits in the heart. A DPD scan, in combination with a series of blood and urine tests, may be sufficient to diagnose cardiac ATTR amyloidosis without a need for demonstration of amyloid within a tissue (heart, fat or nerve) biopsy.
SAP scanning, which helps to show amyloid deposits in organs such as the liver, spleen and kidneys, may not be helpful as it does not show amyloid deposits in the heart or nerves.
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.
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
Reducing variant TTR supply: liver transplantation
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 may therefore be a treatment option for some patients with hereditary ATTR amyloidosis, mainly for patients with the Val30Met mutation. Liver transplantation is not a treatment for wild-type ATTR amyloidosis.
In liver transplantation, 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 amyloid-forming variant 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:
- in younger patients in patients with the TTR Val30Met mutation
- early in the course of disease before there has been too much damage to the nerves or the heart
Unfortunately, in most patients with pre-existing amyloid deposits in the heart, the amyloid continues to deposit in the heart even after liver transplantation. It seems that the abnormal TTR fibrils which formed amyloid deposits before the liver transplant procedure act as a ‘template’ encouraging deposition in the heart of normal TTR as amyloid. Thus the normal TTR protein (‘wild-type’ TTR) produced by the new liver builds up in the heart on top of the existing amyloid deposits containing the abnormal TTR. This problem has occurred in most patients with mutations other than Val30Met who have undergone liver transplantation and it is therefore rarely used to treat patients with other amyloid-causing mutations.
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.
Supporting amyloidotic organ function
In all types of amyloidosis it is important that treatment should support the function of organs containing amyloid. In hereditary ATTR amyloidosis this may include:
Heart disease treatment
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.
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. Many patients with ATTR cardiac amyloidosis should limit their fluid intake. This advice is extremely important, but is often overlooked.
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:
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.
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.
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.
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. Patients may benefit from instruction in how to change position carefully from lying to sitting, sitting to standing and standing to walking. Drug treatment with midodrine or fludrocortisone may also be helpful to maintain blood pressure and allow higher diuretic doses. 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.
Tips from an experienced patient
(Vince Nicholas, member of the UK Amyloidosis Advisory Group – diagnosed with hereditary ATTR amyloidosis, over 20 years ago, at age 35 )
Here are some tips for dealing with common symptoms:
Dealing with postural hypotension
- After sitting down for more than 1/2 hour always stand for about 30 seconds before moving off.
- 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!
- 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.
- 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.
- When getting up from bed in the morning I always sit on the side for a few moments before walking off.
- Never run and always pace yourself.
- Always allow more time than you think you need!
Dealing with painful neuropathy symptoms
- I find doing weekly muscle build-up and light exercise at the gym helps a lot.
- I find having a regular leg and feet massage eases my leg pains and stiffness.
- Keep your legs and feet always moisturised.
- Carry out daily hand exercise to keep them working.
Over the last 6 years since having my liver transplant I have found that by adjusting my diet my bowel problems have reduced:
- By reducing the amount of wheat has helped a lot. I very rarely eat sandwiches, cakes and eat very little pastry.
- I try not to have processed foods and have cooked food at lunchtime and in the evenings.
- I have cut out sugar as much as I can. (Chocolate seems to still be good!!!)
- I have cut out all beer and lager and tend to drink water, wine and some spirits.
- I restrict to only having mild curries.
A number of new drugs for TTR amyloidosis are in various stages of development. Some of these drugs are not yet available, but they offer hope for the future.
This 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 with hereditary ATTR amyloidosis affecting 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.
Tafamidis was developed as a specific drug for ATTR amyloidosis. It is bound by TTR in the blood. This binding is thought to stabilise the TTR and makes it less amyloidogenic. The pivotal trial of tafamidis included 441 patients, some of whom had wild type ATTR amyloidosis while others had hereditary ATTR amyloidosis. Patients who received the active drug had better outcomes than those who received placebo, including fewer hospitalisations for heart disease, a 30% reduction in death over a period of 2.5 years, reduced decline in functional capacity and improved quality of life. Tafamidis is approved in Europe for treatment of hereditary ATTR amyloidosis patients with stage 1 symptomatic polyneuropathy to delay neurological impairment and before liver transplantation, but it is not currently available within the NHS. In the U.S, the Food and Drug Administration (FDA) have approved tafamidis for cardiomyopathy caused by ATTR amyloidosis although it is not approved for ATTR polyneuropathy. Regulatory submissions for the use of tafamidis in patients with ATTR cardiomyopathy have been submitted to the European Medicines Agency (EMA) and NICE and are under review.
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 hereditary ATTR amyloidosis and symptomatic neuropathy had very encouraging results, serving as a landmark in the field of amyloidosis treatment.
A drug called patisiran belongs to the small interfering RNA drug class and has been shown to reverse neuropathy in a majority of patients who participated in a phase 3 study called the APOLLO trial. This trial enrolled 225 patients with hereditary ATTR amyloidosis and randomised them to receive either patisiran or placebo by intravenous injection every 3 weeks for 18 months. Patients who received patisiran fared significantly better than those who received placebo, in terms of neuropathy symptoms, quality of life, daily activities and disability. According to standardised scores, neuropathy symptoms 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 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 function. Once this was observed, all patients receiving inotersen were monitored with regular blood tests.
Patisiran and inotersen have been approved by the European Medicines Agency and the U.S. Food and Drug Administration (FDA) for treating neuropathy caused by hereditary ATTR amyloidosis.
On 22 May 2019 NICE published guidance recommending inotersen for treating stage 1 and stage 2 polyneuropathy in adults with hereditary transthyretin amyloidosis.
On 14 August 2019 NICE published guidance recommending patisiran for treating hereditary transthyretin amyloidosis in adults with stage 1 and stage 2 polyneuropathy.
Both inotersen and patisiran have now been approved by NHS England for this indication.
So far trials have only assessed the impact of these drugs on nerve damage caused by ATTR amyloidosis. Effects on cardiac ATTR amyloidosis have not been formally assessed.
The NAC can now offer patients with ATTR amyloidosis, subject to various eligibility criteria demanded by the pharmaceutical companies, various opportunities for treatment with the new drugs or for participation in clinical trials. For details of ongoing trials at the NAC see here.