ATTR Amyloidosis

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ATTR amyloidosis is caused by amyloid deposits made up of a protein called transthyretin (TTR). There are three distinct different types of ATTR amyloidosis:

  1. Familial amyloid polyneuropathy (FAP) (hereditary – runs in families and can overlap with FAC)
  2. Familial amyloid cardiomyopathy (FAC) (hereditary – runs in families and can overlap with FAP)
  3. Senile systemic amyloidosis or wild-type ATTR amyloidosis (not hereditary – does not run in families or cause polyneuropathy).

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”. People with mutations in the TTR gene produce abnormal, amyloidogenic, “variant” TTR throughout their lives.

Amyloid deposits consisting of abnormal “variantTTR may cause:

  1. Familial amyloid polyneuropathy (FAP). This disease affects the nervous system, often the heart and sometimes the kidneys and eyes.  It is very rare, with the commonest type, associated with the Val30Met mutation 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.
  2. Familial Amyloid cardiomyopathy (FAC) (heart disease), most commonly in men over age 60 of African American ancestry. There is often carpal tunnel syndrome but other organs are not affected. This condition has only been recognised recently and is probably common in this population and widely underdiagnosed.

Normal, “wild type” TTR may also be amyloidogenic, causing:

3. Senile systemic amyloidosis (wild type ATTR amyloidosis). Until recently it was thought that amyloid deposits consisting of “wild type” TTR hardly ever caused disease. However, as a result of the use of new imaging techniques at the NAC, it has recently become apparent that in fact, disease caused by “wild type” ATTR deposits may be far commoner than anyone thought. Until 2014 this disease was called 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. Amyloid deposits consisting of “wild type” TTR mainly affect the heart but may also cause carpal tunnel syndrome in some people. This condition is not hereditary (it does not run in families).

These three distinct conditions are discussed below in more detail. Treatment of patients with ATTR amyloidosis is discussed lower down on this webpage.

1. Familial amyloid polyneuropathy (FAP) – hereditary ATTR amyloidosis

People with mutations in the TTR gene produce abnormal, amyloidogenic (“variant”) TTR throughout their lives. Over the course of several decades, usually by the time these people are middle aged, they may develop symptoms of disease caused by the build-up of amyloid deposits. This is called Familial Amyloid Polyneuropathy – FAP.

  • More than 100 amyloid forming variants of TTR have been observed.
  • The most common mutation worldwide is called TTR Val30Met (V30M).
    • 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 most common mutation in the UK is called TTR Thr60Ala (T60A), often seen in people with 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.
  • FAP is rare in most parts of the world, but common in some parts of:
    • Portugal
    • Sweden
    • Japan
  • FAP is sometimes seen in people living in the UK, with ancestors from these regions.

 

FAP

FAP is relatively common in people with ancestors originating in the marked countries

Symptoms of FAP

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
    • leg swelling (oedema)
    • weight loss
    • nausea
    • fatigue
    • 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 :
    • eye
    • kidneys
    • 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 and treatment of FAP and other types of ATTR amyloidosis are discussed further down this webpage.

2. Familial amyloid cardiomyopathy (FAC):

In this condition, amyloid deposits in the heart are made up of variant TTR fibrils. These amyloid deposits cause thickening and stiffening of the heart. It is a hereditary, genetic condition, caused by mutations in the TTR gene which lead to production of the abnormal, “variantTTR. Symptoms usually start after age 60. Heart disease onset is often preceded by carpal tunnel syndrome. There is usually no nervous system disease, and  other organs are usually not affected.

Symptoms of amyloid heart disease 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
  • nausea
  • fatigue
  • dizziness and collapse (syncope or fainting), which may occur after exertion, or after eating
  • disrupted sleep
  • angina (chest pain)

This condition is seen most often in people of Afro-Caribbean or African American heritage, amongst whom a particular mutation known as Val122lle in the TTR gene was recently found to be very widespread. This mutation has been found in almost 4 in every 100 (4%) African Americans and almost 1 in 4 (23%) African Americans with a diagnosis of cardiac amyloidosis.

This condition has only been recognised in the past few years. It is therefore likely that ATTR cardiac amyloid is widely underdiagnosed. This is important because medications that are helpful in other causes of heart failure are not appropriate when there is amyloidosis in the heart.

Diagnosis and treatment of FAC and other types of ATTR amyloidosis are discussed further down this webpage.

3. Senile Systemic Amyloidosis (wild type ATTR amyloidosis)

patient being checked by doctorSenile systemic amyloidosis (wild type ATTR amyloidosis) is a slowly progressive disease. The symptoms usually start after age 65. This condition is not hereditary, and it is far more common in men than in women. No-one knows just how common symptomatic senile systemic amyloidosis (wild type ATTR amyloidosis) really is but it is almost certainly underdiagnosed at present. This diagnosis may become more common in future as the population ages and diagnostic methods continue to improve.

People with this condition do not have a mutation in the TTR gene and the amyloid fibrils are made up of normal, “wild type” TTR.  These types of amyloid deposits are found at autopsy in 1 in 4 people over age 80, but in most cases they do not appear to cause any symptoms. Some patients with small ATTR amyloidosis deposits in the heart and minimal symptoms may not require any treatment.

Symptoms of senile systemic amyloidosis (wild type ATTR amyloidosis) result from stiffening of the heart due to amyloid deposits (restrictive cardiomyopathy). These symptoms 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
  • nausea
  • fatigue
  • dizziness and collapse (syncope or fainting), which may occur after exertion, or after eating
  • disrupted sleep
  • angina (chest pain)

Almost 50% of patients with senile systemic amyloidosis (wild type ATTR amyloidosis) experience carpal tunnel syndrome – tingling and pain in the wrists, pins and needles in the hands. Carpal tunnel syndrome often appears 3-5 years before the symptoms of heart disease.

It not clear at present just how commonly the deposits actually do lead to symptomatic disease. Recent developments with diagnostic tests such as cardiac magnetic resonance (CMR) have greatly improved the detection of amyloid in the heart during life. This has led to the belief that senile systemic amyloidosis (wild type ATTR amyloidosis) is more common than was previously thought.

This is demonstrated in the following NAC statistics :

  • Up until 2001 wild type ATTR amyloidosis was diagnosed in just 1 out of every 200 (0.5%) of NAC patients.
  • Between 2009 -2012 it accounted for 7 out of every 100 patients – a 14 fold increase in the frequency with which this diagnosis was made.

Patients with ATTR in the heart often have fewer symptoms than those with AL amyloidosis in the heart, and senile systemic amyloidosis (wild type ATTR amyloidosis) usually progresses slowly.

Diagnosis and treatment of all types of ATTR amyloidosis are discussed below.

Diagnosis 

When doctors suspect ATTR amyloidosis, the diagnosis can be confirmed (or eliminated) by tests including:

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 senile systemic amyloidosis.

These techniques are discussed in more detail in the section on tissue biopsy.

  • genetic testing: 

genetic testing

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.

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 just in the heart, not in the nerves.

In senile systemic amyloidosis (wild type ATTR amyloidosis), amyloid fibril analysis detects “wild type” ATTR protein and genetic testing will not detect any abnormalities in the ATTR gene.

ECG, echocardiogram, DPD scanning and in some cases cardiac MR scanning may give helpful information.  

SAP scanning may not be helpful as it does not show amyloid deposits in the heart or nerves.

Treatment

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

  1. Reducing the supply of amyloid forming precursor proteins.
  2. 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

Reducing variant TTR supply: liver transplantation

Diagram representing the liver

Liver transplantation may be helpful for some patients with hereditary, variant ATTR amyloidosis, mainly for  patients with FAP associated with the Val30Met mutation. Liver transplantation is not a treatment for senile systemic amyloidosis (wild type ATTR amyloidosis).

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 FAP. The liver which forms the abnormal, “variantTTR 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 FAP 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.

Heart transplantation

For hereditary, “variant” 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 senile systemic amyloidosis 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.

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 – discussed in more detail here.

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.

New drugs for ATTR amyloidosis

test tubesA 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.

Diflunisal:

This belongs to a class of drugs called “non-steroidal anti-inflammatories” (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 FAP and familial amyloid cardiomyopathy. 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 familial amyloid polyneuropathy (hereditary ATTR amyloidosis which affects 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:

Tafamidis was developed as a specific drug for FAP. 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 FAP neuropathy. Neuropathy progression was slightly slower in patients who received the drug than in those who did not. However, many of the participants had very early, often barely clinically significant disease at baseline. Given the major clinical unmet need, tafamadis 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 has not been approved by the FDA in the USA. It is also not available in the NHS. The drug has not been tested in cardiac TTR amyloidosis and has not received approval for this indication.

Other therapies that are currently in early stages of development and clinical trials include:

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 is simply not produced.

A drug called ALN-TTRsc, which belongs to the small interfering RNA drug class, was shown to reduce blood levels of TTR by up to 94% in healthy volunteers. ALN-TTRsc is currently undergoing preliminary clinical trials in patients with ATTR cardiac amyloidosis, both senile systemic amyloidosis and the inherited forms of ATTR cardiac amyloidosis.

Another drug called ISIS TTR Rx belongs to the antisense oligonucleotide drug class. ISIS TTR Rx is currently undergoing trials in patients with familial amyloid polyneuropathy, a hereditary type of ATTR amyloidosis. Current trials are only assessing the impact of this drug on nerve damage caused by ATTR amyloid.

Antibody mediated amyloid elimination:

Two SAP molecules bound together by the drug CPHPC

Two SAP molecules bound together by the drug CPHPC

The Wolfson Drug Discovery Unit has developed a drug called CPHPC, which clears all the SAP from the blood but leaves some SAP bound to the amyloid deposits. After CPHPC has been administered, it is therefore safe and feasible to administer antibodies to SAP which we have created. In experimental models these antibodies act like guided missiles, homing in on the amyloid deposits and triggering the body’s normally very efficient systems for removal of debris from the tissues to act on the amyloid. This approach works very well in the models and in collaboration with GlaxoSmithKline it is now being tested for the first time in patients with systemic amyloidosis. If it proves to be safe and effective in humans, it will be applicable to patients with all types of amyloidosis including ATTR amyloidosis.

The National Amyloidosis Centre gratefully acknowledges the financial support of the following companies for its Amyloidosis Awareness programme:

IONIS Pharmaceuticals, Carlsbad, California, US

Ionis logo

Alnylam Pharmaceuticals, Cambridge, Massachusetts, US

Alnylam logo

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