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Amyloidosis

What is 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.

How do amyloid deposits cause disease?

Amyloid deposits cause disease by gradually accumulating within organs and thereby disrupting the structure and damaging the function of the affected tissues.  In some cases, previously healthy organs can be substantially replaced by extensive amyloid deposits.

How common is amyloidosis?

Amyloidosis is rare. About 500-1000 new cases are diagnosed in the UK every year. According to NAC estimates, every year around 1 person in every 100,000 in the UK develops systemic amyloidosis. Only around half of these people are diagnosed. Amyloidosis is recorded as the cause of death in between 0.5 to 1 out of every 1000 people.

AL amyloidosis is the most common type of amyloidosis affecting about 60% of patients diagnosed with amyloidosis at the NAC.

ATTR amyloidosis is the second commonest type of systemic amyloidosis. ATTR amyloidosis may be hereditary or non-hereditary.

Although hereditary ATTR amyloidosis is the most common hereditary type of amyloidosis, it is very rare in most parts of the world. However, it is common in some geographical locations. For example, it has been estimated that 1% of people in county Donegal region of North west Ireland carry a gene mutation (alteration) that can cause ATTR amyloidosis. Many people with hereditary ATTR amyloidosis in the UK have some Irish ancestry. A different gene mutation that can cause ATTR amyloidosis is relatively common in people of Afro-Caribbean ancestry.

The non-hereditary type of ATTR amyloidosis was previously known as senile systemic amyloidosis (SSA) and was recently re-named as wild type ATTR amyloidosis. The rate of diagnosis of this condition has increased dramatically in the last two decades. Up until 2001 wild-type ATTR amyloidosis was diagnosed in just 1 out of every 200 (0.5%) of patients seen at the NAC. In 2016 it accounted for nearly 1 in 5 (18%) of NAC patients diagnosed with amyloidosis - a 40 fold increase, representing greater awareness and new diagnostic imaging methods such as cardiac MRI. Nobody knows whether we are still just seeing the tip of the iceberg. Wild type ATTR amyloidosis may be diagnosed even more frequently in the future.

AA amyloidosis is far less common than it was in the past, as the inflammatory diseases that cause AA amyloidosis are better controlled now, with new medications. In 2012 just 8% of the patients with amyloidosis seen at the NAC had AA amyloidosis.

Non-ATTR hereditary amyloidosis is very rare.

Distribution of different types of amyloidosis amongst patients diagnosed with amyloidosis at the NAC in 2012chart 776

What do the names of the different types of amyloidosis mean?

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

AL amyloidosis:  Light chains (fragments of monoclonal immunoglobulins (antibodies)) are the amyloid precursor protein. This is the most common form of amyloidosis and was formerly known as primary amyloidosis.

AA amyloidosis: Serum amyloid A protein (SAA), a blood protein which is produced in greatly increased amounts when there is prolonged inflammation, is the amyloid precursor protein. This was formerly known as secondary amyloidosis.

ATTR amyloidosis: Transthyretin (TTR), a normal blood protein, present in everybody, is the amyloid precursor protein.

Aβ2M amyloidosis: Beta 2 Microglobulin (β2M) is the amyloid precursor protein.

AFib amyloidosis: Fibrinogen is the amyloid precursor protein.

A wide variety of other proteins can form amyloid in the various rare, hereditary types of amyloidosis.

What is the difference between systemic and localised amyloidosis?

Amyloidosis is usually a systemic disease.  This means that many body organs and systems may be affected.  Systemic amyloidosis may be AL amyloidosis, AA amyloidosis, ATTR amyloidosis (hereditary or non-hereditary) or non-ATTR hereditary amyloidosis.  Less frequently, localised deposits of amyloid may appear just in one area, such as the airways, skin or bladder.  Localised amyloidosis may require no treatment (for example macular amyloidosis in the skin) or may be easily and completely curable.  Localised amyloidosis is usually of AL type and is not hereditary.

For more information on localised amyloidosis, see here.

Is amyloidosis contagious?

No.  Amyloidosis is not a transmissible disease.

Is amyloidosis hereditary (familial)?

The most common type of amyloidosis, AL amyloidosis, is not inherited. If there is a definite diagnosis of AL amyloidosis, then there is no need for any family members to undergo testing.

ATTR amyloidosis, the second commonest type of amyloidosis may be hereditary or non-hereditary (wild type ATTR amyloidosis).

Some other, rare types of hereditary amyloidosis include Afib (more information on Afib amyloidosis is available here), ApoA1, AGel and ALys amyloidosis.

Relatives of patients with hereditary amyloidosis should consult with the NAC doctors to discuss the possibility of genetic testing. Please contact Professor Julian Gillmore.

AA amyloidosis itself is not hereditary. However, the inflammatory diseases that are associated with AA amyloidosis do tend to run in families. The hereditary fever syndromes in particular have a very clear genetic basis. Family members of patients with fever syndromes should consult with the fever syndrome clinic doctors to discuss the possibility of genetic testing. Please contact Dr Helen Lachmann.

Localised amyloidosis is usually of AL type and is not hereditary.

 

Is amyloidosis a form of cancer?

No.

AL amyloidosis is related to a type of bone marrow cancer called multiple myeloma, and it is treated in a similar fashion with chemotherapy drugs and sometimes with stem cell transplantation.  However, amyloidosis is not cancer.

My family member has been diagnosed with amyloidosis. Should I be tested?

The following types of amyloidosis are not inherited:

  • AL amyloidosis
  • Wild-type ATTR amyloidosis (formerly known as senile systemic amyloidosis)
  • Localised amyloidosis

If there is a definite diagnosis of one of these three conditions there is no need for family members to undergo testing.

Some other types of amyloidosis are hereditary:

Hereditary ATTR amyloidosis, AFib ApoA1, AGel and ALys amyloidosis.

Relatives of patients with hereditary amyloidosis should consult with the NAC doctors to discuss the possibility of genetic testing. Please contact Dr Julian Gillmore at j.gillmore@ucl.ac.uk.

AA amyloidosis itself is not hereditary. However, the inflammatory diseases that are associated with AA amyloidosis do tend to run in families. The hereditary fever syndromes in particular have a very clear genetic basis. Family members of patients with fever syndromes should consult with the fever syndrome clinic doctors to discuss the possibility of genetic testing. Please contact Dr Helen Lachmann at h.lachmann@ucl.ac.uk

What is the life expectancy of patients with amyloidosis?

Recent years have seen important strides forwards in treatment and the outlook for patients diagnosed with amyloidosis today is far better than it was even a few years ago.

In some types of amyloidosis currently available treatments may even lead to complete cure, while in others, there may be extended symptom free survival. Twenty years ago the life expectancy of patients diagnosed with amyloidosis was usually only a few months or years, whereas now it is often 10 years or more.

Patient concerns

A doctor suggested I may have amyloidosis. What should I do?

If you are in the UK, you should ask your doctor to refer you to the National Amyloidosis Centre (NAC) at the Royal Free Hospital, London, as soon as possible. You don't need to wait for a definite diagnosis of amyloidosis from your local doctor, or for determination of which type of amyloidosis you have. Just ask to be referred. Information for referring physicians is available here.

The outlook for patients diagnosed with amyloidosis has improved significantly in recent years.  Outcomes are best when treatment is started early in the course of disease.  So, if the possibility of amyloidosis has been raised it is important to be seen by amyloidosis specialists in order to confirm or rule out the diagnosis promptly and reliably.

I’ve been diagnosed with amyloidosis. What should I do?

If you are in the UK, you should ask your doctor to refer you to the National Amyloidosis Centre (NAC) at the Royal Free Hospital, London, as soon as possible. You don't have to wait for the local doctors to determine what type of amyloidosis you have. Just ask to be referred. Information for referring physicians is available here.

The NAC provides a diagnostic 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. We see about 4,000 patients each year, comprising about 50% of all UK patients with systemic amyloidosis.

Wherever possible, patients are discussed with the referring physician, after which we re‑examine any available tissue biopsies.  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 at the Royal Free Hospital.

Most patients with amyloidosis need long‑term surveillance, with six‑monthly or annual specialist follow up at the NAC in the shorter term.

I’ve just been diagnosed with amyloidosis. What should I expect?

When people are first told that they have amyloidosis, a rare disease which they have probably never heard of, they may experience a variety of emotions.  It is normal to feel worried, shocked or confused and concerned about what the future holds.  Sometimes it is a relief to finally have a diagnosis after a prolonged period of ill health and medical uncertainty.

Patients usually feel better about the situation after the first appointment at the NAC.  Our doctors are world experts in amyloidosis and the whole team are very caring and highly experienced.  They will tell you what type of amyloidosis you have and explain your diagnosis to you clearly and answer all your questions.  Most patients feel they can cope much better once they understand what the diagnosis means and what to expect in terms of treatment.

There are several effective treatments available now and a large number of our patients live with amyloidosis for many years with a very good quality of life.  There are also promising new drugs in various stages of development, which offer considerable hope for the future.

Once your diagnosis is confirmed, and when you know what type of amyloidosis you have, you should have a look at the comprehensive NAC patient information website at www.amyloidosis.org.uk.

You can also access the National Amyloidosis Centre’s online patient forum at www.amyloidosis.org.uk/forum  to discuss and interact with other patients and families.  All posts are expertly medically moderated so that speculative or misleading comments and information are excluded.

Myeloma UK organise an annual AL amyloidosis Infoday,  which is an opportunity for patients with AL amyloidosis to meet each other as well as listen to talks by the NAC consultants.

Amyloidosis is a rare disease, but you are not alone, and you will receive the best possible care and treatment from the NAC, so there is cause for optimism.

My abdominal fat biopsy was negative for amyloid. Could I still have amyloidosis?

Yes.  A negative abdominal fat pad biopsy does not rule out the possibility of amyloidosis, as negative results occur in between 20-50% of patients with systemic amyloidosis.  This may be because amyloid deposits are not distributed uniformly in the abdominal fat and it possible that there were no deposits in the small region sampled.  Also, precise laboratory techniques are needed to detect amyloid in biopsy specimens.  The diagnosis may be missed if the biopsy is examined in a laboratory where this test is only performed rarely.  An internal NAC audit at the NAC found 8% false negatives and 8% false positives in biopsy samples sent to us for review for other centres.

If the doctors have a strong clinical suspicion that there is amyloidosis, but the abdominal fat biopsy is negative, then it may be necessary to directly biopsy an affected tissue, such as the kidney or heart.

Imaging studies are also helpful.  The SAP scan can show amyloid deposits in most organs, apart from the heart and the gut.  All patients attending the NAC for evaluation undergo SAP scanning which is only available here.  DPD scans and cardiac MRI can show amyloid deposits in the heart, and the NAC doctors may sometimes recommend these tests.

My organ biopsy was negative for amyloid. Could I still have amyloidosis?

It is possible, though unlikely that you have amyloidosis.

Direct biopsy of a clinically affected tissue usually reveals amyloid if it is present.  However, precise laboratory techniques are needed to detect amyloid in biopsy specimens.  The diagnosis may be missed if the biopsy is examined in a laboratory where this test is only performed rarely.  We see about 4,000 patients at the NAC each year and our expert laboratory staff review hundreds of biopsies from other centres annually.  An internal NAC audit at the NAC found 8% false negatives and 8% false positives in biopsy samples sent to us for review for other centres.

We therefore recommend that, if possible, biopsy slides from other centres should be sent to us for review.

How can I make contact with other people with amyloidosis?

You can access the National Amyloidosis Centre’s online patient forum at www.amyloidosis.org.uk/forum  to discuss and interact with other patients and families.  All posts are expertly medically moderated so that speculative or misleading comments and information are excluded.

Myeloma UK organise an annual AL amyloidosis Infoday, which is an opportunity for patients with AL amyloidosis to meet each other as well as listen to talks by the NAC consultants.

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.  We see about 4,000 patients each year, including about 50% of all UK patients with systemic amyloidosis.

How do I arrange an evaluation at the NAC?

UK patients

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
ramon.lamarca@nhs.net

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
ramon.lamarca@nhs.net

What should I expect at the NAC clinical evaluation?

Our clinical evaluation usually takes 1 -2 days, and hospital or hotel overnight accommodation can be arranged when necessary.  We recommend 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.

Our 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 we re‑examine any available tissue biopsies.

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.  We manage a small proportion of cases are directly 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.

Where is the NAC?

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

Directions are available here.

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.

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.

Symptoms

What are the symptoms of amyloidosis?

Amyloidosis can affect almost any tissue in the body. Therefore the symptoms and signs of the disease can vary greatly and are often vague and not specific .

AL amyloidosis symptoms

In AL amyloidosis, amyloid deposits may affect any part of the body except for the brain. Usually one or two organs are predominantly affected (known as the “dominant” organs). Patients with AL amyloidosis may complain of general problems such as weight loss, fatigue, weakness, loss of appetite and easy bruising. They may also develop symptoms of disease affecting the kidneys, heart, nervous system, gut, liver, spleen, skin and joints.

Macroglossia (enlarged tongue), bruising of the skin round the eyes (‘racoon eyes’ or ‘panda eyes’) and the shoulder pad sign (swelling of both shoulders) are quite rare, occurring in less than 15% of cases. But when these signs do occur, they are very strongly suggestive of AL amyloidosis.

ATTR amyloidosis symptoms

ATTR amyloidosis mainly affects the heart and the nerves. Symptoms of heart disease may include shortness of breath, palpitations, leg swelling, weight loss, nausea, fatigue, fainting and chest pain.

Symptoms of nervous system disease may include weakness, pain and loss of sensation in the arms and legs, disturbances of bowel, bladder, blood pressure and sexual function.

AA amyloidosis symptoms

AA amyloidosis mainly affects the kidneys and spleen. Protein in the urine is usually the first sign. After that, more serious kidney disease can develop, including nephrotic syndrome, when very large amounts of protein in the urine make it appear frothy, and there is ankle swelling and weight gain. The spleen is often enlarged.

Non-ATTR hereditary amyloidosis

Hereditary fibrinogen A alpha chain amyloidosis (Afib)

AFib amyloidosis (fibrinogen Aα-Chain amyloidosis) is a rare inherited genetic condition. People with this condition develop kidney disease caused by build-up of abnormal protein deposits called amyloid in their kidneys. Abnormal kidney function is usually first diagnosed in this condition in middle age. Kidney function then tends to become progressively worse over several years until the kidneys stop functioning altogether. ‘Renal replacement’ treatment (either dialysis or kidney transplantation) is then required. AFib amyloidosis is equally common in men and in women. In the UK it is most common in people of British Caucasian ancestry but it may occur in people of any ethnic origin.

For more information see here.

Hereditary apolipoprotein A1 amyloidosis (ApoA1)

ApoA1 amyloidosis usually causes high blood pressure and kidney disease. It often also affects the liver and sometimes the heart.

Hereditary gelsolin amyloidosis (AGel)

AGel amyloidosis, also known as Familial Amyloidosis Finnish (FAF) type because most patients are from Finland, causes eye, skin and cranial nerve symptoms. Despite kidney amyloid deposits, kidney function is usually not affected.

Hereditary lysozyme amyloidosis (ALys)

ALys amyloidosis mainly causes kidney disease, and there may also be amyloid in the stomach lining. This form of amyloid tends to build up very slowly indeed and patients can remain stable for many years.

What are the symptoms of AL amyloidosis?

In AL amyloidosis, amyloid deposits may affect any part of the body except for the brain.  Usually one or two organs are predominantly affected (known as the “dominant” organs).  Patients with AL amyloidosis may complain of general problems such as weight loss, fatigue, weakness, loss of appetite and easy bruising.  They may also develop symptoms of disease affecting the kidneys, heart, nervous system, gut, liver, spleen, skin and joints.

Macroglossia (enlarged tongue), bruising of the skin round the eyes (‘racoon eyes’ or ‘panda eyes’) and the shoulder pad sign (swelling of both shoulders) are quite rare, occurring in less than 15% of cases.  But when these signs do occur, they are very strongly suggestive of AL amyloidosis.

What are the symptoms of ATTR amyloidosis?

Familial amyloid polyneuropathy (FAP), one of the hereditary types of ATTR amyloidosis mainly affects the nervous system and/or the heart.

Familial amyloid cardiomyopathy (FAC), another hereditary type of ATTR amyloidosis, only affects the heart.

Wild type ATTR amyloidosis, formerly known as senile systemic amyloidosis (SSA), only affects the heart and sometimes the carpal tunnel (wrist).

Symptoms of nervous system disease may include weakness, pain and loss of sensation in the arms and legs, disturbances of bowel, bladder, blood pressure and sexual function.

Symptoms of heart disease may include shortness of breath, palpitations, leg swelling, weight loss, nausea, fatigue, fainting and chest pain.

What are the symptoms of AA amyloidosis?

AA amyloidosis mainly affects the kidneys and spleen.  Protein in the urine is usually the first sign.  After that, more serious kidney disease can develop, including nephrotic syndrome, when very large amounts of protein in the urine make it appear frothy, and there is ankle swelling and weight gain.  The spleen is often enlarged.

AL amyloidosis

How common is AL amyloidosis?

AL amyloidosis was previously known as primary amyloidosis and is currently the most common type of amyloidosis in developed countries.  In the UK about 500-600 new cases are diagnosed each year and it is the cause of death in around 1 out of every 1500 deaths in the UK.  AL amyloidosis is the diagnosis in about 60% of the amyloidosis patients treated at the NAC.  According to NAC estimates, every year around 1 person in every 200,000 in the UK develops AL amyloidosis.

What causes AL amyloidosis?

Patients with AL amyloidosis have an underlying disorder in which there is overproduction of amyloidogenic proteins called light chains.  (The “L” in the name AL amyloidosis stands for “light chain.”)

Light chains are parts of antibodies, also known as immunoglobulins.  They are produced by a type of immune system cell called plasma cells.  In AL amyloidosis abnormal plasma cells produce light chains or light chain fragments which are amyloidogenic.  This means that they aggregate (clump) together in the tissues in the form of long thread-like fibres that the body does not destroy and clear away.  These fibrous aggregates are the amyloid fibrils which form amyloid deposits and as they accumulate in the tissues of the body they disrupt the structure and function of whichever organs are involved.

The abnormal plasma cells are usually, but not always, located in the bone marrow.  Most patients with AL amyloidosis usually have only small numbers of abnormal plasma cells in the bone marrow.

Abnormally increased amounts of free light chain concentrations can be measured in the blood in about 95% of patients with AL amyloidosis.

Who gets AL amyloidosis?

AL amyloidosis is commoner in men than in women and although most patients with AL amyloidosis are aged over 45, it occasionally occurs at younger ages.

What are the symptoms of AL amyloidosis?

In AL amyloidosis, amyloid deposits may affect any part of the body except for the brain.  Usually one or two organs are predominantly affected (known as the “dominant” organs).  Patients with AL amyloidosis may complain of general problems such as weight loss, fatigue, weakness, loss of appetite and easy bruising.  They may also develop symptoms of disease affecting the kidneys, heart, nervous system, gut, liver, spleen, skin and joints.

Macroglossia (enlarged tongue), bruising of the skin round the eyes (‘racoon eyes’ or ‘panda eyes’) and the shoulder pad sign (swelling of both shoulders) are quite rare, occurring in less than 15% of cases.  But when these signs do occur, they are very strongly suggestive of AL amyloidosis.

What is macroglossia?

Macroglossia means enlarged tongue.

Most of the symptoms and signs of AL amyloidosis are non-specific and usually caused by a number of other common conditions.  But macroglossia is one of the few rare complaints that are very suggestive of AL amyloidosis.  Although only around 15% of patients with AL amyloidosis experience this problem, it is hardly ever caused by anything else, so it should certainly prompt doctors to investigate the possibility of AL amyloidosis.

The whole tongue is usually diffusely enlarged and firm and there may be tooth indentations along the border.

Macroglossia

Macroglossia--enlarged tongue, sometimes with bite marks

Symptoms associated with macroglossia in AL amyloidosis, including difficulty in swallowing, quite often gradually improve very slowly following remission of the underlying plasma cell dyscrasia, but there is seldom clear evidence of reduction in size.

If macroglossia becomes marked and impairs swallowing, nutritional supplements may be recommended.  At a very advanced stage, patients may require feeding through a tube to the stomach (percutaneous endoscopic gastroscopy (PEG) feeding).  Surgery is not generally recommended to treat macroglossia as this may cause dangerous bleeding.

What are periorbital purpura? (raccoon eyes/panda eyes/ bruising round the eyes)

Most of the symptoms and signs of AL amyloidosis are non-specific and usually caused by a number of other common conditions.  But a few rare complaints are very suggestive of a diagnosis of AL amyloidosis.  Bruising of the skin around the eyes is one of these.  This is known as periorbital purpura in medical terminology, and may also be referred to as raccoon eyes or panda eyes.  Although less than 15% of patients with AL amyloidosis experience this problem, it is hardly ever caused by anything else, so it should certainly prompt doctors to investigate the possibility of AL amyloidosis.

Periorbital purpura is dark, usually appears quite suddenly, and is quite different from the common phenomenon of shadows under the eyes.  The appearance is usually that of quite severe bruising.  Sometimes the bruising fades or even disappears during or after chemotherapy treatment, but this may take months.  Some patients with AL amyloidosis also experience easy bruising in other parts of the body.  Any rubbing of the skin can cause these to appear and they may then fade.  However the bruising round the eyes usually lasts for much longer.  It does not cause any pain or irritation and is only a cosmetic issue.  It is quite often the trigger for a doctor to start to check for the possibility of amyloidosis.

Raccoon eyes

Raccoon eyes

What is the outlook for patients with AL amyloidosis?

AL amyloidosis is a very serious condition.  If left untreated it is progressive and may lead to death within a year.  However, most patients benefit considerably from current standard therapies for AL amyloidosis, and survive for many years after the diagnosis, with improved health and good quality of life.  Treatment results are best in patients who are diagnosed early or who do not have severe organ damage at the time of diagnosis.  Results are also best at specialist centres, such as the NAC.

In addition, there have been substantial recent advances in the treatments available, as several newer and better chemotherapy drugs have become available and entered routine use over the last few years.  Patients are already experiencing significant benefits from these treatments so there is cautious optimism regarding the future.

Excitingly, there are also a number of new drugs currently in development in research centres around the world.  A new approach to eliminate existing amyloid deposits, invented in the UCL Wolfson Drug Discovery Unit, is being developed and undergoing clinical testing in collaboration with GlaxoSmithKline.  The field of AL amyloidosis has moved into a very exciting era with hope for much more effective treatments.

My family member has AL amyloidosis. Am I at risk and do I need any medical investigations?

AL amyloidosis is never hereditary.  Family members of patients with AL amyloidosis are not at risk of developing this condition and do not need to undergo any particular medical investigations.

How is AL amyloidosis treated?

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.

In AL amyloidosis, treatment is directed towards the abnormal plasma cells (usually in the bone marrow), which produce the abnormal light chains that form amyloid deposits.  Treatment regimes are referred to as ‘chemotherapy’.  The drugs used are similar to those used in the related condition of multiple myeloma.  Both AL amyloidosis and multiple myeloma are caused by abnormal plasma cells in the bone marrow, as explained here.  Treatment regimes for AL amyloidosis have been adapted from those developed for multiple myeloma.  The percentage of plasma cells in the bone marrow is far smaller in AL amyloidosis than in myeloma.  So treatment for AL amyloidosis is often less prolonged and requires less intense dosage of drugs than myeloma.

Patients with AL amyloidosis are usually treated with a combination of different drugs, taken simultaneously.  Each drug acts by a different mechanism to block the activity of the abnormal plasma cells in the bone marrow.

In recent years, newer types of drugs have been introduced, which appear to be more effective than previous regimes, with fewer side effects.

AL amyloidosis is a very varied disease.  Each patient’s disease is caused by their own, unique abnormal light chains.  Manifestations of illness differ considerably between patients.  The most suitable treatment for each individual depends on a number of factors including:

  • age
  • quantity of amyloid
  • organs affected- heart and kidney function are especially important for treatment decisions
  • other diseases and general health
  • personal preference

Treatment should be individually tailored after consultation with the NAC doctors.  When making treatment decisions about which drugs to recommend for patients with AL amyloidosis, the doctors aim to achieve a balance between:

  1. achieving a good response to treatment as rapidly as possible in order to halt the damage caused to organs by the amyloid deposits,

and,

  1. minimising adverse side effects of the drugs.

Many patients achieve a good response to treatment after just 3 cycles of treatment, and laboratory tests sometimes show improvement even earlier than this.

Detailed information on each of the drugs that may be used in treatment of AL amyloidosis is provided in patient Infoguides published by the charity Myeloma UK.  These are distributed to patients at the NAC, and are available here.

How does the treatment work?

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

  • Accumulation of new amyloid ceases
  • Existing amyloid deposits often regress (become smaller)
  • Organ function is often preserved and may also recover

Patients with AL amyloidosis are usually treated with a combination of different drugs, taken simultaneously.  Each drug acts by a different mechanism to block the activity of the abnormal plasma cells in the bone marrow.  This reduces the production of the light chains which form the amyloid deposits.  As a result, new amyloid deposits form more slowly or not at all and existing amsinkyloid deposits may regress.
It may be helpful to envisage amyloid deposits blocking up the organs as somewhat similar to the everyday situation of a blocked sink.  Water running from the tap at full blast represents the amyloidogenic free light chains pouring out of abnormal plasma cells.  The small sink outlet represents the body’s limited capacity to clear amyloid deposits away from the organs.  If the tap is turned on fully so that the rate of running water far exceeds the drainage rate, water builds up in the basin despite some drainage.  If the tap is turned down sufficiently, the water can drain away slowly.

If the rate of light chain production can be turned down sufficiently, amyloid stops accumulating in the tissues.  Amyloid deposits may even be cleared away faster than they are produced.

What are the side effects of chemotherapy for AL amyloidosis?

Intermediate and high dose chemotherapy are inevitably associated with at least some nausea, poor appetite and tiredness.  Temporary hair loss may occur.  Vomiting during the chemotherapy can now largely be prevented.  For further details of the side effects associated with each drug, see here

Will I lose my hair?

Hair loss may occur with some types of chemotherapy, but it is usually temporary, with hair growing back after the treatment is finished.  It may be advisable to look into getting a good wig before starting the chemotherapy so that you are ready if hair loss does occur.  See here for more information.

What are FLCs?

Normal antibody molecules consist of four protein chains – two heavy chains and two light chains, as shown below.

In AL amyloidosis, abnormal plasma cells produce a large quantity of one particular type of light chain.

The abnormal light chains are called ‘free’ light chains because they are not linked to heavy chains within antibodies, like normal light chains.  Instead, they exist freely in the bloodstream until they deposit in the organs as amyloid fibrils.

Under normal circumstances, light chain concentrations are very low in the bloodstream.  Sensitive blood tests can detect abnormal free light chain concentrations in about 95% of patients with AL amyloidosis.

FLC concentration is measured to assess plasma cell response to treatment.  Introduction of this test about 10 years ago was a landmark advance in the management of patients with AL amyloidosis.  FLCs can be detected and measured in over 95% of AL amyloidosis patients.  Blood concentration of FLCs is a sensitive measure of treatment effects on the abnormal plasma cells.

When treatment is successful, the earliest test which shows improvement is the FLC concentration.

FLC concentration drops before there is measurable improvement in the function of affected organs, before patients start to feel better and before there is any visible change in amyloid deposits seen on SAP scans.

What is the free light chain ratio?

When AL amyloidosis is first diagnosed, the free light chain ratio is checked:

  • If the abnormal plasma cells are secreting lambda chains, the lambda/kappa ratio is checked.
  • If the abnormal plasma cells are secreting kappa chains, the kappa/ lambda ratio is checked.

What does dFLC mean?

When monthly FLC tests are used to follow the patient’s response to chemotherapy, the most useful test is called the dFLC (difference between involved and uninvolved FLCs).  For this test, the concentration of the normal light chain type is subtracted from the concentration of the abnormal light chain type.

  • If a patient with AL amyloidosis has amyloid due to abnormal production of kappa chains, dFLC concentration is kappa chain concentration minus lambda chain concentration.
  • If a patient with AL amyloidosis has amyloid due to abnormal production of lambda chains, dFLC concentration is lambda chain concentration minus kappa chain concentration.

What are kappa and lambda chains?

There are two different types of light chain:

  • lambda (λ) chains
  • kappa (κ) chains

In AL amyloidosis, abnormal plasma cells produce a large quantity of one particular type of light chain – either lambda chains or kappa chains.  The blood concentration of the other free light chain usually remains at or close to normal values.  Under normal circumstances, concentrations of both kappa and lambda light chains are very low in the bloodstream.  Sensitive blood tests can detect abnormal free light chain concentrations in about 95% of patients with AL amyloidosis.

Lambda light chains are about three times more commonly associated with AL amyloidosis than kappa light chains.

How is the response to chemotherapy assessed?

Haematological responses to chemotherapy are defined as follows:

  • Complete response (CR): No FLCs detected (ie negative serum and urine immunofixation tests and normal FLC ratio)
  • Very good partial response (VGPR): dFLC concentration below 40 mg/dl
  • Partial response (PR): dFLC decrease more than 50% from previous value

The goal of therapy is to achieve either a complete response (CR) or a very good partial response (VGPR).  In the event of a partial response (PR), doctors often consider a change in treatment regime.

 

At the first visit to the NAC, patients are provided with several empty vials for blood samples and padded envelopes addressed to the NAC.  They can go to the GP or the local hospital clinic for the blood to be taken and then send the sample to the NAC in the post.  The FLC concentration is then measured in the NAC laboratories so the NAC doctors can assess the results and make appropriate treatment recommendations.

How should I expect to feel during chemotherapy?

For patients and their families, the most important measure of treatment success is how they actually feel.  But sometimes there is a good response to treatment according to blood tests (haematological response) before the patient actually starts to feel better.  Some patients feel worse while taking chemotherapy than they did beforehand.  This may be because of the side effects of the drugs, organ damage caused by the amyloidosis or a combination of the two.

Even if the patient does not yet feel better, a good haematological response is cause for optimism.  Successful treatment prolongs life.

Many patients start to actually feel the benefits of the drugs once they stop taking them.  There are often improvements in breathlessness and leg swelling as heart function and kidney function improve.

There are many measures that can be taken to combat drug side effects, so patients should not hesitate to discuss how they are feeling with their local doctors and nurses and with the National Amyloidosis Centre staff if necessary.

How soon after chemotherapy can I expect to feel better?

Once they stop taking chemotherapy some patients feel better right away, others feel the same and some may even feel worse.  Some patients start gradually feeling better over the weeks to months after stopping chemotherapy.  This is a very individual matter and patients and carers usually find it helpful to understand that, even if they feel unwell, it is quite possible that they may have had a good response to treatment.

The goal of chemotherapy is suppression of the abnormal plasma cells so that they no longer produce amyloid forming free light chains.  However chemotherapy does not directly affect the existing amyloid deposits in the organs.  Once new amyloid stops accumulating, the body may start to clear the existing amyloid deposits, but this is usually a slow process.  There is no way of predicting what will happen for each individual patient.  If complete response to chemotherapy is achieved, then amyloid deposits may remain stable in which case organ function will also stabilise.  In some patients, amyloid deposits regress (diminish in size) once the amyloid is no longer building up.  In either situation, it often takes several weeks to months till patients start to actually feel better.  It is important to be aware of this, so that expectations are realistic.

By the time that patients attend the 12 month visit to the NAC, they are often feeling well enough to resume normal day to day life to a greater or lesser extent.

Even if the patient does not yet feel better after stopping chemotherapy, a good response in terms of blood tests is cause for optimism.  Successful treatment prolongs life.

How long does the treatment go on for?

Chemotherapy treatment is given in a series of courses called cycles.  Each cycle lasts between 3 weeks and 5 weeks.  During each cycle, each drug is given on a regular schedule eg the first day of each week.  Sometimes there is a rest period without drugs at the end of each cycle.

All patients receiving chemotherapy for AL amyloidosis should come for a thorough assessment at the NAC after completing 3 cycles of chemotherapy.  This used to be called ‘the three month visit’.  However, it may take a few weeks after the first NAC appointment before local doctors start chemotherapy treatment.  Also, many chemotherapy regimens involve 5 week cycles.  So in fact this crucial appointment which must take place after 3 chemotherapy cycles is often scheduled for 4 months or longer after the first visit to the NAC.

Plans for continued treatment are based on the assessment at this visit.  The ongoing ALchemy study has shown that the earlier that we pick up on treatment responses, and adjust management accordingly, the better the patient’s outcome in the long term.

If there is a good response to chemotherapy, without significant side effects, the consultants may recommend more cycles of the same regime.  The most common regime is CVD (cyclophosphamide, velcade and dexamethasone).  Velcade based regimes may be continued for a maximum of 8 cycles.  In many patients we recommend around 5 cycles.

How long do I need to go on having FLC checks?

All patients need to continue sending in monthly blood samples to the NAC for evaluation of FLC concentration throughout chemotherapy and also after stopping chemotherapy, for the foreseeable future.

Even patients who have achieved a stable complete response and felt well for years must continue with the ongoing follow up of FLC levels as relapse could occur even after several years.  Sometimes, after patients have been stable for some years, the NAC consultants may recommend sending samples for FLC testing every two months rather than every month.

What happens if I relapse after completing chemotherapy?

For most patients there are other treatment options available.

In the case of relapsed disease, the doctors at the NAC often recommend chemotherapy drugs different from those that were used previously.  Such patients may then respond well to the new regime.

Even in patients who have advanced disease at the time of diagnosis, there is sometimes a good response once treatment is started.

Each patient’s situation is unique and should be discussed with the NAC doctors and nurses.

What new treatment is being developed for AL amyloidosis at the NAC?

The Wolfson Drug Discovery Unit directed by Professor Sir Mark Pepys is working on the development of treatments to clear away amyloid deposits. They have developed a drug called CPHPC, which clears almost all the SAP from the blood but leaves some SAP bound to the amyloid deposits. After CPHPC has been administered, it is safe to administer antibodies to SAP. In experimental models these antibodies act like guided missiles, homing in on the amyloid deposits where they trigger 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.

Living with AL amyloidosis

What is supportive care?

Supportive care is a medical term used to describe a number of measures that aim to maintain or improve organ function and maintain the patient’s quality of life while chemotherapy has time to take effect.  AL amyloidosis is a complex condition and several different organ systems are usually affected.  Therefore supportive care is best managed by a coordinated team of specialists familiar with the disease.  This team is called a multidisciplinary team, and usually includes a haematologist, a nephrologist (kidney specialist), a cardiologist and a specialist nurse.  Gastroenterologists, neurologists pulmonologists (lung specialists) and dermatologists may also be involved in patient care, depending on the organs affected.

Why is fluid balance so important?

Fluid overload is the most common serious toxicity experienced by patients with AL amyloidosis.  Many patients with AL amyloidosis have amyloid deposits in the kidneys and/or in the heart.  These two problems mean that the body is unable to cope well with excess fluids.  The combination of kidneys that are unable to sufficiently clear the fluid into the urine and a heart that is too stiff to pump efficiently may be problematic.  Even if just one of these organs is affected by amyloidosis, excess fluids can make matters worse.

Patients with fluid overload may develop swelling in the legs (oedema) and/or difficulty in breathing due to heart failure.

The ALchemy (AL amyloidosis chemotherapy) study is a large, on-going, “real world” study of chemotherapy in AL amyloidosis, started at the NAC in 2009 and funded by a grant from the charity Myeloma UK.  In this study, fluid overload has been clearly identified as the most important serious side effect experienced by patients with AL amyloidosis.  It is far more common than infection, neuropathy or any other severe side effects reported.  Fluid overload comprised nearly 40% of all the episodes of toxicity.  Nearly 1 in 3 of the patients who were hospitalised because of toxicity had fluid overload.

How can I avoid fluid balance problems?

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

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

Patients receiving chemotherapy for other conditions that are not AL amyloidosis are often told to “drink plenty” to avoid dehydration.  But in AL amyloidosis, this well-meaning advice is inappropriate and can prove dangerous.

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.

How can I cope with neuropathy?

Peripheral neuropathy:

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.

Autonomic neuropathy:

If there is orthostatic hypotension (decrease in blood pressure and faintness on standing up from sitting or lying positions), thigh high 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.

Some tips from a patient with neuropathy:

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 peripheral 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.

How can I cope with weight loss?

Both AL amyloidosis itself and treatment side effects may cause weight loss.  Sometimes patients find it hard to eat and drink enough because of feeling generally unwell, or because a sore mouth or altered taste sensation make swallowing difficult.  You may find it easier to eat several small meals each day, if your appetite for larger meals is affected.  Going for a short walks may help you to feel more appetite for food.  If your mouth is uncomfortable, sucking on ice or ice lollies may be helpful.  If you are too tired to cook, it may be helpful to ask family members and friends to help with food preparation.  Consulting a dietician can be helpful.  Under some circumstances special high calorie drinks may be recommended.  It is important to check with your doctor or nurse whether these are safe for you as they are sometimes high in protein content, which may not be recommended if you have problems with kidney function.

How can I cope with diarrhoea?

Patients should tell the medical staff about any diarrhoea they experience.  Medications such as opioids (codeine and loperamide) may help by reducing gut motility.  Octreotride may be prescribed if these do not help.  If there is bacterial overgrowth in the gut, antimicrobial therapy can be helpful.

How can I cope with fatigue?

Patients with AL amyloidosis may experience extreme tiredness, either due to the amyloidosis itself, or as a side effect of some chemotherapy drugs.

Tiredness can be exacerbated by a number of problems, including pain, anaemia, anxiety, depression and poor diet.

Patients should discuss these problems with the doctors and nurses treating them.  Pain can be treated with painkiller medications and sometimes other, non-drug measures; counselling may help with anxiety and depression and referral to a dietician may be helpful.

Is it safe to undergo surgery and anaesthesia?

If patients with amyloidosis become ill or require any treatment for a different condition or surgery it is essential to tell the treating doctors about the amyloidosis so that, if necessary, the NAC doctors can be informed, in order to maintain co-ordinated care.  It is generally advisable for patients with amyloidosis to avoid undergoing surgery, anaesthesia and other invasive procedures.  If such procedures are necessary, patients should request that the surgeons, anaesthetists and other doctors involved contact the NAC doctors beforehand, to discuss any special considerations involved.  For example, it is very important that great care is taken to monitor and maintain blood pressure and fluid balance throughout such procedures.  Care should also be taken because of the tendency of tissues with amyloid in them to bleed and to heal poorly.  If there is macroglossia, anaesthetists may need to take particular care with intubation.

Lifestyle advice for patients with AL amyloidosis

What dietary advice is there?

A balanced, healthy diet including a wide range of foods is usually advisable for most patients with AL amyloidosis.  Some foods should be avoided temporarily if chemotherapy has caused a low white cell count (neutropenia).  Grapefruit should be avoided by people taking chemotherapy drugs as it may interfere with the drugs’ efficacy.  If amyloidosis has affected kidney function patients may be told to limit their protein intake.  Patients experiencing gastrointestinal disturbances such as diarrhoea and/or constipation may also benefit from altered diet.  It can be very helpful to meet with a dietician for precise and personalised dietary advice.

Are vitamins and dietary supplements helpful?

There is no evidence that any vitamins or dietary supplements are beneficial.  You should inform your doctor if you are taking or considering taking any alternative medicines or supplements as these may actually be harmful to patients with AL amyloidosis, or may affect the response to medications.  For example, people taking velcade (bortezomib) should not consume green tea, EGCG (a component of green tea), St John’s Wort or vitamin C as these may reduce the drug’s efficacy.  Similarly, curcumin, the major component of turmeric, may reduce the efficacy of cyclophosphamide so both curcumin and turmeric should be avoided by people taking this drug.

What is a neutropenic diet?

Neutrophils are a class of white blood cells required to fight infection effectively.  Chemotherapy may cause a temporary drop in the neutrophil concentration in the blood.  A low neutrophil concentration is called neutropenia.  People with neutropenia have reduced defence against many infections.  When the absolute neutrophil concentration falls below 500 cells/mm3 doctors may recommend a ‘neutropenic diet.’  The neutropenic diet aims to cut out any exposure to harmful bacteria from food or drink.

General features of the neutropenic diet are listed below, but you should always ask your own doctors and nurses for more detailed personalised instructions on constituents of a neutropenic diet and the recommended duration.

General principles of a neutropenic diet include:

  • frequent handwashing, especially before handling food
  • wash all surfaces, cutting boards and cutting utensils thoroughly
  • Keep hot food hot and cold food cold.

Some foods to avoid and foods that are safe to eat are listed below:

ddafaff

These instructions are not comprehensive and you should always ask your health care providers for personalised advice and recommendations.

Can I exercise if I have AL amyloidosis?

It is believed that exercise is beneficial for the general well-being of patients with amyloidosis.  If there are amyloid deposits in the heart then exercise should usually be limited and light.  It is important to be careful, and to exercise within limits, to avoid exhaustion.  All patients should consult their own doctors for advice about the intensity of exercise that is appropriate for them.  If there are symptoms on exercise, do not push yourself.

Should I try alternative remedies?

There is no evidence that any alternative remedies, vitamins or dietary supplements are beneficial.  You should inform your doctor if you are taking or considering taking any alternative medicines or supplements as these may actually be harmful to patients with AL amyloidosis, or may affect the response to medications.  For example, people taking velcade (bortezomib) should not consume green tea, EGCG (a component of green tea), St John’s Wort or vitamin C as these may reduce the drug’s efficacy.  Similarly, curcumin, the major component of turmeric, may reduce the efficacy of cyclophosphamide so both curcumin and turmeric should be avoided by people taking this drug.

You should never allow alternative remedies and therapies to lead to delay in seeking medical advice and taking the treatments for amyloidosis that doctors recommend and that have been proved to be effective.

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. ATTR amyloidosis can be either hereditary or acquired (non-hereditary).

What are the different 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. 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.

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

How common is hereditary ATTR amyloidosis?

Hereditary ATTR amyloidosis is the most commonly recognised form of hereditary systemic amyloidosis. (‘Systemic’ means that several parts of the body are affected.)  In overall terms it is nevertheless a very rare disease.

We do not know exactly how many people around the world have hereditary ATTR amyloidosis. More than 150 amyloid-forming variants (mutations) of TTR have been observed and different mutations may cause different disease manifestations. The commonest type, associated with a particular mutation of the TTR gene (called Val30Met or V30M), is believed to affect about 10,000 people worldwide.

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.

 

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 was first described in 1952 in a number of families in Portugal.

Since then it 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. 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. It may also be common, but under-diagnosed in several other regions including Spain, France, Brazil, Argentina, Cyprus and Bulgaria.

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 hereditary 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. Most patients with the Val30Met associated hereditary ATTR amyloidosis first experience symptoms in their 30s.

What are the symptoms of hereditary ATTR amyloidosis?

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
    • 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. People 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. 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.

Do different mutations cause different disease patterns?

More than 100 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 in hereditary ATTR amyloidosis. 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.

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.

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.

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 hereditary ATTR amyloidosis Thr60Ala, less than 40% had a definite family history of amyloidosis.

How is hereditary ATTR amyloidosis diagnosed?

Doctors may suspect hereditary 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:

  1. Tissue biopsy
  2. Genetic testing
  3. Imaging studies

All patients in the UK with suspected or diagnosed ATTR amyloidosis should be referred to the NAC.

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 tissue biopsy involve?

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.

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.

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.

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/or heart disease and ATTR amyloid is detected in tissue biopsy.

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 predominantly in the heart, and only occasionally affects the nerves.

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

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.

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

What is wild-type ATTR amyloidosis?

Wild-type ATTR (ATTRwt) amyloidosis (formerly known as senile systemic amyloidosis) is a slowly progressive disease affecting elderly people, mostly men. The symptoms usually start after age 65. There is no mutation in the TTR gene so the condition is not hereditary (it does not run in families).  Normal, 'wild-type' TTR protein misfolds to form the amyloid deposits, with obvious major clinical effect in the heart. There may also be carpal tunnel syndrome (pain and tingling in the hands and wrists), sometimes occurring several years before symptoms of heart disease, and occasionally peripheral neuropathy.

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?

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?

We do not know how common this condition really is.

It has long been known that wild-type TTR commonly forms microscopic amyloid deposits in elderly people. These types of amyloid deposits are found at autopsy in 1 in 4 people over age 80. It was believed until recently that they usually caused no symptoms and clinical disease caused by this type of amyloid was very rarely diagnosed. Some patients with small wild type ATTR amyloidosis deposits in the heart and minimal symptoms may not require any treatment. No-one knows just how common symptomatic wild type ATTR amyloidosis really is but discovery of new imaging techniques, now used extensively at the NAC, has shown it to be much more common than previously recognised. It is believed to be underdiagnosed at present. This diagnosis may become more common in future as the population ages and diagnostic methods continue to improve.

 

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 wild-type ATTR amyloidosis may be far more common than was previously thought. Cardiologists are gradually becoming more aware that wild-type amyloidosis may cause otherwise unexplained heart failure and are referring these patients more frequently to the NAC.

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 patients seen at the NAC.

In 2016 it accounted for nearly 1 in 5 (18%) of NAC patients diagnosed with amyloidosis - a 40 fold increase!

 

Who gets wild-type ATTR amyloidosis?

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 wild-type ATTR amyloidosis at the National Amyloidosis Centre, nearly 90% were men.

When do wild-type ATTR amyloidosis symptoms appear?

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

What are the symptoms of wild-type ATTR amyloidosis?

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

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

Almost 50% of patients with 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.

How is wild-type ATTR amyloidosis diagnosed?

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:

  1. Tissue biopsy
  2. Genetic testing
  3. Imaging studies

All patients in the UK with suspected or diagnosed ATTR amyloidosis should be referred to the NAC.

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, 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.

What does tissue biopsy involve?

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.

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?

If ATTR amyloid fibrils are detected in tissue biopsy, then genetic testing can distinguish between hereditary and wild type ATTR 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 (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. 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 FAP - reducing the supply of amyloid precursor proteins

Liver transplantation may be helpful for some patients with hereditary, variant ATTR amyloidosis, mainly for patients with familial amyloid polyneuropathy (FAP) 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 FAP. 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 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.

Liver transplantation is not a treatment for senile systemic amyloidosis (wild type ATTR amyloidosis) or for familial amyloid cardiomyopathy (FAC), 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, '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 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 encountered in FAP, 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 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;  approval in the EU of tafamidis for cardiomyopathy is expected shortly. It will need to be evaluated by NICE before it can become available within the NHS.

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 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.

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 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. These new treatments are currently being appraised for use within the NHS by NICE.

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 and patients with wild-type ATTR amyloidosis were not included in the drug trials.

 

AFib Amyloidosis

Where can I find information about AFib Amyloidosis?

AFib amyloidosis is a rare, hereditary type of amyloidosis. Information about AFib amyloidosis is available here.

Localised Amyloidosis

Where can I find information about Localised Amyloidosis?

Information about localised amyloidosis is available here.

ALECT2 Amyloidosis

Where can I find information about ALECT2 Amyloidosis?

Information about ALECT amyloidosis is available here.

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