Wild Type ATTR (ATTRwt)

Amyloidosis is the name given to a group of rare disorders in which amyloid deposits, consisting of misfolded proteins which are relatively insoluble, deposit and accumulate in tissues and organs of the body. As these deposits progressively build up they interfere with the working of the organs. Without treatment this will eventually lead to organ failure.

ATTR amyloidosis comprises two groups of multisystem diseases:

  • Non-hereditary wild type (ATTRwt)
  • Hereditary diseases (ATTRv)

This section concentrates on wild type ATTR (ATTRwt).

What is TTR?

TTR is a protein called transthyretin. It is primarily made in the liver and secreted into the blood, transporting thyroxin and vitamin A (retinol). Hence the name Trans-thy-retin. The normal or “wild type” TTR is weakly prone to misfolding and forming amyloid.

What does ATTRwt stand for?

Different types of amyloidosis are named according to the precursor protein which forms the amyloid fibrils. The letter A is always used to denote amyloidosis, followed by the letters identifying the precursor protein. The A in ATTR stands for Amyloidosis. TTR stands for Transthyretin, the precursor protein and “wt” stands for Wild-type ATTRwt which was once known as SCA (senile cardiac amyloidosis) or SSA (senile systemic amyloidosis)

What is ATTRwt?

  • ATTRwt is one of the amyloid diseases in which the amyloid deposits are made from the protein transthyretin.
  • In ATTRwt the amyloid protein typically affects the heart in males usually over the age of 60.
  • It is a systemic disease meaning that the amyloid may be found in different organs and tissues of the body.
  • The heart is the dominant organ affected.
  • About 50% of patents will have experienced carpel tunnel syndrome, often many years before a  diagnosis of ATTRwt amyloidosis is made.
  • It is a slow progressive, incurable disorder.
  • In general, the heart deteriorates at a slower rate in ATTRwt than in AL cardiac amyloidosis.

How common is ATTRwt?

This is not known, but surveys show that this disease is vastly under diagnosed.

  • ATTRwt often goes unrecognized and undiagnosed because of lack of awareness and the fact that the symptoms mimic those seen in other diseases
  • As the population ages and awareness increases, ATTRwt will become more prevalent
  • Early diagnosis remains very important.

What causes ATTRwt?

  • Wild type transthyretin (TTR), a normal protein made by the liver, is found in healthy people and acts as a transporter for the thyroid hormone and vitamin A (retinol) within the blood stream. Hence the name “trans-thy-retin”
  • In people with ATTRwt this wild type TTR protein (previously known as pre-albumin), misfolds and deposits as amyloid fibrils into the organs over a period of time
  • No one knows why some people develop ATTRwt and others do not.

Organ Involvement

  • The amyloid deposits most commonly affect the heart. This causes the heart wall to slowly stiffen and therefore not function properly (restrictive cardiomyopathy), leading to heart failure and heart rhythm problems.
  • Heart involvement in patients with ATTRwt is often less severe at diagnosis than in AL cardiac patients and it usually progresses at a slower pace.
  • Small deposits can occur in the soft tissue of the wrist causing the painful condition known as carpel tunnel syndrome. This condition is often experienced many years before the diagnosis of ATTRwt is made.
  • Amyloid deposits are sometimes found in the lumbar spine and various ligaments and tendons and in the bladder

Click to the section organ involvement for more information on the heart.

Organ involvement in Amyloidosis

Symptoms

Symptoms vary from patient to patient and can often be vague especially in early disease and mimic other diseases.

  • Fatigue
  • Shortness of breath on exertion.
  • Intolerance to exercise
  • Oedema, swelling of feet and legs.
  • Palpitations
  • Slow heart rate leading to dizziness or blackouts when moving from sitting to standing or exercising
  • Chest pain (angina)
  • Disrupted sleep
  • Weight loss
  • Carpel tunnel syndrome (numbness, tingling in the fingers and hands)
  • Nerve pain in a very small number of patients related to Lumbar spinal stenosis.
  • Blood in the urine

Diagnosing Wild type ATTR (ATTRwt)

A cardiologist may suspect amyloidosis when symptoms of heart failure are being investigated.

  • A diagnosis may still be made through a tissue or organ biopsy
  • The biopsy is stained with the dye Congo red in the laboratory.
  • If amyloid is present, the biopsy will appear red under normal light and green (apple-green birefringence) under special polarized light.
  • Now a days a less intrusive method of diagnosis s often used.   A DPD or PYP bone scan can diagnose heart involvement in ATTR amyloidosis, enabling the diagnosis to be reliably made without the need for a tissue biopsy.
  • This procedure is not reliable in patients with a monoclonal gammopathy.

Read

2nd procedure in the laboratory

  • If a biopsy has been taken further testing may be done to classify the type of amyloidosis by identifying the protein composition of the amyloid fibrils.
  • It is imperative to identify the “type” as treatment is different for each type of amyloidosis.
  • This is particularly important as it is easy for ATTRwt amyloidosis to be mistaken for AL amyloidosis. These two types of amyloidosis have very different outcomes and have very different therapies.

Over the decade new diagnostic tools have improved the ability to diagnose cardiac amyloidosis.
These advances, which include echocardiography with strain imaging, cardiac magnetic resonance imaging (MRI) and bone scintigraphy (DPD or PYP scans) are giving cardiologists the option to diagnose ATTRwt amyloidosis earlier, with more confidence, and in some cases without an organ biopsy.

The following tests may be performed to help with diagnosis, assess organ involvement and damage and monitor organ function.

  • Genetic testing to exclude the hereditary type of ATTR
  • Tissue biopsy
  • ECG
  • Echocardiogram
  • MRI of the heart
  • Cardiac biomarkers (troponin and BNP or NT-ProBNP)
  • DPD or PYP scan. (Traditionally used for imaging bones, these scans involve special molecules which are injected into the body and become trapped in the heart when it is full of transthyretin amyloidosis thus helping with the diagnosis and identification of this type of amyloid.)

Once the diagnosis is made the primary care specialist will usually be a cardiologist.

Treatment

The goals of treatment for ATTRwt are:

  • To try and reduce the production of the amyloid forming TTR protein or to interfere with the misfolding process and therefore stop the amyloid depositing into the organs and tissues.
  • To support and preserve the affected organs.
  • To improve the patient’s quality of life.

Chemotherapy has no role in ATTRwt.

Symptomatic and supportive treatments remain the mainstay of treatment.

Treatments are focused on controlling the symptoms of heart failure and will be recommended and monitored for the needs of the individual patient by the cardiologist and other specialists on the amyloidosis treatment team.

Some of these treatments may be:

  • Fluid balance. Avoiding excess fluid. (keeping a diary on daily weight)
  • Diuretics (water tablets) to get rid of excess fluid and thus reduce symptoms of breathlessness and swelling of the ankles and legs (oedema)
  • Salt restriction
  • Anticoagulation medication (thinning the blood)
  • A pacemaker may be suggested if there is a slow or irregular heart beat
  • Heart transplantation is rarely recommended except in highly selected younger patients
  • Reviewing diet. A dietician may be of help.
  • Exercise within limits.

Patients with cardiac amyloidosis typically exhibit heart failure with preserved ejection fraction (otherwise known as diastolic heart failure), This is not the same as more common types of heart failure seen in the general community. Some treatments used in other types of heart failure may lower the already low blood pressure and should only be used with caution.

  • Calcium channel blockers
  • Beta blockers
  • Digoxin
  • ACE inhibitors
  • Angiotensin inhibitors

If this section causes concern DO NOT stop taking the drugs mentioned above without consulting the doctor.

Green tea extract (epigallocatechin-3-gallate, EGCG)

  • Laboratory studies have shown that a component in green tea, called EGCG, can inhibit amyloid fibril formation.
  • EGCG treatment, given in capsule form, is being examined in clinical trials to test whether it can slow down the progression of ATTRwt
  • The treatment may have side effects, particularly with liver damage, and should only be taken under medical supervision
  • Further reading

Diflunisal

  • Diflunisal is a non-steroidal anti-inflammatory drug (NSAID) that has been shown to bind to the TTR protein in the blood, stabilize it so it cannot misfold, and thereby prevent the formation of the amyloid protein. This delays the progression of neurological impairment in hereditary ATTR amyloidosis and may act to delay the progression of heart failure in ATTRwt although this latter point is not yet proven.
  • Diflunisal does have a number of side effects including stomach ulceration, kidney impairment, fluid retention and increased bleeding risk.

Tafamidis

  • Tafamidis is a TTR stabiliser which has recently been shown in a clinical trial to reduce mortality and cardiovascular-related hospitalizations in ATTRv and ATTRwt. It is not yet funded but is becoming available on clinical trial through amyloid specialists in Australia.

Genetic Based Therapies

  • Therapies using small interfering RNA or antisesene oligonucleotides (biological processes in which RNA molecules inhibit gene expression and translation) are being trialed to silence the TTR gene in the liver and thus reduce the production of TTR.