What is amyloidosis?
Amyloidosis is a rare disease that occurs when an abnormal protein – amyloid – builds up in your tissues and/or organs. There are many forms of amyloidosis, some of which are acquired, including: AL (immunoglobulin light chain) amyloidosis; Amyloid A (AA) amyloidosis; dialysis-related amyloidosis (DRA); wild-type ATTR (ATTRwt) amyloidosis and organ-specific amyloidosis. Unlike these acquired forms of the disease, hATTR amyloidosis is hereditary – it is passed down from parents to their children.
What is hATTR amyloidosis?
Hereditary (hATTR) amyloidosis is a rare, progressive, inherited disease caused by a change (or mutation) in a gene that affects the function of a protein in the blood called transthyretin (TTR). hATTR amyloidosis is estimated to affect 50,000 people worldwide with more than 120 different TTR gene mutations identified.
TTR is a natural protein made mostly in the liver. Its role is to transport the hormone thyroxine and retinol (Vitamin A) around the body. Changes in the TTR gene can cause the TTR protein to mis-fold and take on an abnormal shape, known as amyloid fibrils. These amyloid fibrils build up and form deposits in various tissues and organs in the body most commonly in the heart, kidneys, and nervous system.
What causes hATTR amyloidosis?
hATTR amyloidosis is passed down through family members and is an autosomal dominant condition, meaning a person only needs to inherit one copy of the affected gene from one parent in order to develop the condition. If one parent has hATTR amyloidosis, there is a 50 per cent chance their child will inherit the mutation.
Inheriting a mutated copy of the TTR gene does not always lead to disease or symptoms. However, even without symptoms, a parent with an altered copy of the gene is a carrier and still has a 50 per cent chance of passing on the mutation.
Although hATTR amyloidosis is a hereditary condition, some families may be unaware of a history of the condition in their family.
What are the symptoms of hATTR amyloidosis?
hATTR amyloidosis can manifest itself in many ways and with a broad range of symptoms, depending on where the amyloid protein is building up in the body. Most frequently, the protein deposits most occur in the peripheral nervous system, causing polyneuropathy, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands, and feet.
Common symptoms include:
- Cardiomyopathy– Shortness of breath, palpitations and abnormal heart rhythm, ankle swelling (edema), fainting, fatigue, chest pain (angina)
- Peripheral neuropathy – Tingling and numbness in legs and feet, difficulty walking, limb weakness and pain
- Autonomic neuropathy – Light-headedness when standing (orthostatic hypotension), bladder problems, bowel problems, sexual dysfunction
- Gastrointestinal – Decreased appetite, diarrhea, nausea, stomach pain, weight loss
How is hATTR amyloidosis diagnosed?
Misdiagnosis is common with hATTR amyloidosis because the symptoms can resemble those of other conditions. This often results in patients having to see five or more physicians across multiple specialties before receiving an accurate diagnosis of hATTR amyloidosis.
As a first step, it’s important for a physician to conduct a thorough physical exam and get a detailed patient medical history in order to help determine which form of the disease a person has. The physician may also conduct the following tests and procedures:
- Tests are done to determine the effect of the amyloid deposits on the heart, nerves and other organs. These tests include blood, urine ,nerve and muscle tests, echocardiogram (a type of ultrasound test for the heart), magnetic resonance imaging (MRI – a scan that uses a large magnet, radio waves and a computer to create detailed images of the organs and tissues in the body).
- Scintigraphy (bone scans) can be used to non-invasively diagnose hATTR amyloidosis with cardiomyopathy.
- A biopsy to determine the presence of TTR amyloid protein. The tissue sample for the biopsy may be taken from a person’s belly fat, bone marrow, or sometimes the mouth, rectum, or other organs.
- Immunohistochemistry (a lab test that uses antibodies attached to an enzyme or fluorescent dye to test for certain antigens within a tissue sample) and mass spectrometry (a test that measures the masses within a tissue sample) to differentiate between ATTR (wild-type and hereditary) and AL amyloidosis.
- Genetic testing is a crucial component of diagnosing hATTR amyloidosis. In a patient with family history, or confirmed TTR amyloid, genetic testing differentiates between hATTR amyloidosis and wild-type ATTR (ATTRwt) amyloidosis. If diagnosed with hATTR amyloidosis, the physician may recommend that other members of the patient’s family consider getting genetic testing.
People living with hATTR amyloidosis require an early and accurate diagnosis due to the rapid, natural progression of the disease. It’s important to talk to your healthcare provider to learn about treatment options for hATTR amyloidosis.
How is hATTR amyloidosis treated?
Treatment plans include:
Supportive treatment – treating your symptoms. Due to the progressive nature of hATTR amyloidosis, managing symptoms is an ongoing process. Doctors can prescribe medications to help with the symptoms to lessen the pain and the symptom itself. Examples that a physician may recommend include:
- Diuretic medicine to remove extra water from the body
- Thickeners to add to fluids to prevent choking if a person has trouble swallowing
- Compression stockings to relieve swelling in the legs or feet
- Dietary changes, especially for people who have gastrointestinal amyloidosis
Source treatment – slowing down, or stopping, the overproduction of amyloid at the source of the disease.
- Until now, a liver transplant has been the only option for treatment of hATTR amyloidosis. TTR is mostly made by the liver and a transplant will reduce the production of the abnormal TTR protein. The outcome of liver transplantation is largely dependent on the mutation that exists in the patient.
- More recently, several drugs have been developed for the treatment of the underlying cause of hATTR, some of which are still investigational and some of which have been approved by Health Canada. Inotersen (Tegsedi™) was approved following a priority review by Health Canada in October 2018 for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hATTR amyloidosis. Inotersen was also approved in Europe in July 2018 and in the US in October 2018. Inotersen works by ‘silencing’ gene expression and targeting transthyretin (TTR).
Other drugs take different therapeutic approaches to treating hATTR and are aimed at:
Stabilizing the TTR protein – The approach of TTR stabilizers is to stop the TTR protein from forming amyloid deposits.
- Diflunisal – Approved as a non-steroidal, anti-inflammatory drug (NSAID) that has shown to bind to the TTR protein in the blood and may thereby prevent the formation of amyloid. Studies are currently underway to assess the effect of diflunisal on the progression of neuropathy and cardiomyopathy in patients with hATTR amyloidosis.
- Tafamidis (Vyndaqel®) – Completed clinical trials for hATTR neuropathy and cardiomyopathy; currently approved in 41 countries (not including Canada or the US) for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with stage 1 symptomatic polyneuropathy.
Stopping the production of TTR proteins – The approach of stopping the production of TTR proteins is to prevent TTR protein production by blocking or ‘silencing’ the TTR gene.
- Inotersen (Tegsedi™) – Approved following priority review by Health Canada in October 2018 for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hATTR amyloidosis. Inotersen was also approved in Europe in July 2018 and in the US in October 2018.
- Patisiran (Onpattro™) – Approved following priority review by Health Canada in July 2019 for the treatment of polyneuropathy in adult patients with hereditary transthyretin-mediated (hATTR) amyloidosis. Patisiran was also approved in the US and Europe in August 2018 for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy.
Removing the amyloid deposits – There are currently no approved drugs aimed at removing amyloid deposits in hATTR, however there are drugs currently being tested in clinical trials.
Disclaimer: The information provided on this website is not intended to replace the medical advice of your doctor or healthcare provider. Please consult your healthcare provider for advice about your individual medical condition.
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