Transthyretin-mediated (ATTR) amyloidosis

Take-home messages:

  • Understand the pathogenesis of ATTR amyloidosis
  • Be aware of the symptoms of ATTR-PN and ATTR-CM
  • Know when to suspect a diagnosis of ATTR amyloidosis and how this can be confirmed
  • Know what options are available for treatment and how they work

Amyloidosis describes a group of rare protein misfolding and deposition disorders; misfolded proteins aggregate into insoluble fibres, known as amyloid fibrils, and accumulate in organs, where they lead to progressive organ damage. The resulting disease is described as either systemic, when the protein is deposited at sites distant from where it is produced, or localised, when the protein is deposited at the same site as where it is produced. 36 amyloidogenic proteins have been identified to date, with at least 17 of these responsible for systemic amyloidosis.1

In ATTR amyloidosis, the amyloidogenic protein is transthyretin (TTR). TTR is produced predominantly by the liver and circulates as a tetramer, made up of four monomers. In ATTR amyloidosis, instability of the TTR tetramer results in the misfolding and aggregation of TTR monomers in amyloid fibrils. It can be hereditary, caused by mutations that destabilise the tetramer, or acquired. It is unclear why wild-type TTR becomes unstable in acquired cases, although it is thought to be related to ageing.2

Hereditary ATTR amyloidosis is very rare in most parts of the world but is more common in specific parts of Portugal, Sweden and Japan. It may also be common (but underdiagnosed) in certain regions of Spain, France, Brazil, Argentina, Cyprus, Bulgaria and Ireland. The most common TTR mutation in patients with hereditary ATTR amyloidosis worldwide is Val30Met but in the UK most cases are caused by Thr60Ala, often seen in people with Irish ancestry, and Val122Ile, often found in people with African ancestry.3

Wild-type TTR deposits are found at autopsy in one-quarter of people aged >80 years but, until recently, were not thought to cause symptoms and clinical disease was rarely diagnosed. The advent of new imaging techniques has revealed wild-type ATTR amyloidosis to be more common than previously thought and it is currently believed to be underdiagnosed.3

Patients with hereditary ATTR amyloidosis may begin to experience symptoms from 30 years or older, whereas the symptoms of wild-type ATTR amyloidosis usually appear later, around the age of 65 years.4 Symptoms mainly affect the nerves and/or the heart,4 with patients traditionally diagnosed with either ATTR with polyneuropathy (ATTR PN) or ATTR with cardiomyopathy (ATTR CM), depending on their predominant clinical manifestation.5 Some genotypes are associated with specific phenotypes, for instance, the Val30Met mutation causes largely neuropathic disease whereas wild-type ATTR amyloidosis is associated most often with ATTR-CM, but many patients in clinical practice present with overlapping phenotypes.5,6

Polyneuropathy symptoms include:

  • peripheral neuropathy3 - altered sensation in the limbs, such as numbness and pain, progressing to weakness. Usually with greater involvement of lower versus upper limbs7
  • autonomic neuropathy3 - bowel disturbance, sexual dysfunction, gastrointestinal problems (bloating, nausea, vomiting, diarrhoea or constipation (or both alternating)), urinary symptoms, hyperhidrosis, variation in blood pressure and heart rate8

Cardiomyopathy symptoms include:3

  • shortness of breath
  • palpitations and abnormal heart rhythms
  • oedema
  • syncope or fainting, which may occur after exertion, or after eating
  • disrupted sleep
  • angina

Carpal tunnel syndrome often appears 3-5 years before the onset of heart disease symptoms and is present in almost 50% of patients with wild-type ATTR amyloidosis. Amyloid deposits in the eyes and kidneys can also cause symptoms and dysfunction in the associated organs.3

ATTR amyloidosis may be suspected based on symptoms, physical examination, and family history, and can be confirmed through other methods such as TTR gene analysis, biopsy and imaging.3,6

TTR gene analysis:

  • TTR is composed of four exons and found in chromosome 186
  • >130 mutations known, most of which are amyloidogenic6
  • A TTR variant alone does not confirm diagnosis of hereditary ATTR amyloidosis, due to incomplete penetrance, but is useful to support or exclude and can provide information about the likely clinical course of disease3,6

Biopsy:

  • Congo red staining of tissue biopsy can detect the presence of amyloid fibrils and immunohistochemistry and proteomics can identify TTR fibrils and distinguish between variant and wild type3,6
  • Labial salivary gland biopsy, skin biopsy and abdominal fat biopsy are preferred to the more invasive nerve biopsy and cardiac biopsy6
  • Inadequate tissue samples can affect the sensitivity of biopsy6

Imaging:

  • DPD scans (measuring the uptake of the myocardial radiotracer 99mtechnetium (Tc)-labelled 3,3-DPD in bone scintigraphy) can be highly sensitive for detecting ATTR amyloid deposits in the heart and may remove the need for endomyocardial biopsy3,6
  • Heart scans such as echocardiogram, electrocardiogram and cardiac MRI may also be useful for detecting ATTR-CM4

Diagnosis of ATTR amyloidosis in the early stages of disease is associated with improved patient outcomes, however the diversity and non-specificity of the clinical manifestations make this hard to achieve.5 In non-endemic areas, up to three-quarters of hereditary cases occur with no family history of the disease and clinical presentation may be similar to that of other diseases; common misdiagnoses of hereditary ATTR amyloidosis include chronic inflammatory demyelinating polyradiculoneuropathy, idiopathic axonal polyneuropathy, lumbar spinal stenosis and, more rarely, diabetic neuropathy.6

Experts have advised the need for high suspicion indexes in the face of non-specific presenting symptoms of ATTR-PN and ATTR-CM.6,9

Liver transplantation was introduced in the 1990s as a treatment for early-stage hereditary ATTR amyloidosis, removing the source of variant TTR and replacing it with the wild-type TTR of the donor. However, this is associated with a variety of risks and outcomes.5

Targeted drug therapies are now available for ATTR amyloidosis. These therapies aim to either reduce the production of TTR or stabilise its tetrameric form to ultimately reduce the amount of circulating amyloidogenic protein.5

Tafamidis (Vyndaqel®): targets the rate-limiting step in ATTR amyloidosis pathogenesis - the dissociation of the TTR tetramer - by binding to two thyroxine binding sites on the tetramer.10-14

  • Tafamidis meglumine 20 mg once daily is approved in the UK and the EU for the treatment of adults with ATTR amyloidosis with stage 1 symptomatic polyneuropathy10,12,13
  • Tafamidis 61 mg once daily is approved for the treatment of adults with ATTR-CM11

Patisiran (Onpattro®): is a small interfering RNA designed to cause the catalytic degradation of wild-type and variant TTR mRNA in the liver.15-17

  • Patisiran is indicated in the UK and the EU for the treatment of hereditary ATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy15-17

Inotersen (Tegsedi®): is an antisense oligonucleotide that selectively binds to TTR mRNA to induce the degradation of variant and wild-type TTR mRNA.18,19

  • Inotersen is indicated in GB and the EU for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary ATTR amyloidosis18,19

Symptomatic relief is also of utmost importance as polyneuropathy and cardiomyopathy can severely impact patient quality of life.5 For patients with ATTR-PN this may include management of peripheral neuropathy through physiotherapy, prevention and cure of trophic disorders and the help of an orthotist, and control of autonomic dysfunction such as digestive disorders, orthostatic hypotension and urinary dysfunction.20 Prophylactic pacemaker implantation may be useful for patients with polyneuropathy and conduction disorders, while loop diuretics can be used to reduce filling pressure in patients with cardiac involvement. Some drugs commonly used for heart failure management may exacerbate amyloidosis symptoms (for instance vasodilators and digoxin, the distribution of which may be affected by binding to amyloid fibrils) and so caution should be exercised.5

Summary

ATTR amyloidosis is a rare and debilitating systemic amyloidosis characterised by the deposition of misfolded TTR fibrils in the peripheral nerves (ATTR-PN) and/or the heart (ATTR-CM).1 Symptoms of hereditary ATTR amyloidosis can occur from adulthood and many patients present with symptoms of polyneuropathy and cardiomyopathy; symptoms of wild-type ATTR amyloidosis usually begin later in life and are usually limited to cardiac manifestations.4

Targeted treatments that aim to reduce the levels of circulating amyloidogenic TTR are available, and are associated with better outcomes when used early in the course of disease.5 Recognition of the symptoms and confirmation with genetic analysis, biopsy and imaging techniques is therefore important for optimal patient management.6,9

Test your knowledge

1. Which of these is an approved treatment option for adult patients with ATTR-CM?

loading

2. True or false? All known TTR variants are amyloidogenic

loading

3. Which of these statements is correct?

loading

Top image: Design Cells
The content and interpretation of these conference highlights are the views and comments of the speakers/ authors.

References

  1. Muchtar E, Dispenzieri A et al. Systemic amyloidosis from A (AA) to T (ATTR): a review. J Intern Med 2021;289(3):268-292
  2. Ruberg F L, Grogan M et al. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 2019;73(22):2872-2891
  3. Amyloidosis.org. Amyloidosis patient information site. Available at: amyloidosis.org.uk. Accessed July 2022
  4. NHS. Amyloidosis. Available at: nhs.uk. Accessed July 2022
  5. Hawkins P N, Ando Y et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med 2015;47(8):625-638
  6. Adams D, Ando Y et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol 2021;268(6):2109-2122
  7. Arnold R, Issar T et al. Neurological complications in chronic kidney disease. JRSM Cardiovasc Dis 2016;5:2048004016677687
  8. National Institute of Diabetes and Kidney Diseases. Autonomic neuropathy. Available at niddk.nih.gov. Accessed July 2022
  9. Kittleson M M, Maurer M S et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation 2020;142(1):e7-e22
  10. Tafamidis 20 mg Summary of Product Characteristics GB. Available at: medicines.org.uk. Accessed July 2022
  11. Tafamidis 61 mg Summary of Product Characteristics GB. Available at: medicines.org.uk. Accessed July 2022
  12. Tafamidis 20 mg Summary of Product Characteristics NI. Available at: medicines.org.uk. Accessed July 2022
  13. Tafamidis 20 mg and 61 mg Summary of Product Characteristics EU. Available at: ema.europa.eu. Accessed July 2022
  14. Tafamidis 61 mg Summary of Product Characteristics NI. Available at: emcmedicines.com. Accessed July 2022
  15. Patisiran Summary of Product Characteristics. Available at: medicines.org.uk. Accessed July 2022
  16. Patisiran Summary of Product Characteristics EU. Available at: ema.europa.eu. Accessed July 2022
  17. Patisiran Summary of Product Characteristics NI. Available at: emcmedicines.com. Accessed July 2022
  18. Inotersen Summary of Product Characteristics GB. Available at: medicines.org.uk. Accessed July 2022
  19. Inotersen Summary of Product Characteristics EU. Available at: ema.europa.eu. Accessed July 2022
  20. Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv Neurol Disord 2013;6(2):129-139