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 under diagnosed) 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
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
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
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
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
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
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
Top image: Design Cells
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