"Wild-type transthyretin amyloidosis has been increasingly recognised as a cause of heart failure in the elderly 1-9. Misfolding and aggregation seem to increase with age 10-12, with autopsy series indicating TTR amyloid deposits in up to 25% of patients over the age of 80 years 10-12 (however, not all of them to a clinically manifesting degree). The median age at the time of diagnosis is approximately 75 years, and men are far more commonly affected 1-4."
"Transthyretin-related amyloidosis is characterised by misfolding, aggregation and deposition of transthyretin-related protein as insoluble amyloid fibrils in the extracellular space of various organs including the heart, vasculature, the peripheral and autonomic nervous systems, the soft tissues, and the gastrointestinal tract 1-4. The amyloid fibrils are formed by the transport protein transthyretin (TTR) after dissociation of its tetrameric form into monomers and subsequent misfolding, either in the presence of precipitating conditions such as oxidative stress or ageing processes, or in the context of an amyloidogenic mutation facilitating the process 3,5. Transthyretin is mainly synthesised in the liver and to a lesser extent in the choroid plexus and by retinal pigment epithelial cells 3,5."
"Variant transthyretin-related amyloidosis is the most common form of hereditary amyloidosis with variable phenotypes and varying ages at disease onset 1-4. The most common mutation is p.Val50Met (formerly Val30Met) 3,4 with an early onset phenotype mainly seen in Portuguese, Brazilian, Japanese and Swedish populations and a late onset phenotype found worldwide. Other common variants are seen in North America in African-American populations and Western Africa, in the Irish and other European regions such as Denmark and Italy 4,5."
"The tetrameric serum protein transthyretin is encoded by the TTR gene on chromosome 18q12.1 and spans four exons 4. More than 140 different mutations are known 4 with the more common forms causing variant ATTR being p.Val142Ile (formerly Val122Ile), common in African-Americans; p.Val50Met (formerly Val30), common among Portuguese, Japanese and Swedish populations; and p.Thr80Ala (formerly Thr60Ala), common among the Irish 4,12."
"The tetrameric serum protein transthyretin is encoded by the TTR gene on chromosome 18q12.1 and spans four exons 4. More than 140 different mutations are known 4 with the more common forms causing variant ATTR being p.Val142Ile (formerly Val122Ile), common in African-Americans; p.Val50Met (formerly Val30), common among Portuguese, Japanese and Swedish populations; and p.Thr80Ala (formerly Thr60Ala), common among the Irish 4,12."
"The tetrameric serum protein transthyretin is encoded by the TTR gene on chromosome 18q12.1 and spans four exons 4. More than 140 different mutations are known 4 with the more common forms causing variant ATTR being p.Val142Ile (formerly Val122Ile), common in African-Americans; p.Val50Met (formerly Val30), common among Portuguese, Japanese and Swedish populations; and p.Thr80Ala (formerly Thr60Ala), common among the Irish 4,12."
"positive bone scintigraphy (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) with a Perugini grade 2 or 3"
"positive bone scintigraphy (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) with a Perugini grade 2 or 3"
"positive bone scintigraphy (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) with a Perugini grade 2 or 3"
"99mTc-PYP: 370-640 MBq intravenously"
"99mTc-DPD: 370-640 MBq intravenously"
"99mTc-HMDP: 370-640 MBq intravenously"
"uptake time 99mTc-PYP only: 1 hour"
"uptake time 99mTc-PYP/DPD/HMDP: 2- 3 hours"
"positive bone scintigraphy (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) with a Perugini grade 2 or 3"
"positive bone scintigraphy (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) with a Perugini grade 2 or 3"
"positive bone scintigraphy (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) with a Perugini grade 2 or 3"
"99mTc-PYP: 370-640 MBq intravenously"
"99mTc-DPD: 370-640 MBq intravenously"
"99mTc-HMDP: 370-640 MBq intravenously"
"uptake time 99mTc-PYP only: 1 hour"
"uptake time 99mTc-PYP/DPD/HMDP: 2- 3 hours"
"IRGE/PSIR: often diffuse late enhancement with right ventricular involvement 25"
"T1 mapping: increased"
"ECV: markedly increased (often ≥50%) 12,13"
"However, in a significant percentage (>10%) of patients with AL amyloidosis, bone scintigraphy has also been reported to be positive, as well as in various other forms of amyloidosis 7,8. Also, bone scintigraphy can be falsely positive in recent myocardial infarction (< 4 weeks), hydroxychloroquine cardiac toxicity, as well as valvular or annular calcifications 13,21,27."
"uptake time 99mTc-PYP/DPD/HMDP: 2- 3 hours"
"CT attenuation correction: heart recommended. SPECT/CT fusion helps localise tracer uptake to the myocardium"
"Transthyretin (ATTR) amyloidosis is a form of systemic amyloidosis characterised by the misfolding, aggregation, and deposition of transthyretin-related (TTR) protein in various organs 1-6. This can occur in two forms, namely, in the setting of a genetically normal transthyretin-related protein, also referred to as wild-type transthyretin (ATTRwt) amyloidosis, and in the context of an amyloidogenic mutation of transthyretin, which is then termed variant transthyretin (ATTRv) amyloidosis 1-5."
"Wild-type ATTR amyloidosis has been formerly known as “senile” or “age-related” ATTR amyloidosis 1-7."
"Wild-type ATTR amyloidosis has been formerly known as “senile” or “age-related” ATTR amyloidosis 1-7."
"Variant ATTR amyloidosis has also been known as “hereditary”, “familial” or “mutant” ATTR amyloidosis 5,6, with polyneuropathy-predominant variants also known as familial amyloid polyneuropathy (FAP) 6."
"Variant ATTR amyloidosis has also been known as “hereditary”, “familial” or “mutant” ATTR amyloidosis 5,6, with polyneuropathy-predominant variants also known as familial amyloid polyneuropathy (FAP) 6."
"The true incidence and prevalence of ATTR amyloidosis and transthyretin amyloid cardiomyopathy are currently unknown due to population-based and regional variations of the genetic variant and due to low awareness and fragmented knowledge of the disease, resulting in underdiagnosis due to phenotypic heterogeneity and overlap with other clinical conditions 1-9."
"positive bone scintigraphy (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) with a Perugini grade 2 or 3"
"positive bone scintigraphy (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) with a Perugini grade 2 or 3"
"NT-proBNP or troponin levels might be elevated, increase over time and are thus included in staging systems 2-5"
"ECG might show decreased limb QRS voltage (≤5 mV)"
"Genetic sequencing and counselling are considered an essential part of the evaluation of ATTR amyloidosis for the following reasons 1,12:"
"differentiating wild-type ATTR from variant ATTR"
"differentiating wild-type ATTR from variant ATTR"
"The tetrameric serum protein transthyretin is encoded by the TTR gene on chromosome 18q12.1 and spans four exons 4. More than 140 different mutations are known 4 with the more common forms causing variant ATTR being p.Val142Ile (formerly Val122Ile), common in African-Americans; p.Val50Met (formerly Val30), common among Portuguese, Japanese and Swedish populations; and p.Thr80Ala (formerly Thr60Ala), common among the Irish 4,12."
"Cardiac MRI usually shows a significantly increased left ventricular mass, diffusely increased native T1 values and very high ECV values on myocardial mapping, and a variably diffuse-to-transmural non-ischaemic late enhancement pattern as well as abnormal blood-pool gadolinium kinetics 12,13."
"IRGE/PSIR: often diffuse late enhancement with right ventricular involvement 25"
"ECV: markedly increased (often ≥50%) 12,13"
"It is worth mentioning that a reliable differentiation between ATTR and AL on cardiac MRI is not possible 12,13,22,23; still, MRI features favouring ATTR amyloidosis over AL include 24,25:"
"It is worth mentioning that a reliable differentiation between ATTR and AL on cardiac MRI is not possible 12,13,22,23; still, MRI features favouring ATTR amyloidosis over AL include 24,25:"
"It is worth mentioning that a reliable differentiation between ATTR and AL on cardiac MRI is not possible 12,13,22,23; still, MRI features favouring ATTR amyloidosis over AL include 24,25:"
"It is worth mentioning that a reliable differentiation between ATTR and AL on cardiac MRI is not possible 12,13,22,23; still, MRI features favouring ATTR amyloidosis over AL include 24,25:"
"high native T1 mapping values but lower than in AL amyloidosis"
"late gadolinium enhancement is often more diffuse with right ventricular involvement and a QALE score >13"
"Bone scintigraphy with Perugini grading is usually positive in cardiac ATTR-amyloidosis, with a Perugini grade of 2 or 3 pointing to ATTR amyloidosis 12,13,22."
"Bone scintigraphy with Perugini grading is usually positive in cardiac ATTR-amyloidosis, with a Perugini grade of 2 or 3 pointing to ATTR amyloidosis 12,13,22."
"However, in a significant percentage (>10%) of patients with AL amyloidosis, bone scintigraphy has also been reported to be positive, as well as in various other forms of amyloidosis 7,8. Also, bone scintigraphy can be falsely positive in recent myocardial infarction (< 4 weeks), hydroxychloroquine cardiac toxicity, as well as valvular or annular calcifications 13,21,27."
"99mTc-PYP: 370-640 MBq intravenously"
"99mTc-HMDP: 370-640 MBq intravenously"
"uptake time 99mTc-PYP only: 1 hour"
"uptake time 99mTc-PYP/DPD/HMDP: 2- 3 hours"
"uptake time 99mTc-PYP/DPD/HMDP: 2- 3 hours"
"abnormal T1 and T2 mapping and ECV values (if performed)"
"The targeted therapy regimen depends mainly on the ATTR subtype (hereditary or wild type) and thus on the organ involvement of the disease, i.e. the presence of cardiomyopathy or polyneuropathy or both 7 and currently includes the following agents 12,13:"
"Liver transplantation was the main treatment option in variant ATTR before the introduction of stabilising and genetic silencing agents 1,6."
"Senile amyloidosis was first reported by the Czech physician and pathologist Isidor Soyka in 1876 7,37. Hereditary ATTR amyloidosis was first reported in Portugal by the Portuguese neurologist Corino Andrade in 1952 and later in Japan and Sweden 35,38-40."
"The main differential diagnosis of ATTR amyloidosis includes the following 2,12:"
"on cardiac MRI, PSIR is an option to better deal with the difficulties of nulling myocardium 33"
"the abdominal fat pad offers a rather low sensitivity as a biopsy site for ATTR amyloidosis (~45% in ATTRv and ~15% ATTRwt)"
"alternative biopsy sites for suspected ATTR are the labial salivary gland or the sural nerve, the latter, especially in the setting of polyneuropathy 25"
"Imaging protocol"
Expected headings
"Subtypes"
"Echocardiography"
"Signal characteristics"
"Imaging protocol"
"MRI"
"Transthyretin (ATTR) amyloidosis is a form of systemic amyloidosis characterised by the misfolding, aggregation, and deposition of transthyretin-related (TTR) protein in various organs 1-6. This can occur in two forms, namely, in the setting of a genetically normal transthyretin-related protein, also referred to as wild-type transthyretin (ATTRwt) amyloidosis, and in the context of an amyloidogenic mutation of transthyretin, which is then termed variant transthyretin (ATTRv) amyloidosis 1-5."
"The genetically normal form or wild type mainly affects the heart and soft tissues. For the hereditary or variant forms, cardiomyopathy-predominant, polyneuropathy-predominant, and mixed phenotypes are distinguished 1-5, and additionally, a type with oculoleptomeningeal involvement 5,6."
"In wild-type transthyretin-related amyloidosis, presenting symptoms are often cardiac in origin, including heart failure with preserved ejection fraction, fatigue, dizziness, dyspnoea, exercise intolerance, and features of aortic stenosis (low-flow-low-gradient) 1,15. Other clinical associations include 17-19:"
"In variant transthyretin-related amyloidosis, a cardiac and a neurological phenotype are distinguished, with the neurological phenotype showing symptoms of peripheral neuropathy and autonomic dysfunction, the latter potentially causing orthostatic dysfunction, syncope, and gastrointestinal issues 4,12,13,16,20. Other manifestations include vitreous opacities and leptomeningeal involvement 16,20:"
"The prognosis of transthyretin-related amyloidosis varies according to the subtype, mutation and phenotype, time of diagnosis, stage 32, and presence of complications, ranging from less than 3 years in patients with cardiomyopathy-predominant phenotypes up to 8 or 10 years in polyneuropathy-predominant variants 2,5."
"The true incidence and prevalence of ATTR amyloidosis and transthyretin amyloid cardiomyopathy are currently unknown due to population-based and regional variations of the genetic variant and due to low awareness and fragmented knowledge of the disease, resulting in underdiagnosis due to phenotypic heterogeneity and overlap with other clinical conditions 1-9."
"The targeted therapy regimen depends mainly on the ATTR subtype (hereditary or wild type) and thus on the organ involvement of the disease, i.e. the presence of cardiomyopathy or polyneuropathy or both 7 and currently includes the following agents 12,13:"
"Variant transthyretin-related amyloidosis is the most common form of hereditary amyloidosis with variable phenotypes and varying ages at disease onset 1-4. The most common mutation is p.Val50Met (formerly Val30Met) 3,4 with an early onset phenotype mainly seen in Portuguese, Brazilian, Japanese and Swedish populations and a late onset phenotype found worldwide. Other common variants are seen in North America in African-American populations and Western Africa, in the Irish and other European regions such as Denmark and Italy 4,5."
"Transthyretin-related amyloidosis is characterised by misfolding, aggregation and deposition of transthyretin-related protein as insoluble amyloid fibrils in the extracellular space of various organs including the heart, vasculature, the peripheral and autonomic nervous systems, the soft tissues, and the gastrointestinal tract 1-4. The amyloid fibrils are formed by the transport protein transthyretin (TTR) after dissociation of its tetrameric form into monomers and subsequent misfolding, either in the presence of precipitating conditions such as oxidative stress or ageing processes, or in the context of an amyloidogenic mutation facilitating the process 3,5. Transthyretin is mainly synthesised in the liver and to a lesser extent in the choroid plexus and by retinal pigment epithelial cells 3,5."
"The tetrameric serum protein transthyretin is encoded by the TTR gene on chromosome 18q12.1 and spans four exons 4. More than 140 different mutations are known 4 with the more common forms causing variant ATTR being p.Val142Ile (formerly Val122Ile), common in African-Americans; p.Val50Met (formerly Val30), common among Portuguese, Japanese and Swedish populations; and p.Thr80Ala (formerly Thr60Ala), common among the Irish 4,12."
"presence, pattern and distribution of late gadolinium enhancement"
"Management includes guideline-directed therapy for cardiovascular symptoms, prevention and treatment of complications, new targeted therapeutic options aimed at preventing the dissociation of TTR molecules into amyloidogenic fragments by stabilising their circulating forms (stabilising molecules) and interfering with their production (genetic silencers) as well as supportive measures 5,12,13."
"The prognosis of transthyretin-related amyloidosis varies according to the subtype, mutation and phenotype, time of diagnosis, stage 32, and presence of complications, ranging from less than 3 years in patients with cardiomyopathy-predominant phenotypes up to 8 or 10 years in polyneuropathy-predominant variants 2,5."
"Transthyretin-related protein can be detected immunohistochemically in affected tissues using an anti-transthyretin antibody 18. Immunohistochemistry and related methods such as immunofluorescence and immunoelectron microscopy are considered alternatives to mass spectrometry; however, they are less sensitive and less specific 1."
"The tetrameric serum protein transthyretin is encoded by the TTR gene on chromosome 18q12.1 and spans four exons 4. More than 140 different mutations are known 4 with the more common forms causing variant ATTR being p.Val142Ile (formerly Val122Ile), common in African-Americans; p.Val50Met (formerly Val30), common among Portuguese, Japanese and Swedish populations; and p.Thr80Ala (formerly Thr60Ala), common among the Irish 4,12."
"The tetrameric serum protein transthyretin is encoded by the TTR gene on chromosome 18q12.1 and spans four exons 4. More than 140 different mutations are known 4 with the more common forms causing variant ATTR being p.Val142Ile (formerly Val122Ile), common in African-Americans; p.Val50Met (formerly Val30), common among Portuguese, Japanese and Swedish populations; and p.Thr80Ala (formerly Thr60Ala), common among the Irish 4,12."
"It is worth mentioning that a reliable differentiation between ATTR and AL on cardiac MRI is not possible 12,13,22,23; still, MRI features favouring ATTR amyloidosis over AL include 24,25:"
"ECG gating: off; non-gated imaging"
"History and etymology"