Videos: Disease Overview

ATTR Disease Overview
Transthyretin (TTR) is mostly made in the liver. Its role is to transport the hormone thyroxine and retinol (Vitamin A) around the body, hence its name transthyretin.
 
HCP Video: ATTR Disease Overview
In this Mayo Clinic video, Martha Grogan, M.D., Mayo Clinic cardiologist, provides a description of wild-type transthyretin (TTR)-cardiac amyloidosis, common symptoms, and treatment options for those diagnosed with TTR cardiac amyloidosis

1:18-2:30: Disease Overview
4:09-5:48: Heart with Amyloid
9:47-12:10: Symptom Overview (enlarged heart, heart failure, arrythmias)
12:12-13:04: Blood Tests in ATTR-CM
13:04-15:05: Treatment of ATTR-CM
  1. Amyloidosis Research Consortium, https://www.youtube.com/watch?v=lXZsWTUjV7Q
  2. Mayo Clinic. https://www.youtube.com/watch?v=RnWxzRD1NVk

Amyloidosis – Definition & Types

Amyloidosis is a rare disease that occurs when an abnormal protein, called amyloid, builds up in tissues and/or organs, interfering with normal function; there are several types—each with different causes, courses, and treatments.
Responsive Image
  • Over 30 different proteins can misfold to form amyloids, each causing a particular amyloid disease requiring specific treatment [5a,7-9]
    • Each amyloidosis is classified based on the amyloidogenic precursor protein [7,9]
Deep Dive
Protein Precursors
Go to Deep Dive
  • Amyloidosis can be systemic (affecting multiple organs / tissues) or localized (affecting a single organ / tissue)[4c-5]
    • Systemic amyloidosis with cardiac involvement (cardiac amyloidosis) is caused by deposition of amyloid fibrils in the heart, resulting in morphological and functional abnormalities and impacting survival [6-7,9-10]
* ATTR amyloid may occur as a "wild-type" (ATTRwt) associated with aging or as mutant proteins (ATTRv [where “v” indicates a variant—which were formerly termed ATTRm where ”m” meant mutated]) [1b]

a. E.g., unlike AL Amyloidosis, AA Amyloidosis, ATTRv, and ATTRwt are non-neoplastic and will not benefit from chemotherapy [3]​

b. Virtually all heredofamilial amyloidoses associated with nephropathic, neuropathic, or cardiopathic disease are dominantly inherited heterozygous disorders, and both the wild-type and mutant molecules can be identified in the amyloid deposits. In some instances (e.g., TTR, apolipoprotein A-I [ApoAI], Alzheimer APP, and prion protein [PRP]), both the wild-type and mutant molecules are able to form amyloid fibrils under different circumstances, with the wild-type protein implicated in aging-associated diseases. As an example, wild-type TTR; ApoAI; and the beta protein, A-beta, a cleavage product of APPs, may form deposits in association with organ-specific pathology in the aging heart, aorta, and brain, respectively. [6] ​

c. In the case of localized amyloidosis, the amyloid deposits are observed in the organ / tissue where the precursor protein is synthesized; whereas in systemic amyloidosis, the deposition of aggregates and fibrils occurs at locations different than the sites where the precursor protein is expressed. [4] ​

Glossary:​

  • ​Amyloid, fibrillar aggregate of misfolded protein​
  • Amyloidogenic, tending to produce amyloids​
  • Fibril, small or slender fiber​
  • Immunoglobulin, any proteins present in the serum and cells that function as antibodies​
  • Light chain, a component of immunoglobulin (antibody) of 25 kDa molecular weight​
  • Monoclonal, derived from a single cell expanding, also termed clonal​
  • Systemic, occurring throughout the body​
  • Transthyretin (TTR), a transport protein in the serum and cerebrospinal fluid that carries the thyroid hormone thyroxine (T4) and retinol-binding protein bound to retinol​
  • Variant, a permanent alteration in the gene​
  • Wild-type, a naturally prevailing strain, gene, or characteristic among individuals​
 
  1. Gorevic, Peter. Aug. 10, 2021. Overview of amyloidosis. UptoDate. https://www.uptodate.com/contents/overview-of-amyloidosis?search=Symptomatic%20Transthyretin%20Amyloid%20Cardiomyopathy%20&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1.
  2. Rajkumar, Vincent, et al. June 28, 2019. Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis. https://www.uptodate.com/contents/clinical-presentation-laboratory-m...=search_result&selectedTitle=1~83&usage_type=default&display_rank=1.
  3. CirculationVol. 133, No. 3Wild-Type Transthyretin Amyloid Cardiomyopathy https://doi.org/10.1161/CIRCULATIONAHA.115.020351Circulation. 2016;133:245–247.
  4. Almeida ZL, Brito RMM. Structure and Aggregation Mechanisms in Amyloids. Molecules. 2020;25(5):1195. Published 2020 Mar 6. doi:10.3390/molecules25051195.
  5. Baker KR, Rice L. Methodist Debakey Cardiovasc J. 2012;8:3-7.
  6. Cuddy SAM, Faulk RH. Can J Cardiol. 2020;36:396-407.
  7. Kitaoka H, et al. Circ J. 2020;84:1610-1671.
  8. Muchtar E, et al. J Intern Med. 2021;289:268-292.
  9. Kittleson MM, et al. Circulation. 2020;142:e7-e22. Erratum in: Circulation. 2021;144:e11. 
  10. Chacko L, et al. Curr Cardiol Rep. 2019;21:108.

What is transthyretin amyloidosis (ATTR)?

ATTR is a severe, progressive, systemic disease characterized by cardiomyopathy and/or neuropathy and associated with high mortality [7-9]
  • Amyloidosis types are named according to the precursor protein that forms the amyloid fibrils
    • “A” is always used to denote amyloidosis, followed by letters identifying the precursor protein, e.g., 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) [2]
    • ATTR occurs when this protein “misfolds” or changes its shape in an abnormal way, and forms into fibrous clumps; depending on ATTR type, the amyloid is deposited into various organs and/or nerves, which can lead to permanent damage and organ malfunction [3]
ATTR has two forms
  1. Hereditary (ATTRv): caused by a genetic mutation inherited from a family member [3]
    • Single point mutations in the TTR gene destabilize the TTR homotetramer, precipitating misfolding and aggregation
    • “v” indicates a variant, which were formerly termed ATTRm where “m” meant mutated, to indicate a mutant protein*; also called familial ATTR or TTR-FAP
  2. Non-hereditary (ATTRwt): emerges from a normal transthyretin molecule that (for reasons unknown) becomes unstable and misfolds, forming amyloid [3]
    • Cause for instability of the homotetramer is unknown, but age-associated factors are implicated
    • “wt” stands for wild-type, which was once known as SCA (senile cardiac amyloidosis) or SSA (senile systemic amyloidosis) [5]
* The name “hereditary” rather than “familial” is recommended by the International Society of Amyloidosis (ISA) for amyloid diseases associated with mutant proteins. Moreover, “hereditary ATTRv,” where “v” stands for variant instead of “m” for mutant, is recommended by the ISA; however, at times, ATTRm (or hATTR for hereditary ATTR) may be encountered in the literature as an alternative to ATTRv. [4]
Transthyretin Overview
  • TTR (previously known as thyroxin-binding prealbumin) [9,10]
    • Highly conserved normal plasma protein of 127 amino acids encoded by a gene on chromosome [18]
    • Produced primarily (95%) in the liver
    • Also synthesized in the choroid plexus, retinal pigment epithelium, and pancreas [11,12]
  • TTR binds thyroxin and retinol-binding protein (which binds retinol [vitamin A]) and serves as a plasma transport protein [11,12]
    • Also prevents excretion of retinol by the kidneys [13]
  • Native TTR exists as a tetramer of 4 identical monomers [14]
    • Monomers dimerize via strong hydrogen bonds
    • 2 dimers join via weaker interactions to form the tetrameric structure containing the thyroxine-binding site [14]
Responsive Image
Image from the PDBe of PDB ID 1f41: Hornberg A, et al. J Mol Biol. 2000;302:649-669.​

Glossary:​

  • ​Cardiomyopathy, a disease of the heart muscle
  • Choroid plexus, a network of blood vessels in the ventricles of the brain that secretes cerebrospinal fluid
  • Neuropathy, a disease involving nerves
  • Retinal pigment epithelium, a pigmented layer of cells outside the retina that provides nourishment to and maintains retinal visual cells
  • Thyroxin, the main hormone produced by the thyroid gland that helps regulate growth and development
 
  1. ALXN: ATTR Amyloidosis: Epidemiology Dossier. August 20, 2021. Citing Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-43. and Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38.
  2. Australia Amyloidosis Network. https://amyloidosis.net.au/patients-and-carers/wild-type-attr-attrwt/.
  3. https://www.pfizer.com/news/featured_stories/featured_stories_detail/understanding_this_rare_disease_called_ttr_amyloidosis.
  4. Picken, MM. The Pathology of Amyloidosis in Classification: A Review. Acta Haematol. 2020;143:322–334. https://doi.org/10.1159/000506696.
  5. https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178.
  6. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-91.
  7. Chacko L, et al. Curr Cardiol Rep. 2019;21:108.
  8. Gertz MA. Am J Manag Care. 2017;23(7 suppl):S107-S112.
  9. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31.
  10. Kittleson MM, et al. Circulation. 2020;142:e7-e22. Erratum in: Circulation. 2021;144:e11.
  11. OMIM Entry 176300, Transthyretin; TTR. Accessed August 15, 2021. https://www.omim.org/entry/176300#201.
  12. 12 Ruberg FL, et al. J Am Coll Cardiol. 2019;73:2872-2891.
  13. 13 Lai Z, et al. Biochemistry. 1996;35:6470-6482.
  14. 14 Azavedo E, et al. 2013; In: Amyloidosis, Dali Feng, IntechOpen. Accessed August 15, 2021. https://www.intechopen.com/chapters/44833.

ATTR Pathophysiology

In ATTR, naturally occurring TTR homotetramers dissociate into unstable monomers that misfold and aggregate into insoluble TTR amyloid fibrils [1]
•Cause for instability of the homotetramer remains unknown, but age-associated factors are implicated [2] 
•In ATTRv, single point mutations in the TTR gene destabilize the TTR homotetramer, precipitating misfolding and aggregation [2]
Responsive Image

Glossary:​

  • ​Amorphous, lacking a clearly defined shape
  • Homotetramer, a molecule comprising 4 identical subunits
  • Mutation, change in a gene (to the DNA sequence) such that the genetic message is altered
  • Oligomer, a molecule consisting of a few similar repeating units
  • Pathophysiology, the disordered physiological process associated with any disease or injury
Deep Dive
ATTR Path
Go to Deep Dive
ALXN: Acoramidis ​for the Treatment of ATTR-CM: Training Deck. November 22, 2021. 34_Acoradmidis Training Deck_22Nov21 FINAL. Citing:
  1. Saelieces L, et al. J Biol Chem. 2015;290:28932-28943.
  2. Ruberg FL, et al. J Am Coll Cardiol. 2019;73:2872-2891.
  3. Muchtar E, et al. J Intern Med. 2021;289:268-292.
  4. Koike H, Katsuno M. Neurol Ther. 2020;9:317-333.
  5. Suhr OB, et al. J Intern Med. 2017;281:337-347.

Comparing the Two Types of ATTR

ATTRwt mainly presents with cardiomyopathy (ATTRwt-CM), whereas ATTRv presents with cardiomyopathy (ATTRv-CM) or polyneuropathy (ATTRv-PN), depending on the variant [1-3]
Responsive Image
Notes: eGFR = estimated glomerular filtration rate; NT-proBNP = N-terminal pro-brain natriuretic peptide

Notes: Early-onset ATTRv (polyneuropathy): common in endemic areas, e.g., Japan, Portugal, Brazil, and Sweden; manifests within 30 or 40 years. In the Japanese and Portuguese populations, onset <50 years with high penetrance rate. Late-onset ATTRv (cardiomyopathy): manifests >50 years[1][5][6​]

Notes: Diflunisal is not available in Japan[4]

Glossary:​

  • ​Estimated glomerular filtration rate (eGFR), a blood test that measures the level of kidney function and determines the stage of kidney disease; depends on age, sex, and body size
  • Heart failure with preserved ejection fraction (HfpEF), a clinical condition in which patients have symptoms and signs of heart failure due to high ventricular filling pressure despite normal or near normal left ventricular ejection fraction​
  • Hypertrophic, enlargement of a body part due to an increase in the size of the constituent cells​
  • N-terminal proBNP (NT-proBNP), N-terminal pro-brain natriuretic peptide, a nonactive prohormone released when pressures inside the heart increase
  • Penetrance, proportion of individuals carrying a particular gene that is expressed as a characteristic phenotype
  • Pro-brain natriuretic peptide (proBNP), a nonactive precursor of BNP, 108 amino acids long
ALXN: Acoramidis ​for the Treatment of ATTR-CM: Training Deck. November 22, 2021. 34_Acoradmidis Training Deck_22Nov21 FINAL. Citing:
 
  1. Ruberg FL, et al. J Am Coll Cardiol. 2019;73:2872-2891.
  2. Kittleson MM, et al. Circulation. 2020;142:e7-e22. Erratum in: Circulation. 2021;144:e11. 
  3. Maurer MS, et al. Circ Heart Fail. 2019;12:e006075.
  4. Kitaoka H, et al. Circ J. 2020;84:1610-1671.
  5. Cuddy SAM, Faulk RH. Can J Cardiol. 2020;36:396-407.
  6. Muchtar E, et al. J Intern Med. 2021;289:268-292.
  7. Winburn I, et al. Cardiol Ther. 2019;8:297-316.
  8. Koike H, Katsuno M. Neurol Ther. 2020;9:317-333. For neuropathic V30M (early-onset) mutations: 20-40 years.
  9. Ruberg FL, Berk JL. Circulation. 2012;126:1286-1300. For cardiomyopathic variants (V122I): >65 years.
  10. Adams D, et al. Nat Rev Neurol. 2019;15:387-404.
  11. González‐Duarte A, et al. Neurol Ther. 2020;9:135-149.
  12. Ishii T, et al. Clin Ther. 2020;42:1728-1737.
  13. Liu PP, Smyth D. Circulation. 2016;133:245-247.
  14. ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier.

ATTR and Cardiac Amyloidosis (CA) Overview

Traditionally ATTR has been categorized into cardiomyopathy (ATTR-CM) or polyneuropathy (ATTR-PN) phenotypes; however, patients may experience a spectrum of symptoms [1]
  • ATTR-PN has historically been associated with ATTRv, although patients with ATTRv may experience a spectrum of symptoms ranging from predominantly cardiomyopathic to neuropathic [1]
  • ATTR-CM may be due to ATTRv or ATTRwt; common symptoms are heart failure, atrial fibrillation and arrhythmias [5]
Responsive Image
There are 3 main types of Cardiac Amyloidosis (CA): AL, ATTRv, and ATTRwt amyloidosis, which share common features in terms of clinical signs and laboratory findings [7]
  • Prognosis depends on the extent of cardiac involvement and the subtype of amyloid precursor protein
  • The clinical practical guideline for cardiomyopathy compiled by the Japanese Circulation Society / Japan Heart Failure Society also classifies CA as one of the secondary cardiomyopathies clearly associated with a specific cause or systemic disease that needs to be differentiated and emphasizes the importance of appropriate diagnosis [7]
Responsive Image
  1. ALXN: ATTR Amyloidosis: Epidemiology Dossier. August 20, 2021. Citing Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-43. and Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38.
  2. Australia Amyloidosis Network. https://amyloidosis.net.au/patients-and-carers/wild-type-attr-attrwt/.
  3. https://www.pfizer.com/news/featured_stories/featured_stories_detail/understanding_this_rare_disease_called_ttr_amyloidosis.
  4. Picken, MM. The Pathology of Amyloidosis in Classification: A Review. Acta Haematol. 2020;143:322–334. https://doi.org/10.1159/000506696.
  5. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-91.
  6. Cruz Rodriguez JB, Tallaj JA. Narrative review of pharmacotherapy for transthyretin cardiac amyloid. Ann Transl Med. 2020;9(6):519.
  7. Kitaoka H, et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J. 2020. 84(9), 1610-1671. https://doi.org/10.1253/circj.CJ-20-0110.

Cardiac Amyloidosis Types

While >30 proteins are known to be capable of aggregating as amyloid in vivo, only 9 amyloidogenic proteins accumulate in the myocardium to cause significant cardiac disease
Nevertheless, some forms (AApoAI, AApoAII, AApoAIV, Ab2M, AFib, AGel) are very rare and cardiac amyloidosis secondary to chronic inflammatory and infectious diseases (AA), although still encountered, is now much less frequent

Accordingly, >98% of currently diagnosed cardiac amyloidosis results from fibrils composed of monoclonal immunoglobulin light chains (AL) or transthyretin (ATTR), either in its hereditary (ATTRv) or acquired (ATTRwt) form
Amyloidosis Subtypes that Affect the Heart
Responsive Image
AA = serum amyloid A amyloidosis; AApoAI = apolipoprotein AI amyloidosis; AApoAII = apolipoprotein AII amyloidosis; AApoAIV = apolipoprotein A-IV amyloidosis; Aβ2M = β2-microglobulin amyloidosis; AFib = fibrinogen amyloidosis; AGel = gelsolin amyloidosis; AL = light-chain amyloidosis; ATTRv = hereditary transthyretin amyloidosis; ATTRwt = wild-type transthyretin amyloidosis; CTS = carpal tunnel syndrome; HF = heart failure; LSS = lumbar spinal stenosis​
Cardiac amyloidosis is characterized by the extracellular deposition of mis-folded proteins in the heart with the pathognomonic histological property of green birefringence when viewed under cross polarized light after staining with Congo red
  1. Garcia-Pavia P, et al. Diagnosis and Treatment of Cardiac Amyloidosis: A Position Statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021;42(16):1554-1568. DOI: https://doi.org/10.1093/eurheartj/ehab072.

ATTR-CM is an Infiltrative Cardiomyopathy

What happens at a microscopic level when amyloid infiltrates the heart: amyloid (pale pink) infiltrates the cardiac muscle and progressively occupies the extracellular space between single cells or groups of myocytes (red), subverting the original structure—this results in a progressive thickening of the ventricular walls that become rigid and lose elasticity
What one would call “cardiomyopathy with hypertrophic phenotype and restrictive physiology"
Responsive Image
Responsive Image
The black in the figure reflects where amyloid is located
  1. ALXN 2060 Differentiation Workshop Pre-reads