Co-author: Dr. Nitasha Sarswat
Transthyretin amyloidosis (ATTR) is a progressive and often fatal disease occurring when the liver produces tetramers that become unstable, which leads to dissociation into component monomers prone to misfolding and aggregating, eventually forming amyloid fibrils.1-3 Over time, these amyloid fibrils deposit and build up in tissues, including the heart, kidneys and peripheral nerves. This buildup can cause significant organ damage and failure, severely impacting these patients’ quality of life (QoL).3-8
The underlying mechanism for TTR instability can either be genetic (hereditary transthyretin-mediated amyloidosis) or non-genetic (wild-type or wild-type transthyretin-mediated amyloidosis).3
“I have seen patients present with a wide range of symptoms, including decompensated heart failure, a sensation of ‘walking on bubbles,’ copious diarrhea after each meal and severe orthostasis that prevents one from being able to get up and walk across the room. This variable presentation contributes to delays in diagnosis when there is no high index of suspicion.”
ATTR is a multisystem disorder
ATTR can manifest in various ways depending on the location of the amyloid fibril deposits. Fibrils can accumulate in multiple organs and systems, including the heart, kidneys, peripheral nervous system and brain.4 Polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) is a form of ATTR that predominantly impacts the peripheral nervous system.1 Without treatment, patients can experience a decline in motor skills and the disease can turn fatal within ten years.1,7 Cardiomyopathy of transthyretin-mediated amyloidosis can be either hereditary (hATTR-CM) or wild-type (ATTRwt-CM), predominantly affecting the heart, which presents as restrictive cardiomyopathy which progresses to heart failure.6 If treatment is delayed, mortality can occur within five years.6 Patients afflicted with hereditary ATTR often present with predominant polyneuropathy or cardiomyopathy symptoms, which is referred to as mixed phenotype.6,9
Why is ATTR so challenging to diagnose?
Diagnosing and promptly treating ATTR can slow disease progression, maintain quality of life and address the unmet needs of these patients.7 There are several factors that may impede the timely and accurate diagnosis of ATTR.
Diagnosing a rare disorder requires disease awareness and a certain degree of clinical suspicion. Despite a growing body of clinical and basic scientific research and the introduction of new treatment options for ATTR, there remains a persistently low level of disease awareness.10,11 Increased awareness and education can allow clinicians to diagnose and treat patients earlier.
ATTR causes seemingly unrelated multi-system symptoms with a staggered onset over several years. ATTR typically causes cardiovascular (heart failure, atrial fibrillation, conduction disease), musculoskeletal (carpal tunnel syndrome, trigger finger, arthropathies), gastrointestinal (diarrhea, constipation, weight loss) and neurological symptoms (polyneuropathy, which encompasses both autonomic neuropathy—orthostatic hypotension, sexual dysfunction—and sensorimotor neuropathy— neuropathic pain in hands/feet, sensory loss, muscle weakness).6,9,12-14 The diverse symptoms of ATTR are often incorrectly attributed to other plausible and more prevalent causes, contributing to a significant delay in accurate diagnosis—an average of four years following symptom onset.9,14
Clinicians typically diagnose their patients by using specialized genetic tests, nerve conduction studies and advanced cardiac imaging. A detailed patient history is a vital element in diagnosis, especially for the hereditary forms of ATTR, where red flags (such as gait disorders, heart rhythm disorders and renal abnormalities) can alert the clinician that greater scrutiny is warranted.1
Healthcare collaboration can expedite ATTR diagnosis and treatment
Timely diagnosis of ATTR begins with healthcare professionals conducting a thorough and comprehensive review of a patient’s history and signs and symptoms of cardiac, musculoskeletal, gastrointestinal and peripheral and autonomic nervous system involvement.6
Unfortunately, many patients will unfortunately endure one, or even several, misdiagnoses prior to the initiation of appropriate treatment.4 After the failure of initial treatments to alleviate presenting symptoms, specialists such as cardiologists and neurologists need to be engaged to conduct more complex tests, including tissue biopsies, echocardiograms, cardiac magnetic resonance imaging, radionuclide bone scans and nerve conduction studies.15
For hATTR-PN, the process begins with a clinical suspicion based on the presentation of sensory motor axonal neuropathy or inflammatory demyelinating polyneuropathy, plus supporting evidence from a patient’s family history or the presence of symptoms, such as bilateral carpal tunnel syndrome and gait disorders. To help confirm diagnosis, clinicians should use TTR gene sequencing for amyloidogenic variants or biopsy and amyloid typing.1
If there is suspicion of ATTR-CM, clinicians should scrutinize the patient’s family history and perform an echocardiogram or a cardiac magnetic resonance test (MRI). From there, it is important to rule out light-chain cardiac amyloidosis (AL-CM) using a monoclonal protein screen, which should include the evaluation of the kappa/lambda values and ratio, serum and urine electrophoresis and immunofixation. Once AL-CM has been eliminated, cardiac scintigraphy and genetic testing should be performed to confirm whether it is hATTR-CM or ATTRwt-CM.16
For those suspected of having any form of amyloidosis and who have access to specialized amyloidosis centers, highly specialized tests such as immunogold electron microscopy and radiolabeled serum amyloid P (SAP) scanning may be performed.3,6 It is paramount for healthcare professionals, especially primary care physicians, to refer patients to specialists as soon as possible and not automatically attribute symptoms to more common disorders.
Treatment will also be a collaborative effort with specialists (such as cardiologists, neurologists and gastroenterologists) as healthcare providers will play a vital part in monitoring patient quality of life and efficacy of prescribed treatment.
Advancing ATTR care improves patient outcomes
It is crucial to identify the initial symptoms of this debilitating disease and promptly initiate treatment to help slow the disease progression, ultimately allowing people to lead longer and more fulfilling lives.6 For healthcare professionals in the United States who want to learn more about ATTR and improve their ability to recognize its associated symptoms pattern, visit SeeThePattrns.com for more information.
References
Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122. doi: 10.1007/s00415-019- 09688-0.
Suhr OB, Lundgren E, Westermark P. One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition. J Intern Med. 2017;281(4):337-347. doi: 10.1111/joim.12585.
NORD. Amyloidosis. Accessed January 10, 2024. https://rarediseases.org/rare-diseases/amyloidosis/.
Rintell D, Heath D, Mendendez FB, et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis. 2021;16(1):70. doi: 10.1186/s13023-021-01706-7.
Amyloidosis Foundation. Wild-type ATTR. Accessed August 12, 2024. https://www.amyloidosis.org/facts/wild-type.
Nativi-Nicolau JN, Karam C, Khella S, Maurer MS. Screening for ATTR amyloidosis in the clinic: overlapping disorders, misdiagnosis, and multiorgan awareness. Heart Fail Rev. 2022;27(3):785-793. doi: 10.1007/s10741-021-10080-2.
González-Duarte A, Conceição I, Amass L, Botteman MF, Carter JA, Stewart M. Impact of non-cardiac clinicopathologic characteristics on survival in transthyretin amyloid polyneuropathy. Neurol Ther. 2020;9(1):135-149. doi: 10.1007/s40120-020-00183-7.
Maurer MS, Bokhari S, Damy T. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail. 2019;12(9):e006075. doi: 10.1161/CIRCHEARTFAILURE.119.006075.
Dispenzieri A, Coelho T, Conceição I, et al. Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update. Orphanet J Rare Dis. 2022;17(1):236. doi: 10.1186/s13023-022-02359-w
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):2872-2891. doi: 10.1016/j.jacc.2019.04.003.
Gertz M, Adams D, Ando Y, et al. Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner. BMC Fam Pract. 2020;21(1):198. doi: 10.1186/s12875-020-01252-4.
Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(7 Suppl):S107-S112.
Adams D, Algalarrondo V, Polydefkis M, et al. Expert opinion on monitoring symptomatic hereditary transthyretin-mediated amyloidosis and assessment of disease progression. Orphanet J Rare Dis. 2021;16(1):411.
Benson MD, Dasgupta NR, Rao R. Diagnosis and screening of patients with hereditary transthyretin amyloidosis (hATTR): current strategies and guidelines. Ther Clin Risk Manag. 2020;16:749-758. doi: 10.2147/TCRM.S185677.
Teng C, Li P, Bae JY, Pan S, Dixon RAF, Liu Q. Diagnosis and treatment of transthyretin-related amyloidosis cardiomyopathy. Clin Cardiol. 2020;43(11):1223-1231. doi: 10.1002/clc.23434.
Kittleson MM, Ruberg FL, Ambardekar AV, et al. 2023 ACC Expert Consensus Decision Pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023;81(11):1076-1126. doi: 10.1016/j.jacc.2022.11.022
