Transcript
Announcer:
Welcome to ReachMD. This medical industry feature, titled “Uncovering Unmet Needs in ATTR Amyloidosis” is sponsored by AstraZeneca. Here’s your host, Dr Charles Turck.
Dr Turck:
This is ReachMD, and I’m Dr Charles Turck.
Joining me today is Dr Nitasha Sarswat, who’s an Assistant Professor of Medicine, as well as the Director of Infiltrative Cardiomyopathy, at the University of Chicago in Illinois. Dr Sarswat is a board-certified cardiologist specializing in advanced heart failure and heart transplantation. Together, we’ll be discussing the significant burden and unmet needs in transthyretin-mediated amyloidosis, otherwise known as ATTR amyloidosis. Dr Sarswat, thanks for being here today.
Dr Sarswat:
Thanks for inviting me.
Dr Turck:
So to begin our discussion, Dr Sarswat, could you provide us with a brief overview of ATTR amyloidosis?
Dr Sarswat:
Absolutely. So ATTR amyloidosis is a protein misfolding disorder of transthyretin, which is a protein that normally transports thyroxine and retinol in the bloodstream.1–3 The misfolded transthyretin leads to the formation of insoluble amyloid fibrils that can deposit heterogeneously throughout tissues and organs, ultimately causing damage.1,2,4,5
The disease is driven by one of two mechanisms. Wild-type ATTR amyloidosis occurs due to age-related misfolding of transthyretin, while hereditary ATTR amyloidosis is caused by a mutation in the gene encoding transthyretin.3–6
Both hereditary and wild-type ATTR result in debilitating, multisystem disorders with diverse clinical manifestations, including combinations of cardiomyopathy and polyneuropathy symptoms.3,7–15 Polyneuropathy may affect autonomic and/or sensorimotor systems.12,14,16–18
And so, these patients are often seen by cardiologists and neurologists, but may also present to primary care physicians, gastroenterologists, and orthopedic surgeons. However, due to the non-specific, heterogeneous symptoms, reaching an accurate diagnosis can be difficult as the clinical presentation often mimics more common diseases.8,11,12,14,16
Dr Turck:
So given that, what data do we have about the prevalence of ATTR amyloidosis in the United States?
Dr Sarswat:
Great question. The exact prevalence of ATTR amyloidosis is difficult to establish due to:
- its rare nature,
- the variable geographic distribution of transthyretin pathogenic variants,
- variability between endemic and non-endemic regions,
- and underdiagnosis due to its diverse clinical manifestations.3,8,16,19–26
In the US, it’s estimated that 40 percent of all ATTR patients have the hereditary form.27 The most common hereditary variants in the US are V122I and T60A at 45 and 20 percent of cases, respectively.20 And about 3.5 percent of Afro-Caribbean Americans carry the V122I pathogenic variant.28 Allow me to note here that there’s been a change in nomenclature for all variants. For example V122I, which is isoleucine replacing valine at the 122nd amino acid position, is V142I with the new nomenclature.29 But, many of us still refer to it as V122I.
Additionally, it’s important to note that 10 percent of heart failure patients with preserved ejection fraction in the US have underlying ATTR amyloidosis.30
Dr Turck:
Excellent insights, Dr Sarswat. Now if we go back to your initial point on how ATTR amyloidosis often mimics other diseases, could you elaborate on what makes diagnosis challenging for these patients?
Dr Sarswat:
Certainly. I’d like to start by emphasizing that there’s a constellation of red-flags that are frequently mistaken for other diseases.11,12,14 These early indicators often appear before the most common presenting symptoms of ATTR amyloidosis, which are heart failure and peripheral neuropathy.11,14,31,32 This results in incorrect diagnosis and delayed screening and treatment for patients with the disease.11,14,32
From my experience in cardiology, I think we aren’t always looking for initial symptoms of ATTR amyloidosis beyond the cardiac manifestations. We may assess for indicators like:
- discordance between electrocardiogram voltage and myocardial wall thickness,
- orthostatic hypotension,
- or intolerance to conventional heart failure medications, such as beta-blockers and ACE inhibitors.
- And then, we might also look for paradoxical low flow or low gradient aortic stenosis.14,31,32
However, we should also be asking our patients about early multisystem indicators, like a ruptured biceps tendon and dysautonomia. In fact, a history of bilateral carpal tunnel syndrome or lumbar spinal stenosis is a clear red flag for ATTR amyloidosis and warrants further evaluation.14,31,32
That’s why building strong relationships with neurologists and neurosurgeons treating patients with bilateral carpal tunnel syndrome or lumbar spinal stenosis is essential. Because by the time these patients finally see a cardiologist like me, opportunity for early intervention has often already passed.33
Dr Turck:
That’s a valuable perspective. And could you tell us more about the bilateral carpal tunnel syndrome and lumbar spinal stenosis you pointed out?
Dr Sarswat:
Yes. So, bilateral carpal tunnel syndrome occurs due to compression caused by amyloid deposition on the median nerve. These symptoms can precede other symptoms of hereditary ATTR amyloidosis by 4 to 6 years.3,11
In the hereditary disease type, a study found that 74 percent of patients had concurrent carpal tunnel syndrome.34 And we have data showing that symptoms of carpal tunnel syndrome preceded a diagnosis of hereditary ATTR in over 50 percent of patients.26,34
We see a similar pattern in patients with wild-type ATTR, with as many as 55 percent experiencing carpal tunnel syndrome as an initial symptom and up to 65 percent develop carpal tunnel syndrome before a wild-type ATTR diagnosis.3,11,26,35
Let’s take a moment to let that sink in. Because this means that we as physicians are missing a major opportunity to halt the progression of an irreversible and fatal disease in our patients.14,19,36 If every cardiologist asked their heart failure patients about their history of bilateral carpal tunnel syndrome, we could make significant strides towards early recognition of ATTR amyloidosis.
Dr Turck:
It certainly seems so, especially since as you mentioned, one in 10 heart failure patients with preserved ejection fraction have underlying ATTR amyloidosis.30
Dr Sarswat:
Exactly. Now if we focus on hereditary ATTR cardiomyopathy, another significant musculoskeletal red-flag symptom to consider is lumbar spinal stenosis. It’s characterized by compression of sensory and motor nerves in the lower limbs due to the thickening of the ligamentum flavum.37,38 Lumbar spinal stenosis affects about 20 percent of hereditary ATTR amyloidosis patients with cardiomyopathy.39 And it can manifest before cardiac symptoms, providing another opportunity for earlier diagnosis and disease intervention.37
So in summary, an improved awareness of the broad spectrum of red-flag symptoms, beyond those that are specific to our specialties, is critical for earlier recognition of ATTR amyloidosis. This way we can maximize patient function, quality of life, and survival.
Dr Turck:
For those just tuning in, you’re listening to ReachMD. I’m Dr Charles Turck, and today I’m speaking with Dr Nitasha Sarswat about the significant burden and pressing unmet needs associated with the rare and complex disease, transthyretin-mediated amyloidosis, or ATTR amyloidosis.
So now that we’ve covered some of the key warning signs, Dr Sarswat, are there any other diagnostic hurdles that healthcare teams should consider?
Dr Sarswat:
Yes, another major challenge is that physicians may not always be aware of the scope of the mixed presentation of ATTR amyloidosis beyond the initial symptoms.
As I previously mentioned, the most common presenting signs are heart failure and peripheral neuropathy.31
However, both hereditary and wild-type ATTR often present as mixed phenotypes with symptoms of polyneuropathy and cardiomyopathy.3,7–10,15,40 In fact, globally, 60 to 80 percent of patients with hereditary ATTR amyloidosis have a mixed phenotype, depending on the pathogenic variant.27,41–46
Additionally, multiple studies have shown that patients with V122I and T60A, which are the most common variants of hereditary ATTR amyloidosis in the US, have neuropathy despite their common association as cardiomyopathy-dominant variants.20,44,47,48 For example, one retrospective study of patients with the V122I variant reported 30 percent of patients had peripheral neuropathy.44
And even in wild-type TTR, which is predominantly characterized by cardiac symptoms, we also see polyneuropathy symptoms in about 31 percent of patients, while 65 percent of them have a mixed phenotype.49,50
So again, ATTR amyloidosis is under-recognized due to its broad presentation and is often misdiagnosed.8,36 In fact, up to 57 percent of all ATTR amyloidosis patients are misdiagnosed, and 23 percent of patients report seeing over five physicians before getting a correct diagnosis.8,16,26 There is a 3 to 4-year diagnostic delay.8,36
Dr Turck:
And what kind of impact can those diagnostic delays have on patient survival?
Dr Sarswat:
Well, sadly, patient survival from the point of diagnosis is short. In hereditary ATTR amyloidosis with polyneuropathy, the median survival time from diagnosis is only 5 to 15 years. While in hereditary ATTR amyloidosis with predominant cardiac manifestations, the median survival time from diagnosis is just 2 to 5 years.19,51 And so, time is of the essence, and we must do better to halt disease progression sooner.
Dr Turck:
Agreed, Dr Sarswat. Now if we take a moment to consider the irreversible nature of ATTR amyloidosis, could you share how polyneuropathy symptoms can be particularly debilitating for a patient’s quality of life?
Dr Sarswat:
Of course. So to begin, polyneuropathy can present as peripheral and autonomic symptoms, and both can significantly affect a patient’s quality of life.7,8,52,53
A small study involving 14 patients with hereditary ATTR polyneuropathy found that 80 percent of patients were unable to participate in social activities. A separate 80 percent had difficulty gripping objects. Additionally, 60 percent of the patients had problems with getting dressed and bathing.54
In sensorimotor polyneuropathy, symptoms often begin in the feet with numbness, pain, and/or pinprick sensation before proximal progression and progressive sensory loss, leading to impairment of fine hand movements, gait, and balance.8,13,52
Now it’s important to note that the severity and rapid progression of neuropathic symptoms from onset in hereditary ATTR amyloidosis with polyneuropathy is distinguishable compared to other polyneuropathies, like diabetic peripheral neuropathy and Charcot-Marie-Tooth disease. More specifically, the annual rate of symptom progression from walking without assistance to being confined to a wheelchair or bed is about eight times faster.53
Additionally, two studies observed that untreated patients with hereditary ATTR amyloidosis with polyneuropathy experienced a progressive decline in neuropathic impairment and quality of life within 15-18 months.55,56
Now moving to autonomic symptoms, these occur in 50 to 80 percent of patients with hereditary ATTR amyloidosis and can be the first clinical presentation of symptoms in early-onset cases.57,58 They can affect cardiovascular, gastrointestinal, and urogenital systems.11
And from my own clinical experience, autonomic neuropathy is highly detrimental to my patients’ social lives. I mean, think of the burden of uncontrolled diarrhea, intermittent constipation, vomiting, urinary incontinence, nocturia, and sexual dysfunction, among others, can have on daily life.
So with all this being said, patients can experience severe impacts on their physical, mental, and social functioning, as well as their overall well-being.59
Dr Turck:
Now as we come to a close, what are some key takeaways you’d like to leave with our audience?
Dr Sarswat:
So, I’d like to start by underscoring that ATTR amyloidosis is a rapidly progressive and fatal disease that’s often misdiagnosed due to its multisystemic presentation of symptoms. These include polyneuropathy, cardiomyopathy, and mixed phenotypes resulting in poor patient outcomes.3,7–10,14–16,19,36
That’s why there’s a critical unmet need for increased awareness among healthcare professionals regarding the early signs and symptoms of ATTR amyloidosis to facilitate rapid and accurate diagnosis, improve patient outcomes, and address the current delays in diagnosis that contribute to the irreversible progression and mortality associated with the disease.8,14,36,51,60,61
And to re-emphasize the data, despite being a rare disease, 10 percent of heart failure patients with preserved ejection fraction have ATTR amyloidosis.
Also, 50 percent of patients with hereditary ATTR amyloidosis develop carpal tunnel syndrome prior to diagnosis.26,34 This number increases to 65 percent in patients with wild-type TTR amyloidosis.26
So ultimately, this means that ATTR amyloidosis is most prevalent in patient populations seen by cardiologists and neurologists who are well-positioned to identify the spectrum of red-flag symptoms and the rapid progression of polyneuropathy.
Dr Turck:
Those are some great comments for us to think on as we come to the end of today’s program. And I want to thank my guest, Dr Nitasha Sarswat, for helping us better understand the burden and unmet needs in transthyretin-mediated amyloidosis. Dr Sarswat, it was great speaking with you today.
Dr Sarswat:
You as well.
Announcer:
This medical industry feature was sponsored by AstraZeneca. If you missed any part of this discussion or to find others in this series, visit Industry Features on ReachMD.com, where you can Be Part of the Knowledge.
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