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ATTR-CM (cardiomyopathy) vs ATTR-PN (peripheral neuropathy)

 

Over the course of the past few months, we spent time discussing two of the most common hallmark symptoms of ATTR amyloidosis: cardiomyopathy and peripheral neuropathy. In this article, we’ll briefly recap both hallmark symptoms as well as bring it all together by discussing the two most common forms of ATTR amyloidosis: ATTR cardiomyopathy (ATTR-CM) and ATTR peripheral neuropathy (ATTR-PN).

To recap …

 

Cardiomyopathy

Cardiomyopathy is a broad term that is used to describe disease of the heart muscle, making it difficult for the heart to provide the body with an adequate blood supply. It is a common cause of sudden cardiac arrest and sudden cardiac death, which can lead to heart failure and even death. 

Types of Cardiomyopathy:

  • Dilated Cardiomyopathy → dilation of the left ventricle prevents the heart from pumping effectively
  • Hypertrophic Cardiomyopathy → abnormal thickening of the heart muscle most commonly surrounding the left ventricle
  • Restrictive Cardiomyopathy → stiffening of the heart muscle results in an inelasticity
  • Arrhythmogenic Right Ventricular Dysplasia → scar tissue replaces healthy tissue of the right ventricle
  • Unclassified Cardiomyopathy → all other forms of cardiomyopathy fall within this category

 

Peripheral Neuropathy

Peripheral neuropathy, also referred to as polyneuropathy, is a very broad term used to describe damage of the peripheral nerves. Damage to these nerves most commonly causes numbness, pain, and weakness but can affect other areas of the body including, but not limited to, circulation, digestion, and urination. 

Types of Neuropathy:

  • Motor Neuropathy → damage to the motor nerves 
  • Sensory Neuropathy → damage to sensory nerves 
  • Autonomic Nerve Neuropathy → damage to autonomic nerves that control involuntary functions 
  • Combination Neuropathies → damage to a mix of 2 or 3 of these other types of neuropathies

 

ATTR Amyloidosis

The origin of this disease can be genetic (hATTR) or non-genetic, or “wild-type” (ATTRwt). Regardless, in ATTR amyloidosis, the transthyretin (TTR) protein is misfolded and aggregates, forming amyloid fibers that deposit into tissues and organs. The deposition of protein causes organ dysfunction and can even cause organ failure and death. 

 

ATTR-CM and ATTR-PN

Depending on the location of protein deposition, the disease is referred to in different ways. For instance, when the primary location of amyloid deposit is in the heart, the disease is referred to as ATTR cardiomyopathy (ATTR-CM). On the other hand, when the primary location of amyloid deposit is in the nerves, the disease is referred to as ATTR peripheral neuropathy (ATTR-PN).

ATTR-CM impairs the heart’s ability to pump effectively. A major challenge surrounding this disease is that symptoms of ATTR-CM are often similar to other heart conditions like enlarged heart and heart failure. This makes diagnosing the disease increasingly more difficult. Individuals with hATTR typically present symptoms in their 50s and 60s, whereas those with ATTRwt may not present symptoms until their 70s and later. 

Common Symptoms of ATTR-CM:

  • Fatigue
  • Swelling of legs, ankle, or abdomen
  • Shortness of breath with activity
  • Orthostatic hypotension
  • Difficulty breathing when lying down
  • Arrhythmia

ATTR-PN impairs the function of the nervous system. While amyloid most commonly builds up in the peripheral nervous system, deposition can also occur in the autonomous system. This results in a diversity of symptoms that are specific to the site of amyloid deposition. Symptom presentation is much more diverse, occurring as early as the 20s, or as late in life as the 70s. 

Common Symptoms of ATTR-PN:

  • Carpal tunnel syndrome
  • Diarrhea and/or constipation
  • Nausea, vomiting
  • Loss of appetite
  • Sexual dysfunction
  • Muscle weakness
  • Eye problems
  • Orthostatic hypotension

Expert Insights – Cardiac Clues and Clinical Signs

In part 1 of a 2-part series, Dr. Keyur Shah, cardiologist from VCU Health’s cardiac amyloidosis care team, discusses the two most common types of transthyretin (TTR) amyloidosis: hereditary and wild-type. He details how ATTR cardiomyopathy amyloidosis presents and manifests itself to impair the heart. Dr. Shah lists clinical clues, “red flags,” and biomarkers which can raise suspicion of the presence of amyloidosis. Next, he discusses insights that can be gained from echocardiograms, electrocardiograms, and cardiac MRIs and how they offer possible indicators of the disease presence. Once amyloidosis is suspected, definitive diagnosis testing is next.

 

In part 2 of a 2-part series, Sarah Paciulli, Heart Failure Nurse Practitioner, from VCU Health’s cardiac amyloidosis care team, continues from where Dr. Keyur Shah ended in Part I and discusses here in Part II the non-cardiac clues of transthyretin (TTR) amyloidosis. She expands the list of clinical clues and “red flags” that clinicians should be alert to, including orthopedic manifestations, erectile dysfunction, and polyneuropathy.

 

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References:

https://www.pfizer.com/news/articles/understanding_this_rare_disease_called_attr_amyloidosis

https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709

https://www.yourheartsmessage.com

https://healthjade.net/familial-amyloidosis/

https://my.clevelandclinic.org/health/diseases/14737-neuropathy

https://www.hopkinsmedicine.org/health/conditions-and-diseases/peripheral-neuropathy

https://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/symptoms-causes/syc-20352061

https://practicalneurology.com/articles/2021-july-aug/neuromuscular-amyloidosis

https://healthjade.net/familial-amyloidosis/



Carpal Tunnel & Amyloidosis

Look to the Wrist for an Early Diagnostic Clue: Tissue samples from carpal tunnel surgery hold screening utility

According to the Cleveland Clinic, tenosynovial tissue biopsy at the time of carpal tunnel surgery can be a useful tool for detecting cardiac amyloidosis at an earlier stage, suggests a recent Cleveland Clinic study in the Journal of the American College of Cardiology (JACC) (2018;72:2040-2050).

“We found that 1 in 10 older patients who underwent carpal tunnel release surgery for idiopathic carpal tunnel syndrome had either ATTR [transthyretin] or AL [light chain] amyloidosis in a sample of patients who had tenosynovial tissue removed,” says Cleveland Clinic cardiologist Mazen Hanna, MD, the study’s primary investigator. “This may be an early marker or precursor of amyloid heart disease.”

An accompanying editorial in JACC (2018;72:2051-2053) calls the investigation “a well-conducted pilot study that should be seen as a justification for larger screening efforts.”

Better defining the amyloid/carpal tunnel connection

The study was prompted by recognition that, despite the classic association of amyloidosis with carpal tunnel syndrome, the frequency of cardiac involvement at the time of carpal tunnel release surgery had never been established.

“The index patient that got us thinking about this project was operated on by Cleveland Clinic orthopaedic surgeon William Seitz, MD, a key collaborator on the study, who noted thickened tenosynovial tissue and astutely asked for a Congo red stain,” Dr. Hanna explains. “In the wake of that, we decided to undertake this study to determine the prevalence and type of amyloid deposits in carpal tunnel surgery patients and assess for cardiac involvement.”

So Drs. Hanna and Seitz, together with colleagues from Cleveland Clinic’s Heart & Vascular and Orthopaedic & Rheumatologic Institutes, ended up prospectively studying consecutive men aged 50 or older and women aged 60 or older undergoing carpal tunnel release surgery at Cleveland Clinic over a one-year period. They stained samples of tenosynovial tissue from all patients; those with confirmed amyloid deposits were typed with mass spectrometry and the patients underwent cardiac evaluation consisting of electrocardiography, echocardiography with longitudinal strain, technetium pyrophosphate scintigraphy and blood tests for biomarkers.

Findings prompt therapy initiation in three patients

Of the 98 patients enrolled, 10 (10.2 percent) had a positive biopsy for amyloid — seven ATTR, two AL and one untyped. Two of these patients were diagnosed with hereditary ATTR, two were determined to have cardiac involvement (one AL, one ATTR wild-type) and three were started on pharmacologic therapy.

Notably, patients with ATTR demonstrated no difference in plasma transthyretin concentration or tetramer kinetic stability, which indicates that these measures likely cannot serve to detect cardiac amyloidosis on their own.

Low-cost method of early detection

“Amyloid cardiomyopathy is an underrecognized cause of heart failure with preserved ejection fraction,” Dr. Hanna observes. “We believe that screening patients for amyloidosis when they have carpal tunnel surgery can be an inexpensive way to diagnose cardiac involvement early and help avert progressive heart failure.”

This is particularly true, he notes, with the advent of the first effective therapies for cardiac amyloidosis, which recently have rendered the condition medically treatable for the first time.

“The early recognition made possible by tenosynovial tissue biopsy is critical, since current treatment strategies suppress the production of precursor protein or prevent protein misfolding but do not directly target current amyloid deposits,” Dr. Hanna explains. “This allows for implementation of disease-modifying therapy prior to development of cardiac symptoms.”

He adds that the detection of AL in two of the 10 patients with biopsy-diagnosed amyloidosis is especially notable since AL cardiac amyloidosis tends to progress more rapidly and has a poor prognosis once cardiac involvement advances.

Time for a screening algorithm

Dr. Hanna and his colleagues are continuing to follow up the study cohort to observe and report additional noteworthy findings. In the meantime, these initial results, together with emerging data related to soft tissue amyloidosis, have prompted implementation of a new screening algorithm at Cleveland Clinic.

The algorithm, available as a supplementary online figure to the JACC study report, guides hand surgeons on the appropriateness of tenosynovial biopsy at the time of carpal tunnel release surgery. If Congo red staining is positive, typing with mass spectrometry and referral to an amyloidosis specialist is indicated.

The authors of the accompanying JACC editorial note that while the best screening methodology remains to be determined, “a screening algorithm will likely be incorporated into everyday clinical practice in the near future.”

Learn more about other orthopedic manifestations

 

Closing Words



Orthopedic Manifestations in Amyloidosis

Dr. Mazen Hanna, cardiologist at the Cleveland Clinic and co-director of the Amyloid Program, discusses orthopedic manifestations in amyloidosis. Increasingly, such manifestations are known to be associated with multiple orthopedic pathologies and recognized as a missed opportunity for earlier diagnosis of transthyretin (ATTR) amyloidosis. He recounts the development of a pioneering study connecting carpal tunnel release surgery and amyloidosis. Dr. Hanna concludes this presentation with patient cases and the importance of biopsying tenosynovial tissue from CTR surgery; it’s easy, quick, and inexpensive.

Clinical Signs that Suggest Transthyretin Amyloidosis: Non-cardiac Clues – Part II

In part 2 of a 2-part series, Sarah Paciulli, Heart Failure Nurse Practitioner from VCU Health’s cardiac amyloidosis care team, continues from where Dr. Keyur Shah ended in Part I and discusses here in Part II the non-cardiac clues of transthyretin (TTR) amyloidosis. She expands the list of clinical clues and “red flags” that clinicians should be alert to, including orthopedic manifestations, erectile dysfunction, and polyneuropathy.  See Part I: “Cardiac Clues that Suggest Transthyretin Amyloidosis” for more.

 

Testing Carpal Tunnel for Amyloidosis: One Patient’s View

Linda, one of the ASB’s patient educators, shares highlights from her experience with carpal tunnel syndrome and a recent interaction with one of her hand surgeons.

Key take-away … biopsy the tissue from CTR surgery, as it may offer advance awareness of the disease.

 

Musculoskeletal Pathology as an Early Warning Sign of Systemic Amyloidosis

Dr. Shari Liberman, a hand and upper extremities surgeon from Houston Methodist Orthopedics & Sports Medicine, discussed six orthopedic manifestations and their pathology as it relates to systemic amyloidosis. Published studies, coupled with her experience, has led to a belief that these manifestations can offer important evidence of amyloidosis. She concludes with thoughts regarding an orthopedic differential and biopsy considerations for each of these manifestations.

Patient Insights: Best kept secret

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights.

Have a listen to this brief clip from Ozzie on his discovery of the ‘best kept secret’ as it pertains to diagnosing amyloidosis – carpal tunnel syndrome.

Patient Insights: Biopsy the CTR tissue!

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights.

Have a listen to this brief clip from Linda with thoughts on how orthopedic hand surgeons can be on the front line of diagnosis through CTR tissue biopsy.

Carpal Tunnel & Amyloidosis – An Update

The connection between carpal tunnel and amyloidosis is one that is already established. In fact, carpal tunnel syndrome is one of many potential symptoms of amyloidosis, but it is a symptom that tends to present early. It is not uncommon to hear patients started experiencing carpal tunnel five to ten years before they were diagnosed with amyloidosis.

TWO STUDIES

Clinicians are becoming aware of this connection and are starting to investigate the connection. Two studies have been published that investigate the connection between carpal tunnel and amyloidosis.

The first study from 2018 was a “prospective, cross-sectional, multidisciplinary study of consecutive men age ≥ 50 years and women ≥ 60 years undergoing carpal tunnel release surgery. Biopsy specimens of tenosynovial tissue were obtained and stained with Congo red.”3 Of the patients that were eligible for Congo red staining (n=98), a total of 10 came back positive for amyloidosis.3 That is a hit rate of just over 10%.

In a larger second study from 2022, a total of 185 patients underwent carpal tunnel release surgery, where 54 biopsies confirmed evidence of amyloidosis with Congo red staining.1 That is a hit rate of 29%.

The results of these studies are powerful and provide an opportunity to change the trajectory of diagnosing amyloidosis, particularly doing so much earlier. According to the Bureau of Labor and Statistics and the National Institute for Occupational Safety and Health, carpal tunnel release surgery is the second most common type of surgery, performed over 230,000 times every year.4

PERSPECTIVE FROM AN ORTHOPEDIC SURGEON

“Since carpal tunnel syndrome is often one of the earliest signs of underlying amyloidosis, those with undiagnosed disease could greatly benefit from tissue biopsies at the time of surgery. A positive biopsy result could initiate the road to disease stabilization and hopefully future cures, avoiding the all-too-often rapid decline of health before final recognition. Bringing the surgeon into the arena of amyloidosis diagnosis and care broadens the net for catching this disease early and prepares the surgeon as a team-player for future medical support.”

Charles Williams Sr., MD

Retired Orthopedic Surgeon

 

CONCLUSION

Screening for amyloidosis in carpal tunnel release surgery can be a low-cost method of detecting amyloidosis that should be considered.2

Most importantly, identifying and diagnosing amyloidosis early has the potential to significantly improve patient outcomes and substantially alter the course of disease.

Truly life changing.

P.S. Click here to read our previous post on Carpal Tunnel & Amyloidosis

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Resources:

  1. https://pubmed.ncbi.nlm.nih.gov/35469694/
  2. https://consultqd.clevelandclinic.org/cardiac-amyloidosis-look-to-the-wrist-for-an-early-diagnostic-clue/
  3. https://www.sciencedirect.com/science/article/pii/S0735109718381634?via%3Dihub
  4. https://www.orthoarlington.com/contents/patient-info/conditions-procedures/11-astounding-carpal-tunnel-statistics
  5. https://www.verywellhealth.com/open-surgery-or-endoscopic-carpal-tunnel-surgery-4083069
  6. https://mailchi.mp/ea0a0bb441eb/carpal-tunnel-amyloidosis

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