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Often called “Popeye Deformity,” bicep bunching is visible when the patient flexes their arm, giving the appearance of Popeye-like arms. While it is the result of a torn tendon, it can be a leading indicator of more serious issues.

WHAT IS IT?

When the bicep tendon is ruptured, patients develop a bunching of the biceps upon flexion of the arm against gentle resistance. Tendon ruptures occur largely in the dominant arm of each patient, with one-quarter of patients developing ruptures in both arms. Interestingly, of those who had a rupture, 37.8% didn’t know it.

Below watch a video from The Lancet showing what bicep bunching looks like.

WHAT DOES IT POTENTIALLY INDICATE?

Two things.

1. Bicep bunching may be a marker for ATTRwt. According to MedPage Today, spontaneous ruptures of the distal biceps tendon may be a marker of wild-type transthyretin (TTR) cardiac amyloidosis, a single-center study found. The presentation of a tendon rupture, an easily elicited diagnostic sign, in a patient with HFpEF should raise suspicion for wild-type TTR cardiac amyloidosis.

The picture below (Source: JAMA September 12, 2017 Volume 318, Number 10) offers examples of ruptured biceps tendon in two patients with biopsy-proven ATTRwt Cardiac Amyloidosis. ATTRwt indicates wild-type transthyretin amyloidosis. Patient 1 with prior rupture of the biceps tendon and bunching of the biceps with flexion. Patient 2 with acute rupture of the biceps tendon in the left arm; the tendon rupture occurred with trivial trauma, five years after Cardiac Amyloidosis diagnosis.

2. ATTRwt may contribute to heart failure. Wild-type transthyretin amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure with preserved ejection fraction (HFpEF).

WHY IS IT IMPORTANT?

Bicep bunching may be a marker of wild-type transthyretin (TTR) cardiac amyloidosis, potentially giving physicians an easy way to determine the underlying cause of heart failure with preserved ejection fraction (HFpEF) in some patients. Those who were aware, reported that the distal biceps tendon ruptured approximately five years prior to heart failure diagnosis, thus perhaps offering a leading insight.

In addition, early diagnosis of wild-type TTR cardiac amyloidosis (ATTRwt) is important because treatments are now available to slow, if not halt, disease progression. Unfortunately, the diagnosis of ATTRwt is often not considered in bicep bunching cases due to the perceived rarity of the disease.

“The clinical importance [of this study] is that the detection of a ruptured distal biceps tendon may be a clue for the diagnosis of wild-type TTR amyloidosis as the cause for heart failure. This diagnosis is often overlooked in clinical practice, so this relatively simple evaluation could increase detection of the disease,” said Stuart Katz, MD, of NYU Langone Health. “Enhanced detection could lead to better treatment.”

EXPERT INSIGHTS VIDEO ON MUSCULOSKELETAL MANIFESTATIONS

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.

Sources ———————————————————————————————————————

https://www.healthline.com/health/popeye-deformity

https://www.medpagetoday.com/cardiology/chf/67850

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818850/

https://www.researchgate.net/publication/319657750_Association_Between_Ruptured_Distal_Biceps_Tendon_and_Wild-Type_Transthyretin_Cardiac_Amyloidosis

https://www.shoulderdoc.co.uk/article/721

https://www.thelancet.com/doi/story/10.1016/vid.2019.02.26.107679

https://www.youtube.com/watch?v=fHXu_0IZ3vU

The treatment for patients with Transthyretin Cardiac Amyloidosis has advanced significantly since 2018 when there were no FDA-approved therapies. In this presentation, Dr. Mat Maurer from Columbia University shares how diagnostic imaging techniques have significantly improved, thereby reducing the need for an invasive heart biopsy. In addition, he shares fascinating statistics on how the age and stage of diagnosis has been evolving. Based on today’s clinical trials, providers are optimistic that the expansion of options for patient care will continue.

The future is indeed looking brighter.

Patients with ATTR amyloidosis are commonly faced with neurological complications. In this presentation, Dr. Chafic Karam from the University of Pennsylvania goes through four areas: an overview of the neurological systems, how amyloid damages the nerves, neurological signs of ATTR amyloidosis, and how to detect amyloid and diagnose ATTR amyloid neuropathy.

Dr. Sarah Lee, Assistant Professor of Medicine at the University of Washington, provides a brief clinical overview of amyloidosis.

Amyloidosis can present in many types with the three most prevalent being light chain (AL) amyloidosis, hereditary variant transthyretin (ATTRv) amyloidosis, and wild type transthyretin (ATTRwt) amyloidosis. Being a rare disease, diagnosis can be particularly challenging, given that the general medical community is not well educated on the malady and symptoms are often associated with other more common ailments.

Successfully diagnosing the disease requires a two-step process before an appropriate treatment program can be determined and implemented for each patient.

First, if amyloidosis is suspected, testing must be done to confirm the presence of amyloid.
Second, once the presence of amyloid is confirmed, testing must then be done to identify and confirm the type of amyloidosis.

It is crucial that the second step, where the correct type of amyloidosis is identified, as the treatment regime can be different for each type. Here we share two different patient experiences which illustrate successful execution of the two-step diagnostic process.

Patient Case #1

The first case involved a 23-year old female. In 2017 she experienced an episode of coughing up blood, after which she looked in her throat with a flashlight and discovered a sizable lump. The patient met with a local ENT, who incorrectly diagnosed allergies, and prescribed over-the-counter medicine. With no improvement, she met with a second ENT. Testing was performed on the patient’s left oral pharynx utilizing a Congo red staining biopsy process which confirmed the presence of amyloid in the tissue. Additionally, mass spectrometry was performed which successfully differentiated the type of amyloidosis as being ALH (lambda light chain and delta heavy chain). Subsequently, she was referred to a hematologist who ordered a bone marrow biopsy and blood testing. The bone marrow biopsy summary notes read “….in conjunction with the concurrent finding of monoclonal lambda light chain restricted plasma cells in the marrow by flow cytometry, the findings are consistent with involvement of the marrow by a plasma cell neoplasm.”

Additionally, the blood testing confirmed elevated light chains as shown below.

Patient Case #2

The second case involved a man in his mid-fifties. He began experiencing disease symptoms approximately 6-7 years prior to being diagnosed in early 2019. He initially experienced gradually progressing numbness in his feet, legs, hands and forearms, as well as bilateral carpal tunnel syndrome. Soon after, he began experiencing symptoms of lightheadedness and fainting. Additionally, he started experiencing progressive gastro-intestinal issues such as acid reflux, chronic coughing, and frequent bouts of constipation and diarrhea. By 2018, his physical condition was rapidly deteriorating, including a total weight loss of approximately 80 pounds. During this extended period of time he was seen by a variety of physicians including internal medicine, neurology, endocrinology, gastroenterology, oncology, and cardiology, none of who were successful in arriving at a conclusive diagnosis. His list of maladies included cardiomyopathy, peripheral neuropathy, autonomic neuropathy, bilateral carpal tunnel syndrome, and gastroparesis, all which are classic symptoms of amyloidosis.

Finally, in early 2019 his condition was successfully diagnosed by an amyloidosis specialist. An echocardiogram was performed as well as a cardiac MRI (utilizing a gadolinium tracer) to identify amyloid fibrils and related damage in the heart tissue. These tests confirmed the presence of amyloid. A free light chain serum test was performed which ruled out AL amyloidosis, and Transthyretin DNA sequencing was performed to differentiate between the hereditary variant and wild-type of ATTR, which identified the T80A (legacy T60A) variant of transthyretin (ATTRv) amyloidosis. The two tests were successful in identifying the type of amyloidosis. The associated testing results are show below.

Echocardiogram Summary Notes

Associated Cardiac MRI Interpretation

DNA Sequencing Result

Once Diagnosed, Next is a Treatment Plan

Once the presence of amyloid is confirmed, and the type is identified, then it is time to treat the disease. In each of these patient cases the disease was diagnosed utilizing the two-step process to identify and confirm the type of amyloidosis. In both cases, successful treatment regimens were implemented which were effective in putting the disease into remission and/or halting disease progression.

Treatment options for amyloidosis have been vastly improved over the past several years. What was previously considered to be a foregone fatal disease can now be a manageable chronic disease. To ensure the best patient outcome, a timely diagnosis utilizing the two-step process, is essential.

Amyloidosis is a multi-system disease, making diagnosis challenging. In this informative patient guide, the American Society of Nuclear Cardiology (ASNC) discusses common symptoms, types of amyloidosis, red flags to be aware of, diagnostic tests and available treatment options.

CLICK HERE to read/download ASNC’s Guide for Understanding Amyloidosis

Multi-systemic diseases such as amyloidosis are complex to diagnose, but also complex in treatment and ongoing patient care. It takes a village. In this seminal piece, the American College of Cardiology (ACC) provides an Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis.

According to Dr. Vaishali Sanchorawala, Director of the Amyloidosis Center at Boston Medical Center, “The results and progress in the therapeutic landscape of systemic amyloidosis are unbelievable, unprecedented and unheard of for this uniformly fatal disease of the 1990s. But they are not enough, and therefore we need to work together to make a difference.”

This paper is an absolute must-read for cardiologists and other specialties such as neurology, gastroenterology, nephrology and hematology. To read, click on the image below.

Thank you.

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Source:

Kittleson M, Ruberg F, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. J Am Coll Cardiol. 2023 Mar, 81 (11) 1076–1126.

https://www.jacc.org/doi/10.1016/j.jacc.2022.11.022

Historically it has been thought that the majority of elderly cardiomyopathy patients diagnosed with amyloidosis, ATTR-CM, transthyretin amyloid cardiomyopathy, suffered from wild-type, a non-genetic version of the disease that most commonly affects but is not exclusive to men over seventy years of age. A study in the UK conducted from January 2010 through August 2022 was conducted to determine whether this was true. It is thought that this study was the first time such a large population of ATTR-CM patients was studied to consider the actual prevalence of the differing disease types. The researchers stated purpose was “ …to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR-CM.”¹

A paper detailing the results of the study, ‘Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy’ by A. Porcari et al.¹, published January 16, 2023 in the European Journal of Heart Failure provide specifics about the methodology, statistical analysis of the results, and an analysis of the findings. An invited editorial about that article, ‘Variant and wild type transthyretin amyloidosis: two sides of the same coin or different currencies in different pockets?’, by Osnat Itzhaki Ben Zadok and Rodney H. Falk provides comments and an assessment of the study discussed in the A. Porcari paper.² A helpful summary of the differences between wild-type and hereditary amyloidosis can be found here.³

With increased awareness of amyloidosis and the various types as well as developments in the technology used to diagnose and type ATTR amyloidosis, it has now become relatively easy to determine whether a patient is suffering from the hereditary version or the wild-type. Imaging has become preferred over the previous “gold standard” of endomyocardial biopsy. The study population was selected from those for whom ATTR-CM was established as the diagnosis using echocardiography, nuclear scintigraphy, and TTR gene sequencing at the National Amyloidosis Center (NAC) in London, the single center for diagnosing and treating amyloidosis patients in the UK. Correct diagnosis and typing of the disease could allow for appropriate treatment to begin resulting in the likelihood of an improved disease management and outcome for the patient.

A total of 2,029 patients were accepted into the study, none of whom had previously received genetic testing for the disease. Patients identified through gene sequencing as having the hereditary version of the disease, 141 total, were moved to medication as soon as it became available. Of note, all patients who had been treated with any of the then available medication for ATTR amyloidosis — tafamidis, inotersen, diflunisal, or patisiran, and all patients who were participating in clinical trials for therapies for the disease — were excluded from the study. This was to remove the possibility of the therapies skewing the results. All participants were 70 years of age or older. The patients were all followed at the NAC in London, the only center for the diagnosis and treatment of Amyloidosis in the UK. This allowed for unprecedented access to what is thought to be the majority of ATTR-CM in the country. All causes of death were tracked for the duration of the study.

The table below illustrates the number of ATTM-CM patients in the study who were thought to be suffering from wild-type amyloidosis but after testing were actually found to have a hereditary, variant, version of the disease instead. Specific data from the tests used to make this determination can be found in the article where the following table is found.

Correcting the diagnosis then allowed the patients to be moved to more appropriate therapies.

Further discussion in the Porcari article considers the study population and those currently listed in the THAOS registry⁴ by percentage of total ATTR-CM patients in the United Kingdom, the United States, and the rest of the World for both wild-type and variant disease with the more common variants also identified. It is thought that as many as 20% of ATTR-CM identified as having the wild-type disease likely have a variant version but have not had genetic testing to correctly determine that.¹

The article goes on to discuss the most commonly seen demographics and presentations of ATTRwt-CM and ATTRv-CM in the elderly, and the effects of the various therapies currently available as well as their mechanisms and limitations.

While some symptoms of wild-type amyloidosis and hereditary, variant, amyloidosis are similar, it is easy to differentiate between the two diseases. With careful testing, as noted in the article, this then allows for the proper management and treatment of the disease. The concluding paragraph of the paper really sums up the findings and sends an important message.

“In conclusion, up to 20.7% of elderly patients with ATTR-CM carry a pathogenic TTR mutation with a higher proportion still among specific ethnic groups. Among patients diagnosed with ATTR-CM, younger age at diagnosis, female gender, Afro-Caribbean ethnicity, AF, IHD, polyneuropathy and orthostatic hypotension are independently associated with ATTRv-CM. A diagnosis of ATTR-CM should prompt sequencing of the TTR gene in all patients, regardless of age, gender and ethnicity.”¹

Sources:
1. https://onlinelibrary.wiley.com/doi/full/10.1002/ejhf.2776 Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy, Aldostefano Porcari, Yousuf Razvi, Ambra Masi, Rishi Patel, Adam Ioannou, Muhammad U. Rauf, David F. Hutt, Dorota Rowczenio, Janet Gilbertson, Ana Martinez-Naharro, Lucia Venneri, Carol Whelan, Helen Lachmann, Ashutosh Wechalekar, Candida Cristina Quarta, Marco Merlo, Gianfranco Sinagra, Philip N. Hawkins, Marianna Fontana, Julian D. Gillmore, January 2023

2. https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2808 Variant and wild type transthyretin amyloidosis: two sides of the same coin or different currencies in different pockets?
Osnat Itzhaki Ben Zadok, Rodney H. Falk, February 2023

3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500251/ Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies
Haruki Koike and Masahisa Katsuno, September 2020

4. https://www.jns-journal.com/article/S0022-510X(15)00745-5/fulltext THAOS – The Transthyretin Amyloidosis Outcome Survey , F. Barroso, M. Waddinton-Cruz, et. Al., October 2015

Per the National Institute of Health, “One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions.” In this piece we provide a clinical trial update for transthyretin (TTR) amyloidosis using this technology.

CRISPR FIXES GENES INSIDE THE BODY (3)

CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings.

APPLYING THE CRISPR TECHNOLOGY (3)

Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis, a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat.The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.”

Facts about Transthyretin (ATTR) Amyloidosis. Source: https://ir.intelliatx.com/

CLINICAL TRIAL UPDATE — NTLA-2001 (1)

Intellia Therapeutics and Regeneron shared a press release recently announcing initial data from the cardiomyopathy arm of the ongoing Phase 1 trial of NTLA-2001, an investigational single-dose in vivo CRISPR-Cas9 therapy for the treatment of transthyretin (ATTR) amyloidosis.

According to that press release, the interim data include 12 adult patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) with New York Heart Association (NYHA) Class I – III heart failure. Single doses of 0.7 mg/kg and 1.0 mg/kg of NTLA-2001 were administered intravenously, and the change from baseline in serum transthyretin (TTR) protein concentration was measured for each patient. The data revealed that treatment with NTLA-2001 led to rapid and deep reductions of up to 94 % in serum TTR by day 28. In February 2022, the companies reported clinical data that revealed rapid, deep and sustained responses in a cohort of 15 patients with hereditary transthyretin (TTR) amyloidosis with polyneuropathy (ATTRv-PN).

ATTR is a rare, progressive disease, in which a protein known as TTR becomes misfolded and accumulates as plaques in tissues throughout the body. This causes serious complications that mainly involve the heart and nerves, and most patients die 2-15 years after disease onset. NTLA-2001 was the first in vivo CRISPR therapy to be administered to humans via the bloodstream. It is designed to treat ATTR by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-based inactivation of the TTRgene in liver cells.

Read more about the available clinical data for NTLA-2001 in a previous CMN clinical trial update here.

BACKGROUND

Back in May, 2021 we wrote about the breakthrough gene-editing technology CRISPR being applied to hereditary transthyretin amyloidosis (hATTR), worthy of a background read for those unfamiliar with this science or those looking for a refresher.

BLOG – CRISPR/Cas9 – Editing the Code of Life

Sources:

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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