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Diagnosing Amyloidosis: A Two-Step Process

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.

  1. First, if amyloidosis is suspected, testing must be done to confirm the presence of amyloid.
  2. 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.

 

Diagnosing AL and ATTR Cardiac Amyloidosis

Dr. Justin Grodin, a cardiologist and co-director of the UT Southwestern Multidisciplinary Amyloidosis Program, goes through the diagnostic process for AL and ATTR cardiac amyloidosis. He discusses key differences between AL and ATTR, and how typing of amyloidosis is paramount to consider in order to subsequently develop a treatment plan. He goes through a diagnostic algorithm to help clinicians arrive at an accurate diagnosis. Finally, he stresses the importance of genetic testing and counseling for ATTR to differentiate between wild-type and hereditary, as well as identifying the specific genetic variant.

Building an Index of Suspicion for Cardiac Amyloidosis

Understanding that amyloidosis exists BEFORE organs become involved is critical to developing an early diagnosis. Dr. Grodin, a cardiologist and co-director of the UT Southwestern Multidisciplinary Amyloidosis Program, discusses these early symptoms, family history, and red flags to be aware of in order to build an index of suspicion.

Raising Awareness of Cardiac Amyloidosis

Dr. Barry Trachtenberg, cardiologist at Houston Cardiovascular Associates, shares ways that physicians can raise their awareness of cardiac amyloidosis, whether AL or ATTR. He discusses multiple organ systems and how test results may present clues to consider amyloidosis. He offers a diagnostic algorithm with early red flags that can aid in the identification and typing of amyloidosis. Dr. Trachtenberg concludes with keys to remember, including questions to ask patients, which can elevate the suspicion of amyloidosis.

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.

A Patient Guide for Understanding Amyloidosis

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

 

Multidisciplinary Care for Cardiac Amyloidosis Patients

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 HERE.

 


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



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.

Heart Failure & Amyloidosis

 

We would like to thank the Cleveland Clinic for this information, unless specifically noted otherwise.

 

WHAT IS HEART FAILURE?

Heart failure occurs when the heart muscle doesn’t pump blood as well as it should. Heart failure can occur if the heart cannot pump (systolic) or fill (diastolic) adequately.

 

Almost six million Americans have heart failure, and more than 870,000 people are diagnosed with heart failure each year. Heart failure (congestive heart failure) is the leading cause of hospitalization in people older than 65.

 

WHAT ARE THE TYPES OF HEART FAILURE?

There are many causes of heart failure, but the condition is generally broken down into these types:

Left-sided heart failure

Heart failure with reduced left ventricular function (HF-rEF)

The lower left chamber of the heart (left ventricle) gets bigger and cannot squeeze (contract) hard enough to pump the right amount of oxygen-rich blood to the rest of the body.

Heart failure with preserved left ventricular function (HF-pEF)

The heart contracts and pumps normally, but the bottom chambers of the heart (ventricles) are thicker and stiffer than normal. Because of this, the ventricles can’t relax properly and fill up all the way. Because there’s less blood in the ventricles, the heart pumps out less blood to the rest of the body when it contracts.

Right-sided heart failure

Heart failure can also affect the right side of the heart. Left-sided heart failure is the most common cause of this. Other causes include certain lung problems and issues in other organs.

 

WHAT ARE THE SYMPTOMS OF HEART FAILURE?

Symptoms of heart failure include:

  • Shortness of breath.
  • Feeling tired (fatigue) and having leg weakness when active.
  • Swelling in ankles, legs and abdomen.
  • Weight gain.
  • Need to urinate while resting at night.
  • Rapid or irregular heartbeats (palpitations).
  • A dry, hacking cough.
  • A full (bloated) or hard stomach, loss of appetite or upset stomach (nausea).

Symptoms of heart failure can range from mild to severe and may come and go. Unfortunately, heart failure usually gets worse over time. As it worsens, patients may have more or different signs or symptoms.

 

WHAT CAUSES HEART FAILURE?

Although the risk of heart failure doesn’t change with age, you’re more likely to have heart failure when older. Many medical conditions that damage the heart muscle can cause heart failure. Common conditions include:

 

WHAT TYPES OF TESTS ARE USED TO DIAGNOSE HEART FAILURE?

Common tests include:

 

WHAT IS THE IMPORTANCE OF EJECTION FRACTION?

Ejection fraction (EF) is one way to measure the severity of the condition. If it’s below normal, it can mean the patient has heart failure. The ejection fraction tells the healthcare provider how good of a job the left or right ventricle is doing at pumping blood. Usually, the EF number is talking about how much blood the left ventricle is pumping out because it’s the heart’s main pumping chamber.

Several non-invasive tests can measure the EF. A normal left ventricular ejection fraction (LVEF) is 53% to 70%. An LVEF of 65%, for example, means that 65% of the total amount of blood in the left ventricle is pumped out with each heartbeat. The EF can go up and down, based on the heart condition and how well the treatment works.

 

HOW IS AMYLOIDOSIS RELATED TO HEART FAILURE?

As stated by the Cleveland Clinic, cardiomyopathy is one of the medical conditions that damage the heart muscle and can cause heart failure. Cardiomyopathy refers to conditions that affect the myocardium (heart muscle). Cardiomyopathy can make your heart stiffen, enlarged or thickened and can cause scar tissue. As a result, your heart can’t pump blood effectively to the rest of your body. In time, your heart can weaken and cardiomyopathy can lead to heart failure. 

One of the common types of cardiomyopathy is Transthyretin amyloid cardiomyopathy (ATTR-CM), characterized by an abnormal protein buildup (ATTR amyloidosis) in the heart’s left ventricle (primary blood-pumping chamber). ATTR-CM is a life-threatening, underrecognized, and underdiagnosed type of amyloidosis that affects the heart and is associated with heart failure. It was once considered a rare disease, but recently, improved diagnostic tools and greater attention to early manifestations of the disease are leading to an increasing number of diagnosed cases. (3)

 

Listen to an American Heart Association podcast (12 minutes) titled “What is ATTR-CM?”

 

ATTR-CM Basics (5)

 

Recent Research (4)

Davies et al.(2022) published an informative paper titled “A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure with Preserved Ejection Fraction.” In conclusion, they believe their findings can increase recognition of ATTR-CM among patients with HFpEF in the community.

Key Points

Question.  Which patients with heart failure and preserved ejection fraction (HFpEF) have an increased risk of transthyretin amyloid cardiomyopathy (ATTR-CM) warranting technetium Tc 99m pyrophosphate scintigraphy?

Findings.  The study team developed and validated an ATTR-CM score comprising of 3 clinical (age, male sex, hypertension diagnosis) and 3 echocardiographic (ejection fraction, posterior wall thickness, relative wall thickness) variables to predict increased risk of ATTR-CM in HFpEF cohorts with variable ATTR-CM prevalence.

Meaning.  Because specific and highly effective therapy for ATTR-CM exists, the ATTR-CM score can provide a simple tool to guide use of technetium Tc 99m pyrophosphate scintigraphy and increase recognition and appropriate therapy of ATTR-CM in patients with HFpEF.

Abstract

Importance.  Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP.

Objective  To derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF.

Design, Setting, and Participants.  Retrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation.

Main Outcomes and Measures.  Performance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials.

Results.  Participant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48% ), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6% ), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range −1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P < .001) and calibration (Hosmer-Lemeshow; χ2 = 4.6; P = .46) were strong. Discrimination (AUC ≥ 0.84; P < .001 for all) and calibration (Hosmer-Lemeshow χ2  = 2.8; P = .84; Hosmer-Lemeshow χ2  = 4.4; P = .35; Hosmer-Lemeshow χ2 = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score.

Conclusions and Relevance  A simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community.

 

In closing … a known condition of heart failure is cardiomyopathy, of which one type – Transthyretin Amyloid Cardiomyopathy (ATTR-CM) – may be the underlying cause. In seeking answers to heart failure, keep this in mind.

 

 

Sources:

  1. https://my.clevelandclinic.org/health/diseases/17069-heart-failure-understanding-heart-failure
  2. https://my.clevelandclinic.org/health/diseases/16841-cardiomyopathy
  3. https://www.emergency-live.com/health-and-safety/cardiac-amyloidosis-what-it-is-and-tests-for-diagnosis/?fbclid=IwAR0lNrxqubUbFAhNcew233YU_CqN6Udf_RYj1FhBAErSrqou5CKjypZPk4A
  4. Davies DR, Redfield MM, Scott CG, et al. A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction. JAMA Cardiol. 2022;7(10):1036–1044. doi:10.1001/jamacardio.2022.1781
  5. https://www.yourheartsmessage.com/about-attr-cm 
  6. American Heart Association – What is ATTR-CM

https://www.heart.org/-/media/Files/Health-Topics/Answers-by-Heart/What-Is-ATTRCM.pdf

 

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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