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Expert Insights: AL Amyloidosis: Symptoms, Diagnostics and Challenges

Dr. Gurbakhash Kaur, co-director of the amyloidosis program at UT Southwestern Medical Center, opens with a brief overview of the disease. Focusing on AL Amyloidosis, she shares how heterogeneously this disease presents – it can be very different from patient to patient, amplifying the diagnostic challenge. Symptoms may also be more commonly associated with other diseases. For example, proteinuria is often associated with diabetes and hypertension. However, clinicians should look at the bigger picture to be sure, as amyloidosis can also be a cause. Dr. Kaur reviews what should be in a basic workup when one has a clinical suspicion for amyloidosis. Once tested positive for amyloidosis, a second necessary step is to determine the type of amyloidosis. This is critical as it will determine the appropriate course of treatment. In closing Dr. Kaur summarizes the goals of treatment, what is available today, and what drugs are in clinical trials, giving lots of hope to the AL amyloidosis community.

Diagnosing Amyloidosis: From Cardiology to Neurology – When to Think About Amyloidosis

Dr. J. Mark Sloan, Associate Professor of Medicine, Boston University Chobanian & Avedisian School of Medicine. He is a member of the BU Amyloidosis Center, the Evans Center for Interdisciplinary Biomedical Research at BU, and the program director for the hematology/oncology fellowship at Boston University. In this video, developed exclusively for the Amyloidosis Speakers Bureau, he provides a comprehensive clinical overview of diagnosing amyloidosis, from cardiology to neurology, and when to think about amyloidosis.

Peripheral Neuropathy & Amyloidosis

Neuropathy, also known as peripheral neuropathy, is a broad term that is used to describe damage to the nerves outside of the brain and spinal cord. There are over 100 types of peripheral neuropathy that can be classified into four categories, with each type having their own symptoms and prognosis. In this article, we’ll discuss the types of peripheral neuropathy and its connection to amyloidosis.

 

Symptoms

One of the challenges with neuropathy is the fact that symptoms can vary significantly based on what nerve is damaged. Additionally, symptoms can develop over the course of months to years (chronic neuropathy) or come on suddenly (acute neuropathy). Some of the most commonly seen symptoms are listed below:

  • Muscle weakness
  • Cramps
  • Muscle twitching
  • Loss of muscle and bone
  • Changes in skin, hair, or nails
  • Numbness
  • Loss of sensation or feeling in body parts
  • Loss of balance or other functions as a side effect of the loss of feeling in the legs, arms, or other body parts
  • Emotional disturbances
  • Sleep disruptions
  • Loss of pain or sensation that can put you at risk, such as not feeling an impending heart attack or limb pain
  • Inability to sweat properly, leading to heat intolerance
  • Loss of bladder control, leading to infection or incontinence
  • Dizziness, lightheadedness, or fainting because of a loss of control over blood pressure
  • Diarrhea, constipation, or incontinence related to nerve damage in the intestines or digestive tract
  • Trouble eating or swallowing
  • Life-threatening symptoms, such as difficulty breathing or irregular heartbeat

 

Types of Neuropathy

  1. Motor Neuropathy → Damage to the motor nerves control how you move.
  2. Sensory Neuropathy → Damage to sensory nerves control what you feel.
  3. Autonomic Nerve Neuropathy → Damage to autonomic nerves that control functions that are involuntary (ie. you do not consciously control).
  4. Combination Neuropathies → Damage to a mix of 2 or 3 of these other types of neuropathies. For example, damage to both sensory and motor nerves would result in sensory-motor neuropathy.

 

Amyloidosis

Peripheral Neuropathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-PN, or transthyretin amyloid polyneuropathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the nerve tissue, resulting in damage to these nerves. While amyloid deposits primarily in the peripheral nerves, it is not uncommon for amyloid deposition in the autonomic nerves as well. 

While peripheral neuropathy is most commonly associated with ATTR amyloidosis, it should be noted that peripheral neuropathy is also seen in 15-35% of patients with AL amyloidosis.

Most importantly, these are the most common and important signs and symptoms to be aware of, in order to diagnose ATTR amyloidosis.

 

Neurological Complications of ATTR Amyloidosis

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.

 

 

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References:

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/

 

Cardiomyopathy & Amyloidosis

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 can lead to heart failure and even death. In this article, we’ll discuss the types of cardiomyopathy and its connection to amyloidosis. 

 

Risk Factors 

It has no ideal target, as it can affect a person of any age, race, or gender. However, there are a number of risk factors that can put one at an increased chance of developing cardiomyopathy. 

  • Genetic History → Family history of cardiomyopathy, heart failure, or sudden cardiac arrest
  • High Blood Pressure → Over a long period of time
  • Heart Conditions → Past history of heart attack, coronary artery disease, or infection of the heart
  • Obesity → Tends to make the heart work harder to perform its normal function
  • Alcohol Use → Long period of alcohol use
  • Drug Use → Use of illicit drugs, such as cocaine, amphetamines, and anabolic steroids
  • Medications → Drugs used in the treatment of cancer, such as chemotherapy and radiation

Additionally, there are a number of diseases that increase the risk of developing cardiomyopathy, including:

  • Amyloidosis
  • Connective Tissue Disorders
  • Diabetes
  • Hemochromatosis (excess iron storage)
  • Sarcoidosis
  • Thyroid Disease

 

Types of Cardiomyopathy

  • Dilated Cardiomyopathy → Dilation of the left ventricle prevents the heart from pumping effectively. It most commonly occurs in middle-aged men and is typically the result of coronary artery disease, heart attack, or genetic defects.

  • Hypertrophic Cardiomyopathy → Abnormal thickening of heart muscle, most commonly affecting the muscles surrounding the left ventricle. This type of cardiomyopathy is strongly associated with a family history of the disease. There have been genetic mutations linked specifically with this type of cardiomyopathy.

  • Restrictive Cardiomyopathy → Stiffening of the heart muscle results in an inelasticity, making it difficult for the heart to expand and fill. It is most commonly seen in the elder population. The disease can be of idiopathic origin or of disease such as amyloidosis. This is the least common type of cardiomyopathy. 
  • Arrhythmogenic Right Ventricular Dysplasia → Scar tissue replaces healthy tissue of the right ventricle. This form of cardiomyopathy is rare and often the result of genetic mutations.
  • Unclassified Cardiomyopathy → All other forms of cardiomyopathy fall within this category.

 

Amyloidosis

Cardiomyopathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-CM, or transthyretin amyloid cardiomyopathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the heart muscle, resulting in thickening and stiffening of the heart. 

The two types of ATTR-CM are wild-type ATTR-CM (wtATTR) or hereditary ATTR-CM (hATTR). wtATTR-CM is the most common form of ATTR-CM, affecting predominantly white males 60+ years old. hATTR-CM is genetic affecting both men and women, and presents as early as 50+ years old. Interestingly, one of the mutations causing hATTR, V122I, is seen almost exclusively in individuals of African ancestry. It is believed that approximately 3-4% of African Americans carry this mutation, regardless of whether or not they develop symptoms. 

Most importantly, these are the most common and important signs and symptoms to be aware of, in order to diagnose ATTR amyloidosis.

 

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

https://www.yourheartsmessage.com

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

 

Proteinuria & Amyloidosis

According to the Cleveland Clinic, “Proteinuria is due to increased levels of protein in the urine.” Your kidneys filter waste products from your blood while retaining what your body needs — including proteins. However, some diseases and conditions allow proteins to pass through the filters of your kidneys, causing protein in the urine.

 

HOW DOES PROTEIN GET INTO URINE? (1)

Protein gets into the urine if the kidneys aren’t working properly. Normally, glomeruli, which are tiny loops of capillaries (blood vessels) in the kidneys, filter waste products and excess water from the blood.

Glomeruli pass these substances, but not larger proteins and blood cells, into the urine. If smaller proteins sneak through the glomeruli, tubules (long, thin, hollow tubes in the kidneys) recapture those proteins and keep them in the body.

However, if the glomeruli or tubules are damaged, if there is a problem with the reabsorption process of the proteins, or if there is an excessive protein load, the proteins will flow into the urine.

 

WHAT ARE THE SYMPTOMS OF PROTEINURIA? (2)

Often, someone with proteinuria doesn’t experience symptoms, especially if kidneys are just beginning to have problems. However, if proteinuria is advanced, symptoms can include:

  • More frequent urination
  • Shortness of breath
  • Tiredness
  • Nausea and vomiting
  • Swelling in the face, belly, feet or ankles
  • Lack of appetite
  • Muscle cramping at night
  • Puffiness around the eyes, especially in the morning
  • Foamy or bubbly urine

Conditions that can cause a temporary rise in the levels of protein in urine, but don’t necessarily indicate kidney damage, include:

  • Dehydration
  • Emotional stress
  • Exposure to extreme cold
  • Fever
  • Strenuous exercise

However, according to the Mayo Clinic (2), there are diseases and conditions that can cause persistently elevated levels of protein in urine, which might indicate kidney disease, such as:

TESTING FOR PROTEINURIA

The only way to know if you have protein in your urine, an established marker for chronic kidney disease, is to have a urine test.

“Integral to the process of evaluating for proteinuria is quantification of the total amount of protein spilling into the urine. The various methods to detect proteinuria include urine dipstick and sulfosalicyclic acid test (SSA); quantification methods include the ratio of albumin or protein to creatinine (UACR or UPCR) and the 24-hour urine protein collection.

The gold standard for quantification of proteinuria is the 24-hour urine collection. The test is performed by voiding upon waking and then collecting all urine on subsequent voids until the first void of the next day.“ (11)

In a retrospective study (5), researchers evaluated data from 265 patients with systemic AL amyloidosis who visited the Amyloidosis Center at Boston University Medical Center between July 1, 2018, and Jan. 1, 2020. This study examined the correlation between 24-hour urine testing and [urine protein-to-creatinine ratio] UPCR at various proteinuria levels in patients with AL amyloidosis. All patients underwent proteinuria measurement by 24-hour collection and UPCR in the same day. According to Andrea Havasi, MD, “In summary, although 24-hour urine collection is cumbersome, we continue to recommend it in patients with AL amyloidosis and kidney involvement.

 

CONCLUSION (12)

Amyloidosis can be a life-threatening disease because it can cause progressive organ damage and irreversible failure. Although it may affect any organ, one of the most frequently involved organs is the kidney, and clinically evident renal disease occurs in about 50-80% of cases. Typical manifestations of renal involvement are proteinuria, nephrotic syndrome (i.e., concomitant proteinuria, hypoalbuminemia, and peripheral edema), renal insufficiency, and end-stage renal disease (ESRD) requiring hemodialysis. All forms of systemic amyloidosis can lead to renal involvement. AL amyloidosis induces proteinuria and renal insufficiency in up to 73% and 50% of cases, respectively. ATTR amyloidosis typically does not involve the kidneys, but it can induce proteinuria and ESRD in some patients.

 

Therefore, when you have a patient with proteinuria, investigate why and don’t assume a benign origin. There are many serious causes, one of which may be amyloidosis.

 

Stay curious.

 

 

 

======== References  =========

  1. https://my.clevelandclinic.org/health/diseases/16428-proteinuria
  2. https://my.clevelandclinic.org/health/diseases/16428-proteinuria
  3. https://www.mayoclinic.org/symptoms/protein-in-urine/basics/causes/sym-20050656
  4. https://www.kidneyfund.org/kidney-disease/kidney-problems/protein-in-urine.html
  5. https://www.kidney.org/atoz/content/proteinuriawyska
  6. https://www.healio.com/news/nephrology/20220209/researchers-regard-24hour-proteinuria-collection-best-for-amyloid-light-chain-amyloidosis
  7. https://medlineplus.gov/lab-tests/albumin-blood-test/#:~:text=Albumin%20is%20a%20protein%20made,and%20enzymes%20throughout%20your%20body.
  8. https://www.kidney.org/content/kidney-failure-risk-factor-urine-albumin-to-creatinine-ration-uacr
  9. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/24hour-urine-collection#:~:text=A%2024%2Dhour%20urine%20collection%20is%20a%20simple%20lab%20test,is%20returned%20to%20the%20lab
  10. https://www.kidneyfund.org/all-about-kidneys/tests-for-kidney-disease/urine-tests
  11. https://www.mdedge.com/clinicianreviews/article/210146/nephrology/proteinuria-and-albuminuria-whats-difference
  12. https://emedicine.medscape.com/article/238158-workup
  13. Talamo G, Mir Muhammad A, Pandey MK, Zhu J, Creer MH, Malysz J. Estimation of Daily Proteinuria in Patients with Amyloidosis by Using the Protein-To-Creatinine ratio in Random Urine Samples. Rare Tumors. 2015 Feb 18;7(1):5686. doi: 10.4081/rt.2015.5686. PMID: 25918613; PMCID: PMC4387359.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387359/#:~:text=AL%20amyloidosis%20induces%20proteinuria%20and,50%25%20of%20cases%2C%20respectively.&text=ATTR%20amyloidosis%20typically%20does%20not,and%20ESRD%20in%20some%20patients

 

 

Expert Insights: Amyloidosis – A Brief Clinical Overview

Dr. Sarah S. Lee, Assistant Professor, Division of Hematology, at the City of Hope, provides a brief yet comprehensive clinical overview of amyloidosis. In this video Dr. Lee discusses the breadth of amyloidosis, the wide range of symptom presentations, and which organs are typically involved. Focusing on AL (light chain) and TTR (transthyretin) types, she then goes through a diagnostic workup to arrive at a diagnosis, stressing the importance of typing once the presence of amyloid has been confirmed. Concluding her overview, Dr. Lee describes treatments available and how they impact patient prognosis and quality of life.

 

Expert Insights: What is the Relationship between AL Amyloidosis and Multiple Myeloma?

While both AL Amyloidosis and Multiple Myeloma are plasma cell disorders and share similar patient care treatments, they diverge in pathogenic mechanisms. In this presentation, Dr. Giada Bianchi from Brigham & Women’s Amyloidosis Program shares that 10-15% of Multiple Myeloma patients will experience overlapping AL Amyloidosis, elevating the importance of understanding the similarities and differences in diagnostic criteria and patient care.

Expert Insights: Why is Amyloidosis Bad for Your Kidneys?

One of the organs most frequently impacted by amyloidosis is the kidney. Dr. Jeffrey Zonder from the Karmanos Cancer Institute provides a brief summary of amyloidosis and the most common types of this disease. From there, he goes on to describe how AL (Light Chain) and AA ((Apo)serum Amyloid A) are the two most prevalent types to affect the kidneys, detail how amyloidosis affects the kidneys, how this damage is assessed, and strategies for reducing kidney damage.

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.

 

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

 

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