Dr. Ahmad Masri, Director of the Cardiac Amyloidosis Program at Oregon Health & Science University (OHSU), reminds us about the traditional approach to diagnosis of cardiac amyloidosis. Unfortunately, this has not been enough. Thankfully, over the past decade that has all changed. He talks about OSHU’s approach to diagnosis today and what other data is used to arrive at a diagnosis of cardiac amyloidosis, offering four sample patient cases for insights.
Slider
Macroglossia & Amyloidosis
WHAT IS IT?
According to the NIH (1), macroglossia is the abnormal enlargement of the tongue in proportion to other structures in the mouth. It usually occurs secondary to an underlying disorder that may be present from birth (congenital) or acquired.
SYMPTOMS
Symptoms associated with macroglossia may include drooling, speech impairment, difficulty eating, noisy and/or high-pitched breathing (stridor), snoring, airway obstruction, abnormal growth of the jaw and teeth, and ulceration. In some cases, the tongue may protrude from the mouth. (1) (3)
Talking may be affected. The large size of the tongue may also cause abnormal development of the jaw and teeth, resulting in misaligned or protruding teeth. Ulceration and dying tissue on the tip of the tongue may be other symptoms of the disorder. (3)
In addition to an enlarged tongue it is common to see indentations around the tongue perimeter from the constant pressure against the teeth.
Patients who graciously offered their picture for this blog reinforce many of these symptoms, including TMJ, difficulty swallowing, and breathing. Reiterated almost unanimously, eating is a problem – chewing and swallowing, clearing food from their mouth. Food gets stuck in front of their teeth. Speech is affected, and they often sound “slushy.” Snoring can get so bad it wakes them (and partners) up during the night. In addition, sometimes, their tongue gets sore from rubbing against their teeth.
WHAT CAUSES IT?
Macroglossia can be associated with a wide range of congenital (present from birth) and acquired conditions (e.g., malignancies, metabolic/endocrine disorders, inflammatory or infectious diseases; amyloidosis), or it can occur as an isolated feature (with no other abnormalities). In most cases, it is due to vascular malformations (blood vessel abnormalities) and muscular hypertrophy (an increase in muscle mass). (1)
Macroglossia is the most frequent oral manifestation of amyloidosis and may be found as the only presenting symptom of the disease or included in a longer list of other symptoms. In addition, while occurring much more frequently in AL Light Chain amyloidosis, it can also accompany hereditary ATTR Transthyretin amyloidosis. (2, 4)
HOW IS IT TREATED?
There is no cure, but treatments can manage the symptoms. Treatment depends upon the underlying cause and severity and may range from speech therapy in mild cases, to orthodontic procedures, to surgical reduction in more severe cases. (1) (3)
Sources
- National Institutes of Health
- NIH National Library of Medicine
- National Organization for Rare Disorders
- https://ashpublications.org/blood/article/116/21/5007/66459/Macroglossia-Not-Always-AL-Amyloidosis
Ref 5 (picture only)
https://www.mayoclinic.org/diseases-conditions/amyloidosis/multimedia/enlarged-tongue/img-20008056
Systemic Amyloidosis: You’ve Got to Think of IT to Diagnose IT
Dr. Mat Maurer, cardiologist at Columbia University Irving Medical Center, discusses the importance of developing a broad differential in order to diagnose this rare, potentially life-threatening, yet treatable disease. He shares a typical but unfortunate case of cardiac amyloidosis, along with statistics of misdiagnosis and delayed diagnosis. He shares his view on the appropriate process for diagnosis based on Dr. David Eddy’s 1982 New England Journal of Medicine piece “The Art of Diagnosis” and the need to create a broad enough differential in order to consider less common diseases such as systemic amyloidosis. Dr. Maurer lists common reasons for missing diagnosis of cardiac amyloidosis all clinicians should be aware of, punctuated by his concluding point … “The Key to Correct Treatment is Diagnosis, Diagnosis, and Diagnosis.” It’s simple … you cannot treat what has not been diagnosed.
This is a MUST VIEW video for clinicians who diagnose patients, regardless of sub-specialty.
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.
AL and ATTR Amyloidosis: Recognition and Diagnosis — The Key to Successful Treatment
Dr. Heather Landau, Associate Attending Physician at Memorial Sloan Kettering, provides a comprehensive clinical overview of amyloidosis. Spanning recognition and diagnosis – the key to successful treatment.
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.”
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
- Motor Neuropathy → Damage to the motor nerves control how you move.
- Sensory Neuropathy → Damage to sensory nerves control what you feel.
- Autonomic Nerve Neuropathy → Damage to autonomic nerves that control functions that are involuntary (ie. you do not consciously control).
- 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.
===========================================================
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/
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:
- Amyloidosis (buildup of abnormal proteins in your organs)
- Certain drugs, such as nonsteroidal anti-inflammatory drugs
- Chronic kidney disease
- Diabetes
- Endocarditis (an infection of the inner lining of the heart)
- Focal segmental glomerulosclerosis (FSGS)
- Glomerulonephritis (inflammation in the kidney cells that filter waste from the blood)
- Heart disease
- Heart failure
- High blood pressure (hypertension)
- Hodgkin’s lymphoma (Hodgkin’s disease)
- IgA nephropathy (Berger’s disease) (kidney inflammation resulting from a buildup of the antibody immunoglobulin A)
- Kidney infection (pyelonephritis)
- Lupus
- Malaria
- Multiple myeloma
- Nephrotic syndrome (damage to small filtering blood vessels in the kidneys)
- Orthostatic proteinuria (urine protein level rises when in an upright position)
- Preeclampsia
- Pregnancy
- Rheumatoid arthritis (inflammatory joint disease)
- Sarcoidosis (collections of inflammatory cells in the body)
- Sickle cell anemia
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 =========
- https://my.clevelandclinic.org/health/diseases/16428-proteinuria
- https://my.clevelandclinic.org/health/diseases/16428-proteinuria
- https://www.mayoclinic.org/symptoms/protein-in-urine/basics/causes/sym-20050656
- https://www.kidneyfund.org/kidney-disease/kidney-problems/protein-in-urine.html
- https://www.kidney.org/atoz/content/proteinuriawyska
- https://www.healio.com/news/nephrology/20220209/researchers-regard-24hour-proteinuria-collection-best-for-amyloid-light-chain-amyloidosis
- https://medlineplus.gov/lab-tests/albumin-blood-test/#:~:text=Albumin%20is%20a%20protein%20made,and%20enzymes%20throughout%20your%20body.
- https://www.kidney.org/content/kidney-failure-risk-factor-urine-albumin-to-creatinine-ration-uacr
- 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
- https://www.kidneyfund.org/all-about-kidneys/tests-for-kidney-disease/urine-tests
- https://www.mdedge.com/clinicianreviews/article/210146/nephrology/proteinuria-and-albuminuria-whats-difference
- https://emedicine.medscape.com/article/238158-workup
- 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.
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.
