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WHAT IS SPINAL STENOSIS?

Spinal stenosis is narrowing of the spinal column that causes pressure on the spinal cord, or narrowing of the openings (called neural foramina) where spinal nerves leave the spinal column.

This can develop as you age from drying out and shrinking of the disk spaces. (The disks are 80% water.) The narrowing can cause compression on nerve roots resulting in pain or weakness of the legs. If this happens, even a minor injury can cause inflammation of the disk and put pressure on the nerve. You can feel pain anywhere along your back or leg(s) that this nerve supplies.¹

SYMPTOMS¹

Symptoms often get worse slowly over time. Most often, symptoms will be on one side of the body, but may involve both legs. Symptoms include:

Numbness, cramping, or pain in the back, buttocks, thighs, or calves, or in the neck, shoulders, or arms
Weakness of part of a leg or arm

Symptoms are more likely to be present or get worse when you stand or walk. They often lessen or disappear when you sit down or lean forward. Most people with spinal stenosis cannot walk for a long period. More serious symptoms include:

Difficulty or poor balance when walking
Problems controlling urine or bowel movements

A POTENTIAL CLUE TO AMYLOIDOSIS?

Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits. Lumbar spinal stenosis is also a condition of usually elderly individuals in whom narrowing of the lumbar spinal canal leads to compression of nerves to the lower limbs.

“Another very important historical clue is spinal stenosis, and actually that’s much more commonly seen in patients with ATTR than AL, and in fact, again, almost exclusively in wild type,” according to Dr. Mazen Hanna²

WHAT IS SENILE, AKA WILD-TYPE, AMYLOIDOSIS (ATTRwt)?

Amyloidosis is a generic name for a very diverse group of protein folding disorders, all characterized by creation of cross-beta-sheet fibrils. At least 30 different human proteins have been shown to form amyloid fibrils in vivo (7). Two main groups of amyloid conditions exist: systemic and localized. In the systemic conditions, deposits occur in many organs and tissues, and the diseases are usually life-threatening; in each of these diseases one out of at least 15 plasma proteins forms amyloid fibrils far from the place of parent protein synthesis. In the localized conditions, the proteins are expressed at the site of deposition (8). In both groups, fibrils usually deposit extracellularly and can form conspicuous masses that deform a tissue and interfere with its normal functions.⁵

Senile systemic amyloidosis (SSA), derived from wild-type transthyretin (TTR), is common in association with aging, although symptom-giving disease usually is comparably rare and affects males at least 10 times more often than women. Restrictive cardiomyopathy is the main clinical expression. However, carpal tunnel syndrome is common in SSA, and widely spread wild-type ATTR amyloid deposits at other connective tissue sites have been demonstrated (25).⁵

Joint cartilage and ligaments are targets of both localized and systemic amyloid. Of the systemic forms, Aβ2-microglobulin [for nomenclature, see (7)] amyloidosis is well-known to engage skeletal and joint structures in patients under hemodialysis due to renal insufficiency (9-13). Also, immunoglobulin light chain (AL) amyloidosis is known to generate a variety of symptoms from joints and skeleton, sometimes with neural lesions. Carpal tunnel syndrome is often noted in transthyretin (ATTR) and Aβ2-microglobulin amyloidosis (15–17).⁵

HEAR FROM AN EXPERT ON MUSCULOSKELETAL SYMPTOMS RELATED TO AMYLOIDOSIS

Dr. Shari Liberman, a hand and upper extremities surgeon from Houston Methodist Orthopedics & Sports Medicine, discusses 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.

CONCLUSION

From the studies referenced therein, results suggest that transthyretin-derived amyloid deposits may occur more frequently in various ligaments and tendons than originally expected³and that lumbar spinal stenosis quite frequently may be a consequence of senile systemic amyloidosis [also known as wild-type amyloidosis; ATTRwt]⁵.

Stay suspicious. It’s more common than you may think.

Sources:

¹https://www.mountsinai.org/health-library/diseases-conditions/spinal-stenosis

² https://www.neurologylive.com/view/cardiac-amyloidosis-management

³ https://pubmed.ncbi.nlm.nih.gov/21334722/

Sueyoshi T, Ueda M, Jono H, Irie H, Sei A, Ide J, Ando Y, Mizuta H. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol. 2011 Sep;42(9):1259-64. doi: 10.1016/j.humpath.2010.11.017. Epub 2011 Feb 21. PMID: 21334722.

⁴ https://pubmed.ncbi.nlm.nih.gov/14640042/

Westermark P, Bergström J, Solomon A, Murphy C, Sletten K. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 2003 Aug;10 Suppl 1:48-54. PMID: 14640042.

⁵ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116761/

Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. doi:10.3109/03009734.2014.895786

⁶ https://en.wikipedia.org/wiki/Spinal_stenosis

Amyloidosis can indeed be found in the eye according to Dr. Chafic Karam, professor of neurology from the University of Pennsylvania. In addition, while most of the transthyretin protein originates in the liver, local production is found in other areas of the body such as the brain and retina.

AMYLOIDOSIS

Amyloidosis is a rare disease that happens when abnormal transthyretin proteins called amyloid build up in different parts of the body, including the eye and surrounding areas.

Some people develop localized amyloidosis, meaning the protein buildup only affects the eye. Others have systemic amyloidosis, where amyloid deposits form in multiple organs, including the kidneys and heart. Systemic amyloidosis can increase the risk of kidney damage and heart failure.

HOW AMYLOIDOSIS CAN AFFECT THE EYE

Amyloidosis can affect multiple structures of the eye including the eyelids, cornea, retina, and the gel-like substance inside the eye, with symptoms such as droopy eyelids, vision changes, and dry eyes, while certain types of amyloidosis are more likely to affect specific parts of the eye. Ocular amyloidosis (amyloidosis in the eye) can cause symptoms that range from mild discomfort to serious vision problems.

Symptoms can include:

Lumps under the skin
Ptosis (a droopy eyelid)
Diplopia (double vision)
Constant eye irritation, which may feel like dryness
Blurred vision or seeing “floaters,” cobwebs, or sheets
Globally displaced or protruded eye
Purpura (purple or blue skin) surrounding the eyes, which may appear or worsen when you touch or rub your eyes

AMYLOIDOSIS IN THE EYELIDS, ORBIT, AND CONNECTIVE TISSUE OF THE EYE

Amyloid proteins can build up in the outer parts of the eye, including the eyelid skin, the orbit (the bones that form the eye socket), and the connective tissues that help the eyes move.

AMYLOIDOSIS IN THE CONJUNCTIVA

The conjunctiva is a thin, moist membrane that lines the inside of the eyelids and covers the white part of the eye. In some cases, amyloid proteins may be deposited in this membrane, leading to conjunctival amyloidosis.

Conjunctival amyloidosis usually appears as a small, yellow, waxy mass on the eye. It can occur in both AL amyloidosis and AA amyloidosis. Some people with conjunctival amyloidosis have other amyloidosis-related symptoms in the body, while others do not.

A specific type of amyloidosis, called hereditary amyloidosis (familial amyloidosis), is strongly linked to amyloidosis in the conjunctiva. Hereditary transthyretin (TTR) amyloidosis (hATTR amyloidosis) happens when the liver makes an abnormal form of the TTR protein, which can lead to amyloid buildup in various organs, including the eyes. Since hATTR amyloidosis runs in families, people with a family history should be aware of potential symptoms.

One small-scale study found that among 37 people with hATTR amyloidosis, 75 percent developed abnormal blood vessels in the conjunctiva. This eye problem can lead to severe vision loss, especially if not identified and treated early.

AMYLOIDOSIS IN THE CORNEA

The cornea is the clear, dome-shaped layer over the iris (colored part of the eye). It helps focus light into the eye, allowing you to see clearly. Amyloidosis can affect the cornea in several ways.

Gelatinous Drop-Like Corneal Dystrophy

A hereditary form of amyloidosis can cause gelatinous drop-like corneal dystrophy, a condition where amyloid proteins build up on the cornea. This buildup makes it harder to see and can cause vision problems over time.

Lattice Stromal Dystrophies

Amyloid proteins can also lead to lattice stromal dystrophies, where branching, white lines form inside the cornea. People with this condition may notice white dots and a hazy appearance in the cornea. These dystrophies are caused by specific genetic mutations (changes) linked to amyloidosis.

Keratoconjunctivitis Sicca and Corneal Neuropathy

Hereditary TTR amyloidosis is often associated with corneal neuropathy (loss of corneal sensitivity), which is important for blinking and eye protection. It can also lead to corneal ulcers (open sores on the cornea). Amyloid deposits in the cornea may cause a disease called keratoconjunctivitis sicca (KCS), also known as dry eye disease. KCS can cause severe corneal dryness, which may lead to damage if untreated.

AMYLOIDOSIS IN THE IRIS OR LENS

When amyloidosis affects the iris or lens, it can lead to glaucoma, a group of eye diseases that damage the optic nerve, which carries signals from the eye to the brain. This damage can cause vision loss. Types of glaucoma linked to amyloidosis include rubeotic glaucoma and particle/particulate glaucoma.

Amyloidosis can also cause a condition called scalloped pupils. In this condition, the border between the iris (the colored part of the eye) and the pupil is uneven, giving the pupil a wavy or scalloped appearance. This happens when amyloid deposits build up around the pupil, pushing it out of shape. In some cases, scalloped pupils can be a sign of systemic (whole-body) amyloidosis.

Hereditary amyloidosis is the most common cause of amyloidosis in the iris or lens. Specifically, familial amyloidosis is strongly linked to chronic open-angle glaucoma, a condition that slowly increases pressure inside the eye, leading to vision loss over time.

Additionally, people with hATTR amyloidosis often develop more cataracts and far-sightedness earlier than usual.

AMYLOIDOSIS IN THE RETINA OR VITREOUS

The vitreous is the gel-like substance that fills much of the inside of the eye. When amyloidosis affects the vitreous, it produces opaque (cloudy) areas in the gel that can look like cobwebs, sheets, or pearls. The severity of vision problems depends on how dense the amyloid deposits are.

The retina is the light-sensitive membrane at the back of the eye that helps the brain process images. Amyloid proteins in the retina can change how the eye detects light. This can lead to discolorations in the retina or distortion of its shape.

Amyloidosis in the retina or the vitreous is usually caused by hereditary amyloidosis. About 20 percent of people with hATTR have hemorrhages and cotton wool spots (fluffy white patches of retinal damage) on eye exams, which are signs of retinal and vitreous disease. Retinal amyloidosis may also occasionally occur in primary amyloidosis that affects the whole body.

AMYLOIDOSIS AND OCULAR INVOLVEMENT FROM AN EXPERT

Dr. Chafic Karam, professor of neurology from the University of Pennsylvania, provides an informative overview of how certain mutations of transthyretin amyloidosis are being diagnosed in the central nervous system (CNS), which includes the eye. Starting at 8:15 in the video below, Dr. Karam discusses ocular involvement with amyloidosis – symptoms, how and where the eye can be impacted, and treatment considerations. With patients living longer due to successful amyloidosis therapies now available, he predicts neurologists will see more and more patients with CNS complications and ocular involvement.

Sources

https://www.myamyloidosisteam.com/resources/does-amyloidosis-affect-the-eyes

Ocular Manifestations of Systemic Amyloidosis

Reynolds MM, Veverka KK, Gertz MA, Dispenzieri A, Zeldenrust SR, Leung N, Pulido JS. OCULAR MANIFESTATIONS OF SYSTEMIC AMYLOIDOSIS. Retina. 2018 Jul;38(7):1371-1376. doi: 10.1097/IAE.0000000000001901. PMID: 29068915.

Amyloidosis and Ocular Involvement: an Overview

Dammacco R, Merlini G, Lisch W, Kivelä TT, Giancipoli E, Vacca A, Dammacco F. Amyloidosis and Ocular Involvement: an Overview. Semin Ophthalmol. 2020 Jan 2;35(1):7-26. doi: 10.1080/08820538.2019.1687738. Epub 2019 Dec 12. PMID: 31829761.

Ocular Amyloidosis

https://mdsearchlight.com/eye-health/ocular-amyloidosis/

Heart failure is a complex and debilitating condition affecting millions of individuals worldwide. While it has several underlying causes, one often-overlooked contributor to heart failure is amyloidosis.

In this month’s piece we look to the Heart Failure Society of America and their piece titled “The Silent Intruder: Amyloidosis’ Hidden Role in Heart Failure.”

Understanding Amyloidosis

Amyloidosis is a rare but serious disease characterized by the buildup of abnormal proteins in various organs, including the heart. Amyloidosis occurs when a protein called amyloid builds up in different parts of the body, including the nervous system, tissues or even organs. These abnormal proteins (amyloids) are misfolded and can impair the normal functioning of organs, including the heart. There are different types of amyloidosis, but two forms stand out for their connection to heart failure: AL amyloidosis (immunoglobulin light chain) and ATTR amyloidosis (transthyretin). Symptoms of amyloidosis may vary, depending on which organs are affected. Signs and symptoms of amyloidosis may include:

Severe fatigue and weakness
Shortness of breath
Numbness, tingling, or pain in the hands or feet (polyneuropathy)
Swelling of the ankles and legs
Diarrhea, possibly with blood, or constipation
An enlarged tongue, which sometimes looks rippled around its edge
Skin changes, such as thickening or easy bruising, and purplish patches around the eyes

Due to the similarity of these symptoms with other heart conditions, amyloidosis is often misdiagnosed or diagnosed late, emphasizing the importance of raising awareness about its hidden role in heart failure.

The Hidden Role in Heart Failure (HF)

Amyloidosis can affect the heart in several ways, leading to heart failure:

Cardiac Amyloidosis: In cardiac amyloidosis, sometimes called stiff heart syndrome, amyloid deposits take the place of normal heart muscle, disrupting the heart’s normal structure and function. This can lead to restrictive cardiomyopathy, a condition where the heart becomes stiff and less able to pump blood effectively.
Diastolic Dysfunction: Amyloid deposits in the heart can make it difficult for the heart to relax properly during the diastolic phase, impairing its ability to fill with blood. This diastolic dysfunction can result in heart failure with preserved ejection fraction (HFpEF).
Arrhythmias: Amyloidosis can disrupt the heart’s electrical system, leading to arrhythmias (irregular heart rhythms) that can further exacerbate heart failure symptoms.

Diagnosing Amyloidosis

Amyloidosis can be confirmed through specialized tests, including tissue biopsies or imaging scans such as MRIs. Some cases of amyloidosis are hereditary, so if you or anyone else in your family has or had amyloidosis, it can be beneficial for you to take a genetic test to determine if you carry the gene.

Learn More About Amyloidosis

Amyloidosis, which can be a hidden contributor to heart failure, deserves greater recognition and awareness within the medical community and among patients. Timely diagnosis and appropriate management can make a significant difference in the prognosis of individuals affected by amyloidosis.

WATCH: Cardiac Amyloidosis from a Cardiologist

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.

SOURCE

Heart Failure Society of America

https://hfsa.org/silent-intruder-amyloidosis-hidden-role-heart-failure

Systemic amyloidosis is comprised of a group of rare disorders characterized by extracellular deposition of amyloid fibrils that can damage a body’s organs, tissues, and nerves. Below we discuss both acquired and inherited types of amyloidosis and, in particular, how it can affect the body’s nervous systems – both peripheral and autonomic.

ACQUIRED TYPES OF AMYLOIDOSIS

Acquired forms of the disease include AL or “light chain” amyloidosis, where increased levels of misfolded light chain proteins lead to amyloid formation and deposition, and “wild type” transthyretin (ATTRwt) amyloidosis where amyloid fibrils deposit slowly over time, typically becoming symptomatic in the elderly.

Acquired forms of the disease tend to predominantly impact the heart and kidneys, however less common or pronounced neuropathic manifestations of the disease may also preside. In the case of AL amyloidosis, although not a prominent symptom, peripheral neuropathy is seen in 15% of patients at disease onset and in about 35% of patients as the disease progresses. In the case of wild type transthyretin amyloidosis some degree of neuropathy is found in approximately 50% of patients.

The two graphics below illustrate the most common organs affecting AL amyloidosis and wild type amyloidosis, including the nervous system.

INHERITED TYPES OF AMYLOIDOSIS

The most prominent inherited form of the disease is hereditary transthyretin amyloidosis (hATTR or ATTRv), which includes over 120 genetic variants. With many of the variants, neuropathic symptoms frequently accompany, or even dominate, over cardiac symptoms. ₍₁₎

The graphic below illustrates the most common organs affecting hATTR amyloidosis, including the nervous system.

HOW AMYLOIDOSIS CLINICALLY IMPACTS THE NERVOUS SYSTEM

Amyloidosis can impact the bodies peripheral and/or the autonomic nervous system. When the disease affects both systems it is defined as polyneuropathy.

Peripheral Nervous System

The peripheral nervous system consists of nerves that branch out from the brain and spinal cord to the extremities (periphery) of the body. Sensory nerves carry electrical signals from the extremities towards the brain and motor nerves (afferent nerves) carry signals from the brain to the extremities. The figure below illustrates a basic layout of the system. ₍₂₎

The peripheral nervous system includes dorsal root ganglion, which functions to branch sensory and motor nerves from the spine to the periphery of the body. The figure below illustrates a dorsal root ganglion. Amyloid fibrils damage the dorsal root ganglion, often early in disease progression.

Additionally, amyloid deposits in and damages peripheral nerve endoneurium and Schwann cells. The endoneurium is a layer connective tissue around the protective sheath of each nerve fiber in the peripheral nervous system. Schwann cells function to produce the myelin sheath around cell axons. Schwann cell entanglement with amyloid fibrils causes axon degeneration. Both of these processes contribute to nerve damage and can result in symptoms such as numbness in ankles, feet, and hands, and in many cases muscular atrophy, particularly in the legs.

The figure shown below provides an illustrated summation of the production of amyloid fibrils and their impact on both the peripheral and autonomic nervous systems.

Autonomic Nervous System

The autonomic nervous system controls involuntary bodily functions such as regulation of the heart rate, blood pressure, breathing, and digestion, amongst other functions. The system contains sympathetic ganglia, which signal various organs and tissues, contributing to the “fight or flight” response. Amyloid fibrils damage the sympathetic ganglia. ₍₃_).Involvement of the autonomic nervous system can lead to symptoms such as compromised heart rate and blood pressure regulation, which can result in chronic orthostatic hypotension, and even syncope (fainting), to name a few.

HEAR FROM AN EXPERT NEUROLOGIST

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.

Bibliography

Neuromuscular Complications of Systemic Amyloidosis, Dina Namiranian, MD, Stefanie Geisler, MD, Department of Neurology, Neuromuscular Division, Washington University School of Medicine in St. Louis, Mo, 2022 Elsevier Inc. The American Journal of Medicine (2022)

Peripheral nervous system, Adrian Rad. https://www.kenhub.com/en/library/anatomy/the-peripheral-nervous-system

Autonomic Ganglia. https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Anatomy_and_Physiology_(Boundless)/14%3A_Autonomic_Nervous_System/14.2%3A_Structure_of_the_Autonomic_Nervous_System/14.2B%3A_Autonomic_Ganglia#:~:text=Learning%20Objectives,fight%2Dor%2Dflight%20response.

Peripheral Nerve Fibers-Endoneurium

https://www.elsevier.com/resources/anatomy/peripheral-nerve-fibers/nerve-fascicles/endoneurium/16249

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. In this clip, Dan shares how his provider commented on his heart’s thickened walls – you’ve got athlete’s heart, and all’s good. A shocking missed opportunity to suspect cardiac amyloidosis.

The diagnosis of amyloidosis can be challenging for several reasons.

First and foremost, presenting symptoms are often nonspecific and common to other conditions that can send clinicians in multiple directions.
Second, due to the variability of presenting symptoms, rarely are two patient presentations identical.
Third, the diagnostic process requires (a) the confirmation of amyloidosis, and (b) the typing of amyloidosis, only after which can an appropriate treatment regimen be developed.

The perceived rarity of the disease itself gives providers pause to consider. Collectively, as a result of these reasons, diagnosis is often delayed and/or misdiagnosed, leading to devastating consequences for patients. Often, the key to diagnosis begins with developing a clinical suspicion.

DEVELOPING A CLINICAL SUSPICION FROM SYMPTOMS

The first step in diagnosing AL amyloidosis is to develop a clinical suspicion, done through connecting the seemingly random presenting symptoms.

As seen in the figure above, multiple pathologies are often present with AL amyloidosis¹. The most common is cardiac involvement, which also brings the highest mortality. Other common presentations range from nephropathy, including proteinuria (> 60% of patients), hepatomegaly (>50% of patients), neuropathy, whether autonomic (20% of patients) or peripheral (10-20% of patients), macroglossia (17% of patients), periorbital purpura (15% of patients) and GI manifestations (approximately 7% of patients).

Symptoms do not develop at the same time, nor in the same sequence from patient to patient. As a result, patients and providers often play “whack-a-mole,” going from specialist to specialist for specific symptoms. Misdiagnoses along the way are common, leading patients down paths that prove unproductive and, in some cases, counterproductive. This takes time, which is exactly what patients do not realize they do not have.

Suspicion of amyloidosis should be very high when a patient presents with heart failure combined with a constellation of unexplained extracardiac symptoms such as neuropathy, bleeding, carpal tunnel syndrome, nephrotic syndrome, proteinuria, diarrhea, hepatomegaly, peripheral and autonomic neuropathy, macroglossia, and periorbital purpura.¹

ALGORITHM FOR DIAGNOSING AL AMYLOIDOSIS¹

The figure below illustrates the current systematic, stepwise process for diagnosing amyloid light chain (AL) amyloidosis and differentiating it from other cardiomyopathies. It identifies each type of test that is essential for suspicion of AL amyloidosis, diagnosing the disease and typing of the amyloidogenic free light chains (FLCs).

ACR = albumin/creatinine ratio

DPD = 99mTc-3-diphosphono-1,2-propanodicarboxylic acid

Echo = echocardiography

EKG = electrocardiography

LFT = liver function test

MRI = magnetic resonance imaging

NT-proBNP = N-terminal pro–brain natriuretic peptide

PYP = 99mTc-pyrophosphate

SIFE = serum immunofixation electrophoresis

UIFE = urine immunofixation electrophoresis

TYPING AND CONFIRMING DIAGNOSIS¹

Once the presence of amyloid has been confirmed, it is imperative to next identify the type of amyloid fibril in order to avoid misdiagnosis and initiation of incorrect or inappropriate treatment, which could have disastrous consequences for a patient.

The most common methods of amyloid fibril typing include immunohistochemistry or laser capture, followed by mass spectrometry. As the accuracy of immunohistochemistry is dependent on the expertise of the laboratory and needs an extensive panel of antibodies for accurate reporting, laser capture with mass spectrometry has become the method of choice for amyloid fibril typing.

Despite advances in noninvasive imaging, tissue biopsy remains a common and important confirmational step in most cases.

Once a diagnosis of amyloidosis has been confirmed, along with the specific type, an appropriate treatment regime can then be determined.

CONCLUSION – WHY EARLY DIAGNOSIS MATTERS

With AL amyloidosis, time is of the essence for patients. This is an aggressive disease where early treatment intervention can truly extend lives and improve QoL. As recently as the 1990s, this was considered a terminal disease with a high mortality rate, often offering patients months to a few years to live. With earlier diagnosis and advancements in treatments, survival is extending and QoL is improving.

IN CLOSING

The key take-aways are two-fold: (1) when confronted with multiple unexplained symptoms, suspect multi-system diseases like amyloidosis, and (2) remember that early diagnosis is key for patient survival.

For more detail on diagnosing and treating AL amyloidosis, please see the paper referenced below.

Source:

⁽¹⁾Wechalekar, A, Fontana, M, Quarta, C. et al. AL Amyloidosis for Cardiologists: Awareness, Diagnosis, and Future Prospects: JACC: CardioOncology State-of-the-Art Review. J Am Coll Cardiol CardioOnc. 2022 Nov, 4 (4) 427–441.

https://doi.org/10.1016/j.jaccao.2022.08.009

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

Dr. Melissa Hershman, assistant professor from the OHSU Division of Gastroenterology & Hepatology, provides an informative overview of how, and where, amyloidosis can present in the G.I. tract. She reviews patient symptoms, many of which are nonspecific and can be associated with other more common issues, delaying diagnosis. Dr. Hershman goes through how G.I. amyloidosis is tested for, where in the G.I. tract biopsies are most commonly performed, and how the tissue is stained for diagnosis by pathology. In closing, she reviews the array of treatments available to assist patients.

Hereditary Amyloidosis in Americans of African Descent: ATTR V122I Variant

Amyloidosis, still considered a relatively rare disease, can take several forms. Each slightly different, but most sharing similar debilitating symptoms of cardiac and/or neurological impairment, or both. It is viewed by many experts that amyloidosis has been presenting in plain sight and missed, or wildly underdiagnosed, for decades and, in some cases, generations. Thankfully, education to raise awareness within the healthcare community, along with improvements in diagnostic tools and testing, the journey to diagnosis and treatment is becoming more visible.

The hereditary transthyretin amyloidosis (hATTR; also called variant amyloidosis ATTRv) type results from a genetic mutation of a protein, transthyretin, which is produced in the liver and circulates throughout the body. The mutation causes the TTR protein to misfold, becoming unstable and depositing in organs and nerve systems causing impairment and eventual organ failure. Common symptoms for the disease include bilateral carpel tunnel syndrome, muscle weakness, cardiomyopathy, polyneuropathy, GI issues especially chronic diarrhea and constipation, and both nuisance and serious concerns and if untreated can lead to death. Early diagnosis, genetic testing to identify the exact genetic mutation, and treatment are important to slow the progression of the disease and conserve quality of life.

SIGNIFICANTLY UNDER-DIAGNOSED

Considered a rare disease, advances in diagnosis have shown that it is less rare than originally thought.

Familial amyloidosis caused by a transthyretin mutation occurs in approximately 1 in 100,000 Caucasians in the U.S, and more commonly in African Americans (approximately 4% in that population). This condition is prevalent in Portugal, Sweden, Japan, Ireland, Spain, France, Finland, Germany and Greece. Symptoms usually begin between 40 and 65 years of age.

https://rarediseases.org/rare-diseases/amyloidosis/

To date over one hundred variants of TTR have been identified as causing ATTR amyloidosis and they are distributed worldwide with concentrations in various ethnic populations. One variant, V122I is most commonly found in people with African and especially West African ancestry. It has been distributed worldwide but especially in North America and the Caribbean through historic slave trade and the migration of populations. This variant is most often associated with ATTR-CM (Amyloidosis with cardiomyopathy) and heart failure.

Worldwide Carrier Rates of TTR V122I in Self-Reported Countries/Regions

From Multicenter Study JAMA 2019 Dec 10;322(22):2191-2202.

doi: 10.1001/jama.2019.17935.

In an article by J. Buxdaum and F. Ruberg in the Journal Genetics in Medicine January 2017, the authors stated the following findings.

Since the identification of a valine-to-isoleucine substitution at position 122 (TTR V122I; pV142I) in the transthyretin (TTR)-derived fibrils extracted from the heart of a patient with late-onset cardiac amyloidosis, it has become clear that the amyloidogenic mutation and the disease occur almost exclusively in individuals of identifiable African descent. In the United States, the amyloidogenic allele frequency is 0.0173 and is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicates that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. At autopsy, the allele was found to be associated with cardiac TTR amyloid deposition in all the carriers after age 65 years; however, the clinical penetrance varies, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. At this time there are potential forms of therapy in clinical trials. The combination of a highly accurate genetic test and the potential for specific therapy demands a greater awareness of this autosomal dominant, age-dependent cardiac disease in the cardiology community.

Genet Med advance online publication 19 January 2017

The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa.

1:CAS:528:DC%2BC28XhsFSlsbfJ 10.1002/mgg3.231 Mol Genet Genomic Med. 2016; 4: 548-556

Dr. Martha Grogan, director of the Cardiac Amyloid Clinic of Mayo Clinic in Rochester, Minnesota commented in an interview published in the Mayo News Network (https://newsnetwork.mayoclinic.org/discussion/expert-alert-cardiac-amyloidosis-masquerades-as-other-conditions-1-type-affects-more-black-americans/) that amyloidosis can be tricky to suspect because symptoms may not be initially present and they may mimic other more common diseases. Currently there are options for free saliva or blood tests through several pharmaceutical companies. To determine the type of the disease genetic testing is important.

The University of Pennsylvania and the Icahn School of Medicine at Mount Sinai conducted a study of 52,492 participants of which 11,143 were of self-reported African ancestry. https://jamanetwork.com/journals/jama/fullarticle/2757227

An excellent discussion of the results emphasizes the conclusion that a significant association of TTR V122I and heart failure in the tested population, primarily in those of West African ancestry, exists. In addition, they confirm previous studies that have suggested a high rate of underdiagnosis of hATTR-CM in cases of cardiomyopathy and heart failure in elderly patients of African Ancestry. The discussion further suggests that this is likely due to lack of information and familiarity with the disease in the medical community.

CITATION: Damrauer SM, Chaudhary K, Cho JH, et al. Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry. JAMA. 2019;322(22):2191–2202. doi:10.1001/jama.2019.17935. https://pubmed.ncbi.nlm.nih.gov/31821430/

Discussion of a different study of 7,514 African American participants in the US considered the question of the association between genetic variation and the risk of heart failure. This study was conducted by the University of Alabama, University of Colorado, Columbia University, and Cornel University. The results are similar to those in the University of Pennsylvania study discussed above, with additional comments that more subtle symptoms and changes may be apparent well before the typical onset of significant disease, average age 65, and the need for earlier screening for early detection and treatment.

An autosomal-dominant disease, hATTR-CM has a median survival of nearly 2.5 years without treatment after receiving a diagnosis.³⁴^,³⁵ Extrapolating the hATTR-CM–associated Val122Ile variant frequency to the population level suggests that approximately 1.4 million Black individuals carry this variant implicated in the development of heart failure and reduced overall survival. Despite the possible clinical implications, the Val122Ile TTR variant, which is seen relatively more commonly among individuals of African ancestry, is not included in the list of clinically actionable deleterious variants compiled by the American College of Medical Genetics and Genomics.⁹ Thus, this potentially deleterious variant may not be reported as clinically actionable, thereby reducing physician vigilance for hATTR-CM.

Findings In this retrospective cohort study that included 7,514 Black participants in the US with a median 11.1 years of follow-up, the incidence of heart failure was 15.6 per 1000 person-years among Val122Ile variant carriers compared with 7.2 per 1000 person-years among noncarriers, with an adjusted hazard ratio of 2.43.

Meaning Being a carrier of the Val122Ile variant was significantly associated with an increased risk of heart failure among Black individuals living in the US.

CITATION: Parcha V, Malla G, Irvin MR, et al. Association of Transthyretin Val122Ile Variant With Incident Heart Failure Among Black Individuals. JAMA. 2022;327(14):1368–1378. doi:10.1001/jama.2022.2896

https://pubmed.ncbi.nlm.nih.gov/35377943/

From Dr. Kevin Alexander, Stanford Amyloid Center

SUMMARY

Despite the evidence that a meaningful 3-4% of the US Black population of West African ancestry likely carries the V122I genetic mutation, hereditary TTR amyloidosis remains significantly underdiagnosed and undertreated in this population.

Cardiac symptoms in elderly black patients have too often been treated for more common cardiomyopathy and heart conditions, resulting in lack of appropriate treatment and often death. Because of lack of awareness in the medical community and reduced access to expert medical care, more subtle symptoms in younger black patients generally have not caused the physicians to consider amyloidosis. Additionally, lack of genetic testing can mean that entire families are unaware of the implications of the disease.

Amyloidosis can be devastating to both patients and their families. Increased awareness of the disease, availability of testing, and FDA-approved therapies are slowly beginning to shift this dynamic. However, there is still much work to be done to close the gap between diagnosed cases and the population estimated to be affected.

Early diagnosis is key.

For additional information regarding hereditary amyloidosis:

Worldwide Hotspots of Hereditary TTR Amyloidosis (ATTRv)

Hereditary Amyloidosis: T60A Variant

Dr. Chafic Karam, professor of neurology from the University of Pennsylvania, provides an informative overview of how certain mutations of hereditary transthyretin amyloidosis are being diagnosed in the central nervous system (CNS), such as the eye. It has been long believed that amyloidosis did not cross the blood brain barrier; however, evidence is showing otherwise. In addition, while most of the transthyretin protein originates in the liver, local production is found in other areas of the body such as the brain and retina. Dr. Karam will discuss how patients might present, the developing state of diagnostics, and treatments available. A slower developing symptom, with patients now living longer he predicts neurologists will see more and more patients with CNS and ocular involvement.

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Spinal Stenosis & Amyloidosis

Amyloidosis and the Eye

Amyloidosis’ Hidden Role in Heart Failure