What are the Clinical Features of Systemic Amyloidosis?
Delayed diagnosis of amyloidosis, which pushes back the start of treatment, increases the mortality risk and negative quality of life for patients. It is one of the biggest issues for this disease today. Dr. Joselle Cook, hematologist from the Mayo Clinic, and Dr. Hira Shaikh, hematologist from the University of Iowa Healthcare, discuss the findings from a systematic scoping review they led during the two-year development of the American Society of Hematology AL Amyloidosis Guidelines. It was identified relatively early on that a gap exists as to WHEN clinicians could begin to suspect systemic amyloidosis and WHAT were early signs and symptoms that clinicians may see that could prompt testing for the disease. This is a must-watch video for all frontline clinicians, regardless of specialty.
Patient Insights: Getting Older May Not Be the Reason
Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Joan. She talks about how her doctor attributed her symptoms to her age, even though she was convinced something was wrong.
Spinal Stenosis & Amyloidosis
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
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 expected3 and 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.
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.
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
For Pharmacists: Advancing Care in Amyloidosis: From Pathophysiology to Patient-Centered Care
Course description
The goal of this eLearning activity is to educate pharmacists about amyloidosis. From epidemiological characteristics to risk factors, clinical presentation and treatment pathways this course will ensure pharmacists have knowledge needed to answer questions and support care coordination for patients affected. Additionally, the information provided will support pharmacists in improving outcomes within patient-centered team-based care.
The annual Boston Globe Rare Disease Day Summit is a day of curated, in-person thought leadership addressing how Boston companies are tackling rare diseases and helping patients who are afflicted by them. Over 1,000 were expected to attend this virtual event on February 24, 2026.
During the morning session, Mackenzie and Deb Boedicker from Mackenzie’s Mission joined Gianluca Pirozzi from Alexion for a panel session titled “Living It, Leading It: When Lived Rare Disease Experience Becomes Professional Purpose”
Many patients, caregivers and professionals in the rare disease community often carry their personal experiences into their work, influencing how they approach care, advocacy, research and industry. This panel centered on shared lived experience as a catalyst for purpose and action across the rare disease ecosystem. Featuring perspectives from a patient turned healthcare provider, a parent and nonprofit leader, and an industry executive and caregiver, panelists will share how lived experience has shaped their professional paths. Through personal stories, the discussion explored where the system continues to fall short and what must change to create a more connected and responsive future for rare disease patients and their families.
As the lead sponsor of this event, it was an opportunity to highlight Alexion’s leadership and commitment to advancing rare disease care, while connecting directly with the people whose lives are shaped by this work. Thank you, Alexion!
Navigating Mental Health Challenges in Cardiac Amyloidosis
Dr. David Rintell is a licensed psychologist with experience working with individuals and families living with long-term illness. In this video Dr. Rintell, in his personal expert capacity, explores what we know about mental health, depression, and anxiety in those with cardiac amyloidosis. He offers two items to screen for depression, how it may impact caregivers as well, and treatment considerations. In closing, he discusses how quality of life is often impacted and ways to address it.
Light Chain (AL) Amyloidosis Clinical Practice Guidelines – American Society of Hematology 2026
The American Society of Hematology (ASH) has released new Clinical Practice Guidelines on the diagnosis of light chain (AL) amyloidosis, a rare and life-threatening bone marrow disorder. The guidelines present 12 evidence-based recommendations designed to help clinicians and facilitate early and accurate diagnosis of AL amyloidosis. Participating in the two-year research was a large group of multi-disciplinary amyloidosis experts, as well as Deb Boedicker from Mackenzie’s Mission/Amyloidosis Speakers Bureau. Below we summarize the 12 recommendations, followed by a link to the full publication. In addition, at the end you’ll find a link to a comprehensive Resource Center which support these Clinical Practice Guidelines.
The primary goals of these guidelines are to review, critically appraise and implement evidence-based recommendations that will enhance early detection, timeliness and accuracy of diagnosis of AL amyloidosis. Through improved provider and patient education of the available evidence and creation of evidence-based recommendations, these guidelines aim to provide clinical decision support that will result in clear diagnostic decision making with known potential outcomes and enable timely diagnosis of AL amyloidosis by multidisciplinary teams.
ENHANCING CLINICAL SUSPICION
Should serum and urine immunofixation (SIFE and UIFE) and serum free light chains (sFLC) be used to increase suspicion of AL amyloidosis in individuals with cardiac symptoms? Recommendation 1
For individuals with suspected cardiac amyloidosis, the ASH Guideline Panel recommends the use of serum and urine immunofixation (SIFE and UIFE) and serum free light chain (sFLC) assay to increase clinical suspicion of cardiac AL amyloidosis.
Should serum and urine immunofixation (SIFE and UIFE) and serum free light chains (sFLC) be used to increase suspicion of AL amyloidosis in individuals with unexplained proteinuria? Recommendation 2
For individuals with unexplained proteinuria, the ASH Guideline Panel suggests performing paraprotein testing (SIFE/UIFE/sFLC) to increase clinical suspicion of AL amyloidosis.
Should cardiac MRI (CMR) be used to diagnose cardiac AL amyloidosis in individuals suspected of having cardiac amyloidosis (positivity in any of the following studies: SIFE, UIFE, or sFLC, abnormal cardiac biomarkers, and non-diagnostic echocardiographic findings)? Recommendation 3
For individuals with positivity in any of the following studies SIFE, UIFE, or sFLC, and abnormal cardiac biomarkers, and non-diagnostic echocardiography, the ASH Guideline Panel suggests performing cardiac magnetic resonance (CMR) rather than not performing CMR to increase clinical suspicion of cardiac amyloidosis.
Should cardiac MRI (CMR) be used to diagnose cardiac AL amyloidosis in individuals with abnormal cardiac biomarkers, echocardiography, and positivity in any of the following studies: SIFE, UIFE, or sFLC? Recommendation 4
For individuals with positivity in any of the following studies SIFE, UIFE, or sFLC, and abnormal cardiac biomarkers, and echocardiography consistent with amyloidosis, the ASH Guideline Panel suggests against performing cardiac magnetic resonance (CMR) and instead performing tissue biopsy to diagnose cardiac AL amyloidosis.
DIAGNOSIS
Should Bone Scintigraphy with technetium 99m – pyrophosphate (PYP), technetium 99 m – 3, 3 diphosphono –1,2 propranodicarboxylic (DPD) and technetium 99 m-hydroxymethylene Diphosphonate (HMDP) be used to diagnose amyloidosis in suspected individuals? Recommendation 5
For individuals with a suspicion of AL amyloidosis, the ASH Guideline Panel recommendsagainst the use of bone scintigraphy (PYP, DPD, HMDP) for the diagnosis of AL cardiac amyloidosis.
Should Bone Scintigraphy (PYP, DPD, HMDP) be used to diagnose ATTR amyloidosis in suspected individuals? Recommendation 6
For patients without evidence of a plasma cell disorder (normal serum free light chain levels and no monoclonal proteins on serum and urine immunofixation) and suspicion of cardiac amyloidosis, the ASH Guideline Panel recommends the use of bone scintigraphy (PYP, DPD, HMDP) for the diagnosis of Cardiac ATTR amyloidosis.
Should surrogate biopsy vs. cardiac biopsy be used to diagnose AL amyloidosis in individuals suspected to have cardiac amyloidosis? Recommendation 7
For individuals with suspected AL cardiac amyloidosis with abnormal cardiac biomarkers, diagnostic echocardiogram, and positivity in any of the following studies: SIFE, UIFE, or sFLC, the ASH Guideline Panel suggests either starting with performing both fat pad sampling and bone marrow biopsy or with endomyocardial biopsy.
Should surrogate biopsy vs renal biopsy be used to diagnose AL amyloidosis in individuals suspected to have renal amyloidosis? Recommendation 8
For individuals with suspected light chain renal amyloidosis and positivity in any of the following studies SIFE, UIFE, or sFLC, the ASH Guideline Panel suggests starting with performing both abdominal fat pad sampling and bone marrow biopsy over renal biopsy.
Should surrogate biopsy vs. peripheral nerve biopsy be used to diagnose AL amyloidosis in individuals suspected to have neurological amyloidosis? Recommendation 9
For individuals with a monoclonal gammopathy and generalized small or large fiber peripheral neuropathy or autonomic neuropathy suspected of having AL amyloidosis, the ASH Guideline Panel suggests performing both fat pad sampling and bone marrow biopsy over nerve biopsy.
Should surrogate biopsy vs target organ biopsy be used to diagnose AL amyloidosis in individuals suspected to have AL amyloidosis with multiorgan presentation? Recommendation 10
For individuals with suspected multiorgan AL amyloidosis, the ASH Guideline Panel suggests starting with surrogate biopsies (combination of fat pad sampling and bone marrow biopsy) over target organ biopsy if surrogate biopsies can be performed expeditiously. If endomyocardial biopsy or renal biopsy are more feasible than fat pad sampling and bone marrow biopsy, these symptomatic target tissues should be preferentially biopsied.
Should Congo Red Staining on bone marrow biopsy that has already been performed be used to diagnose AL amyloidosis in individuals with Multiple Myeloma and Smoldering Myeloma? Recommendation 11
For individuals with plasma cell dyscrasias (multiple myeloma and smoldering multiple myeloma), the ASH Guideline Panel suggests performing Congo red staining on bone marrow biopsies that may have already been performed.
ORGAN INVOLVEMENT
In individuals with AL amyloidosis with no cardiac symptoms, should clinicians use cardiac biomarkers/investigations [BNP, NT-proBNP, troponin (I,C,T, Highly Sensitive), 2D Echo with strain, Cardiac MRI] or not to evaluate for cardiac involvement? Recommendation 12
For individuals with proven AL amyloidosis and with no cardiac symptoms, the ASH Guideline Panel recommends performing cardiac biomarkers (high sensitivity troponin, and BNP or NT-proBNP) and cardiac imaging rather than not performing these tests to define the presence and extent of cardiac involvement at diagnosis.
KEY CONCLUSIONS
The use of serum immunofixation, urine immunofixation and serum free light chains enhances the clinical suspicion of AL amyloidosis. The diagnosis of AL amyloidosis can be made effectively through surrogate biopsies which require both a bone marrow biopsy and fat pad sampling. However, target organ biopsies may be favoured in certain clinical situations.
Overarching good practice statements:
1. The ASH panel agreed that it is essential to assess for major organ involvement in patients with confirmed AL amyloidosis, as this guides further management and risk stratification.
2. A multidisciplinary team is typically required for the timely and accurate diagnosis and management of AL amyloidosis.
The red flag signs and symptoms provide a summarized way to elevate suspicion and hopefully accelerate the diagnostic timeline.
RED FLAG SIGNS AND SYMPTOMS FOR CARDIAC INVOLVEMENT
HFpEF (heart failure with preserved ejection fraction)
Moderate or Severe LVH in absence of a significant history of untreated hypertension on imaging.
Echocardiogram: Severe left ventricular hypertrophy, advanced diastolic dysfunction, reduced left ventricular global longitudinal strain with an apical sparing pattern
EKG/Arrhythmia: Low voltage and/or discordance between voltage on EKG and left ventricular wall thickness on imaging, pseudo-infarct pattern, and arrhythmias including atrial fibrillation, heart block, and ventricular tachycardia/ventricular fibrillation
Elevated biomarkers (Troponin and NT-Pro BNP) in absence of CAD
Constellation of symptoms suggesting cardiac, renal, and peripheral nervous system disease
Low Flow, Low Gradient Aortic Stenosis
RED FLAG SIGNS AND SYMPTOMS FOR RENAL INVOLVEMENT
Inability to tolerate ACE/ARB
Change in hypertension status unexplained by medication i.e. intolerance/hypotension on previously tolerated therapy.
Unexplained proteinuria (albumin predominant) without diabetes (or not thought to be related to be diabetes or any other reason) and positive laboratory tests (monoclonal proteins and/or abnormal light chains (must be clonal or above renal limits)
Proteinuria in diabetic with positive monoclonal protein
RED FLAG SIGNS AND SYMPTOMS FOR NEUROLOGICAL INVOLVEMENT
Small fiber neuropathy: pain and temperature impairments, allodynia and hyperalgesia
A snapshot of the ASH Clinical Practice Guidelines — “Diagnosis of Light Chain (AL) Amyloidosis: What You Should Know”
What it covers
Why it matters
Who it affects
What are the highlights
A Disease State Infographic
A Visual Summary: a concise visual aid intended to support understanding of the recommendations and to aid in clinical decision-making.
A Pocket Guide: a brief, evidence-based pocket guide intended to help physicians provide quality care to patients.
Teaching Slides: educational slides intended to teach about the diagnosis of amyloidosis.
Audit Report: A set of metrics intended to assess compliance with the ASH Clinical Practice Guidelines on Diagnosis of Light Chain Amyloidosis. This audit report can be used to identify quality gaps at your institution and improve care for patients with light chain amyloidosis.
ASB Recognized as Leader in Early Medical Education
The Amyloidosis Speakers Bureau (ASB) is recognized as a leader in enhancing medical education and awareness, starting in medical school and continuing through fellowship, which is essential for improving early disease recognition.
The editorial commented on the recent transformation in the field of amyloid cardiomyopathy. It references a comprehensive retrospective analysis leveraging data from the Veterans Health Administration, the nation’s largest integrated health care system, to examine diagnostic patterns in patients with heart failure (HF) and ATTR-CM between 2016 and 2022. This study underscores a critical gap: Even within a highly integrated health system with access to diagnostic tools and longitudinal data, under-recognition and delayed diagnosis of ATTR-CM remain pervasive.
“Why does diagnostic delay matter so much? Although it may seem less urgent given that patients are eventually diagnosed and ATTR-CM is generally considered a more indolent condition than amyloid light-chain amyloidosis, the clinical impact of delayed diagnosis is significant. Studies have shown that even a delay of 3 months can result in patients presenting with a higher NYHA classification, indicating more advanced disease at the time of diagnosis.8 Most importantly, we now have 3 U.S. Food and Drug administration–approved therapies for ATTR-CM that not only extend survival but also reduce HF hospitalizations and improve quality of life. Crucially, these treatments are most effective when initiated in the earlier stages of disease. With this growing arsenal of disease-modifying therapies, timely diagnosis is no longer just ideal, it is imperative.
To reduce diagnostic delays and shift clinical focus from treating isolated comorbidities to the broader picture, we must begin to “see the forest” instead of just the trees. Three strategies may help. First, enhancing education and awareness, starting in medical school and continuing through fellowship, is essential for improving early recognition. Advocacy organizations like the Amyloidosis Speakers Bureau, a nonprofit entity dedicated to educating medical trainees and early-career clinicians, lead the way with raising awareness among providers.9 Second, clinicians should more consistently apply existing diagnostic tools, such as the ATTR-CM score,10 to avoid overlooking amyloidosis in patients with HFpEF. Third, integrating artificial intelligence into diagnostic workflows could identify potential cases by identifying red flags, within electronic medical records, prompting consideration of cardiac amyloidosis alongside common comorbidities such as atrial fibrillation, coronary artery disease, and chronic kidney disease. If we do not think of amyloidosis, we will not diagnose it. In 2025, we have the tools to identify and treat ATTR-CM. We just need to look up from the trees in time to recognize the forest, often hiding in plain sight.”
Patient Insights: It’s All In Your Head
Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Sean. He talks about how his PCP and those around him suggested his symptoms were all in his head, and that an appropriate next step would be to see a therapist.
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