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Amyloidosis: A Brief Overview


Amyloidosis is a “group of diseases” that have the common feature where abnormal proteins (or in some cases normal proteins) behave abnormally, and the breakdown product of these proteins fold upon themselves, creating amyloid” fibrils” which deposit in various organs throughout the body. This potentially life-threatening disease can affect the heart, kidneys, liver, spleen, nervous system and digestive tract. (Falk, R., MD, 2018) A basic illustration of the creation of amyloid “fibrils” is shown below.

(Cleveland Clinic, 2020)


There are different types of the disease including AL or Light Chain Amyloidosis, AA Amyloidosis, Transthyretin Amyloidosis (referred to as TTR amyloidosis), and Localized Amyloidosis. TTR amyloidosis includes a hereditary type and a non-hereditary type. (Falk, R, MD, 2018)


Common symptoms of amyloidosis are shown in the following figure.

(The Canadian Amyloidosis Support Network)


Light Chain (AL) Amyloidosis

AL amyloidosis is the most common type of amyloidosis in developed countries, accounting for approximately 85% of all cases. There are approximately 3,000-5,000 new AL amyloidosis cases a year in the United States. (Falk, R., MD, 2018)  


The disease usually affects the heart, kidneys, liver and nerves. This type of amyloidosis is blood related, associated with the abnormality of proteins from plasma cells associated with bone marrow. Plasma cells normally create antibodies, known as immunoglobulins, that serve to combat bacteria and viruses. Antibodies are made up of “heavy chains” and “light chains.” AL amyloidosis stems from an abnormal expansion of plasma cells. The abnormal plasma cells secrete abnormal “free light chains” (FLCs) into the bloodstream. These abnormal light chain mutations become “sticky.” The sticky light chains bind together to form amyloid fibrils which can then accumulate in various body organs, as shown below. (Sherwood, A.L.)

(Cleveland Clinic, 2020)


Diagnostic testing for AL amyloidosis includes blood testing, urine tests and biopsies. Blood and/or urine tests are used to indicate the presence of amyloid protein, however bone marrow tests or other small biopsy samples of tissue or organs are needed to positively confirm the diagnosis of amyloidosis. Specific types of blood/urine testing include:

  • A 24-hour urine collection to look at the level of protein in your urine sample. Excess protein in the urine may be an indication of kidney involvement.
  • The level of ALP (an enzyme called “alkaline phosphatase”) in your regular blood workup.
  • Blood tests to look for stress and strain on the heart. Cardiac biomarkers that are used include troponin T or troponin I, and NT-proBNP (which stands for N-terminal pro-brain natriuretic peptide) or BNP (brain natriuretic peptide). 
  • Tests for abnormal antibody (immunoglobulin) proteins in the blood include the Free Light Chain Assay, which shows the level of kappa and lambda light chains in a separate blood test. The Free Light Chain Assay test is often referred to as FLC, which is an abbreviation for free light chains.
  • Another test for abnormal immunoglobulin can be done with blood and/or urine. It is called “immunofixation electrophoresis.”


Echocardiogram and imaging are performed so that the doctor can look for amyloid deposits in the heart, while viewing the size and shape of it and the location and extent of any impact of amyloid.


Tissue biopsy are performed to identify evidence of amyloid deposits. Tissue samples are sent to a lab for microscopic examination, where the tissue is stained with a dye called “Congo-red.”  After putting it under a microscope, amyloid protein is discovered if it turns an apple-green color, resulting in a diagnosis of amyloidosis. The most common tissue sample, which is almost always involved in generating an AL diagnosis, is called a fat-pad biopsy. Fat-pad biopsies are taken from the stomach. Biopsy samples may also be taken from the liver, kidney, nerves, heart, stomach, or intestines.


Bone marrow tests are also performed. These involve the removal of some liquid bone marrow and/or the removal of bone tissue. These samples can help to determine the percentage of amyloid producing plasma cells, and when tested in the lab they can assist in identifying whether the abnormal plasma cells are producing kappa or lambda light chains. (Amyloidosis Foundation, 2021)


If treatment begins during the early onset of clinical symptoms, the overall success rate is higher, so early detection is essential.


Patients with AL amyloidosis have benefited from the recent development of new drugs for myeloma, many of which work effectively on the plasma cells that cause AL amyloidosis. In addition, the FDA approved the first drug treatment specifically for AL amyloidosis in January 2021, called DARZALEX (daratumumab). Drug combinations are more effective than single drugs in attacking the abnormal plasma cells. Drugs that may be useful include traditional chemotherapy drugs (such as melphalan, and cyclophosphamide), as well as “proteasome inhibitor” and “immunomodulator” drugs. (Amyloidosis Foundation, 2021)


Stem cell transplant is also a preferred therapy, as it can provide long-term control of the underlying disease. However, only a minority of AL patients (typically less than 25%) are eligible. (Amyloidosis Foundation, 2021)


AA Amyloidosis

AA amyloidosis results from increased levels of the circulating serum “amyloid A protein.” Amyloid A protein levels normally elevate in the bloodstream as a response to infection and inflammation. If a patient has an infection or inflammatory condition for an extended period of time (six months or more) they would be at risk for developing AA amyloidosis. The amyloidosis can arise due to chronic inflammatory and infectious conditions, including rheumatic disease, inflammatory bowel disease, tuberculosis, osteomyelitis, lupus, and hereditary fever syndromes. Amyloid deposition usually begins in the kidneys, but the liver, spleen, lymphnodes, and intestines are also commonly affected.


If a patient has been diagnosed with a chronic inflammatory disease or chronic infection and they develop high levels of protein in the urine or other associated AA symptoms, then the physician should test for AA amyloid deposition. When kidney damage occurs, it can be clinically shown as protein found in the urine (nephrotic syndrome) or impairment of kidney function.


A test involving a 24-hour urine collection can be performed to look at the level of protein in the patient’s urine. If amyloidosis is suspected in most cases a biopsy of the kidney tissue performed.


In order to identify AA amyloid, the most common diagnostic test is staining the tissue sample with antibodies that are specific to AA amyloid, the “anti-AA serum.” If the anti-AA serum result is positive then AA amyloidosis is diagnosed. Once AA amyloidosis is confirmed the primary underlying inflammatory condition should then be identified.  


With AA amyloidosis it is most important to treat the underlying infection or inflammation in order to reduce the level of the precursor for the AA amyloid deposits.  These treatments vary depending on the underlying condition. Some treatments that exist for inflammatory diseases include surgery on the infection or tumor, drug therapies for rheumatoid arthritis, antibiotics for chronic infection, among others.


With effective treatment of the underlying inflammation amyloid deposits have been known to reduce and nephrotic syndrome can improve. If the kidney function has become significantly impaired, it rarely recovers. 


Supportive treatment is very important, including nephrology, cardiology, and neurology. (Amyloidosis Foundation, 2021)


TTR (Transthyretin) Amyloidosis

As stated earlier, TTR amyloidosis includes a hereditary type and a non-hereditary type.


Hereditary (Familial) Amyloidosis, also referred to as ATTRv amyloidosis, is associated with an inherited genetic mutation. There are various subtypes of familial amyloidosis that are associated with specific demographic groups including Portuguese, Irish, Swedish, Afro-American, and Japanese lineage. 


The non-hereditary type of TTR amyloidosis, known as Wild Type Amyloidosis is a disorder predominately of older men in their 70s and beyond. This form of the disease may actually be responsible for up to 10% of male patients having heart failure due to stiff heart tissue. (Falk, R., MD, 2018)  


As with AL and AA Amyloidosis, TTR Amyloidosis can manifest itself with a multitude of symptoms. In a vast majority of cases the resultant symptoms are cardiological and/or neuropathic in nature. A basic illustration of the production method for TTR amyloid fibrils is shown below.

Early diagnosis if TTR amyloidosis is essential so as to help minimize the extent of bodily tissue or system damage. First, a patient is tested to determine if they have amyloid proteins in their body. The main diagnostic testing is similar to that described above for AL Amyloidosis, including blood tests, urine tests and biopsies. If amyloidosis is confirmed but the type is not initially identified, additional tests are performed to determine the existence and variation of ATTR.


Once it is determined that there is transthyretin amyloid protein (via biopsy and Congo red staining), the specific protein needs to be identified by protein sequence analysis and DNA sequencing. A blood sample is sent to a lab where the DNA chains are analyzed. Sections of the DNA chain are checked for genetic markers of the DNA defect. Hereditary amyloidosis variations affect patients differently. It is critical to establish which variation exists in order to identify a tailored treatment plan.


Treatment of TTR amyloidosis include treating the source and symptoms. Source treatment involves slowing down, or stopping, the overproduction of amyloid at the source of the disease. Historically, liver transplant has been helpful, however, the statistics vary as to who can benefit from these transplants, with the outcome dependent largely on the specific mutation that exists in the patient. In some situations, combined heart and liver transplants have helped patients with an ATTR variant that produces cardiac problems. 


In 2019, two drugs were approved for treatment of ATTR polyneuropathy associated with TTR amyloidosis in adults.  The first was ONPATTRO (patisiran), a first of its kind RNA interference therapeutic drug which aims to silence the gene expression for patients with the hereditary type TTR.  The second drug approved is TEGSEDI (inotersen), which reduces the production of TTR protein. Also, in 2019, VYNDAQEL and VYNDAMAX (tafamidis) were approved by the FDA for ATTR cardiomyopathy.  (Amyloidosis Foundation, 2021)


There is supportive treatment for the various symptoms associated with TTR Amyloidosis, possible symptoms include peripheral neuropathy, autonomic neuropathy, cardiac and kidney problems. There are medications that can be prescribed to treat the effects of peripheral neuropathy, such as tingling or burning sensations. Many patients experience autonomic neuropathy and may require treatment for blood pressure, heart rate, digestion, and perspiration, depending on the location of the damage to the nerves. Other gastrointestinal dysfunctions may require treatment for symptoms that include poor nutritional health, diarrhea or constipation, and nausea or vomiting. (Amyloidosis Foundation, 2021)


Localized Amyloidosis

Localized amyloidosis often has a better prognosis than the types that affect one or more organ systems. Typical sites for localized amyloidosis include the bladder, skin, throat or lungs. Correct diagnosis is important so that treatments that affect the entire body can be avoided. (Mayo Clinic. 2021)



Amyloidosis is a complex multi-systemic disease where no two patients are alike. Symptoms are often vague and vary from patient to patient, even within the same disease type, making diagnosis one of the biggest hurdles for the medical community. It is not uncommon to hear from patients that it took multiple years and multiple doctors to ultimately arrive at a correct diagnosis, all the while the disease continued to progress. While treatment is type-specific, it is individualized from patient to patient depending on organ involvement. 


In the words of Morie A. Gertz, M.D., M.A.C.P., of the Mayo Clinic and regarded as a leading world expert on amyloidosis.


“Thanks to the Amyloidosis Speakers Bureau, providers across the country are being instructed on techniques to suspect and recognize amyloidosis and how to efficiently make the diagnosis in a timely fashion.  Incorporating testing for amyloidosis into the work flow of patients with cardiomyopathy, proteinuria, peripheral neuropathy, unexplained weight loss, and smoldering multiple myeloma has been successful. 

Comprehensive education remains the best strategy to save lives for this rare disorder.”




Falk, Rodney, MD, Understanding Amyloidosis. (2018).https://www.youtube.com/watch?v=bE68vvDtnyM&t=134s. 
Cleveland Clinic. (2020, June 2). Amyloidosis: AL (Light Chain). https://my.clevelandclinic.org/health/diseases/15718-amyloidosis-al-amyloid-light-chain. 
Sherwood, A. L. (n.d.). Understanding Freelite®, the lab test for serum free light chains. Lecture. 
The Canadian Amyloidosis Support Network. (n.d.). About Amyloidosis. http://thecasn.org/home-2/what-is-amyloidosis/al-amyloidosys/al-amyloidosis-symptoms/
Mayo Clinic. 2021. Amyloidosis – Symptoms and causes. [online] Available at: <https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178> [Accessed 14 July 2021].
Amyloidosis Foundation. 2021. AL – Amyloidosis Foundation. [online] Available at: <https://amyloidosis.org/facts/al/#diagnosis> [Accessed 14 July 2021].


A Clinical & Patient Perspective of Wild-Type Amyloidosis

Wild-type ATTR is also referred to as ATTRwt. It is not caused by any known genetic mutations, such as in the case of hereditary forms of the disease (hATTR). This disease used to be called SSA or SCA, which stood for Senile Systemic Amyloidosis and Senile Cardiac Amyloidosis, respectively, which are now outdated terminologies. The disease is not known to be directly related to dementia, but it is related to aging.

Deposits of TTR amyloid can be found throughout the body, so it is a systemic amyloidosis disease.  The most common place it is found is in the heart. Wild-type ATTR is also known to cause some cases of carpal tunnel syndrome, which can be the first (early) symptom. Recent data suggests that lumbar spine involvement as well as a rupture of the biceps tendon in the forearm can precede cardiac involvement by many years.

This is a disease that has traditionally been found mostly in men, originally reported in those aged 80 and over. As awareness of the disease increases, wild-type ATTR average age at diagnosis is 75. It is often overlooked as an amyloidosis disease because so many people experience heart problems in their later years.

As with hereditary forms of the disease (hATTR), wild-type ATTR causes problems due to the breaking apart, misfolding and deposition of amyloid protein fibrils in healthy tissue. “Wild-type” refers to this form of the disease because it is the natural form of this protein, without genetic mutation. These deposits can interfere with the heart’s normal function, by causing stiffness of the heart tissue, making it more difficult for the heart to fill, leading to heart rhythm problems and heart failure.


In this special video, hear world-renowned expert Dr. Mathew S. Maurer and his patient John Basdavanos presenting to a group of medical students. Dr. Maurer provides a brief overview of ATTRwt, while John provides the patient perspective. Together, these insights offer a compelling story about battling a life threatening disease.


AI, Protein Folding & Amyloidosis

The Protein Folding Problem

Proteins are the building blocks of life. They are large complex molecules, made up of chains of amino acids, and what a protein does largely depends on its unique 3D structure. Figuring out what shapes proteins fold into is known as the “protein folding problem.”  For decades and decades, one of biology’s biggest challenges has been finding a solution for the “protein folding problem” and is explained in the linked video below.

AI, DeepMind and Google Find Answers

Founded in 2010, DeepMind researches and builds safe AI (Artificial Intelligence) systems that learn how to solve problems and advance scientific discovery for all. They joined forces with Google in 2014 to accelerate their work. They’re a team of scientists, engineers, machine learning experts and more, working together to advance the state of the art in AI.

In a major scientific breakthrough, DeepMind’s AI system AlphaFold has been recognized as a solution to this grandest of all biological problems – the “protein folding problem.”  Here is an excellent video explaining AlphaFold and the making of a scientific breakthrough.

According to Professor Venki Ramakrishman, Nobel laureate and President of the Royal Society,

This computational work represents a stunning advance on the protein-folding problem, a 50-year-old grand challenge in biology.  It has occurred decades before many people in the field would have predicted. It will be exciting to see the many ways in which it will fundamentally change biological research.


Potential Impact for Amyloidosis

For diseases which originate with misfolded proteins, such as amyloidosis, “investigators have been doing this exercise by ‘brute force’ until now,” according to Dr. Angela Dispenzieri from the Mayo Clinic.  This AI research is likely to open a whole new world of insight and answers, from which new and more effective treatments can be developed.

Marina Ramirez-Alvarado, Ph.D., whose research laboratory at the Mayo Clinic studies misfolding and amyloid formation in light chain amyloidosis, had this to say.

The protein folding problem, one of the most important scientific questions of the 20th century is making headlines today with the artificial intelligence work from DeepMind. It is clear that DeepMind will provide important basic understanding of the folding process and will significantly benefit those amyloidosis diseases that involve secreted, folded proteins, such as light chain (AL), and Transthyretin (ATTR) amyloidosis.

Dr. Morie Gertz, a hematologist/oncologist from the Mayo Clinic who has decades of clinical experience with amyloidosis, weighs in on some of the possible outcomes from this ground-breaking research.

The ability to predict protein folding in three dimensions may result in the ability to predict which protein sequences are likely to form amyloid fibrils. In light chain amyloidosis this could allow for long-term monitoring of selected patients likely to develop amyloidosis. This would permit extremely early diagnosis long before symptoms developed. It would also allow for the exploration of why wild-type TTR amyloidosis forms amyloid fibrils in the heart in some patients but not in others.


However, it won’t answer all questions …

Dr. Vaishali Sanchorawala, director of Boston University’s Amyloidosis Center offers these words of perspective.

The “protein folding problem” that DeepMind’s AlphaFold is designed to solve is predicting the native, functional state of a protein from just its amino acid sequence. Amyloidosis, though, is caused by our bodies’ failure to solve that problem, resulting in misfolded and aggregated proteins. AlphaFold’s remarkable achievement can definitely help to better understand native structure of amyloidogenic light chain proteins. However, amyloid fibrils are different from the native states of their precursor proteins and therefore the adaptation of AlphaFold to study protein misfolding and aggregation, perhaps by predicting the structures of complex amyloid fibrils, might be better able to predict the effects of mutations that alter people’s risk of developing amyloidosis.


In closing …

AI is rapidly advancing the knowledge of protein misfolding, unlocking answers for amyloidosis which should lead to earlier diagnosis, improved treatment, and better patient survival.






Angela Dispenzieri, M.D.

Morie A. Gertz, M.D., M.A.C.P.

Vaishali Sanchorawala, M.D.

Marina Ramirez-Alvarado, Ph.D.


High Accuracy Protein Structure Prediction Using Deep Learning

John Jumper, Richard Evans, Alexander Pritzel, Tim Green, Michael Figurnov, Kathryn Tunyasuvunakool, Olaf Ronneberger, Russ Bates, Augustin Žídek, Alex Bridgland, Clemens Meyer, Simon A A Kohl, Anna Potapenko, Andrew J Ballard, Andrew Cowie, Bernardino Romera-Paredes, Stanislav Nikolov, Rishub Jain, Jonas Adler, Trevor Back, Stig Petersen, David Reiman, Martin Steinegger, Michalina Pacholska, David Silver, Oriol Vinyals, Andrew W Senior, Koray Kavukcuoglu, Pushmeet Kohli, Demis Hassabis.


In Fourteenth Critical Assessment of Techniques for Protein Structure Prediction (Abstract Book), 30 November – 4 December 2020. Retrieved from here.



Spinal Stenosis & Amyloidosis


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



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



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



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 (). 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 (). 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 ().5

Joint cartilage and ligaments are targets of both localized and systemic amyloid. Of the systemic forms, Aβ2-microglobulin [for nomenclature, see ()] amyloidosis is well-known to engage skeletal and joint structures in patients under hemodialysis due to renal insufficiency (). 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 ().5



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.






1 https://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



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