As there are different types of amyloidosis, the number of individuals affected varies with type. Risk factors that may be associated with amyloidosis include advanced age 60-70, having a chronic infection or inflammatory disease, having a family history of amyloidosis, being on dialysis with end stage renal failure. In total diagnosed cases, 70% are men. 

• About 4000 new cases of AL amyloidosis are diagnosed each year in the US, the most common type in the developed world.

• Secondary amyloidosis acquired due to inflammatory diseases occurs in less than 5% of individuals with the following diseases: rheumatic arthritis, psoriatic arthritis, chronic juvenile arthritis, ankylosing spondylitis in children, inflammatory bowel disease, and familial Mediterranean fever. 

• Familial amyloidosis caused by mutation in the TTR gene occurs in 1 in 100,000 white Americans and in 4% of African Americans.

When amyloid protein is abnormally folded or a mutation occurs to alter the protein abnormally, it can aggregate to form plaques in different parts of the body. This can occur in the same organ that produced the protein (localized amyloidosis) or travel to other parts of the body to form these deposits (systemic amyloidosis). These amyloid deposits can lead to the decline of function and eventual failure of the affected organ. Several causes are known for the different types of amyloidosis, including hereditary or familial amyloidosis caused by a genetic mutation or external factors related to inflammatory diseases and/or long-term dialysis. The following lists more specific amyloidosis disorder types, their causes, and risk factors associated with their development:

1. AL - Primary amyloidosis, or the most common form in developed countries, refers to the build-up of light chain antibody fragments in organs such as the heart, kidneys, liver, nerves, and other tissues. Bone marrow white blood cells known as plasma cells produce antibody proteins that attach to foreign objects and mark them for removal or destruction. When these plasma cells are dysfunctional, they can produce light chain protein fragments that aggregate into plaques and cause amyloidosis. This disorder is more likely to occur in individuals with multiple myeloma or the bone marrow illness Wadenstrom’s macroglobulinemia.

2. AA - Secondary amyloidosis is caused by the buildup of serum amyloid A protein (SAA) which is released in the liver in response to cytokines, an immune response mechanism.  Associated with the buildup of amyloid A protein, AA is often triggered by an inflammatory or autoimmune disease such as rheumatoid arthritis, familial Mediterranean fever, chronic inflammatory bowel, tuberculosis, or empyema. It can affect the kidneys, liver, and spleen but is often associated with amyloid A protein buildup in the liver.

3. ATTR - Hereditary/familial amyloidosis is an inherited disorder caused by the mutation in the gene TTR which encodes the liver protein transthyretin. The mutated form of transthyretin aggregates and forms plaques leading to amyloidosis. The most common mutation of TTR is V30M but there are over 100 mutation types that determine the affected organ of amyloidosis, including nerves, heart, and kidneys. This genetic mutation is an autosomal dominant inheritance pattern, meaning that it can be inherited from one parent, and is more likely expressed in people of African descent.

4. ATTRwt - Wild-type amyloidosis is caused by the normal form of transthyretin protein forming plaques after an extended period of time, often when the individual is older. This disorder is also known as senile amyloidosis and is more common in men over age 70, and often affects the heart and leads to congestive heart failure. 

5. ABM2 - Dialysis-related beta2-microglobulin amyloidosis occurs in individuals on long-term dialysis due to their kidney’s inability to properly filter impurities out of the blood. The cause of beta2-microglobulin buildup is unknown, but only occurs in individuals with end stage renal disease.

The symptoms of amyloidosis vary based on the type and affected organ or system. Often, a combination of symptoms indicating multiple affected organs can lead to an individual seeking care and a diagnosis. Signs and symptoms of amyloidosis that warrant seeking medical care include: fatigue, weakness, shortness of breath, numb or tingling hands and feet, swelling in ankles and legs, diarrhea (bloody), constipation, enlarged tongue (sometimes with ripples around the edges), any skin changes such as thickening or bruising, or purplish patches (purpura) around the eyes. The different symptoms associated with amyloidosis in specific organs and tissues are further addressed below:

1. Kidney - The buildup of proteins in the kidneys can damage the filtering units and cause blood or protein in the urine. Signs and symptoms include hematuria, proteinuria, edema, and hypercholesterolemia. This can occur in amyloidosis types AL, AA, or sometimes in ATTR.

2. Heart - The buildup of proteins in the heart thickens the walls and can lower its ability to pump blood, leading to congestive heart failure. Signs and symptoms include enlarged heart, arrhythmia, and low voltage readout on electrocardiogram. This can occur in amyloidosis types AL, ATTR, and ATTRwt.

3. Neuropathy - This is often a painless yet progressive loss of sensorimotor function, numbness, tingling, carpal tunnel syndrome, diarrhea, loss of sweat production, drop in blood pressure and dizziness upon standing (postural hypotension), and erectile dysfunction. This can occur in amyloidosis types AL and ATTR. 

4. Liver and spleen - The buildup of proteins in the liver and spleen can go undetected and is often associated and diagnosed with the presentation of other affected organs. This can occur in amyloidosis types AL and AA.

5. Gastrointestinal - The plaques of proteins that form in the esophagus and other areas of the gastrointestinal tract can cause difficulty swallowing, malabsorption, ulceration, bleeding, weak gastric activity, obstruction, protein loss, diarrhea, loss of taste, difficulty eating, and weight loss. This can occur in amyloidosis type AL.

6. Skin - The soft tissue such as vascular areas, the skin around the eyes, neck, underarms, groin, ear canals, and tongue can be affected by AL amyloidosis. Periorbital purpura (or a purplish bruising around the eyes) may occur after coughing, sneezing, straining, or rubbing the eyelids

7. Respiratory - Difficulty breathing and talking can be associated with cardiac amyloidosis (systemic) or due to deposits clogging the air passage and ducts, sinuses, larynx, and bronchial tree (localized).

8. Joints - Signs and symptoms of amyloidosis in the joints present similarly to rheumatoid arthritis, with muscle weakening or changes, bleeding, carpal tunnel, shoulder pain, or inflammation of tendons in hands. This can occur in amyloidosis types AL and ABM2. 

A diagnosis of amyloidosis is dependent on identifying deposits of amyloid protein as the source of an individual’s symptoms. This can be achieved via different physical tests, including urine and blood tests, an examination of the organs that may be affected, and a genetic test to identify familial amyloidosis. A combination of multiple symptoms indicating multiple affected organs can indicate a systemic form of amyloidosis.

Amyloid can be diagnosed by microscopic examination of affected tissue.

There are various tests that are administered by a physician to determine a diagnosis of amyloidosis in one area or different areas of the body:

1. Urine test - determines if buildups have occurred in the kidneys

2. Blood test - high circulation of amyloid A or light chain proteins can indicate improper production of proteins and amyloidosis

3. Imaging tests to examine different organs

4. Echocardiogram or nuclear heart test to determine health of heart

5. Liver ultrasound

6. Biopsy - kidney, bone marrow, or other piece of tissue is extracted and labeled with a dye that, when producing a green color, indicates the presence of amyloid

As there are various forms that amyloidosis can take, the treatment must be tailored to the type of amyloidosis diagnosed as well as which organ/tissue is affected.

Treatment for ATTR: Medication that lowers amyloid production – FDA approved therapy for transthyretin amyloidosis that “silences” the TTR gene or stabilizes the TTR protein to prevent the growth of amyloid plaques in affected organs; Evomela (melphalan) and Dextenza (dexamethasone) can be administered orally or through IV but may be associated with more side effects than Velcade (bortezomib), Revlimid (lenalidomide), or Cytoxan (cyclophosphamide)

Treatment for AL: Chemotherapy or other strong drugs - target and deplete the cells producing abnormal light chain proteins; often followed by bone marrow or stem cell transplant with the individual’s healthy stem cells that replace those that were destroyed

Treatment for hereditary ATTR: Liver transplant - healthy liver will produce non-mutated form of TTR protein; In some cases, TTR gene silencers such as FDA-approved  Onpattro (patisiran) and Tegsedi (inoteresen) can also be prescribed.

Treatment in cases where amyloidosis affects the heart: Treatments focused on preventing congestive heart failure, improving nutrition, and treating autonomic neuropathy

Disease progression and complications associated with individuals with amyloidosis vary depending on many factors, such as age of onset and affected organ(s). Some individuals may not experience symptoms until much later or be completely benign. Others will have more symptoms and complications. Extensive damage to the following organ systems can affect an individual’s prognosis:

1. Heart – high levels of amyloid in bloodstream lower the heart’s ability to fill with blood properly between heartbeats, causing shortness of breath and heart rhythm problems which can be life-threatening

2. Kidneys – high levels of amyloid in bloodstream cause damage to the kidneys and prevent the proper filtration of waste out of the blood into the urine, which can cause kidney failure

3. Nervous system – damage to the nerves can cause pain, numbness, tingling, control of bowels, and blood pressure problems

https://amyloidosis.org/

Current Clinical Trials:

https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

Private Clinical Trials:

www.centerwatch.com

European Clinical Trials:

https://www.clinicaltrialsregister.eu/

Amyloidosis Treatment Centers:

https://www.amyloidosissupport.org/

1. https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178#:~:text=Amyloidosis%20(am%2Duh%2Dloi,nervous%20system%20and%20digestive%20tract.

2. https://www.hopkinsmedicine.org/health/conditions-and-diseases/amyloidosis

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

4. https://emedicine.medscape.com/article/335414-overview

5. https://www.nhs.uk/conditions/amyloidosis/