Amyloidosis is a rare heterogeneous acquired or hereditary systemic group of disorders caused by a build-up of an abnormal protein called amyloid in organs and tissues throughout the body. The build-up of amyloid proteins (deposits) can make it difficult for the organs and tissues to work properly. The different types of amyloidosis are classified as systemic or localized. AL (immunoglobulin light chain, historically known as primary) amyloidosis is the most common type of systemic amyloidosis. AL amyloidosis results from an abnormality (dyscrasia) of a type of white blood cell called plasma cells in the bone marrow and are closely related to multiple myeloma. AA (historically known as secondary) amyloidosis is derived from the inflammatory protein serum amyloid A. AA amyloidosis occurs in association with chronic inflammatory diseases such as rheumatic diseases, familial Mediterranean fever, chronic inflammatory bowel disease, tuberculosis, or empyema.
Hereditary amyloidosis is a rare type of amyloidosis that is caused by an abnormal gene. Several abnormal genes can cause hereditary amyloidosis, but the most common type of hereditary amyloidosis is called ATTR and is caused by mutations in the transthyretin (TTR) gene.
Age-related amyloidosis, in which the amyloid is derived from wild-type (normal) transthyretin, is a slowly progressive disease that affects the hearts of elderly men and is called ATTRwt amyloidosis. Amyloid deposits may occasionally occur in isolation without evidence of a systemic disease; isolated bladder or tracheal amyloidosis is the most common such presentation.
Dialysis-related beta2-microglobulin amyloidosis is a type of systemic amyloidosis that can occur in individuals who have experienced long-term kidney dialysis to remove accumulated impurities or wastes in the blood by mechanical filtration. This form of amyloidosis, also known as ABM2 (amyloid associated with the beta-2m protein), is associated with the aggregation of beta2-microglobulin, a type of amyloid protein that is cleared in the normally-functioning kidney.
Dialysis-related beta2-microglobulin amyloidosis occurs in patients with near end-stage renal disease. It does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant.
The disease can be localized or systemic. Amyloid can accumulate in the liver, spleen, kidney, heart, nerves, and blood vessels, causing different clinical syndromes, including cardiomyopathy, hepatomegaly, proteinuria, macroglossia, autonomic dysfunction, ecchymoses, neuropathy, renal failure, hypertension, and corneal and vitreous abnormalities.[rx][rx][rx]
Types of amyloidosis
There are different types of amyloidosis. They are named for the type of protein that is affected by the illness. The types of amyloidosis include:
- AL amyloidosis. This is the most common type of amyloidosis in the United States. AL amyloidosis is a disorder of the plasma cells. Plasma cells are a type of white blood cell responsible for the production of immunoglobulins or antibodies, which are a type of protein that fights infection. The amyloid proteins that build up in the tissues in this condition are known as light chains. They can either be kappa or lambda light chains. “AL” stands for amyloid and light chain. In AL amyloidosis, the light chain proteins are misshapen and there are too many of them. These are deposited in tissues and can damage one or more organs. The heart, kidneys, nerves, and gastrointestinal system are the most common organs affected. Because AL amyloidosis is associated with the overproduction of plasma cell proteins, it is linked to multiple myeloma.
- AA amyloidosis. AA amyloidosis is also called “autoimmune amyloidosis,” “secondary amyloidosis,” or “inflammatory amyloidosis.” In this condition, the amyloid protein that builds up in the tissues is called the A protein. AA amyloidosis is associated with some chronic diseases, such as diabetes, tuberculosis, rheumatoid arthritis, and inflammatory bowel disease. It may also be linked to aging. AA amyloidosis can affect the spleen, liver, kidneys, adrenal glands, and lymph nodes. Lymph nodes are tiny, bean-shaped organs that fight infection.
- Hereditary or familial amyloidosis. Hereditary amyloidosis is rare. It can be passed from generation to generation within a family. The proteins produced in hereditary amyloidosis may cause problems with the heart and may cause carpal tunnel syndrome and eye abnormalities. The most common subtypes involve a protein called transthyretin (TTR). This is sometimes called ATTR amyloidosis.
Type of amyloidosis According to Diagnosis Criteria
- AA amyloidosis (Secondary) – AA amyloidosis is caused by a chronic infection or an inflammatory disease such as rheumatoid arthritis, familial Mediterranean fever (FMF), osteomyelitis, or granulomatous ileitis. Infection or inflammation causes elevation of an acute-phase protein, SAA, a portion of which deposits as amyloid fibrils. Therefore, it is termed AA amyloidosis. AA amyloidosis usually begins as a disease in the kidneys, but other organs can be affected. Medical or surgical treatment of the underlying chronic infection or inflammatory disease can slow down or stop the progression of this type of amyloidosis.
- ATTR amyloidosis (ATTRm or ATTRwt) – There are several types of inherited amyloidoses, the most common of which is caused by a mutation in the transthyretin (TTR) gene that produces abnormal transthyretin protein. The abnormal TTR protein deposits as amyloid fibrils: Hence, it is termed ATTR amyloidosis. Symptoms of the disease are usually neuropathy and cardiomyopathy and occur in mid to late life. ATTR amyloidosis is found in families of nearly every ethnic background. More than 100 different mutations in transthyretin are known and most cause amyloidosis. ATTR can also occur with the wild-type unmutated TTR protein, usually causing cardiomyopathy in older men; this was formerly termed “senile systemic amyloidosis” but now is known as ATTRwt amyloidosis. Treatment options include TTR stabilizers (Diflunisal or Tafamidis), or gene silencers, or TTR production or liver transplantation.
- Hereditary amyloidosis – There are other gene mutations that produce proteins that cause amyloidosis. These are very rare. They include apolipoprotein A-I (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys). A protein known as Lect2 can also cause amyloidosis; it is not clear if this is inherited or not.
- Beta-2 Microglobulin amyloidosis (Abeta2m) – Beta-2 microglobulin amyloidosis is caused by chronic renal failure and often occurs in patients who are on dialysis for many years. Amyloid deposits are made of the beta-2 microglobulin protein that accumulated in tissues, particularly around joints, when it cannot be excreted by the kidney because of renal failure.
- Localized amyloidosis (ALoc) – There are many types of localized amyloidoses. Localized amyloid deposits in the airway (trachea or bronchus), eye, or urinary bladder are often caused by local production of immunoglobulin light chains, not originating in the bone marrow. Localized AL can be treated with radiation therapy, and it and other localized forms sometimes are amenable to surgery. Other localized types of amyloidosis are associated with endocrine proteins, or proteins produced in the skin, heart, and other sites. These usually do not become systemic.
Causes
The most common causes of amyloidosis are the immunoglobulin-light-chain related amyloidosis (AL), ATTR amyloidosis, and reactive amyloidosis (AA) due to chronic inflammatory diseases like chronic infections and rheumatoid arthritis. AL amyloidosis is acquired and is caused by a small plasma cell clone that produces misfolded amyloidogenic light chains that deposit in different organs and tissues.[rx][rx] AA amyloidosis is associated with various chronic inflammatory conditions, chronic or local microbial infections, and rarely with neoplasms. In AL amyloidosis, the cause is the abnormal plasma cells and as such, chemotherapy is aimed at eradicating those cell forms.
Amyloidosis is caused by abnormal folding of normally soluble proteins leading to fibril formation in one or more body organs, systems, or soft tissues. These clumps of protein are called amyloid deposits and the accumulation of amyloid deposits causes the progressive malfunction and eventual failure of the affected organ. Normally, proteins are broken down at about the same rate as they are produced, but these unusually stable amyloid deposits are deposited more rapidly than they can be broken down.
The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with the production of an abnormal light chain protein (part of an antibody). Usually, an excess amount of antibody protein is produced and the abnormal light chain portion of the whole antibody molecule accumulates in the body tissues in the form of amyloid deposits.
AA amyloidosis is caused by the inflammatory disease process that is part of the underlying disease. Approximately 50% of the people with secondary amyloidosis have rheumatoid arthritis as the underlying disease.
Familial amyloidosis (hATTR) is caused by an abnormality in the gene for one of several particular proteins. The most common form of hereditary amyloidosis is caused by an abnormality (mutation) in the gene for transthyretin. More than 100 different mutations in the transthyretin gene have been reported and the most common mutation has been termed V30M. Different TTR gene mutations are associated with amyloidosis which affects different organ systems. Rarely, mutations in genes for proteins that cause amyloidosis are fibrinogen A alpha chain, apolipoprotein A1 and A2, gelsolin, LECT2, and cystatin C.
All the hereditary amyloidoses follow autosomal dominant inheritance. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Not every person getting the gene, however, will ultimately get sick with amyloidosis.
The exact cause of dialysis-related beta2-microglobulin amyloidosis is not fully understood. A normally-functioning kidney can clear out beta 2-microglobulin. In some individuals on long-term dialysis or some individuals on continuous ambulatory peritoneal dialysis (CAPD), the kidneys’ inability to function properly leads to the abnormal retention and accumulation of the beta2-microglobulin protein. Some individuals with near end-stage renal failure have also developed this form of amyloidosis. Although this retention and accumulation are believed to be the main underlying factor, additional factors are required for the disorder to develop, which is why only a percentage of individuals on dialysis develop dialysis-related beta2-microglobulin amyloidosis.
See below for a list of amyloid fibril proteins that have been found in humans
| Fibril protein | Precursor protein | Target Organs | Systemic and/or localized | Acquired or hereditary |
|---|---|---|---|---|
| AL | Immunoglobulin light chain | All organs, usually except CNS | S, L | A, H |
| AH | Immunoglobulin heavy chain | All organs except CNS | S, L | A |
| AA | (Apo) serum amyloid A | All organs except CNS | S | A |
| ATTR | Transthyretin, wild typeTransthyretin, variants | Heart mainly in males, lung, ligaments, tenosynoviumPNS, ANS, heart, eye, leptomeninges | SS | AH |
| Aβ2M | β2-microglobulin, wild typeβ2-microglobulin, variants | Musculoskeletal systemANS | SS | AH |
| AApoAI | Apolipoprotein A I, variants | Heart, liver, kidney, PNS, testis, larynx (Cterminal variants), skin (C terminal variants) | S | H |
| AApoAII | Apolipoprotein A II, variants | Kidney | S | H |
| AApoAIV | Apolipoprotein A IV, wild type | Kidney medulla and systemic | S | A |
| AApoCII | Apolipoprotein C II, variants | Kidney | S | H |
| AApoCIII | Apolipoprotein C III, variants | Kidney | S | H |
| AGel | Gelsolin, variants | Kidney, PNS, cornea | S | H |
| ALys | Lysozyme, variants | Kidney | S | H |
| ALECT2 | Leukocyte chemotactic factor-2 | Kidney, primarily | S | A |
| AFib | Fibrinogen a, variants | Kidney, primarily | S | H |
| ACys | Cystatin C, variants | CNS, PNS, skin | S | H |
| ABri | ABriPP, variants | CNS | S | H |
| ADanb | ADanPP, variants | CNS | L | H |
| Aβ | Aβ protein precursor, wild typeAβ protein precursor, variant | CNSCNS | LL | AH |
| AαSyn | α-Synuclein | CNS | L | A |
| ATau | Tau | CNS | L | A |
| APrP | Prion protein, wild typePrion protein variants
Prion protein variant |
CJD, fatal insomniaCJD, GSS syndrome, fatal insomnia
PNS |
LL
S |
AH
H |
| ACal | (Pro)calcitonin | C-cell thyroid tumorsKidney | LS | AA |
| AIAPP | Islet amyloid polypeptide | Islets of Langerhans, insulinomas | L | A |
| AANF | Atrial natriuretic factor | Cardiac atria | L | A |
| APro | Prolactin | Pituitary prolactinomas, aging pituitary | L | A |
| AIns | Insulin | Iatrogenic, local injection | L | A |
| ASPCd | Lung surfactant protein | Lung | L | A |
| ACor | Corneodesmosin | Cornified epithelia, hair follicles | L | A |
| AMed | Lactadherin | Senile aortic, media | L | A |
| AKer | Kerato-epithelia | Cornea, hereditary | L | A |
| ALac | Lactoferrin | Cornea | L | A |
| AOAAP | Odontogenic ameloblast-associated protein | Odontogenic tumors | L | A |
| ASem1 | Semenogelin 1 | Vesicula seminalis | L | A |
| AEnf | Enfuvirtide | Iatrogenic | L | A |
| ACatKe | Cathepsin K | Tumor-associated | L | A |
| AEFEMP1e | EGF-containing fibulin-like extracellularmatrix protein 1 (EFEMP1) | Portal veins, Aging-associated | L | A |
Symptoms
Amyloidosis is usually a multisystem disease resulting in a wide spectrum of clinical presentations. Consequently, a patient may present to, or be referred to, one of several subspecialists, most commonly a nephrologist, cardiologist, or neurologist. Recent advances in therapy have rendered early and precise diagnosis critical if the patient is to fully benefit. Most patients have more than one organ involved and therefore the finding of a combination of any of the features below should heighten the suspicion of amyloidosis:
The kidney is the organ most commonly involved in AL amyloidosis and AA amyloidosis, however, rarely involved in hATTR amyloidosis. Excessive amounts of protein in the urine (proteinuria) is the usual manifestation of renal involvement and is commonly heavy, resulting in nephrotic syndrome. Less commonly, amyloid causes an excess of urea and other nitrogenous wastes in the blood (progressive azotemia) as the initial manifestation of renal disease. An abnormal accumulation of fluid (edema), such as swelling of the legs and abdomen, in the absence of heart failure, is a feature of nephrotic syndrome, as is the presence of excess cholesterol in the blood (hypercholesterolemia) that may be profound. The kidneys often become small, pale, and hard, but in amyloidosis, large kidneys are commonly seen as well.
Amyloidosis frequently involves the heart. The heart is commonly involved in AL and ATTRm amyloidosis and is the most common phenotype of ATTRwt amyloidosis. Amyloid infiltration of the heart results in ventricular wall thickening and the development of heart failure. Rapidly progressive congestive heart failure with thick ventricular walls is the classical presentation of AL cardiac amyloidosis. The heart is invariably involved in senile amyloidosis, often in TTR amyloidosis and rarely in secondary amyloidosis. Common symptoms of heart involvement include an enlarged heart (cardiomegaly); an irregular heartbeat (arrhythmias); and abnormalities of the heart seen on electrocardiograms (for example low voltage). Congestive heart failure is the most common cardiac complication of amyloidosis. Nodular deposits of amyloid may be present on the membranous sac that surrounds the heart (pericardium) and on the lining of the heart chambers or heart valves (endocardium).
Although less common than renal or cardiac involvement, neuropathy may be a significant problem in amyloidosis. Occasionally, it is the presenting and predominant feature of AL amyloidosis. In specific mutations of hereditary amyloidosis (particularly V30M originally known as familial amyloid polyneuropathy), it is the primary feature of the disease. The neuropathy is often painless and sensorimotor although neuropathic pain may be occasionally significant. These symptoms may include sensory neuropathy with numbness and tingling sensations in the feet that progresses to the legs and eventually the upper extremities; motor neuropathy with loss of motion beginning in the feet and extending upward. Carpal tunnel syndrome is commonly seen, not due to direct nerve involvement, but rather too soft tissue infiltration causing median nerve compression. In hATTR amyloidosis, peripheral neuropathy is frequently accompanied by an autonomic neuropathy characterized by diarrhea and a decrease in the amount of sweat production (hypohidrosis), a sudden drop in blood pressure when the patient stands up (postural hypotension), and, in the male, erectile dysfunction. Postural hypotension may be profound and result in recurrent fainting (syncopal) episodes. Systemic amyloidosis does not involve the central nervous system and is unrelated to Alzheimer’s disease.
Amyloidosis may affect the liver and the spleen. Amyloid involvement in the spleen increases the risk of spontaneous rupture of that organ. Some degree of hepatic involvement is common in AL amyloidosis. It is also common in AA amyloidosis but is not seen in hATTR amyloidosis. In most patients, hepatic involvement is asymptomatic. An enlarged liver (hepatomegaly) and an enlarged spleen (splenomegaly) are the most notable signs. Generally, the amyloid-infiltrated liver feels very hard, and elevated liver enzymes (particularly alkaline phosphatase) and other liver function abnormalities may be detected early. Generally, the function of the liver is not significantly affected until late in the course of the disease. Elevation of bilirubin is an ominous sign and may portend hepatic failure. Hepatic amyloidosis rarely occurs in isolation and is usually associated with organ involvement elsewhere.
Amyloidosis may also affect the gastrointestinal (digestive) system. Amyloid accumulation in the gastrointestinal tract may cause a lack of movement (motility) in the esophagus and the small and large intestines. Malabsorption, ulceration, bleeding, weak gastric activity, pseudo-obstruction of the gastrointestinal tract, protein loss, and diarrhea may also occur. Loss of taste, and difficulty eating solid foods because of enlargement of the tongue (macroglossia) from amyloid infiltration, may contribute to weight loss, or weight loss may be a non-specific manifestation of the systemic disease. In patients with autonomic neuropathy, gastric emptying is impaired, resulting in a sensation of early satiety.
The skin is frequently involved in primary amyloidosis. Dermatologic involvement is almost exclusively limited to AL amyloidosis and consists of soft tissue, skin, and vascular abnormalities. Periorbital purpura is a result of capillary fragility and may appear after coughing, sneezing, or straining for a bowel movement. Not infrequently, purpuric lesions may arise after such simple actions as rubbing the eyelids. Soft tissue infiltration may cause macroglossia and hoarseness, although examination of the vocal cords may appear normal. Lesions of the skin may be visible or may be so small that they may be seen only with a microscope. Waxy-looking papular lesions may appear on the face and the neck. They may also occur under the arms (axillary region), near the anus, and the groin. Other areas that may be affected are the mucous areas such as the ear canal or tongue. Areas of swelling, hemorrhages under the skin (purpura), hair loss (alopecia), inflammation of the tongue (glossitis), and a dry mouth (xerostomia) may also be present.
Problems with the respiratory system that are associated with amyloidosis often parallel cardiac symptoms. In the localized form of amyloidosis, air passages and ducts may be obstructed by amyloid deposits in the nasal sinuses, voice box (larynx) and throat (trachea), and bronchial tree. Fluid collecting in the pleural space (pleural effusion) is quite common in patients with congestive heart failure due to amyloidosis, but large recurrent pleural effusions disproportionate to the degree of heart failure suggest pleural amyloidosis.
Joint abnormalities (arthropathy) occur in amyloidosis due to the accumulation of amyloid deposits in the lining of joints (synovial membranes). This occurs in AL amyloidosis and occasionally in dialysis-related amyloidosis. Articular cartilage or the synovial membrane and fluid may become involved as well. Symptoms are similar to those of rheumatoid arthritis. Amyloid deposits in muscle tissue may cause muscle weakness and muscle changes (pseudomyopathy). Symptoms of amyloidosis may also be manifested by bleeding disorders. These may result from deficiency of certain clotting factors or small amyloid deposits in blood vessels within the skin.
Dialysis-related beta2-microglobulin amyloidosis usually affects the bones and joints. Initial symptoms include carpal tunnel syndrome, shoulder pain, and inflammation of the tendon sheaths of the hands. Case reports of severe pulmonary hypertension and heart failure also exist.
Signs and symptoms of amyloidosis may include:
- Swelling of your ankles and legs
- Severe fatigue and weakness
- Shortness of breath with minimal exertion
- Unable to lie flat in bed due to shortness of breath
- Numbness, tingling or pain in your hands or feet, especially pain in your wrist (carpal tunnel syndrome)
- Diarrhea, possibly with blood, or constipation
- Unintentional weight loss of more than 10 pounds (4.5 kilograms)
- An enlarged tongue, which sometimes looks rippled around its edge
- Skin changes, such as thickening or easy bruising, and purplish patches around the eyes
- An irregular heartbeat
- Difficulty swallowing
Hepatomegaly, nephrotic syndrome, macroglossia, orthostatic hypotension, ecchymosis, and autonomic and peripheral neuropathy can be present. Carpal tunnel syndrome, jaw claudication, and articular deposits of amyloid can also be a manifestation of systemic amyloidosis. In secondary amyloidosis (AA), hepatosplenomegaly, proteinuria, renal failure, and orthostasis can be seen. ATTR amyloidosis onset is during midlife and presents with peripheral and autonomic neuropathy, cardiomyopathy, and vitreous opacities. Amyloid beta-amyloidosis is localized to the central nervous system and presents as sporadic Alzheimer’s disease and aging
Diagnosis
Particularly in the case of AL amyloidosis, early diagnosis is the key to survival and post-treatment regaining of quality of life. The diagnosis of amyloidosis is suspected following a detailed patient history and clinical evaluation but requires aspiration of the abdominal fat pad and/or biopsy of the involved organ. If the disease is suspected on clinical grounds, a biopsy of the involved organ will give the highest yield. The biopsy material is examined microscopically and is stained with a dye called Congo red that will produce a green color when looked at in a polarizing microscope if amyloid is present. When amyloidosis is diagnosed on a tissue biopsy the affected individual must be further evaluated to determine what organs are affected.
Once a tissue biopsy of amyloidosis has been established, it is crucial to determine the type of amyloidosis. In AL amyloidosis, manifestations of a plasma cell dyscrasia will be found 98% of the time. In 2% of cases, a B-cell lymphoma is identified as the cause of AL amyloidosis. The specific tests that are used to make a diagnosis of the plasma cell dyscrasia or B-cell clone are immunofixation and protein electrophoresis of the blood and urine, bone marrow biopsy with immunochemical staining of plasma cells for kappa and lambda light chains, and a serum-free light chain assay. The diagnosis of TTR hereditary amyloidosis can be confirmed by performing molecular genetic testing for mutations in the TTR gene on a blood sample. In the absence of mutations of transthyretin, very rare forms of familial amyloidosis may be present.
If the patient is an elderly man with clinically isolated cardiac involvement, the most likely diagnosis is ATTRwt amyloidosis a condition in which wild-type (normal) transthyretin is deposited in the heart.
Specific immunostaining (for example, immunogold electron microscopy) of appropriately preserved tissue is available at specialized centers and offers a high specificity for determining the accurate type of amyloid. In difficult diagnostic cases, mass spectrometry can determine precisely the molecular structure of the amyloid deposits– this technique is being used more and more frequently. A technique called radiolabeled serum amyloid P (SAP) scanning is available in a few centers in Europe that specialize in amyloidosis. This test is used to monitor and evaluate the extent of the accumulation of amyloid deposits.
Clinical suspicion, family history, and tissue biopsy establish the diagnosis.[rx][rx]
Tissue biopsy
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The subcutaneous abdominal fat aspirate is an easy and innocuous procedure that will stain Congo red positive with apple-green birefringence and has an 81% diagnostic sensitivity in AL amyloidosis.
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Biopsy of minor salivary glands can establish systemic amyloidosis diagnosis 60% of the times when fat aspirates are negative.
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Biopsy of the liver should be done by the transjugular route, since an amyloid-loaded liver may result in fatal bleeding.[rx]
Plasma cell clone identification
Serum and urine electrophoresis with immunofixation and free light chains (FLC) should be requested to rule out plasma cell dyscrasia. When monoclonal light chains are not present, bone marrow biopsy can help establish the diagnosis by immunohistochemical staining. Immunofluorescence in situ hybridization (FISH) should be ordered along with a skeletal survey.
When plasma cell dyscrasia is ruled out, other types of amyloidosis should be considered. Tissue typing can be done by mass spectrometry, immune electron microscopy or immunohistochemistry. Transthyretin can be detected by isoelectric focusing on the serum which separates wild-type (or formerly known senile cardiac amyloidosis) and variant transthyretin.[rx]
Gene sequencing
Should be done when hereditary amyloidosis has to be ruled out based on clinical grounds.
When transthyretin has not been identified, and patients have macroglossia and other typical organ involvement, AL should still be suspected despite plasma cell dyscrasia absence. ATTRwt is diagnosed by cardiac biopsy showing positivity to antibodies against normal transthyretin. Cardiac Scintigraphy with bone tracers can help differentiate AL amyloidosis which shows mild or no uptake from transthyretin amyloidosis which has strong uptake. This could potentially spare cardiac biopsy.
AA amyloidosis is considered when transthyretin and AL have been ruled out, and there are kidney involvement and neuropathy. Immunohistochemistry aids in the diagnosis of AA.
Organ involvement and staging of the disease should be established to design the treatment plan. For cardiac function, evaluation should include an echocardiogram with an assessment of strain, NT-proBNP, troponins, ECG, Holter ECG, and cardiac MRI should be solicited. For kidney function, evaluation of 24-hour urinary protein and eGFR are needed. Liver function tests and imaging (ultrasound (US), MRI, or CT scan) can help with hepatic function assessment. In individuals on long-term dialysis or with end-stage renal failure, lab tests may be performed that can analyze blood or urine samples to detect increased levels of B2M protein.
Treatment
AL amyloidosis: This disease is treated most likely in the framework of clinical trials and depending on the risk stratification according to the Standard Mayo Clinic staging system.[rx][rx][rx]
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Low-risk patients: NT-proBNP less than 5000 ng/L, troponins of less than 0.06 ng/ml, eGFR more than 50 ml/min per 1.73m, age less than 65 years, performance status of 0-2, NYHA class less than III, ejection fraction above 45%, systolic blood pressure above 90 mmHg standing and diffusion capacity of carbon monoxide (DLCO) above 90%). Low-risk patients receive autologous stem cell transplant (ASCT) with Melphalan 200mg/m2. Induction with cyclophosphamide, bortezomib, and dexamethasone should be considered if the bone marrow and plasma cell infiltration is more than 10% or if a patient refuses a transplant. Post-transplant treatment with bortezomib increases the complete response (CR) rates, and if CR is not achieved, a bortezomib and dexamethasone combination should be given.
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Intermediate risk patients (ineligible for ASCT and stage I-IIIa): Melphalan and Dexamethasone are the preferred regimens, especially in the case of neuropathy or t(11;14) translocation. Cyclophosphamide with Bortezomib and dexamethasone combination is a stem cell sparing regimen preferred in patients with renal failure and with 1q21 gain. If noninvolved Free Light Chains (FLC) is above 180 mg/l, the preferred regimen is a bortezomib, melphalan, and dexamethasone combination.
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High-risk patients (stage IIIb, NYHA class III or above): bortezomib can be preferred due to a rapid onset of action or low-dose combination regimens are preferred as well.
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ATTR amyloidosis: Transthyretin is a protein predominantly synthesized in the liver. Upon liver transplant, mutant transthyretin disappeared from blood, and neuropathy improvement was observed.
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Supportive therapy: The treatment of systemic amyloidosis involves supportive therapy aiming to maintain the quality of life and prevent organ dysfunction. If patients are on a heart transplant waiting list, they should receive low-dose chemotherapy due to increased survival.
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Splenectomy: An option with proper prior vaccination when there is severe factor-X deficiency leading to bleeding diathesis. Factor X deficiency is seen in 2.5% of patients with AL amyloidosis. Splenectomy is effective in patients who have splenomegaly, but not usually in patients with a normal size spleen.[rx]
- Supportive therapy: (treatment of congestive heart failure, attention to nutrition, treatment of autonomic neuropathy, etc.) is a very important concomitant measure. Given the complexity of the disease, it is recommended that treatment be performed in a center with experience in amyloidosis, or at least that the patient should have an initial evaluation at such a center, with continued communication during treatment in the local community.
Various regimens have been studied but the ones with the most historical evidence are Evomela (melphalan) and Dextenza (dexamethasone) given orally or high-dose melphalan given intravenously with autologous stem cell transplantation. Both are equally effective but the treatments and side effects are different. High-dose melphalan with stem cell transplantation is an involved treatment that often involves a 2-3 week hospital stay and a few months of additional recovery time. The use of oral melphalan every month is less toxic but is associated with a higher risk of treatment-related leukemia. Newer agents active in multiple myelomas (another disease of abnormal plasma cells), such as Velcade (bortezomib) or Revlimid (lenalidomide), are also very effective in AL amyloidosis and have been shown to provide a benefit in patients with relapsed disease. Often, these drugs are incorporated into upfront treatment. Currently, most patients not getting high dose melphalan with stem cell support transplantation are having to get novel therapies upfront. The combination of bortezomib, Cytoxan (cyclophosphamide), and dexamethasone is associated with good tolerability and rapid responses. The specific treatment for any individual has to be personalized to their unique situation.
Hereditary TTR amyloidosis is treated, if possible, by removal of the source of the abnormal TTR production. Since the dominant source is the liver, liver transplantation is performed in carefully selected patients whose disease is not too far advanced. Onpattro (patisiran) and Tegsedi (interested) are TTR gene silencers and have been approved by the Food and Drug Administration (FDA) for the treatment of ATTRm amyloidosis with peripheral neuropathy. In 2019, the FDA approved Vyndaqel (tafamidis meglumine) to treat the cardiomyopathy (heart disease) caused by ATTR (ATTR-CM).
In ATTRwt amyloidosis, therapy is supportive, but both for this disease and for ATTR, pharmacologic therapies aimed at stabilizing the transthyretin molecule and thus preventing amyloid formation are being actively investigated. The mainstay of AA amyloidosis treatment is the therapy of the underlying disease. Renal transplantation has been performed successfully for renal disease due to AA amyloidosis.
Eprodisate is a small molecule that inhibits the formation of amyloid fibrils, and which seems to have a modest clinical effect in patients with AA amyloidosis.
In 2015, the FDA authorized the use of a medical device called Lixelle Beta 2-microglobulin apheresis column to treat dialysis-related beta2-microglobulin amyloidosis. The device works by removing the beta 2m protein from the blood.Genetic counseling is recommended for individuals with hereditary amyloidosis and their family members.
References
Amniotic Fluid Embolism (AFE)
