Last updated: July 26, 2023

Summarytoggle arrow icon

Amyloidosis is a collective term for the extracellular deposition of abnormal proteins, in a single organ (localized amyloidosis) or throughout the body (systemic amyloidosis). The different subtypes of amyloidosis are classified according to the identity of the deposited proteins. The standardized naming convention dictates that the letter “A” for amyloidosis is followed by an identifier of the protein that forms the amyloid fibril deposits (e.g., AL for immunoglobulin light chain deposits). These abnormal proteins are produced as a result of various diseases. The most common form of systemic amyloidosis in developed nations is light chain amyloidosis (AL amyloidosis), which is associated with plasma cell dyscrasias such as multiple myeloma. The second most common systemic form, reactive amyloidosis (AA amyloidosis), is secondary to chronic inflammation and typically presents with nephrotic syndrome. Depending on which organs are affected, amyloidosis may also manifest with hepatomegaly, macroglossia, cardiac conduction abnormalities, and/or symptoms of restrictive cardiomyopathy. Abdominal fat or rectal mucosa biopsies are used to diagnose systemic amyloidosis. Target organ biopsy is more sensitive but less commonly required for definitive diagnosis because it presents a higher procedural risk. When stained with a Congo red dye, amyloid deposits in the biopsy sample exhibit an apple-green birefringence under polarized light. Management of amyloidosis is dependent on the specific type and is specialist-guided. In AL amyloidosis, chemotherapy with melphalan and corticosteroids may be used, and suitable patients may be referred for autologous HSCT. Treatment of the underlying disease is the mainstay of management for AA amyloidosis. Organ transplantation may also be an option for certain patients as directed by a specialist.

Overviewtoggle arrow icon

Definitions [1]

  • Amyloid: insoluble protein or protein fragments
  • Amyloidosis: extracellular aggregation and subsequent deposition of amyloid in various organs


Classification [3]

  • The standardized nomenclature convention for amyloidosis is “AX.”
    • A denotes amyloidosis.
    • X denotes the affected protein that comprises the fibrillar component.
  • May also be classified as:

Systemic amyloidosistoggle arrow icon


The following list is not exhaustive; > 15 types of systemic amyloidosis have been identified, each caused by a different protein. [1]

Overview of systemic amyloidosis [1][4][5]
Affected protein Etiology Characteristic features
AL amyloidosis (light-chain amyloidosis or primary amyloidosis)
AA amyloidosis (reactive amyloidosis or secondary amyloidosis)
Aβ2M amyloidosis (β2-microglobulin amyloidosis or hemodialysis-associated amyloidosis)
ATTRmt amyloidosis (mutated transthyretin amyloidosis, ATTRv (variant) amyloidosis, or hereditary transthyretin amyloidosis) [8]
ATTRwt amyloidosis (wild-type transthyretin amyloidosis or senile cardiac amyloidosis)
  • Normal (wild-type) transthyretin (ATTRwt) → deposition in cardiac ventricles → cardiac dysfunction (less drastic than in AL amyloidosis) [9]
  • Old age

Approach to management [1][4]

Suspect systemic amyloidosis in patients with constitutional symptoms and multiple affected organs.

Management should be focused on treating the underlying disease, as this may stall disease progression. [1]

Diagnostics of amyloidosis [1][4]

Tissue biopsy

The type of tissue sample depends on the extent of disease and organ involvement. [10]

  • Tissue sample
    • Target organ (e.g., of a kidney or a nerve): preferred in patients with single organ involvement
    • Abdominal fat aspiration or rectal mucosa: preferred in patients with multiorgan and/or tissue involvement [3]
  • Methods

After staining demonstrates amyloid deposition, diagnosis is confirmed by identifying the specific protein fibril in the amyloid deposits of the biopsied tissue sample.

Additional studies [1][4]

Additional studies should be obtained for risk stratification and to guide management decisions. Results will vary depending on the type and degree of end-organ involvement.

AL amyloidosis (primary amyloidosis)toggle arrow icon

Epidemiology [3]

Most common form of amyloidosis

Etiology [3][11]

Low-level expansion of a plasma cell dyscrasia (e.g., multiple myeloma, Waldenstrom macroglobulinemia)

Pathophysiology [3]

Increased production of the light chains of immunoglobulins deposition of amyloid light chain protein (AL protein) in various organs

Clinical features [3][5][12]

AL amyloidosis is a rare, but potentially severe disease that can affect any organ (with the exception of the CNS). [12]

The combination of raccoon eyes, macroglossia, and the shoulder pad sign is highly specific for AL amyloidosis (but only present in ∼ 10 % of patients). [5]

Diagnostics [1][4][11]

Consult a specialist early (e.g., rheumatologist, hematologist).

Suspect AL amyloidosis in patients with multiple affected organs (e.g., heart failure with preserved ejection fraction, nephrotic range proteinuria, peripheral neuropathy, hepatomegaly, and/or noninfectious diarrhea), and/or atypical MGUS or smoldering multiple myeloma.

Management [1][4]

Treatment options are based on the stage of the underlying disease (e.g., multiple myeloma staging), and level of end-organ damage (e.g., NYHA class for heart failure), and include:

The main goal of treatment is to inhibit plasma cells from producing light chains, which in turn reduces amyloid deposition and helps to facilitate organ recovery.

Prognosis [3][11]

  • Rapidly progressive clinical course if left untreated
  • Survival depends largely on the severity of cardiac and/or renal dysfunction at diagnosis.
  • The median survival time without treatment is 1–2 years.

AA amyloidosis (secondary amyloidosis)toggle arrow icon

Etiology [3]

AA amyloidosis is secondary to a chronic disease, such as:

Pathophysiology [3]

Chronic inflammatory process → ↑ production of acute phase reactant SAA (serum amyloid-associated protein)deposition of AA (amyloid-associated) protein in various organs

Clinical features [1][4][5]

The main feature of AA amyloidosis at diagnosis is renal dysfunction (e.g., CKD, nephrotic syndrome). Cardiac involvement is rare. [3][5]

Diagnostics [4][5][14]

Consult a specialist early (e.g., rheumatologist).

Amyloidosis should always be considered in patients who present with kidney, liver, or GI involvement in the setting of chronic inflammatory and/or infectious disease.

Management [1][4][14]

Prognosis [1][12]

ATTRmt amyloidosistoggle arrow icon

Overview [17]

Overview of ATTRmt amyloidosis
Clinical phenotype Familial amyloid cardiomyopathy (FAC) Familial amyloid polyneuropathy (FAP)
  • Common in African Americans (3% of African Americans carry the mutant allele for FAC) [19]
  • Common in Portugal, Sweden, Japan, and among people of Irish descent
Affected sites
  • Peripheral and autonomic nerves

Management [4][5]

Localized amyloidosistoggle arrow icon

  • In localized amyloidosis (e.g., endocrine amyloidosis), a single organ is affected.
  • A definitive diagnosis can only be made on histopathology.
  • Management is specialist-guided and organ-specific.

Examples of localized amyloidosis [22][23]

Type Example diseases Affected protein
Nonneurologic diseases

Isolated atrial amyloidosis (↑ risk of atrial fibrillation)

ANP (physiological in old age)

Type 2 diabetes mellitus

Islet amyloid polypeptide (IAPP) deposits in pancreatic islet

Injection-localized amyloidosis (from insulin injection in diabetes mellitus)

Amyloid at insulin injection site (AIns)

Medullary carcinoma of the thyroid

Calcitonin amyloid (ACal)

Neurodegenerative diseases (cerebral amyloidosis)

Alzheimer disease

(cleaved from the APP)

Prion diseases

APrP (prion protein amyloid)

Referencestoggle arrow icon

  1. Muchtar E, Dispenzieri A, Magen H, et al. Systemic amyloidosis from A (AA) to T (ATTR): a review. J Intern Med. 2020; 289 (3): p.268-292.doi: 10.1111/joim.13169 . | Open in Read by QxMD
  2. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet. 2016; 387 (10038): p.2641-2654.doi: 10.1016/s0140-6736(15)01274-x . | Open in Read by QxMD
  3. Perfetto F, Moggi-Pignone A, Livi R, Tempestini A, Bergesio F, Matucci-Cerinic M. Systemic amyloidosis: a challenge for the rheumatologist. Nat. Rev. Rheumatol. 2010; 6 (7): p.417-429.doi: 10.1038/nrrheum.2010.84 . | Open in Read by QxMD
  4. McCausland KL, White MK, Guthrie SD, et al. Light Chain (AL) Amyloidosis: The Journey to Diagnosis.. The patient. 2018; 11 (2): p.207-216.doi: 10.1007/s40271-017-0273-5 . | Open in Read by QxMD
  5. Bilginer Y, Akpolat T, Ozen S. Renal amyloidosis in children. Pediatr Nephrol. 2011; 26 (8): p.1215-1227.doi: 10.1007/s00467-011-1797-x . | Open in Read by QxMD
  6. Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR Epidemiology, Genetics, and Prognostic Factors. Methodist DeBakey Cardiovasc J. 2022; 18 (2): p.17-26.doi: 10.14797/mdcvj.1066 . | Open in Read by QxMD
  7. Pinney JH, Whelan CJ, Petrie A, et al. Senile Systemic Amyloidosis: Clinical Features at Presentation and Outcome. Journal of the American Heart Association. 2013; 2 (2).doi: 10.1161/jaha.113.000098 . | Open in Read by QxMD
  8. Li T, Huang X, Cheng S, et al. Utility of abdominal skin plus subcutaneous fat and rectal mucosal biopsy in the diagnosis of AL amyloidosis with renal involvement. PLoS ONE. 2017; 12 (9): p.e0185078.doi: 10.1371/journal.pone.0185078 . | Open in Read by QxMD
  9. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical ; 2018
  10. Iadanza MG, Jackson MP, Hewitt EW, Ranson NA, Radford SE. A new era for understanding amyloid structures and disease. Nat. Rev. Mol. Cell Biol. 2018; 19 (12): p.755-773.doi: 10.1038/s41580-018-0060-8 . | Open in Read by QxMD
  11. Gertz MA, Rajkumar SV. Amyloidosis. Humana Press ; 2010
  12. Marin-Argany M, Lin Y, Misra P, et al. Cell Damage in Light Chain Amyloidosis: FIBRIL INTERNALIZATION, TOXICITY AND CELL-MEDIATED SEEDING.. J Biol Chem. 2016; 291 (38): p.19813-25.doi: 10.1074/jbc.M116.736736 . | Open in Read by QxMD
  13. Merlini G, Dispenzieri A, Sanchorawala V, et al. Systemic immunoglobulin light chain amyloidosis. Nat. Rev. Dis. Primers. 2018; 4 (1).doi: 10.1038/s41572-018-0034-3 . | Open in Read by QxMD
  14. Gillmore JD, Hawkins PN. Pathophysiology and treatment of systemic amyloidosis. Nat. Rev. Nephrol. 2013; 9 (10): p.574-586.doi: 10.1038/nrneph.2013.171 . | Open in Read by QxMD
  15. Sucker C, Hetzel GR, Grabensee B, Stockschlaeder M, Scharf RE. Amyloidosis and bleeding: pathophysiology, diagnosis, and therapy.. Am J Kidney Dis. 2006; 47 (6): p.947-955.doi: 10.1053/j.ajkd.2006.03.036 . | Open in Read by QxMD
  16. Real de Asua D, Galvan JM, Filigghedu MT, Trujillo D, Costa R, Cadinanos J. Systemic AA amyloidosis: epidemiology, diagnosis, and management. Cli Epidemiol. 2014; 6: p.369-377.doi: 10.2147/clep.s39981 . | Open in Read by QxMD
  17. Kendi Celebi Z, Kiremitci S, Ozturk B, et al. Kidney biopsy in AA amyloidosis: impact of histopathology on prognosis. Amyloid. 2017; 24 (3): p.176-182.doi: 10.1080/13506129.2017.1350158 . | Open in Read by QxMD
  18. Chamling B, Drakos S, Bietenbeck M, Klingel K, Meier C, Yilmaz A. Diagnosis of Cardiac Involvement in Amyloid A Amyloidosis by Cardiovascular Magnetic Resonance Imaging. Frontiers in Cardiovascular Medicine. 2021; 8.doi: 10.3389/fcvm.2021.757642 . | Open in Read by QxMD
  19. Ando Y, Nakamura M, Araki S. Transthyretin-Related Familial Amyloidotic Polyneuropathy. Arch Neurol. 2005; 62 (7): p.1057.doi: 10.1001/archneur.62.7.1057 . | Open in Read by QxMD
  20. Zhou Y, Khalid S, Abbass A, Hughes L, Hazday M. A Heart too Stiff to Beat: A Case of Familial Transthyretin Amyloidosis Cardiomyopathy. Cureus. 2017.doi: 10.7759/cureus.1106 . | Open in Read by QxMD
  21. Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans.. Amyloid. 2015; 22 (3): p.171-4.doi: 10.3109/13506129.2015.1051219 . | Open in Read by QxMD
  22. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: An update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 2018; 28 (1): p.10-21.doi: 10.1016/j.tcm.2017.07.004 . | Open in Read by QxMD
  23. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018; 379 (11): p.1007-1016.doi: 10.1056/nejmoa1805689 . | Open in Read by QxMD

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