longstanding infections or inflammatory diseases. aa can be identified by immunohistochemistry staining. small bowel duodenum with amyloid deposition congo red 10x amyloidosis, dystrophic calcification small bowel duodenum with amyloid deposition 20x amyloidosis, node, congo red amyloidosis, blood vessels, h&e amyloidosis, lymph node, h&e amyloidosis, lymph node, polarizer cardiac amyloidosis. h&e stain. micrograph showing amyloid deposition (red fluffy material) in the heart (cardiac amyloidosis). congo red stain. classification historical classification systems were based on clinical factors. until the early 1970s, the idea of a single amyloid substance predominated. various descriptive classification systems were proposed based on the organ distribution of amyloid deposits and clinical findings. most classification systems included primary (i.e., idiopathic) amyloidosis, in which no associated clinical condition was identified, and secondary amyloidosis (i.e., secondary to chronic inflammatory conditions). some classification systems included myeloma-associated, familial, and localized amyloidosis. the modern era of amyloidosis classification began in the late 1960s with the development of methods to make amyloid fibrils soluble. these methods permitted scientists to study the chemical properties of amyloids. descriptive terms such as primary amyloidosis, secondary amyloidosis, and others (e.g., senile amyloidosis), which are not based on cause, provide little useful information and are no longer recommended. the modern classification of amyloid disease tends to use an abbreviation of the protein that makes the majority of deposits, prefixed with the letter a. for example, amyloidosis caused by transthyretin is termed "attr". deposition patterns vary between people but are almost always composed of just one amyloidogenic protein. deposition can be systemic (affecting many different organ systems) or organ-specific. many amyloidoses are inherited, due to mutations in the precursor protein. other forms are due to different diseases causing overabundant or abnormal protein production – such as with overproduction of immunoglobulin light chains (termed al amyloidosis), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to aa amyloidosis). about 60 amyloid proteins have been identified so far. of those, at least 36 have been associated with a human disease. all amyloid fibril proteins start with the letter "a" followed by the protein suffix (and any applicable specification). see below for a list of amyloid fibril proteins which 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 type transthyretin, variants heart mainly in males, lung, ligaments, tenosynovium pns, ans, heart, eye, leptomeninges s s a h aβ2m β2-microglobulin, wild type β2-microglobulin, variants musculoskeletal system ans s s a h aapoai apolipoprotein a i, variants heart, liver, kidney, pns, testis, larynx (c terminal 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 type aβ protein precursor, variant cns cns l l a h aαsyn α-synuclein cns l a atau tau cns l a aprp prion protein, wild type prion protein variants prion protein variant cjd, fatal insomnia cjd, gss syndrome, fatal insomnia pns l l s a h h acal (pro)calcitonin c-cell thyroid tumours kidney l s a a aiapp islet amyloid polypeptidec 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-epithelin cornea, hereditary l a alac lactoferrin cornea l a aoaap odontogenic ameloblast-associated protein odontogenic tumours l a asem1 semenogelin 1 vesicula seminalis l a aenf enfurvitide iatrogenic l a acatke cathepsin k tumour associated l a aefemp1e egf-containing fibulin-like extracellular matrix protein 1 (efemp1) portal veins, aging associated l a alternative an older clinical method of classification refers to amyloidoses as systemic or localised: systemic amyloidoses affect more than one body organ or system. examples are al, aa and aβ2m. localised amyloidoses affect only one body organ or tissue type. examples are aβ, iapp, atrial natriuretic factor (in isolated atrial amyloidosis), and calcitonin (in medullary carcinoma of the thyroid) another classification is primary or secondary. primary amyloidoses arise from a disease with disordered immune cell function, such as multiple myeloma or other immunocyte dyscrasias. secondary (reactive) amyloidoses occur as a complication of some other chronic inflammatory or tissue-destroying disease. examples are reactive systemic amyloidosis and secondary cutaneous amyloidosis. additionally, based on the tissues in which it is deposited, it is divided into mesenchymal (organs derived from mesoderm) or parenchymal (organs derived from ectoderm or endoderm). treatment treatment depends on the type of amyloidosis that is present. treatment with high dose melphalan, a chemotherapy agent, followed by stem cell transplantation has shown promise in early studies and is recommended for stage i and ii al amyloidosis. however, only 20–25% of people are eligible for stem cell transplant. chemotherapy treatment including cyclophosphamide-bortezomib-dexamethasone is currently the recommended treatment option for people with al amyloidosis not eligible for transplant. in aa, symptoms may improve if the underlying condition is treated. in people who have inflammation caused by aa amyloidosis, tumour necrosis factor (tnf)-alpha inhibitors such as infliximab and etanercept are used for an average duration of 20 months. if tnf-alpha inhibitors are not effective, interleukin-1 inhibitors (e.g. anakinra, canakinumab, rilonacept) and interleukin-6 inhibitors (e.g. tocilizumab) may be considered. management of attr amyloidosis will depend on its classification as wild type or variant. both may be treated with tafamidis, a low toxicity oral agent that prevents destabilization of correctly folded protein. studies showed tafamidis reduced mortality and hospitalization due to heart failure. previously, for variant attr amyloidosis, liver transplant was the only effective treatment. new therapies include diflunisal, inotersen, and patisiran. diflunisal binds to misfolded mutant ttr protein to prevent its buildup, like how tafamidis works. low-certainty evidence indicates that it mitigates worsening of peripheral neuropathy and disability from disease progression. inotersen blocks gene expression of both wild-type and mutant ttr, reducing amyloid precursor. moderate-certainty evidence suggests that it mitigates worsening of peripheral neuropathy. long-term efficacy and safety of inotersen use in people with mutant ttr-related amyloidosis is still be evaluated in a phase-iii clinical trial as of 2021. both diflunisal and inotersen may also mitigate declines in quality-of-life, though the evidence for this effect is unclear. for people with cardiac attr the effect of inotersen use is inconclusive and requires further investigation. in 2018, inotersen was approved by the european medicines agency to treat polyneuropathy in adults with hereditary transthyretin amyloidosis. it has since been approved for use in canada, the european union and in the usa. patisiran functions similarly to inotersen. moderate-certainty evidence suggests that patisiran mitigates worsening of peripheral neuropathy and disability from disease progression. additionally, low-certainty evidence suggests that patisiran mitigates decreases in quality-of-life and slightly reduces the rate of adverse events versus placebo. there is no evidence of an effect on mortality rate. a review of early data from use of patisiran in people with variant cardiac attr suggests that it may reduce mortality and hospitalization, however this is still being investigated and requires further investigation. in 2018, patisiran was not recommended by nice in the uk for hereditary transthyretin-related amyloidosis. as of july 2019 further review however is occurring. it was approved for this use in the united states, however. the roles of inotersen and patisiran in cardiac attr amyloidosis are still being investigated. in 2021, in a clinical trial using the crispr gene-editing technique, several participants had an "80% to 96% drop in ttr levels, on par or better than the average of 81%" who were given patisiran. vutrisiran was approved by the u.s. food and drug administration (fda) in june 2022, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hattr) amyloidosis in adults. support groups people affected by amyloidosis are supported by organizations, including the amyloidosis research consortium, amyloidosis foundation, amyloidosis support groups, and amyloidosis australia. prognosis prognosis varies with the type of amyloidosis and the affected organ system. prognosis for untreated al cardiac amyloidosis is poor, with a median survival of six months. more specifically, al amyloidosis can be classified as stage i, ii or iii based on cardiac biomarkers like nt-probnp and cardiac troponin. survival diminishes with increasing stage, but recent advancements in treatments have improved median survival rates for stages i, ii, and iii, to 91.2, 60, and 7 months respectively. outcomes in a person with aa amyloidosis depend on the underlying disease, organ(s) affected, and correlate with the concentration of serum amyloid a protein. people with attr, mutant attr and wild-type attr have a better prognosis when compared to people with al and may survive for over a decade. survival time is not associated with gender or age, however, some measures of reduced heart function are associated with a shorter survival time. senile systemic amyloidosis was determined to be the primary cause of death for 70% of people over 110 who have been autopsied. epidemiology amyloidosis has a combined estimated prevalence of 30 per 100,000 persons with the three most common forms being al, attr, and aa. the median age at diagnosis is 64. al has the highest incidence at approximately 12 cases per million persons per year and an estimated prevalence of 30,000 to 45,000 cases in the us and european union. aa amyloidoses is the most common form in developing countries and can complicate longstanding infections with tuberculosis, osteomyelitis, and bronchiectasis. aa amyloidosis is caused by an increase in extracellular deposition of serum amyloid a (saa) protein. saa protein levels can rise in both direct and indirect manners, through infection, inflammation, and malignancies. the most common causes of aa amyloidosis in the west are rheumatoid arthritis, inflammatory bowel disease, psoriasis, and familial mediterranean fever. people undergoing long-term hemodialysis (14–15 years) can develop amyloidosis from accumulation of light chains of the hla 1 complex which is normally filtered out by the kidneys. wild-type transthyretin (attr) amyloidosis is found in a quarter of elderly at postmortem. attr is found in 13–19% of people experiencing heart failure with preserved ejection fraction, making it a very common form of systemic amyloidosis. research treatments for attr-related neuropathy include ttr-specific oligonucleotides in the form of small interfering rna (patisiran) or antisense inotersen, the former having recently received fda approval. research into treatments for attr amyloidosis have compared liver transplantation, oral drugs that stabilize the misfolding protein (including tafamidis and diflunisal), and newer therapeutic agents still being investigated (including patisiran). based on available research, liver transplant remains the most effective treatment option for advanced attr amyloidosis, protein stabilizing drugs may slow disease progression but were insufficient to justify delay of liver transplant, and newer agents such as patisiran require additional studies.