Overview of amyloidosis

INTRODUCTION — Amyloidosis is the general term used to refer to the extracellular tissue deposition of highly ordered fibrils composed of low molecular weight subunits of a variety of proteins, many of which, in their native form, circulate as normal constituents of plasma. Amyloid deposits may result in a wide range of clinical manifestations depending upon their type, location, and amount. In the genesis of amyloid deposits, previously soluble precursor peptides undergo conformational changes that lead to the adoption of a predominantly antiparallel beta-pleated sheet configuration, allowing them to stack as protofilaments in a twisted fibrillar configuration (figure 1).

At least 42 different human protein precursors of amyloid fibrils are known. Some are produced at the site of amyloid formation (localized amyloid) and some circulate in the blood to deposit in a variety of tissues and organs (systemic amyloidosis). Amyloid has a characteristic gross pathologic and microscopic appearance, demonstrating birefringence with polarized light microscopy of Congo red stained tissue, which may have a typical "apple-green" dichroic appearance [1,2]. (See 'Pathology' below.)

A general overview of the pathogenesis, clinical manifestations, diagnosis, and treatment of the different amyloid disorders is presented here. The role of genetic factors in amyloidosis is discussed in detail elsewhere (see "Genetic factors in the amyloid diseases" and "Genetics of Alzheimer disease"). More detailed discussions of the individual disorders are also presented separately. (See appropriate topic reviews as indicated in the relevant sections below.)

PATHOLOGY — The presence of amyloid is associated with characteristic histopathologic findings, including apple-green birefringence with Congo red staining on polarized light microscopy (picture 1A-D). The term "amyloid," first introduced by Schleiden in 1838 to describe plant starch, was adopted by Rudolf Virchow in 1854 to refer to tissue deposits of material that stained in a similar manner to cellulose when exposed to iodine [3]. In these original descriptions, amyloid deposits were noted by Rokitansky to have a "waxy" or "lardaceous" appearance grossly and by Virchow to be amorphous and hyaline on light microscopy. Congo red, a direct cotton dye and pH indicator that was developed by Paul Böttinger in 1883, was later shown to confer typical apple-green birefringence with polarized microscopy and introduced in the 1920s by Bennhold for the better demonstration of amyloid [4]. The use of thioflavin T, producing an intense yellow-green fluorescence, was popularized in the 1950s [3]. Virchow recorded the prescient observation in his Cellular Pathology (1858) that "I am as yet much more inclined to admit, that the blood in this disease undergoes a chemical alteration in its fluid constituents, than that it contains the pathological substances in a material form."

Electron microscopic examination of amyloid deposits, first performed in 1959, generally demonstrates straight and unbranching fibrils 8 to 10 nm in width, which may be composed of protofilaments at higher resolution [5,6]. Transmission electron, atomic force, and cryo-electron microscopy have had a role in elucidating the three-dimensional structure of these macromolecular aggregates in fibril preparations extracted from tissue or created in vitro and in defining folding intermediates, including small oligomers and amorphous aggregates [1,7,8]. In many instances, the type of amyloid fibril unit can be further defined by immunohistology (immunofluorescence or immunoenzymatic techniques) or by immunoelectron microscopy [9-11] and in subsequent developments by proteomics on fixed tissue using laser-capture microdissection and mass spectroscopy [12].

PATHOGENESIS

Overview of amyloidogenesis — Amyloidosis results from the predominantly extracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of proteins, typically in the range of 5 to 25 kD; many of these proteins normally circulate as constituents of plasma. Genetic factors play an important role in many forms of amyloidosis. Point mutations, deletions, and premature stop codons may result in structural changes predisposing to fibril formation (fibrillogenesis) and the development of hereditary amyloidosis.

Depending upon the type of amyloidosis, factors affecting protein folding and stability, including molecular chaperones and failure of disaggregating pathways, may be operative [13]. There are also major contributions from non-fibrillar components found in all types of amyloid, including serum amyloid P component (SAP), apolipoprotein E, and glycosaminoglycans. Disorders leading to increased production or reduced clearance of potential amyloid precursor proteins (APPs), including chronic inflammation, plasma cell dyscrasias, and chronic renal failure, are important, particularly in systemic amyloidoses. (See 'Fibril formation' below and 'Genetics' below.)

Fibril formation — Amyloid fibrils are insoluble polymers comprised of low molecular weight protein subunits. These subunits are derived from soluble precursors and undergo conformational changes that lead to the adoption of a predominantly antiparallel beta-pleated sheet configuration (figure 1) in which state they auto-aggregate in highly ordered fibrils [14-17]. Oligomeric intermediates that are pre-fibrillar may contribute to tissue toxicity and disease pathogenesis in certain amyloid related disorders [18].

Routes to fibrillogenesis include partial folding or unfolding of the precursor protein that may be facilitated by acidification or proteolysis and accelerated by nucleation [19]. In vivo fibril formation is associated with codeposition of non-fibrillar substances, notably including glycosaminoglycans (particularly heparan sulfate), SAP (a member of the pentraxin family that includes C-reactive protein [CRP]), and specific apolipoproteins (E and J) [20,21]. Cofactors may significantly modulate fibrillogenesis at any of several steps involved in the conversion of soluble precursors to fibrils and may potentially influence the deposition phase of amyloid in tissue, as well as resorption [22].

Circulating precursors are presumed to deposit as amyloid in the systemic forms of disease (see 'Organ-specific amyloid' below). By contrast, in localized immunoglobulin light chain (AL) amyloidosis (which can involve sites such as the conjunctiva, lungs, skin, gastrointestinal or genitourinary tract), the precursor protein (immunoglobulin light chain) is thought to be synthesized and processed at local sites contiguous to amyloid deposition [23-25]. This model for amyloid formation at the sites of protein synthesis has been corroborated in some in vitro models of AA amyloid, in which deposition occurs around cell types such as monocytes, macrophages, or mesangial cells in tissue culture [26].

Genetics — At least 38 different human and 10 different animal protein precursors of amyloid fibrils are now known, and the corresponding amyloid diseases associated with each of the affected molecules and nomenclature for the subunit proteins have been described (table 1) [27-29].

Several types of amyloidosis are clearly hereditary, and clinical disease has been linked in most familial forms to missense mutations of the precursor proteins. In some instances, deletions or premature stop codon mutations have been described [14,30]. Heritable factors in amyloidosis include the following, which are discussed in greater detail separately (see "Genetic factors in the amyloid diseases"):

●Genetic variants resulting in protein products that are more prone to aggregation and fibrillogenesis than their wild-type counterparts.

●Polymorphisms of cofactors (eg, apolipoprotein E) or of subunit proteins (eg, serum amyloid A, leukocyte cell-derived chemotaxin-2 [LECT2]).

●Heritable disorders that affect the level or accumulation of precursor proteins (eg, presenilin mutations in familial Alzheimer disease).

●Heritable disorders that may result in chronic inflammation and deposition of wild-type precursor serum amyloid A protein as AA amyloidosis in susceptible populations (eg, pyrin and cryopyrin mutations in familial Mediterranean fever [FMF] and cryopyrin-associated periodic syndrome [CAPS], respectively, and tumor necrosis factor [TNF] receptor mutations in the TNF receptor-associated periodic syndrome [TRAPS]).

Virtually all heredofamilial amyloidoses associated with nephropathic, neuropathic, or cardiopathic disease are dominantly inherited heterozygous disorders, and both the wild-type and mutant molecules can be identified in the amyloid deposits. In some instances (eg, transthyretin [TTR], apolipoprotein A-I [ApoAI], Alzheimer APP, and prion protein [PRP]), both the wild-type and mutant molecules are able to form amyloid fibrils under different circumstances, with the wild-type protein implicated in aging-associated diseases. As an example, wild-type TTR; ApoAI; and the beta protein, A-beta, a cleavage product of APPs, may form deposits in association with organ-specific pathology in the aging heart, aorta, and brain, respectively [30-32]. (See "Genetic factors in the amyloid diseases".)

TYPES OF AMYLOIDOSIS

Major forms of systemic amyloidosis — There are 18 different types of systemic and 28 localized forms of amyloidosis, including four precursor proteins that can form both localized and systemic deposits [27]. The principal systemic types seen in tertiary referral centers and inpatient medical services are the primary (immunoglobulin light chain [AL]) and transthyretin (ATTR) types. However, other types of amyloid (eg, secondary [AA]) are clinically important, some of which are common and others rare. A review of more than 11,000 patients seen at a single center from 1987 through 2019 showed that systemic AL amyloidosis accounted for 56 percent, ATTR 21 percent, and AA 8 percent of typed cases [33]; in particular, there has been a substantial increase in the recognition of systemic amyloid due to ATTR in major referral centers. Nomenclature for amyloid subunit proteins includes the letter "A," followed by the abbreviation of the name of the precursor protein (table 1). Major forms include:

●AL amyloid – AL amyloid, caused by a plasma cell dyscrasia, is due to deposition of protein derived from immunoglobulin light chain fragments. (See 'AL amyloidosis' below.)

●ATTR amyloid – ATTR amyloid may occur as a "wild-type" (ATTRwt) associated with aging or as mutant proteins (ATTRv or hATTR [where v indicates a variant and h indicates hereditary; these were formerly termed ATTRm, to indicate a mutant protein]) associated with familial neuropathy and/or cardiomyopathy [27]. (See 'Wild-type transthyretin systemic amyloidosis' below and 'Heritable amyloidoses' below.)

●AA amyloidosis – AA amyloidosis is a potential complication of chronic diseases in which there is ongoing or recurring inflammation that results in sustained high-level production of serum amyloid A protein, an acute phase reactant, which can form amyloid deposits. (See 'AA amyloidosis' below.)

●Other types of amyloidosis – Additional forms of amyloid seen clinically include dialysis-related amyloidosis (see 'Dialysis-related amyloidosis' below), heritable amyloidoses (see 'Heritable amyloidoses' below), organ-specific amyloid (see 'Organ-specific amyloid' below), leukocyte cell-derived chemotaxin-2 (LECT2) amyloid (see 'Systemic amyloidosis of poorly understood etiology' below), insulin amyloid [34], and others.

AL amyloidosis — AL amyloidosis is due to deposition of protein derived from immunoglobulin light chain fragments. It is a potential complication of any plasma cell dyscrasia that produces monoclonal immunoglobulin light chains. These can be subtle, but a monoclonal protein is detectable in urine and/or serum in >95 percent of affected patients if both serum and urine immunofixation and a free light chain (FLC) assay (which is most commonly done on serum) are performed [35]. (See "Monoclonal immunoglobulin deposition disease".)

AL amyloidosis is a systemic disorder that can present with a variety of symptoms or signs, including heavy proteinuria (usually in the nephrotic range) and edema (see 'Renal disease' below), hepatosplenomegaly (see 'Gastrointestinal disease' below), otherwise unexplained heart failure (see 'Cardiomyopathy' below), and the carpal tunnel syndrome (see 'Neurologic abnormalities' below). Although virtually all patients have multisystem amyloid deposition, it is not uncommon to present with evidence of mainly one organ being affected. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

AL amyloidosis usually complicates lower-grade plasma cell clones but can occur in association with multiple myeloma or, much less often, Waldenström macroglobulinemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia [36]. Light chain deposition disease has a similar pathogenesis and shares some clinical manifestations with AL amyloidosis; the primary difference is that deposited light chain fragments generally do not form fibrils and do not engender deposition of amyloid cofactors [37]. In rare instances, AL amyloid and non-amyloid light chain deposition may coexist in the same organ [38]. The recognition that B cell or plasma cell clones can cause renal disease related to the production of monoclonal immunoglobulin in the absence of direct tumor complications and without reaching current hematologic criteria for specific therapy led to the concept of monoclonal gammopathy of renal significance (MGRS), and renal AL amyloidosis remains the best characterized of these disorders [39]. (See "Monoclonal immunoglobulin deposition disease" and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Amyloidosis' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'AL amyloidosis and light chain deposition disease' and "Diagnosis and treatment of monoclonal gammopathy of renal significance".)

Amyloid can be derived from immunoglobulin heavy chain fragments [40]. In this case, it is designated AH amyloidosis. Coexisting AH and AL amyloid occurs rarely.

Wild-type transthyretin systemic amyloidosis — Deposition of otherwise normal (wild-type) TTR in myocardium and other sites may result in a form of amyloidosis that is now referred to as wild-type transthyretin systemic amyloidosis (ATTRwt), superseding the previous terminology of systemic senile amyloidosis (SSA) [41,42]. Some experts prefer to reserve use of the term TTR amyloid cardiomyopathy for those patients who develop cardiomegaly and heart failure from the infiltrative cardiomyopathy, as asymptomatic amyloid deposition in the heart is a common autopsy finding, often without clinical consequence.

Compared with patients with cardiac involvement from AL amyloidosis, heart failure due to ATTR is less severe than that in AL, and those with the ATTRwt disease survive longer (75 versus 11 months) despite having ventricular free wall and septal thickening due to amyloid deposits [43]. In this study, all 18 affected patients were older men. A history of carpal tunnel syndrome is common and spinal stenosis well recognized [44], but significant renal involvement is very rare in the systemic disorder. Amyloid cardiomyopathies are discussed in detail separately. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

There may be considerable overlap clinically between cardiac amyloidosis due to deposition of wild-type TTR, and late-onset cardiomyopathy due to mutant TTR (see 'Heritable amyloidoses' below). A family history may not be apparent, and a screen for informative mutations (notably Ile122, particularly in African American patients) may be necessary to distinguish the two causes of restrictive cardiomyopathy in older adults [45]. Differentiation from cardiac AL amyloidosis is of vital importance, and there are published consensus criteria to aid both disease recognition and diagnosis [46,47]. (See 'Organ-specific amyloid' below and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

AA amyloidosis — AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections; and heredofamilial periodic fever syndromes (eg, familial Mediterranean fever [FMF]). It may occur in association with other causes, including neoplasms, and in a significant proportion of patients is idiopathic [48]. The fibrils are composed of fragments of the acute phase reactant serum amyloid A protein. (See "Pathogenesis of AA amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)

The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients). This is usually characterized by glomerular amyloid deposition, typically leading to the nephrotic syndrome, although the renal presentation may vary (see 'Renal disease' below and "Renal amyloidosis", section on 'AA amyloidosis'). Cardiac and other organ involvement may also be seen, although generally in very advanced disease. (See 'Cardiomyopathy' below and 'Clinical manifestations' below.)

Dialysis-related amyloidosis — Dialysis-related amyloidosis is due to deposition of fibrils derived from beta2-microglobulin, which accumulate in patients with end-stage kidney disease who are being maintained for prolonged periods of time by dialysis. This disorder has a predilection for osteoarticular structures [49,50]. Patients with dialysis-related amyloidosis most commonly complain of shoulder pain related to scapulohumeral periarthritis and rotator cuff infiltration by amyloid, neck pain due to a destructive spondyloarthropathy, and of symptoms of carpal tunnel syndrome. (See "Dialysis-related amyloidosis" and 'Musculoskeletal disease' below and 'Neurologic abnormalities' below.)

Heritable amyloidoses — Many mutations lead to at least 12 heritable types of systemic amyloidosis, each of which has a characteristic pattern of clinical features (table 1). An example of this heterogeneous group of disorders is heritable neuropathic and/or cardiomyopathic amyloidosis due to deposition of fibrils derived from transthyretin (TTR; also referred to as prealbumin) [51]. (See "Genetic factors in the amyloid diseases" and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Types of amyloidosis'.)

In addition to heritable forms due to mutations in proteins that may form amyloid subunits or changes that may otherwise promote fibrillogenesis, patients with systemic autoinflammatory diseases (also termed hereditary periodic fever syndromes) are also susceptible to AA amyloidosis [52]. (See "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases", section on ''Hereditary' AA amyloidosis'.)

Systemic amyloidosis of poorly understood etiology — Some types of late-onset amyloid are not associated with either recognized underlying diseases or rare pathogenic mutations in the precursor protein. One example is LECT2-associated amyloidosis. It may account for approximately one-quarter of cases of hepatic amyloid in the United States and has also been reported as the second most common cause of renal amyloidosis [53,54]. Another example is apolipoprotein A-IV (ApoAIV)-derived amyloidosis, which is commonly a constituent of the amyloid proteome in various forms of the disease, but may also be associated with clinically significant renal and cardiac amyloidosis [55,56]. In these cases, the amyloid may be associated with polymorphisms of the precursor proteins, but these are sufficiently common in the population that they are clearly not the sole cause of these rare diseases. (See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management", section on 'Hepatic amyloidosis' and "Renal amyloidosis", section on 'Introduction'.)

Iatrogenic amyloidosis — Several therapeutic peptides have been associated with localized and/or systemic amyloid deposits, including recombinant IL-1 receptor antagonist (eg, anakinra) [57,58], somatostatin [59], glucagon-like peptide analogues (eg, liraglutide) [60], and insulin [61].

Organ-specific amyloid — Amyloid deposition can be isolated to a single organ, such as the skin, eye, heart, pancreas, and gastrointestinal or genitourinary tract, resulting in specific syndromes. Locally produced proteins (eg, immunoglobulin light chain from plasma cells) rather than circulating forms of the relevant subunit protein tend to be the precursors of the fibril in several forms of localized or organ-specific amyloidosis, in contrast with the systemic amyloids in which such circulating forms are presumed to be the precursors.

Examples of organ-specific amyloid include the following:

●Alzheimer disease-associated amyloid – The most common clinically important form of organ-specific amyloid occurs in patients with Alzheimer disease in which plaques and amyloid-laden cerebral vessels are composed of the beta protein (A-beta), a 39 to 43 residue polypeptide that is cleaved out of the much larger amyloid precursor protein (APP) by secretases that are specific for its amino (beta-secretase) and carboxy (gamma-secretase) terminal residues. Similar to other forms of amyloidosis, A-beta polypeptides may exist in soluble forms, oligomers, and amyloid fibrils. The role of amyloid in Alzheimer disease is discussed in detail separately. (See "Genetics of Alzheimer disease", section on 'Early-onset Alzheimer disease' and "Cerebral amyloid angiopathy" and "Epidemiology, pathology, and pathogenesis of Alzheimer disease".)

●Cutaneous amyloid – Forms of primary localized cutaneous amyloidosis include macular, nodular, and lichen amyloidosis, with the last occurring in some families with multiple endocrine neoplasia type 2 [23,62-64]. The major fibril subunit proteins for the overlapping syndromes of lichen and macular amyloid are keratins 5 and 14 [65]. (See "Cutaneous manifestations of amyloidosis" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Cutaneous manifestations of internal malignancy", section on 'Amyloidosis' and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Localized amyloidosis'.)

●Bladder amyloid – Isolated bladder amyloidosis can be the cause of symptoms varying from life-threatening hemorrhage to subclinical hematuria or irritative voiding symptoms; in most instances, this appears to be a localized form of AL amyloid disease [66], although it may also be an extracardiac site of deposition in ATTR. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Localized amyloidosis'.)

●Ocular amyloid – Isolated ocular amyloidosis, most commonly presenting as conjunctival lesions biopsied to exclude the diagnosis of lymphoma, may also be a localized form of AL; it is more rarely a presenting manifestation of systemic AL [67].

●Laryngeal amyloid – Laryngeal amyloid is a particularly common form of localized amyloidosis, most often due to AL [68] and rarely to hereditary apolipoprotein A-I (ApoAI) amyloidosis and as an incidental finding in ATTR amyloidosis [69,70]. This form of amyloid may involve supra-, infra- or subglottic sites, is frequently multifocal, and is typically locally recurrent [70]. (See "Hoarseness in adults", section on 'Laryngeal amyloidosis'.)

VARIATION IN GEOGRAPHIC DISTRIBUTION — The prevalence of the most common types of amyloidosis varies between different parts of the world. In resource-abundant countries, primary (AL) and transthyretin (ATTR) are the most common types of systemic amyloidosis, while in resource-limited countries, secondary (AA) amyloid is more frequent.

This variation likely results from a higher burden of chronic infectious diseases such as tuberculosis, leprosy, and osteomyelitis in resource-limited countries and regions [71]. By contrast, advances in resource-intensive diagnostics, most strikingly increased availability of cardiac magnetic resonance imaging (MRI), has led to increasing recognition of ATTR as a cause of amyloid cardiomyopathy in older individuals [72,73].

CLINICAL MANIFESTATIONS

Overview of common clinical features — The type of precursor protein, the tissue distribution, and the amount of amyloid deposited largely determine clinical manifestations. Some clinical and laboratory features that suggest amyloidosis include waxy skin and easy bruising (see 'Skin manifestations' below), enlarged muscles (eg, tongue, deltoids) (see 'Musculoskeletal disease' below), symptoms and signs of heart failure and cardiac conduction abnormalities (see 'Cardiomyopathy' below), hepatomegaly (see 'Gastrointestinal disease' below), evidence of heavy proteinuria or the nephrotic syndrome (see 'Renal disease' below), peripheral and/or autonomic neuropathy (see 'Neurologic abnormalities' below), and impaired coagulation (see 'Hematologic abnormalities' below). Coexistence of any of these features, particularly in combination with nonspecific symptoms such as fatigue, change in taste, dry mouth, or weight loss, should further raise suspicion of amyloidosis and prompt specific investigations. (See 'Diagnosis' below.)

In immunoglobulin light chain (AL) amyloidosis, the major sites of clinically important amyloid deposition are in the kidneys, heart, and liver; and in AA amyloidosis, kidneys, liver, and intestines; whereas in ATTR amyloidosis, heart and nervous system involvement predominate. In some disorders, clinically important amyloid deposition is limited to one organ. (See 'Types of amyloidosis' above and 'Organ-specific amyloid' above and 'Renal disease' below and 'Cardiomyopathy' below and 'Gastrointestinal disease' below.)

Renal disease — Renal involvement most often presents as asymptomatic proteinuria or clinically apparent nephrotic syndrome. However, if amyloid deposition predominantly affects the renal blood vessels or tubules, patients may present with advanced renal failure with little or no proteinuria [74]. The renal manifestations of amyloidosis are discussed in detail separately. (See "Renal amyloidosis".)

Amyloid nephropathy is common in AA and AL amyloidosis, but is rare in ATTR. Leukocyte cell-derived chemotaxin-2 (LECT2), fibrinogen A-alpha chain, and apolipoproteins A-I, A-II, and A-IV are rarer causes of predominantly nephropathic amyloidosis worldwide [75]. (See 'AA amyloidosis' above and 'AL amyloidosis' above.)

Familial or sporadic disease may be important in certain countries or regions. As examples, mutations in the fibrinogen alpha chain were the most common form of hereditary nephropathic amyloid in a large survey from the United Kingdom, and LECT2 disproportionately affects specific populations including Punjabi, North African, and Hispanic [76].

Cardiomyopathy — At least 11 biochemically distinct forms of amyloidosis affect the heart, two of which (wild-type ATTR [ATTRwt] and isolated atrial amyloidosis [atrial natriuretic factor amyloidosis (AANF)]) are considered to be diseases of aging. Cardiac involvement can lead to diastolic or, usually later in the disease course, systolic dysfunction and symptoms of heart failure. Other manifestations include palpitations, syncope due to arrhythmia or heart block, and angina or infarction due to accumulation of amyloid in the coronary arteries [77,78]. The cardiac manifestations of amyloidosis are discussed in detail separately. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

Cardiac amyloidosis is common in ATTR and AL amyloidosis and can rarely complicate AA amyloidosis; it is rare in A-beta2-microglobulin (dialysis-related) amyloidosis. Familial forms of amyloid in which cardiac disease may be significant include those due to a wide variety of transthyretin (TTR) variants (hATTR or ATTRv, formerly termed ATTRm), as well as apolipoproteins A-I and A-II. Lastly, isolated atrial amyloidosis due to atrial natriuretic peptide is a common, often asymptomatic, concomitant of aging that may be associated with atrial fibrillation [79].

Gastrointestinal disease — Hepatomegaly with or without splenomegaly is a common finding in some forms of amyloidosis. Other gastrointestinal manifestations include bleeding (due to vascular fragility, loss of vasomotor responses to injury, and coagulopathy in some cases of AL), gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from dysmotility [80]. The gastrointestinal manifestations of amyloidosis are discussed in detail separately. (See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management".)

AL and AA amyloidosis commonly affect the gastrointestinal tract; ATTR may cause dysfunction either directly or via concomitant autonomic neuropathy; familial amyloid due to variant lysozyme may have significant gastrointestinal manifestations [81].

Neurologic abnormalities — Several forms of neurologic involvement may occur, including peripheral and autonomic neuropathy, central nervous system (CNS) involvement, and ischemic stroke:

●Peripheral and autonomic neuropathy – Length-dependent mixed sensory and motor peripheral neuropathy and/or autonomic neuropathy may occur and are prominent features in some of the heritable amyloidoses (called familial amyloidotic polyneuropathy) and in AL amyloidosis.

Symptoms of numbness, paresthesia, and pain are frequently noted, as in peripheral neuropathy of many other etiologies. Compression of peripheral nerves, especially the median nerve within the carpal tunnel, can cause more localized sensory changes. Symptoms of bowel or bladder dysfunction and findings of orthostatic hypotension may be due to autonomic nervous system damage [82,83].

●Central nervous system disease – CNS involvement is unusual in patients with the more common AL and AA amyloidoses. Amyloid deposits can lead to extensive cortical pathology and dementia in patients with sporadic or familial Alzheimer disease, while cerebral amyloid angiopathy can cause spontaneous cortical and subcortical intracranial bleeding, primarily in older adults [84]. ATTRv amyloidoses due to several different mutations associated with peripheral neuropathy may have prominent CNS manifestations [85]. (See "Genetics of Alzheimer disease" and "Cerebral amyloid angiopathy".)

●Ischemic stroke – Ischemic embolic stroke may be the initial manifestation of amyloid cardiomyopathy of any type. Atrial fibrillation and/or echocardiographic evidence of myocardial or valvular involvement are often present, supporting a cardioembolic source in the majority [86]. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Cardiac involvement'.)

Musculoskeletal disease — Amyloid deposition may affect the muscles, joints, and periarticular soft tissues. The musculoskeletal and rheumatologic manifestations of amyloidosis are discussed in detail separately. (See "Musculoskeletal manifestations of amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)

Briefly, infiltration of muscles may cause visible enlargement (ie, pseudohypertrophy). A large tongue (ie, macroglossia) or lateral scalloping of the tongue from impingement on the teeth is characteristic of AL amyloid. Arthropathy may be due to amyloid deposition in joints and surrounding structures. The "shoulder pad" sign is visible enlargement of the anterior shoulder due to fluid in the glenohumeral joint and/or amyloid infiltration of the synovial membrane and surrounding structures. Synovial fluid in AL and A-beta2-microglobulin amyloid is typically noninflammatory; it can be identified by Congo red staining of spun sediment [87].

Shoulder involvement is characteristic of AL amyloid and dialysis-related amyloidosis due to deposition of beta2-microglobulin. Other musculoskeletal features of dialysis-related amyloidosis include scapulohumeral periarthritis, spondyloarthritis, large amyloid-containing bone cysts that may fracture, and carpal tunnel syndrome [88]. (See "Dialysis-related amyloidosis".)

Musculoskeletal disease including carpal tunnel syndrome, lumbar spinal stenosis, and requirement for hip or knee arthroplasty may precede the diagnosis of ATTRwt amyloidosis by considerably more than a decade and may provide an opportunity for early diagnosis by histologic examination of tenosynovial or ligamentum flavum biopsies [89].

Hematologic abnormalities — Increased bleeding may occur in patients with amyloidosis due to one or more of several causes, including reduced activity of factor X, vascular infiltration with amyloid, and abnormal liver function due to amyloid deposition [90-92].

In one report of 337 patients, abnormal bleeding and abnormal coagulation tests were seen in 28 and 51 percent, respectively [91]. Two major mechanisms have been described: factor X deficiency due to binding on amyloid fibrils primarily in the liver and spleen and decreased synthesis of coagulation factors in patients with advanced liver disease. Amyloid-associated isolated factor X deficiency resulting from the binding of factor X to amyloid fibrils has also been described [93-96]. In a series of 368 consecutive patients with AL amyloidosis, 32 and 12 patients had factor X levels below 50 and 25 percent of normal, respectively [94]. Bleeding was noted in 18 patients and was more severe in the 12 patients whose factor X levels were <25 percent of normal. Factor X levels improved following high-dose melphalan chemotherapy and autologous hematopoietic cell transplantation in four of four patients obtaining complete remission and in one of two obtaining partial remission. However, some patients with abnormal bleeding have no abnormalities in any coagulation test [90]. In such patients, amyloid infiltration of blood vessels may contribute to the bleeding diathesis. Bleeding due to acquired von Willebrand disease or factor IX deficiency has also been described in AL amyloidosis [97,98].

Other hematologic manifestations are related to the degree of organ involvement. These include anemia in patients with renal failure, gastrointestinal bleeding, or multiple myeloma and thrombocytopenia due to splenomegaly. Instances of bone marrow replacement by amyloid associated with pathologic fractures have also been described [99]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Systemic presentations' and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Factor X inhibitors'.)

Pulmonary disease — Pulmonary manifestations of amyloidosis include tracheobronchial infiltration, persistent pleural effusions, parenchymal nodules (amyloidomas), and, rarely, pulmonary hypertension [100-109]. The pleuropulmonary manifestations of amyloidosis are discussed in detail separately. (See "Pleuropulmonary manifestations of amyloidosis".)

Briefly, pulmonary involvement by amyloid is particularly important for AL amyloidosis, which may be systemic or occur in localized forms sometimes associated with Sjögren's disease. Tracheobronchial amyloid infiltration can cause hoarseness, stridor, airway obstruction, and dysphagia; bronchoscopic or surgical resection of airway abnormalities may be required [110-115]. ATTR amyloidosis due to variant (mutant) protein or in aging patients with ATTRwt (systemic senile amyloidosis [SSA]) or familial amyloid polyneuropathy (FAP), respectively, may also result in alveolar deposits; these are generally asymptomatic and identified incidentally [116]. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

Persistent pleural effusions develop in 1 to 2 percent of patients with systemic amyloidosis and appear to be caused by pleural infiltration with amyloid deposits [102,117,118]. However, it is difficult to distinguish primary effusions from those caused by amyloid-induced cardiomyopathy on the basis of echocardiographic findings alone, and the sensitivity of pleural biopsy in this setting has not been studied extensively [102]. They are associated with a poor prognosis and limited response to treatment, although pleurodesis has been useful in some cases [102]. (See "Pleural fluid analysis in adults with a pleural effusion" and "Management of nonmalignant pleural effusions in adults".)

Skin manifestations — Signs of skin involvement in systemic amyloidosis include waxy thickening, easy bruising (ecchymoses), and subcutaneous nodules or plaques. Purpura, characteristically elicited in a periorbital distribution (raccoon eyes) by a Valsalva maneuver or minor trauma, is present in only a minority of patients but is highly characteristic of AL amyloidosis (picture 2) [119]. More subtle purpuric manifestations can also be seen in other types of systemic amyloidosis including inherited ATTRv [120], as well as amyloid associated with variants of lysozyme and apolipoprotein A-I (ApoAI) where a propensity to bruising may predate other symptoms by several decades. Infiltration of the subcutaneous fat is generally asymptomatic but is common and can be a convenient site for biopsy [64]. Amyloidosis limited to the skin may also occur [63]. (See 'Organ-specific amyloid' above.)

Cutaneous manifestations of amyloidosis are described in detail separately. (See "Cutaneous manifestations of amyloidosis".)

Other — Other manifestations include dry eyes and visual and hearing loss in some heritable amyloidoses [121,122]. Bladder deposition may cause hematuria, which can be gross, albeit rarely, and irritative urinary symptoms [24,66]. Ischemic symptoms and tissue infarction due to vascular infiltration have also been reported. Additional manifestations include jaw claudication suggestive of giant cell (temporal) arteritis, which can occur in AL amyloidosis [123], and symptomatic ischemic coronary heart disease, which is associated with the presence of obstructive intramural deposits of AL amyloid [124].

DIAGNOSIS

When to suspect amyloidosis — The different forms of amyloidosis may affect any tissue and organ systems, with a spectrum of clinical manifestations. These in turn can coexist both within a single patient and between different types of amyloidosis. Early diagnosis of amyloidosis relies upon a high index of suspicion, and the following features, particularly the coexistence of two or more clinical features in the context of predisposing conditions, should prompt urgent specific investigation:

●"Red flag" clinical features (see 'Overview of common clinical features' above):

•Non-organ specific: unintentional weight loss, loss of appetite, severe fatigue

•Visible tissue infiltration: macroglossia, easy bruising, skin fragility, nail dystrophy, waxy or thickened skin

•Proteinuria with or without nephrotic syndrome

•Heart failure

•Orthostatic hypotension, arrhythmia

•Carpal tunnel syndrome and/or progressive "glove and stocking" peripheral neuropathy

•Features of autonomic dysfunction including constipation and/or diarrhea, orthostatic hypotension, erectile dysfunction, gustatory sweating

•Hepatosplenomegaly

●Known underlying predisposing conditions:

•Monoclonal gammopathy, multiple myeloma, or other lymphoplasmacytic disorders known to result in production of monoclonal immunoglobulins

•Persistent uncontrolled inflammatory diseases such as autoinflammatory disease (eg, familial Mediterranean fever [FMF]), inflammatory arthritis (eg, rheumatoid arthritis [RA]), inflammatory bowel disease (eg, Crohn disease or ulcerative colitis), or chronic infection (eg, bronchiectasis, urosepsis, or skin sepsis complicating spinal injury)

•A family history of amyloidosis, neuropathy, renal disease, or cardiomyopathy, raising the possibility of dominantly inherited amyloidosis or of kappa AL (which can very rarely be inherited [125]); or of inflammatory symptoms, suggesting inherited autoinflammatory diseases that carry a high risk of AA amyloidosis

Diagnostic approaches — The definitive method for diagnosis of amyloidosis is tissue biopsy, although the presence of amyloidosis may be suggested by the history and clinical manifestations (eg, nephrotic syndrome in a patient with multiple myeloma or longstanding, active RA) (see 'When to suspect amyloidosis' above). In many patients, the biopsy need not be from the known affected organ but can be from another site likely to have deposits, most often the bone marrow or abdominal fat pad (see 'Selection of biopsy site' below). In some patients, the presence of amyloid is demonstrated by findings on imaging (see 'Imaging' below). In some patients, a biopsy result consistent with amyloid is an unexpected diagnosis following routine laboratory Congo Red staining. As an example, AA amyloidosis is only one cause of the nephrotic syndrome in patients with RA; other causes include drug side effects, immune-complex disease, or an unrelated disorder. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Kidney disease' and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Drugs' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs'.)

Even when amyloidosis is expected, tissue biopsy is important because assumptions regarding the type of amyloid may be incorrect.

Depending upon the presentation and findings, consultation with relevant specialists (eg, a hematologist, nephrologist, cardiologist, neurologist, clinical geneticist, others) and a coordinated multidisciplinary evaluation are important. Referral to a specialized center for the evaluation and management of amyloidosis is preferred, whenever feasible, to access experts in the interpretation and further processing of pathologic specimens, identification of the type of amyloid, detailed characterization of the distribution and extent of disease, and determination of optimal management approaches.

For most patients, the diagnostic evaluation is based upon the clinical presentation and the suspected type of amyloidosis, as described in detail separately for different types of amyloid disorders:

●Initial evaluation in all patients with suspected amyloidosis

Any patient with suspected amyloidosis, whether before or concurrent with scheduling a biopsy or after detection of amyloid as an unexpected biopsy finding, should undergo the following initial evaluation:

•Detailed history to define the presence of underlying conditions known to predispose individuals to developing amyloidosis (such as a hematologic disorder resulting in production of monoclonal immunoglobulin, a chronic inflammatory disorder, or end-stage renal failure) and to ascertain the onset and rate of progression of signs and symptoms systemically and/or related to specific organ system involvement.

•Detailed family history with attention to sex (in hereditary transthyretin amyloidosis [ATTR], inheritance down the female line may be associated with greater penetrance), ancestry, and specific organ involvement.

•Thorough physical examination for cutaneous findings (eg, pinch purpura, skin fragility or thickening, nail fragility), macroglossia, organomegaly, adenopathy, and neuropathy suggestive of amyloidosis.

•Review of recent and past laboratory testing, to include immunoglobulin abnormalities, renal and liver function, and inflammatory (C-reactive protein [CRP], serum amyloid A, and erythrocyte sedimentation rate [ESR]) and cardiac (N-terminal pro-brain natriuretic peptide [NT-proBNP] and troponin) biomarkers.

•Review of recent and past radiographic studies, including computed tomography (CT) scans and echocardiograms.

•Initial evaluation includes a complete blood count, comprehensive metabolic panel, thyroid function tests, and urinalysis.

•Inflammation is screened with an ESR and CRP and may be further defined by a serum amyloid A protein level and proinflammatory cytokine (tumor necrosis factor [TNF] alpha, interleukin [IL] 6) measurements.

•Monoclonal gammopathy is sought by obtaining all quantitative immunoglobulins, serum and urine immunofixation, and measurement of immunoglobulin free light chains (FLC) as elevated levels and/or skewed kappa/lambda ratio in serum.

•Cardiac function is screened with measurements of brain natriuretic peptide (BNP or proBNP) and troponin (T or I).

•Transthyretin (TTR) can be quantitated directly and assessed indirectly by quantitation of retinol binding protein 4 (RBP4) and vitamin A.

●Suspected AL amyloidosis – The clinical presentation in immunoglobulin light chain (AL) amyloidosis depends on the number and nature of the organs affected (see 'AL amyloidosis' above). As AL is the most frequently seen type of systemic amyloidosis and is potentially both life threatening and treatable, it should be suspected in all patients with amyloid demonstrated on biopsy until proven otherwise, even with a coexistent history of chronic infectious or inflammatory disease, end-stage kidney disease, or a family history of neuropathy or solid organ failure. Patients should undergo evaluation to determine if paraproteins and a plasma cell dyscrasia are present (see 'Search for monoclonal immunoglobulin' below), including bone marrow aspiration and biopsy. The diagnostic evaluation for AL amyloidosis (algorithm 1) is described in detail separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

●Suspected AA amyloidosis – Patients with clinical features of systemic amyloidosis and medical conditions that convey an increased risk of AA amyloidosis require a diagnostic evaluation, including a biopsy, to document and determine the extent of disease. Staining with anti-AA antibodies may be helpful. The evaluation and diagnosis of AA amyloidosis is described in detail separately. (See "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)

●Suspected hereditary amyloidosis – Patients with a family history of amyloidosis or of neuropathy or cardiac, renal, or liver failure should be suspected of having a heritable form of the disease. A biopsy to document the presence of amyloidosis and detailed analysis to identify the form of amyloid that is present should be performed. A thorough family history and exclusion of these heritable disorders are also warranted if a plasma cell dyscrasia or a cause of AA amyloid cannot be documented [76,126]. (See "Genetic factors in the amyloid diseases".)

●Suspected amyloid cardiomyopathy – Amyloid cardiomyopathy should be distinguished from other causes of apparent left ventricular hypertrophy, including hypertensive heart disease, hypertrophic cardiomyopathy, and infiltrative cardiomyopathies such as sarcoidosis and Fabry disease. Multiple forms of amyloidosis can affect the heart, particularly AL and ATTR (both variant [ATTRv] and wild-type [ATTRwt]), as well as rarer hereditary forms, apolipoprotein A-IV (ApoAIV) and AA type. Amyloid cardiomyopathy may be suspected based on apical sparing on strain doppler echocardiograms, typical late gadolinium enhancement (LGE) on cardiac MRI, or uptake over the heart by bone tracer scintigraphy performed with technetium 99 (99Tc)-pyrophosphate (PYP), 99Tc-3,3 diphosphono-1,2-propanodicarboxylic acid (DPD), or 99Tc-hydroxymethylene diphosphonate (HDMP); the last has been rendered specific for myocardial uptake by single-photon emission CT (SPECT), and graded in quantitative scans as 0 to 3, with grades 2 and 3 being acceptable criteria for diagnosis in lieu of endomyocardial biopsy, and grade 0 making ATTR or AL cardiac amyloidosis unlikely. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

●Dialysis-related amyloidosis – Patients with end-stage kidney disease who are suspected of amyloidosis based upon clinical findings (see 'Dialysis-related amyloidosis' above) should undergo a diagnostic evaluation, as described in detail separately. (See "Dialysis-related amyloidosis".)

Biopsy and related analyses

Selection of biopsy site — Biopsies can be obtained from either clinically uninvolved sites, such as subcutaneous fat, minor salivary glands, or rectal mucosa; or from dysfunctional organs (eg, kidney, nerve). We suggest a fat pad aspiration or biopsy as the initial sampling technique for patients with other than single organ involvement because this procedure is less likely than liver, renal, or rectal biopsy to be complicated by serious bleeding; however, biopsy of other tissues may have greater sensitivity. (See 'Abdominal fat pad biopsy' below.)

●Sensitivity and specificity of fat pad biopsy – Aspiration or biopsy of subcutaneous fat with Congo red staining and examination using polarized microscopy has an overall sensitivity of 57 to 85 percent and a specificity of 92 to 100 percent for AL or AA amyloidosis [127-130]. The diagnostic sensitivity is higher in those with multiorgan involvement who are suspected of having systemic amyloidosis due to immunoglobulin light chain (primary, or AL), AA protein (secondary), or ATTR (senile cardiac or familial amyloid polyneuropathy [FAP]) deposition [131]. Fat pad aspiration or biopsy has a low sensitivity for amyloidosis in patients with a single involved organ. (See 'Abdominal fat pad biopsy' below.)

Combination of fat pad biopsy and bone marrow biopsy has been shown to have an overall diagnostic sensitivity of 83 percent in AL amyloidosis [132].

●Patients with few affected organs – Biopsy of a specifically involved site, rather than an abdominal fat pad biopsy, is suggested for patients with a limited number of affected organs because patients with single-organ involvement are less likely to have biopsies of unaffected tissues reveal amyloid. This was illustrated by a study of 450 patients with peripheral neuropathy who had fat pad aspiration biopsies performed; among the 143 who had only peripheral neuropathy, none had amyloid deposits noted in the aspiration biopsy [133].

●Sensitivity and specificity of other biopsy sites – The sensitivity of rectal biopsy in one large series composed predominantly of patients with systemic amyloid ("primary amyloid" and myeloma associated in 193 patients, "secondary" or localized to a single organ in 41 patients) was 84 percent [134]. The sensitivity of kidney, liver, and carpal-tunnel biopsies were all 90 percent or more in this cohort. Although liver biopsy is rarely complicated by life-threatening bleeding, alternative approaches (eg, transjugular sampling) to diagnosis other than percutaneous liver biopsy are generally preferred. (See "Approach to liver biopsy", section on 'Patients with amyloidosis'.)

Biopsy of the minor salivary glands of the lip, as may be performed for the diagnosis of primary Sjögren's disease, also has a significant yield for both AA and AL amyloidosis, particularly in a subgroup of the latter with major soft tissue manifestations, such as macroglossia, submandibular adenopathy, and arthropathy [135].

Timing of the biopsy — Some patients are under follow-up for a known predisposing underlying disorder, and screening biopsies are performed as soon as there is an index of suspicion, while others present unexpectedly with an amyloid manifestation such as otherwise unexplained heart failure or nephrotic syndrome. In the latter, the diagnosis of amyloidosis comes first, followed by an evaluation for a cause (eg, plasma cell dyscrasia for AL, chronic inflammatory disease for AA).

Abdominal fat pad biopsy — Sampling of subcutaneous tissue was introduced in the 1970s as a diagnostic technique for some systemic forms of amyloidosis and remains a valuable tool, either as an aspiration of the abdominal fat pad or as a deep biopsy of the subcutaneous fat, usually performed by a dermatologist or surgeon [136]. Initial studies involved fine needle aspiration, which has subsequently been used in some studies in combination with ultrastructural and immunohistologic analysis of tissue [137,138].

A protocol has been utilized in clinical studies that involves repeated aspirations carried out at sites approximately 10 cm lateral to the umbilicus using 10 mL syringes with negative pressure through a 16-gauge needle. This procedure is simple and can be performed in the office over 20 to 30 minutes, but the critical steps for analysis are proper preparation of glass slides for microscopic analysis by Congo red birefringence and for immunohistology, which should be carried out by a pathology laboratory that is experienced with appropriate antibodies and that regularly carries out controls to validate testing. The aim of repeated aspiration, which may be done on both sides of the umbilicus as necessary, is to obtain adequate fat (approximately 30 mg) for routine studies, which may be increased to incorporate quantitation of subunit proteins by methods such as enzyme-linked immunoassay [139] and/or proteomic studies (mass spectroscopy, two-dimensional gel electrophoresis, protein sequence analysis). By contrast, skin biopsy has the potential to distinguish patterns of deposition in the various systemic amyloids [140] and to enhance isolation by laser-capture microdissection [141].

Histopathology and protein analysis — Amyloid deposits appear as amorphous hyaline material on light microscopy (picture 1A-D). The fibrils bind Congo red (leading to green birefringence under polarized light) and thioflavin T (producing an intense yellow-green fluorescence). On electron microscopy, they are 8 to 10 nm in width and are straight and unbranching [3,5].

In patients with a pathologic diagnosis of amyloidosis, the following evaluation will help to confirm and characterize the disorder:

●Slides should be independently reviewed by a pathologist familiar with the evaluation of amyloid in tissue, including metachromasia with dyes such as Congo red or crystal violet, thioflavin T fluorescence, and/or typical apple-green birefringence after staining with Congo red.

●Specific review of the localization of amyloid within biopsied tissue (eg, glomerular, interstitial, or medullary in kidney), with general attention to the presence of congophilic angiopathy and lymphoplasmacytic infiltrates contiguous to amyloid deposits.

●Immunohistochemistry with amyloid type-specific (eg anti-AA/anti-TTR) and generic (eg, anti-serum amyloid P component [SAP]) antisera, with special attention to titration and controls.

●Electron microscopy, particularly with reference to renal tissue, as it can help distinguish amyloid from other renal lesions in monoclonal gammopathy of renal significance (MGRS) [39]. Tissue must be processed specifically for electron microscopy at the time of biopsy.

●Laser-capture microdissection and mass spectroscopy to define the proteomics of amyloid deposits, thereby identifying the fibril subunit protein. Note that although this protocol is best carried out in a major referral center, samples can be obtained from stored tissue blocks or slides.

●In patients with suspected amyloid in whom further biopsies are relatively contraindicated, retrieval of biopsies previously taken for other indications may be performed for re-staining for amyloid; if positive for amyloid, mass spectroscopy may provide a histologic diagnosis and amyloid type.

In some cases, immunohistochemistry can be used to identify the type of protein subunit [10,142,143]. This is most reliable for AA and ATTR amyloid and is less so for AL amyloid; variable staining of AL deposits with standard antisera to kappa or lambda constant region determinants is due to loss of antigenic epitopes in the course of proteolytic processing of the constant region that is presumed to precede fibrillogenesis. Variable region-specific antibodies to immunoglobulin light chain subclass determinants may provide an approach to circumventing this limitation [144,145]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Differential diagnosis'.)

Direct identification of the proteins present in the amyloid deposits, either by amino acid sequencing or mass spectroscopy, is the most definitive way to characterize the type of amyloid present in the biopsy specimen [146]. This method is performed using laser-capture microdissection of amyloid from formalin-fixed amyloidotic tissue, followed by trypsin digestion, mass spectroscopy, and direct sequence analysis of peptides [141]. This approach, which was originally used for the analysis of the proteomics of AL amyloid, has also been validated for AA; specific tissues, including nerve in patients with amyloid neuropathy and renal biopsies [75]; and for abdominal fat pad aspirates [147]. It has also been adapted for the identification of pathogenic mutations in cases of hereditary amyloid [148] and for the identification of light chain subgroups in AL amyloidosis [149]. The technique is available at a number of specialist centers and requires biopsy blocks or slides, which may be sent for review after a diagnosis of amyloid is made locally.

Search for monoclonal immunoglobulin — In patients without a history of plasma cell dyscrasia, initial testing is aimed at determining whether a monoclonal population of plasma cells is present. This should be accomplished by testing for a monoclonal protein by serum and urine protein electrophoresis (figure 2 and figure 3) and immunofixation (figure 4 and figure 5) and measurement of serum free immunoglobulin light chains. Quantitation of serum FLCs has been utilized as an adjunctive diagnostic modality that may demonstrate clonality in patients with AL amyloid who do not have monoclonal proteins by immunofixation; this assay may also be used to follow response to treatment [150,151]. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)

The evaluation of a potential plasma cell dyscrasia in patients with suspected AL amyloidosis is described separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

However, the presence of a monoclonal protein alone is not sufficient to make a diagnosis of AL amyloid in a patient with documented amyloidosis unless light chains have been demonstrated in the amyloid deposits by histologic, mass spectroscopy, or protein sequencing techniques [76,152]. In particular, monoclonal gammopathies occur in a significant percent of patients with ATTR, in some cases causing coexisting AL and ATTR amyloidosis [153,154]. The potential for misdiagnosis based upon a serum or urine monoclonal protein alone was illustrated in a study of 350 patients suspected of having AL amyloidosis by clinical and laboratory findings and the absence of a family history [76]. Ten percent of these patients had a mutant gene for an "amyloidogenic" protein, most often involving the alpha chain of fibrinogen A or TTR. In 8 of these 34 patients, the presence of low concentrations of monoclonal immunoglobulins (all less than 0.2 g/dL) contributed to the misdiagnosis. (See "Genetic factors in the amyloid diseases".)

Imaging — Some noninvasive tests can provide supportive but not definitive findings. Imaging studies are particularly useful in the evaluation of cardiac disease thought to be related to amyloidosis, but imaging is also useful in other patients, including those with cystic bone lesions in dialysis-related amyloidosis. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis" and "Dialysis-related amyloidosis".)

Scintigraphy with radioisotope-labeled SAP can identify the distribution of amyloid and provide an estimate of the total body burden of fibrillar deposits [155]. However, the availability of SAP scintigraphy is limited as SAP is obtained from blood donors and the technique is not licensed by the US Food and Drug Administration (FDA). It is less helpful in detecting cardiac amyloid. Sensitivity of SAP scanning of 90 percent for AA and AL amyloid is contrasted with 48 percent for hereditary ATTR amyloidosis; the specificity is 93 percent in all three conditions [156]. Positron emission tomography-CT (PET-CT) with tracers with avidity for systemic amyloid deposits has been explored with ¹⁸F-florbetapir, ¹⁸F-florbetaben, ¹¹C-Pittsburgh compound B, and peptide p5+14 [2]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Serum amyloid P component scintigraphy'.)

Systemic versus localized disease — Several approaches will help to distinguish systemic from local disease. Their application is individualized depending upon the clinical presentation, physical findings, presence of underlying disorders predisposing to amyloidosis, and index of suspicion of systemic disease:

●Systemic disease may be suggested by imaging studies, which include:

•CT scans of the chest and abdomen showing organomegaly and/or significant lymphadenopathy.

•Echocardiograms showing wall infiltration and heart failure with or without preserved ejection fraction.

•Cardiac MRI, which has very high sensitivity and specificity for cardiac amyloidosis.

•Whole-body 99Tc-PYP scans looking for uptake over the heart or relevant musculoskeletal disease (wrist and hand for arthropathy or relevant to carpal tunnel syndrome; axial skeleton relevant to lumbar stenosis) is most sensitive for ATTR but is not completely specific and can also be positive in other types of amyloid. Uptake in the spleen is a rare but well-recognized finding in AL type.

●Localized forms of amyloidosis may be evaluated and biopsied by subspecialists (eg, otorhinolaryngologists for laryngeal amyloid, dermatologists for cutaneous amyloid) with specific relevant expertise.

●Tissue sampling for systemic disease may include abdominal fat pad, minor salivary gland, and gastrointestinal (gastric, rectal) biopsies.

●Cardiac biomarkers NT-proBNP and troponin have prognostic significance in systemic disease but can also be used in combination with clinical assessment to screen for the presence of cardiac involvement and to select patients for cardiac imaging as above.

●Assessment of renal function, including proteinuria and liver function, should be performed in all cases.

TREATMENT

General overview — Treatment of the different types of amyloidosis generally varies with the cause of fibril precursor production (eg, treatment of the plasma cell dyscrasia in patients with immunoglobulin light chain [AL] amyloidosis, control of underlying inflammatory or infectious disease in AA amyloidosis).

Strategies to facilitate the clearance of amyloid deposits in tissue are under development in clinical trials. Novel therapies have been developed for hereditary transthyretin (TTR) amyloid to reduce protein transcription, and these latter techniques may have potential for other hereditary amyloidoses in which the mutant amyloid precursor protein (APP) is produced by the liver (eg, apolipoprotein A-I [ApoAI] and fibrinogen Aa); liver transplantation has been used in such patients as an intervention that may prevent further deposition of amyloid and in some cases, can result in regression of established deposits [157-161].

Treatment protocols utilized in AL amyloidosis (eg, chemotherapy, hematopoietic cell transplantation) have no role in patients with hereditary forms of amyloidosis.

A range of novel approaches to treatment are also being investigated (see 'Other approaches and investigational strategies' below).

Therapies for individual amyloid types — The treatment approaches for major forms of amyloidosis are described in more detail separately:

●AL amyloidosis – In AL amyloidosis, treatment is directed primarily at suppressing the underlying plasma cell dyscrasia. The treatment of AL amyloidosis is described in detail separately. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

●AA amyloidosis – In AA amyloidosis, therapy is aimed primarily at suppressing the underlying infectious or inflammatory disorder, some biologic agents (eg, tumor necrosis factor [TNF], interleukin [IL] 6, and IL-1 inhibitors) have shown particular benefit. The treatment of AA amyloidosis is described in detail separately. (See "Treatment of AA (secondary) amyloidosis".)

●Dialysis-related amyloidosis – In patients with dialysis-related amyloidosis, treatment is directed at either altering the mode of dialysis or considering renal transplantation. The treatment of dialysis-related amyloidosis, which is due to beta2-microglobulin amyloid, is described in detail separately. (See "Dialysis-related amyloidosis", section on 'Treatment'.)

●Transthyretin amyloidosis – Several approaches have become available for the treatment of hereditary TTR amyloidosis (ATTR). These include the use of ribonucleic acid (RNA)-targeted therapies that interfere with hepatic TTR synthesis and other agents that reduce formation of TTR amyloid through stabilization of the tetramer configuration, preventing release of amyloidogenic monomers.

Liver transplantation has also been used for the treatment of hereditary (variant or mutant) ATTR (ATTRv) as a form of "surgical gene therapy." Liver transplantation is not applicable to wild-type ATTR (ATTRwt), and in most cases, access to heart transplantation is limited by the advanced age of the patient. Treatments for ATTR are discussed briefly below, particularly with respect to the treatment of familial amyloid polyneuropathy (FAP), and are also discussed separately, with a focus on amyloid heart disease (see "Cardiac amyloidosis: Treatment and prognosis", section on 'Disease-specific therapy for ATTR amyloidosis'):

•RNA-targeted therapies – RNA-targeted therapies for ATTR amyloidosis-related cardiomyopathy and neuropathy have become available that interfere with hepatic TTR synthesis and the resultant availability of misfolded monomers to aggregate and form amyloid deposits; these include patisiran, vutrisiran, inotersen, and eplontersen [162-164] (see "Cardiac amyloidosis: Treatment and prognosis", section on 'Disease-specific therapy for ATTR amyloidosis'):

-Patisiran – Patisiran is a TTR-specific small interfering RNA (siRNA) formulation in lipid nanoparticles [165], which has been shown to substantially reduce the production of both variant and wild-type forms of TTR in patients with hereditary ATTR and in healthy individuals [162,166,167]. Benefit has been shown in clinical trials in patients with FAP due to ATTR [162] and for patients with amyloid cardiomyopathy due to ATTR. Patisiran is administered every three weeks by intravenous infusion.

-Vutrisiran – Vutrisiran is a transthyretin-directed siRNA for treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults as an every-three-month subcutaneous injection [164]. It is a chemically modified double-stranded siRNA that targets mutant and wild-type TTR messenger RNA (mRNA) and is covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes, which causes degradation of mutant and wild-type TTR mRNA through RNA interference, resulting in a reduction of serum TTR protein and TTR protein deposits in tissues. Benefits have also been shown in patients with amyloid cardiomyopathy due to ATTR.

-Inotersen – Inotersen is an antisense oligonucleotide (ASO) construct that inhibits hepatic production of TTR [168], resulting in reduced levels of TTR in both healthy controls and in patients with hereditary ATTR with polyneuropathy [163,169,170]. Moderate to severe thrombocytopenia and bleeding complications have been reported with this agent. Benefits have also been shown for amyloid cardiomyopathy due to ATTR. Inotersen is administered once weekly by subcutaneous injection.

-Eplontersen – Eplontersen is a ligand-conjugated ASO given by subcutaneous injection [171]. In an open-label trial of patients with FAP related to ATTR amyloidosis, those treated with eplontersen had a greater reduction in serum TTR concentrations, less neuropathy-related impairment, and better quality of life when compared with a historical control group receiving placebo [172].

•Stabilization of transthyretin tetramers – Tafamidis and diflunisal each can reduce formation of TTR amyloid through stabilization of the TTR tetramer configuration, preventing release of amyloidogenic monomers. The use of tafamidis in amyloid cardiomyopathy is described separately (see "Cardiac amyloidosis: Treatment and prognosis", section on 'Disease-specific therapy for ATTR amyloidosis'); both tafamidis and diflunisal have also been studied in patients with FAP [173-175].

•Other agents – Other agents under investigation for ATTR amyloidosis include AG10, a TTR stabilizer that mimics the effect of the protective TTR T119M variant [176]; tolcapone, a previously licensed drug for Parkinson disease, which was shown to be a potent stabilizer in preclinical studies [177,178]; palindromic bivalent cross-linkers that deplete TTR; covalent stabilizers such as beta-aminoxypropionic acids; cyclic oligosaccharides (cyclodextrins); and polyamidoamine (PAMAM) dendrimers that inhibit formation and disrupt fibrils [179].

●Isolated organ involvement – The management of patients with isolated organ involvement depends upon the affected region, organ function, and amyloid type and is discussed separately. (See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management", section on 'Management' and "Cutaneous manifestations of amyloidosis" and "Pleuropulmonary manifestations of amyloidosis" and "Musculoskeletal manifestations of amyloidosis" and "Cerebral amyloid angiopathy".)

Other approaches and investigational strategies — A range of novel approaches to treatment are being investigated by screening of drug libraries and in animal models. They include agents that interfere with fibril formation; that inhibit the production of amyloidogenic precursors (eg, AL, ATTR, AA); gene editing of mutations, which is being tested for ATTRv; therapeutics that neutralize oligomers, non-amyloid aggregates or protofibrils; agents that promote clearance or degradation of existing amyloid deposits (eg, immunotherapy); and molecules that disrupt the interaction between amyloidogenic proteins and accessory molecules, including chaperones [1,180-186].

The following approaches have been of particular interest:

●RNA silencing – In addition to their use for ATTR amyloidosis, RNA silencing using siRNA and ASOs have potential uses as treatment for other amyloidoses. Silencing strategies are potentially applicable to every type of amyloidosis in which reduction in the level of precursor protein has been shown to decrease deposition and fibril formation. A limitation of this approach is that it depends upon being able to knock out a protein so it may not be applicable when the protein has essential functions that cannot be compensated for. The experience with ATTR provides a model for silencing of other amyloidogenic proteins primarily made in the liver, such as acute phase serum amyloid A protein isoforms, and leukocyte cell-derived chemotaxin-2 (LECT2) and has also been examined at the proof-of-concept level for AL amyloidosis [187,188].

●Gene editing – Gene editing designed to knock out TTR production is under investigation in a small group of patients with hereditary ATTR amyloidosis with polyneuropathy by use of an in vivo gene-editing agent based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system [180]; the agent is composed of a lipid nanoparticle encapsulating mRNA for Cas9 protein and a single guide RNA (sgRNA) targeting TTR. In the first part of this ongoing phase 1 clinical study, administration of a single infusion of this agent, NTLA-2001, substantially reduced serum levels of TTR with only mild adverse effects. While consistent with clinical proof of concept for this approach, the study is ongoing with further examination of optimal dosing and monitoring of treatment outcomes. No off-target effects of the gene editing have been detected in preclinical studies and in the phase 1 study.

●Inhibition of proteolysis – Direct extraction and macromolecular characterization of fibrils have identified cleavage products generated at specific amino acids (eg, position 76 for serum amyloid A protein, position 49 for TTR) that have been shown to be more intrinsically amyloidogenic and/or toxic [189,190] or, in the case of ATTR, that generate a distinct fibrillar and phenotypic morphology [191]. The presence in some amyloid deposits of both the intact precursor and proteolytic cleavage products raises the question of whether proteolysis is a pre- or post-fibrillar event [192]. These considerations have led to the concept that protease inhibition might be a target for therapy (eg, gamma-secretase inhibitors for Alzheimer disease; nanobodies directed against furin active sites for familial polyneuropathy due to gelsolin mutations) [193,194].

●Immunotherapy – Recognition that the fibrillar configuration might be accessible to antibodies with conformational specificities shared between different precursor proteins was an observation made a number of years ago [195,196]. Strategies for immunotherapy have included (a) vaccination with antigen preparations that mimic cryptic epitopes, oligomeric or fibrillar configurations, or (b) passive immunotherapy with intravenous gammaglobulin shown to contain amyloid-binding antibody activity, or with monoclonal antibodies that target oligomers, protofibrils, or fibrillar conformations. Active vaccination and passive immunotherapy have been most intensively explored as a strategy for clearance of amyloid for A-beta and tau central nervous system (CNS) diseases [197-199], and remain an area of interest for AL and ATTR [200]. Monoclonal antibodies to ATTR conformational or cryptic epitopes exposed during fibrillogenesis are also under study [201,202].

●Targeting of serum amyloid P component – Targeting of serum amyloid P component (SAP), a normal plasma protein common to all forms of systemic amyloid (including AA, AL, and hereditary forms), may be effective for the reduction or removal of tissue deposits of amyloid. Sequential treatment with the drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), which depletes SAP from the plasma but only partly depletes SAP from tissues, followed by administration of an anti-SAP monoclonal antibody, triggered the clearance of amyloid deposits from liver, kidney, and other organs in animal studies and in patients with AL, AA, and hereditary forms of systemic amyloidosis in early-phase clinical trials [203-207].

●Agents that disrupt fibrils – Fibril disrupters that have progressed to clinical testing include doxycycline (targeting ATTR, AL, and beta2-microglobulin), which disrupts fibril formation and mature fibrils, as well as inhibiting MMP-9; the nutraceuticals [208] epigallocatechin-3-gallate (green tea; targeting ATTR, A-beta, apolipoprotein A-II [ApoAII], and ATGF-beta1), which disrupts mature fibrils and suppresses markers of oxidative stress [209], and curcumin (targeting ATTR and A-beta), which induces oligomerization to a nontoxic "off pathway" [210]. Low molecular weight aggregation inhibitors include beta sheet breaker peptides, antigen-binding fragment (Fab), scFv or single-chain camelid nanobodies, and peptide inhibitors of adhesive segments [210]. (See "Treatment of AA (secondary) amyloidosis", section on 'Investigational approaches' and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Clinical trials'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: AL amyloidosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Types of amyloidosis – Amyloidosis is a generic term for the extracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of proteins, many of which circulate as constituents of plasma. These subunit proteins are derived from soluble precursors that undergo conformational changes that lead to the adoption of a predominantly antiparallel beta-pleated sheet configuration. At least 38 different human protein precursors of amyloid fibrils are known (table 1). (See 'Pathogenesis' above.)

Major forms of amyloidosis include:

•AL amyloidosis – Due to deposition of protein derived from immunoglobulin light chain fragments. It is a potential complication of any plasma cell dyscrasia that produces monoclonal immunoglobulin. (See 'AL amyloidosis' above and 'Clinical manifestations' above.)

•Transthyretin amyloidosis (ATTR) – Due to either specific heritable mutations, which are associated with familial amyloid polyneuropathy (FAP) and/or familial amyloid cardiomyopathy, or which more often may occur in a nonfamilial form as a concomitant of aging without apparent mutations (wild-type transthyretin [TTR] amyloidosis [ATTRwt]). (See 'Heritable amyloidoses' above and 'Wild-type transthyretin systemic amyloidosis' above and 'Clinical manifestations' above.)

•AA amyloidosis – The most common form in resource-limited countries, it may complicate chronic diseases associated with ongoing or recurring inflammation, such as chronic infections; rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; or periodic fever syndromes. (See 'AA amyloidosis' above and 'Clinical manifestations' above.)

Additional major forms include dialysis-related amyloidosis, other heritable amyloidoses, other age-related amyloidoses, organ-specific amyloid, and others. (See 'Dialysis-related amyloidosis' above and 'Heritable amyloidoses' above and 'Organ-specific amyloid' above and 'Clinical manifestations' above.)

●Clinical manifestations – Clinical manifestations vary depending upon the type of amyloid and the distribution of deposition. Some features that suggest amyloidosis include waxy skin and easy bruising, enlarged muscles (eg, tongue, deltoids), carpal tunnel syndrome, heart failure, cardiac conduction abnormalities, hepatomegaly, heavy proteinuria or the nephrotic syndrome, peripheral and/or autonomic neuropathy, and impaired coagulation. (See 'Types of amyloidosis' above and 'Clinical manifestations' above.)

●Diagnosis – Tissue biopsy should be used to confirm the diagnosis in all cases. Fat pad aspiration biopsy is less likely than liver, renal, or rectal biopsy to be complicated by serious bleeding; we thus suggest it as the initial biopsy technique for patients with other than single-organ involvement. In patients with single-organ involvement, biopsy of the clinically involved site is suggested because fat pad aspiration biopsy has a low sensitivity for amyloidosis in such patients. (See 'Selection of biopsy site' above.)

●Monoclonal protein testing – Patients with biopsy-documented amyloidosis and a well-defined plasma cell dyscrasia (eg, multiple myeloma or Waldenström macroglobulinemia) need not undergo further testing for an underlying hematologic disorder. Patients without a known plasma cell disorder should be tested to determine whether a monoclonal protein is present in serum, urine, or both using a combination of serum and urine protein electrophoresis, followed by immunofixation. Quantitation of serum free light chains (FLCs) is suggested for AL patients who do not have monoclonal proteins by immunofixation. (See 'Search for monoclonal immunoglobulin' above.)

The presence of a monoclonal protein alone is not sufficient to make a diagnosis of AL amyloid unless light chains have been demonstrated within the amyloid deposits. Heritable types of amyloidosis should be excluded if a plasma cell dyscrasia cannot be documented. (See 'Search for monoclonal immunoglobulin' above.)

●Treatment – Treatment of amyloidosis generally varies with the cause of fibril production. As examples, treatment is aimed at the underlying infectious or inflammatory disorder in AA amyloidosis, at the underlying plasma cell dyscrasia in AL amyloidosis, and at either altering the mode of dialysis or considering renal transplantation in patients with dialysis-related amyloidosis. Liver transplantation may be effective in certain of the hereditary amyloidoses. Therapies to decrease TTR production are available, and treatments that promote the clearance of amyloid deposits of different types are in development. (See 'Treatment' above.)