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John L. Berk

, MD, Amyloidosis Center, Boston University Medical Center;

Vaishali Sanchorawala

, MD, Boston University School of Medicine and Boston Medical Center

Last review/revision Aug 2021 | Modified Sep 2022
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Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally, causing relatively few symptoms, or widely, involving multiple organs and causing severe multiorgan failure. Amyloidosis can occur de novo or be secondary to various infectious, inflammatory, or malignant conditions. Diagnosis is by biopsy of affected tissue; the amyloidogenic protein is typed using a variety of immunohistologic and biochemical techniques. Treatment varies with the type of amyloidosis.

Amyloid deposits are composed of

  • Small (about 10 nm diameter), insoluble fibrils that form beta-pleated sheets that can be identified by x-ray diffraction

In addition to the fibrillar amyloid protein, the deposits also contain serum amyloid P component and glycosaminoglycans.

Amyloid fibrils are made of misfolded proteins that aggregate into oligomers and then insoluble fibrils. A number of normal (wild-type) and mutant proteins are susceptible to such misfolding and aggregation (amyloidogenic proteins), thus accounting for the wide variety of causes and types of amyloidosis.

For amyloidosis to develop, in addition to production of amyloidogenic proteins, there is probably also a failure of the normal clearance mechanisms for such misfolded proteins. The amyloid deposits themselves are metabolically inert but interfere physically with organ structure and function. However, some prefibrillar oligomers of amyloidogenic proteins have direct cellular toxicity, an important component of disease pathogenesis.

Amyloid deposits stain pink with hematoxylin and eosin, contain carbohydrate constituents that stain with periodic acid-Schiff dye or with Alcian blue, but most characteristically have apple-green birefringence under polarized light microscopy after Congo red staining. On autopsy inspection, affected organs may appear waxy.

Etiology of Amyloidosis

In systemic amyloidosis, circulating amyloidogenic proteins form deposits in a variety of organs. Major systemic types include

Amyloidosis caused by aggregation of beta-2-microglobulin can occur in patients on long-term hemodialysis, but the incidence has declined with use of modern high-flow dialysis membranes. There is a rare hereditary form of beta-2-microglobulin amyloidosis due to a mutation to the relevant gene.

Localized forms of amyloidosis appear to be caused by local production and deposition of an amyloidogenic protein (most often immunoglobulin light chains) within the affected organ rather than by deposition of circulating proteins. Frequently involved sites include the central nervous system (eg, in Alzheimer disease Alzheimer Disease Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ), skin, upper or lower airways, lung parenchyma, bladder, eyes, and breasts.

AL amyloidosis (primary amyloidosis)

AL is caused by overproduction of an amyloidogenic immunoglobulin light chain in patients with a monoclonal plasma cell or other B cell lymphoproliferative disorder. Light chains can also form nonfibrillar tissue deposits (ie, light chain deposition disease). Rarely, immunoglobulin heavy chains form amyloid fibrils (called AH amyloidosis).

Common sites for amyloid deposition include the skin, nerves, heart, gastrointestinal tract (including the tongue), kidneys, liver, spleen, and blood vessels. Usually, a low-grade plasmacytosis is present in the bone marrow, which is similar to that in multiple myeloma Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more Multiple Myeloma , although most patients do not have true multiple myeloma (with lytic bone lesions, hypercalcemia, renal tubular casts, and anemia). However, about 10 to 20% of patients with multiple myeloma develop AL amyloidosis.

AF amyloidosis (familial amyloidosis)

AF is caused by inheritance of a gene encoding a mutated aggregation-prone serum protein, usually a protein abundantly produced by the liver.

Serum proteins that can cause AF include transthyretin (TTR), apolipoprotein A-I, apolipoprotein A-II, lysozyme, fibrinogen, gelsolin, and cystatin C. A recently identified form that is speculated to be familial is caused by the serum protein leukocyte chemotactic factor 2 (LECT2); however, a specific inherited gene mutation for this latter type has not been clearly demonstrated.

Amyloidosis caused by TTR (ATTR) is the most common type of AF. More than 130 mutations of the TTR gene have been associated with amyloidosis. The most prevalent mutation, V30M, is common in Portugal, Sweden, Brazil, and Japan, and a V122I mutation is present in about 4% of American and Caribbean blacks. Disease penetrance and age of onset are highly variable but are consistent within families and ethnic groups.

ATTRwt amyloidosis (senile systemic amyloidosis)

ATTRwt is caused by aggregation and deposition of wild-type TTR, principally targeting the heart.

The genetic and epigenetic factors leading to ATTRwt are unknown. Because ATTRwt and AL amyloidosis both can cause cardiomyopathy, and because amyloidogenic monoclonal gammopathies may be present in patients in this age group, it is essential to accurately type the amyloid so that patients with ATTRwt are not inappropriately treated with chemotherapy (which is used for AL).

AA amyloidosis (secondary amyloidosis)

This form can occur secondary to several infectious, inflammatory, and malignant conditions and is caused by aggregation of isoforms of the acute-phase reactant serum amyloid A.

Common causative infections include

Predisposing inflammatory conditions include

Inflammatory cytokines (eg, interleukin [IL]-1, tumor necrosis factor [TNF], IL-6) that are produced in these disorders or ectopically by tumor cells cause increased hepatic synthesis of serum amyloid A (SAA).

AA amyloidosis shows a predilection for the kidneys, spleen, liver, adrenal glands, and lymph nodes. Involvement of the heart or peripheral and autonomic nerves occurs late in the disease course.

Localized amyloidosis

Localized amyloidosis outside the brain is most frequently caused by deposits of clonal immunoglobulin light chains; within the brain, amyloid beta protein predominates.

Localized amyloid deposits typically involve the airways and lung tissue, bladder and ureters, skin, breasts, and eyes. Rarely, other locally produced proteins cause amyloidosis, such as keratin isoforms that can form deposits locally in the skin. Clonal immunoglobulin light chains produced by mucosal-associated lymphoid tissue in the gastrointestinal tract, airways, and bladder can lead to localized AL in those organs.

Symptoms and Signs of Amyloidosis

Symptoms and signs of systemic amyloidosis are nonspecific, often resulting in delays in diagnosis. Suspicion of amyloidosis should be increased in patients with a progressive multisystem disease process.

Renal amyloid deposits typically occur in the glomerular membrane leading to proteinuria, but in about 15% of cases the tubules are affected, causing azotemia with minimal proteinuria. These processes can progress to nephrotic syndrome Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more with marked hypoalbuminemia, edema, and anasarca or to end-stage renal disease.

Hepatic involvement causes painless hepatomegaly, which may be massive. Liver tests typically suggest intrahepatic cholestasis with elevation of alkaline phosphatase and later bilirubin, although jaundice is rare. Occasionally, portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more develops, with resulting esophageal varices and ascites.

Airway and laryngeal involvement leads to dyspnea, hoarseness, wheezing, hemoptysis, or airway obstruction.

Peripheral neuropathy with paresthesias of the toes and fingers is a common presenting manifestation in AL and ATTR amyloidoses. Autonomic neuropathy Autonomic Neuropathies Autonomic neuropathies are peripheral nerve disorders with disproportionate involvement of autonomic fibers. (See also Overview of the Autonomic Nervous System.) The best known autonomic neuropathies... read more may cause orthostatic hypotension, erectile dysfunction, sweating abnormalities, and gastrointestinal motility disturbances.

Soft tissue amyloid involvement characteristically precedes clinical expression of ATTRwt amyloid cardiomyopathy. Manifestations of soft tissue amyloid disease include carpal tunnel syndrome, trigger finger, bicipital tendon rupture, and spinal stenosis.

Lung involvement (mostly in AL amyloidosis) can be characterized by focal pulmonary nodules and cysts, tracheobronchial lesions, pleural effusions, or diffuse alveolar deposits.

Amyloid vitreous opacities and bilateral scalloped pupillary margins develop in several hereditary amyloidoses.

Other manifestations include bruising, often around the eyes (raccoon eyes), caused by amyloid deposits in blood vessels. Amyloid deposits cause weakening of the blood vessels, which may rupture after minor trauma, such as sneezing or coughing.

Diagnosis of Amyloidosis

  • Biopsy

  • Amyloid typing

  • Testing for organ involvement


Diagnosis of amyloidosis is made by demonstration of fibrillar deposits in an involved organ. Aspiration of subcutaneous abdominal fat detects amyloid deposits in about 80% of patients with AL, 50% in AF, but less than 25% of patients with ATTRwt. If the fat biopsy result is negative, a clinically involved organ should be biopsied. The diagnostic sensitivity of kidney and heart biopsies is nearly 100% when these organs are clinically involved. Tissue sections are stained with Congo red dye and examined with a polarizing microscope for characteristic birefringence. Nonbranching 10-nm fibrils can also be recognized by electron microscopy on biopsy specimens from the heart or kidneys.

Nuclear scanning using bone-avid tracers can diagnose ATTR amyloid cardiomyopathy without heart biopsy, provided AL amyloidosis is ruled out.

Amyloid typing

After amyloidosis has been confirmed by biopsy, the type is determined using a variety of techniques. For some types of amyloidosis, immunohistochemistry or immunofluorescence may be diagnostic, but false-positive typing results occur. Other useful techniques include gene sequencing for AF and biochemical identification by mass spectrometry (the most sensitive and specific method).

If AL is suspected, patients should be evaluated for an underlying plasma cell disorder using quantitative measurement of serum free immunoglobulin light chains, qualitative detection of serum or urine monoclonal light chains using immunofixation electrophoresis (serum protein electrophoresis and urine protein electrophoresis are insensitive in patients with AL), and a bone marrow biopsy with flow cytometry or immunohistochemistry to establish plasma cell clonality.

Patients with > 10% clonal plasma cells should be tested to see if they meet criteria for multiple myeloma Diagnosis Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more Diagnosis , including screening for lytic bone lesions, anemia, renal insufficiency, and hypercalcemia.

Organ involvement

Patients are screened for organ involvement beginning with noninvasive testing:

  • Kidneys: Urinalysis and measurement of serum BUN and creatinine

  • Liver: Liver function tests

  • Lungs: Chest x-ray, chest CT, and/or pulmonary function tests

  • Heart: ECG and measurement of biomarkers such as brain (B-type) natriuretic peptide (BNP) or N-terminal-pro-BNP (NT-proBNP) and troponin

Cardiac involvement can be suggested by low voltage on ECG (caused by a thickened ventricle) and/or dysrhythmias. If cardiac involvement is suspected because of symptoms, ECG, or cardiac biomarkers, echocardiography is done to measure diastolic relaxation and systolic function and to screen for biventricular hypertrophy. In ambiguous cases, cardiac MRI can be done to detect persistent subendocardial gadolinium enhancement, a characteristic finding. Advances in cardiac technetium pyrophosphate nuclear scans have improved detection of ATTR amyloid heart disease and can avoid the need for heart biopsies provided blood tests rule out AL amyloidosis (1, 2 Diagnosis references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Diagnosis references ).

Diagnosis references

Prognosis of Amyloidosis

Prognosis depends on the type of amyloidosis and the organ system involved, but with appropriate disease-specific and supportive care, many patients have an excellent life expectancy.

AL complicated by severe cardiomyopathy has the poorest prognosis, with median survival of < 1 year. Untreated ATTR amyloidosis usually progresses to end-stage cardiac or neurologic disease within 5 to 15 years. ATTRwt was once thought to have the slowest progression of any systemic amyloidosis involving the heart; however, patients with ATTRwt do progress to symptomatic heart failure and death within a median of 4 years from biopsy diagnosis.

Prognosis in AA amyloidosis depends largely upon the effectiveness of treatment of the underlying infectious, inflammatory, or malignant disorder.

Treatment of Amyloidosis

  • Supportive care

  • Type-specific treatment

Currently, there are specific treatments for most forms of amyloidosis, although some therapies are investigational. For all forms of systemic amyloidosis, supportive care measures can help relieve symptoms and improve quality of life.

Supportive care

Supportive care measures are directed at the affected organ system:

Orthostatic hypotension often improves with high doses of midodrine; this drug can cause urinary retention in older males, but the drug complication of supine hypertension is rarely a problem in this population. Support stockings can also help, and fludrocortisone can be used in patients without peripheral edema, anasarca, or heart failure.

AL amyloidosis

For AL amyloidosis:

  • Prompt initiation of anti-plasma cell therapy is essential to preserve organ function and prolong life.

Proteasome inhibitors (eg, bortezomib) and immunomodulators (eg, lenalidomide) also can be effective. Combination and sequential regimens are being investigated.

Localized AL can be treated with low-dose external beam radiation therapy because plasma cells are highly radiosensitive.

ATTR amyloidosis

For ATTR amyloidosis:

  • Liver transplantation

  • Tetramer-stabilizing drugs

  • Gene silencing drugs

Liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more —which replaces the primary site of synthesis of the mutant protein with a new organ producing normal TTR—can be effective in certain TTR mutations if done at disease onset (early neuropathy and no heart involvement). Transplantation later in the course of the disease often leads to progressive amyloid cardiomyopathy and neuropathy due to the misfolding and deposition of wild-type TTR protein onto pre-existing amyloid deposits.

Several drugs have been shown to stabilize TTR tetramers circulating in the plasma, inhibiting TTR misfolding and fibril formation and effectively slowing neurologic disease progression while preserving quality of life. These TTR stabilizers include diflunisal, a widely available generic anti-inflammatory drug, and tafamidis (2, 3 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Treatment references ).

TTR gene silencing using anti-sense RNA or RNA interference to block translation of TTR mRNA efficiently reduces serum levels of TTR, improves neurologic outcomes in about 50% of patients, and appears capable of repairing injured nerves in some patients (4, 5 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Treatment references ). Two gene silencing drugs, patisiran and inotersen, are available .

ATTRwt amyloidosis

For ATTRwt amyloidosis:

  • Tetramer-stabilizing drugs

TTR stabilization using tafamidis, in patients with ATTR amyloid cardiomyopathy has been shown to decrease all-cause mortality and cardiovascular-related hospitalizations (3 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Treatment references ).

Unlike hereditary ATTR amyloidosis, liver transplantation is not effective for patients with ATTRwt because the amyloidogenic protein is a structurally normal TTR.

AA amyloidosis

For AA amyloidosis caused by familial Mediterranean fever, colchicine 0.6 mg orally once or twice a day is effective.

For other AA types, treatment is directed at the underlying infection, inflammatory disease, or cancer.

Colchicine or anti-IL1, anti-IL6, or anti-TNF drugs may be used to interrupt the cytokine signaling, diminishing the inflammatory process driving hepatic production of serum amyloid A (SAA).

Treatment references

Key Points

  • Amyloidosis is a group of disorders in which certain misfolded proteins aggregate into insoluble fibrils that are deposited within organs, causing dysfunction.

  • Many different proteins are prone to misfold; some of these proteins are produced by a genetic defect or by certain disease states, whereas others are immunoglobulin light chains produced by monoclonal plasma cell or other B-cell lymphoproliferative disorders.

  • The amyloidogenic protein determines the amyloid type and clinical course of disease, although the clinical manifestations of the different types may overlap.

  • Many organs can be affected, but cardiac involvement carries a particularly poor prognosis; amyloid cardiomyopathy typically leads to diastolic dysfunction, heart failure, and heart block or arrhythmia.

  • Diagnosis is by biopsy; type of amyloidosis is determined by a variety of immunologic, genetic, and biochemical tests. Mass spectrometry is the most sensitive and specific method for amyloid typing.

  • Appropriate supportive care will help relieve symptoms and improve quality of life; organ transplantation can help selected patients.

  • Treat the underlying process; for AL amyloidosis due to plasma cell or lymphoproliferative disorders, chemotherapy can be highly effective; for secondary AA amyloidosis, anti-infectious and anti-inflammatory drugs can help.

  • For hereditary ATTR amyloidosis, small molecule stabilizer therapeutics and gene-silencing drugs inhibit or potentially reverse neurologic deterioration; for patients with amyloid cardiomyopathy (ATTR or ATTRwt), tafamidis decreases all-cause mortality and cardiovascular-related hospitalizations.

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