Amyloid deposits are composed of
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.
In systemic amyloidosis, circulating amyloidogenic proteins form deposits in a variety of organs. Major systemic types include
AL (primary amyloidosis): Caused by acquired overexpression of clonal immunoglobulin light chains
AF (familial amyloidosis): Caused by inheritance of a mutant gene encoding a protein prone to misfolding, most commonly transthyretin (TTR)
ATTRwt (wild-type ATTR; previously termed senile systemic amyloidosis or SSA): Caused by misfolding and aggregation of wild-type TTR (wild-type ATTR)
AA (secondary amyloidosis): Caused by aggregation of an acute phase reactant, serum amyloid A
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), skin, upper or lower airways, lung parenchyma, bladder, eyes, and breasts.
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, 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 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. ATTR causes peripheral sensory and autonomic neuropathy, chronic kidney disease, and cardiomyopathy. Carpal tunnel syndrome commonly precedes other neurologic disease manifestations. Vitreous deposits may develop due to production of mutant TTR by the retinal epithelium, or leptomeningeal deposits may develop if the choroid plexus produces mutant TTR.
ATTRwt is caused by aggregation and deposition of wild-type TTR, clinically targeting the heart.
ATTRwt is increasingly recognized as a cause of infiltrative cardiomyopathy in older men. Fully 16% of patients with aortic stenosis undergoing transcatheter aortic valve replacement and 13% of those hospitalized for heart failure with preserved ejection fraction (HFpEF) have ATTRwt amyloid cardiomyopathy. 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).
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
Inherited periodic fever syndromes such as familial Mediterranean fever
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 spleen, liver, kidneys, adrenal glands, and lymph nodes. Involvement of the heart and peripheral or autonomic nerves occurs late in the disease course.
Localized amyloidosis outside the brain is most frequently caused by deposits of clonal immunoglobulin light chains and within the brain by amyloid beta protein.
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 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 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 develops, with resulting esophageal varices and ascites.
Airway involvement leads to dyspnea, 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 may cause orthostatic hypotension, erectile dysfunction, sweating abnormalities, and gastrointestinal motility disturbances.
Cerebrovascular amyloid angiopathy most often causes spontaneous lobar cerebral hemorrhage but some patients have brief, transient neurologic symptoms.
Gastrointestinal amyloid may cause motility abnormalities of the esophagus and small and large intestines. Gastric atony, malabsorption, bleeding, or pseudo-obstruction may also occur. Macroglossia is common in AL amyloidosis.
Soft tissue amyloid involvement characteristically precedes clinical expression of ATTRwt amyloid cardiomyopathy. Manifestions of soft tissue amyloid disease include carpal tunnel syndrome, trigger finger, bicipital tendon rupture, and spinal stenosis.
Amyloidosis of the thyroid gland may cause a firm, symmetric, nontender goiter resembling that found in Hashimoto thyroiditis. Other endocrinopathies can also occur.
Lung involvement (mostly in AL amyloidosis) can be characterized by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits.
Amyloid vitreous opacities and bilateral scalloped pupillary margins develop in several hereditary amyloidoses.
Other manifestations include bruising, such as bruising around the eyes (raccoon eyes), which is 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 is made by demonstration of fibrillar deposits in an involved organ. Aspiration of subcutaneous abdominal fat is positive 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 heart or kidneys.
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, including screening for lytic bone lesions, anemia, renal insufficiency, and hypercalcemia.
Patients are screened for organ involvement beginning with noninvasive testing:
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 delayed 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).
1. Gillmore JD, Maurer MS, Falk RH, et al: Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 133(24):2404–2412, 2016.
2. Maurer MS, Bokhari S, Damy T, et al: Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail 12(9):e006075, 2019.
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 yr. 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.
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 measures are directed at the affected organ system:
Renal: Patients with nephrotic syndrome and edema should be treated with salt and fluid restriction, and loop diuretics; because of the ongoing protein loss, protein intake should not be restricted. Kidney transplantation is an option when the underlying disease process is controlled, and can provide long-term survival comparable to that in other renal diseases.
Cardiac: Patients with cardiomyopathy should be treated with salt and fluid restriction and loop diuretics. Other drugs for heart failure, including digoxin, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-blockers, are poorly tolerated and contraindicated. Heart transplantation has been successful in carefully selected patients with AL or ATTR amyloidosis and severe cardiac involvement. To prevent recurrence in the transplanted heart, patients with AL amyloidosis must be given aggressive chemotherapy directed at the clonal plasma cell disorder, and patients with symptomatic ATTR amyloid polyneuropathy or cardiomyopathy should be considered for anti-TTR therapies.
Gastrointestinal: Patients with diarrhea may benefit from loperamide. Those with early satiety and gastric retention may benefit from metoclopramide.
Nervous system: In patients with peripheral neuropathy, gabapentin, pregabalin, or duloxetine may relieve pain.
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.
For AL amyloidosis:
Most drugs used for multiple myeloma have been used in AL amyloidosis; choice of drug, dose, and schedule often must be modified when organ function is impaired.
Chemotherapy using an alkylating agent (eg, melphalan, cyclophosphamide) combined with corticosteroids was the first regimen to show any benefit. High-dose IV melphalan, combined with autologous stem cell transplantation can be highly effective in selected patients (1).
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.
For ATTR amyloidosis:
Liver transplantation—which replaces the hepatic site of synthesis of the mutant protein with one producing normal TTR—can be effective in certain TTR mutations if done at disease onset (early neuropathy and no heart involvement). When done later in the course of the disease, after significant amyloid deposition has occurred in the heart and nerves, liver transplantation often results in progressive amyloid cardiomyopathy and neuropathy due to the misfolding and deposition of wild-type TTR onto pre-existing amyloid deposits.
Several drugs have been shown to stabilize TTR tetramers circulating in the plasma, preventing TTR misfolding and fibril formation and effectively inhibiting neurologic disease progression while preserving quality of life. These TTR stabilizers include diflunisal, a widely available generic anti-inflammatory drug, and tafamidis (2, 3).
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 70% of patients, and appears capable of repairing injured nerves in some patients (4, 5). Two gene silencing drugs, patisiran and inotersen, are available .
For ATTRwt amyloidosis:
TTR stabilization using tafamidis, in patients with ATTR amyloid cardiomyopathy has been shown to decrease all-cause mortality and cardiovascular-related hospitalizations (3).
Unlike hereditary ATTR amyloidosis, liver transplantation is not effective for patients with ATTRwt because the wild type amyloidogenic protein is a structurally normal TTR.
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.
Anti-IL1, anti-IL6, and anti-TNF drugs may be used to interrupt the cytokine signaling, diminishing the inflammatory process driving hepatic production of serum amyloid A (SAA).
1. Sanchorawala V, Sun F, Quillen K, et al: Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience. Blood 126: 2345–2347, 2015. doi: 10.1182/blood-2015-08-662726. Epub 2015 Oct 6
2. Berk JL, Suhr OB, Obici L, et al: Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310: 2658–2667, 2013. doi: 10.1001/jama.2013.283815
3. Maurer MS, Schwart JH, Gundapaneni B, et al: Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 379:1007–1016, 2018.
4. Adams D, Gonzalez-Duarte A, O'Riordan WD, et al: Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 379:11–21, 2018.
5. Benson MD, Waddington-Cruz M, Berk JL, et al: Inotersen treatment for patients with transthyretin amyloidosis. N Engl J Med 379:22–31, 2018.
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 and/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.