Amyloidosis

Author: Robert O Holmes Jr, DO; Chief Editor: Herbert S Diamond, MD

Updated: Jan 19, 2012 Definition of Amyloidosis

Definition of amyloid and amyloidosis
Amyloid is defined as in vivo deposited material distinguished by fibrillar electron
micrographic appearance, amorphous eosinophilic appearance on hematoxylin and eosin
staining (see the first image below), beta pleated sheet structure as observed by x-ray
diffraction pattern, apple-green birefringence on Congo Red histological staining (see the
second image below), and solubility in water and buffers of low ionic strength. All types
of amyloid consist of a major fibrillar protein that defines the type of amyloid.[1, 2]

Amorphous eosinophilic interstitial amyloid observed on a

renal biopsy.
Congo Red staining of a cardiac biopsy
specimen containing amyloid, viewed under polarized light.
Amyloidosis is a clinical disorder caused by extracellular and or intracellular deposition
of insoluble abnormal amyloid fibrils that alter the normal function of tissues.
Approximately 10% of amyloidosis depots consist of components such as
glycosaminoglycans (GAGs), apolipoprotein E (apoE), and serum amyloid P (SAP)
component, while 90% of the depots consist of the amyloid fibrils that are formed by the
aggregation of misfolded proteins. These proteins either arise from proteins expressed by
cells at the deposition site (localized) or precipitate systemically after production at a
local site (systemic).[3] In humans, about 23 different unrelated proteins are known to
form amyloid fibrils in vivo.[4] Many mechanisms of protein function contribute to
amyloidogenesis, including "nonphysiologic proteolysis, defective physiologic
proteolysis, mutations involving changes in thermodynamic or kinetic properties, and
pathways that are yet to be defined."[4]

Classification Systems: Historical (Clinical Based) and Modern

(Biochemical Based)
Historical classification systems (clinical based)
Until the early 1970s, the idea of a single amyloid substance predominated. Various
descriptive classification systems were proposed based on the organ distribution of
amyloid deposits and clinical findings. Most classification systems included primary (ie,
in the sense of idiopathic) amyloidosis, in which no associated clinical condition was
identified, and secondary amyloidosis, ie, associated with chronic inflammatory
conditions. Some classification systems included myeloma-associated, familial, and
localized amyloidosis.
The modern era of amyloidosis classification began in the late 1960s with the
development of methods to solubilize amyloid fibrils. These methods permitted chemical
amyloid studies. Descriptive terms such as primary amyloidosis, secondary amyloidosis,
and others (eg, senile amyloidosis), which are not based on etiology, provide little useful
information and are no longer recommended.

Modern amyloidosis classification (biochemical based)

Amyloid is now classified chemically. The amyloidoses are referred to with a capital
letter A (for amyloid) followed by an abbreviation for the fibril protein. For example, in
most cases formerly called primary amyloidosis and in myeloma-associated amyloidosis,
the fibril protein is an immunoglobulin light chain or light chain fragment (abbreviated
L); thus, patients with these amyloidoses are now said to have light chain amyloidosis
(AL). Names such as AL describe the protein (light chain), but not necessarily the clinical
phenotype.[3]
Similarly, in most cases previously termed senile cardiac amyloidosis and in many cases
previously termed familial amyloid polyneuropathy (FAP), the fibrils consist of the
transport protein transthyretin (TTR); these diseases are now collectively termed ATTR.
Proteins that form amyloid fibrils differ in size function, amino acid sequence, and native
structure but become insoluble aggregates that are similar in structure and in properties.
Protein misfolding results in formation of fibrils that show a common beta sheet pattern
on x-ray diffraction. In theory, misfolded amyloid proteins can be attributed to infectious
sources (prions), de novo gene mutations, errors in transcription, errors in translation,
errors in posttranslational modification, or protein transport. For example, in ATTR, 100
different points of single or double mutations, or deletions in the TTR gene and several
different phenotypes of FAP have been documented.[5] Twenty-three different fibril
proteins are described in human amyloidosis, with variable clinical features. The major
types of human amyloid are outlined and discussed individually in the table below.
Table. Human Amyloidoses (Open Table in a new window)

Type
Systemic

Fibril Protein
Immunoglobulin light
chains
Transthyretin
A amyloidosis

Main Clinical Settings

Plasma cell disorders

Familial amyloidosis, senile cardiac amyloidosis

Inflammation-associated amyloidosis, familial
Mediterranean fever
Beta2 -microglobulin
Dialysis-associated amyloidosis
Immunoglobulin heavy Systemic amyloidosis
chains
Hereditary
Fibrinogen alpha chain Familial systemic amyloidosis
Apolipoprotein AI
Familial systemic amyloidosis
Apolipoprotein AII
Familial systemic amyloidosis
Lysozyme
Familial systemic amyloidosis
Central nervous Beta protein precursor Alzheimer syndrome, Down syndrome,
system
hereditary cerebral hemorrhage with
amyloidosis (Dutch)
Prion protein
Creutzfeldt-Jakob disease, GerstmannStrussler-Scheinker disease, fatal familial
insomnia, Kuru
Cystatin C
hereditary cerebral hemorrhage with
amyloidosis (Icelandic)
ABri precursor protein Familial dementia (British)
ADan precursor protein Familial dementia (Danish)
Ocular
Gelsolin
Familial amyloidosis (Finnish)
Lactoferrin
Familial corneal amyloidosis
Keratoepithelin
Familial corneal dystrophies
Localized
Calcitonin
Medullary thyroid carcinoma
Amylin*
Insulinoma, type 2 diabetes
Atrial natriuretic factor Isolated atrial amyloidosis
amyloidosis
Prolactin
Pituitary amyloid
Keratin
Cutaneous amyloidosis
Medin
Aortic amyloidosis in elderly people
*Islet amyloid polypeptide amyloidosis

Systemic Amyloidoses
A amyloidosis
The precursor protein in A amyloidosis (AA) is a normal-sequence apo-SAA (serum
amyloid A protein) now called "A," which is an acute-phase reactant produced mainly in
the liver in response to multiple cytokines.[3] "A" protein circulates in the serum bound to
high-density lipoprotein.

AA occurs in various chronic inflammatory disorders, chronic local or systemic microbial

infections, and occasionally with neoplasms. The frequency of amyloidosis has been
shown to vary significantly in different ethnic groups.[6] Some of the conditions associated
with AA include the following:

Rheumatoid arthritis (RA)

Juvenile chronic arthritis
Ankylosing spondylitis
Psoriasis and psoriatic arthritis
Still disease
Behet syndrome
Familial Mediterranean fever
Crohn disease
Leprosy
Osteomyelitis
Tuberculosis
Chronic bronchiectasis
Castleman disease
Hodgkin disease
Renal cell carcinoma
Carcinoma of the gastrointestinal, lung, or urogenital tract
Cryopyrin-associated periodic syndromes (CAPS)

Organs that are typically involved include the kidney, liver, and spleen. Worldwide, AA is
the most common systemic amyloidosis; it was formerly termed secondary amyloidosis.
Therapy has traditionally been aimed at the underlying inflammatory condition to reduce
the production of the precursor amyloid protein SAA. Disease modifying antirheumatic
drugs (DMARDS) such as colchicine, a microtubule inhibitor and weak
immunosuppressant, can prevent secondary renal failure due to amyloid deposition
specifically in familial Mediterranean fever.
Newer therapies have become more targeted to avoid the cytotoxicity of older agents
(chlorambucil, cyclophosphamide). Recently, the SAA amyloid seen in CAPS was
reduced with a new biologic interleukin (IL)1 beta trap called rilonacept. Tumor
necrosis factor (TNF)alpha is also thought to be involved in amyloid deposition.[7]
Aggressive use of newer biologic therapies for RA, such as etanercept (a TNF-alpha
blocker), have been used to decrease the concentration of SAA, serum creatinine,
creatinine clearance, and proteinuria in renal AA associated with RA.[8]
Additionally, SAA isoforms have been studied using high-resolution 2-dimensional gel
electrophoresis and peptide mapping by reverse-phase chromatography, electrospray
ionization tandem mass spectrometry, and genetic analysis down to the posttranslational
modification level.[9] SAA is coded by 4 genes SAA1, SAA2, SAA3, and SAA4. The
SAA1 gene contributes to most of the deposits and contains a single nucleotide
polymorphism that defines at least 3 haplotypes. The saa1.3 allele was found to be a risk
factor and a poor prognostic indicator in Japanese patients with RA. Genetic analysis has

proven useful not only in selecting patients for biologic therapy but also in predicting
outcome (see below).[10]

Light chain amyloidosis

The precursor protein is a clonal immunoglobulin light chain or light chain fragment. AL
is a monoclonal plasma cell disorder closely related to multiple myeloma, as some
patients fulfill diagnostic criteria for multiple myeloma. Typical organs involved include
the heart, kidney, peripheral nerve, gastrointestinal tract, respiratory tract, and nearly any
other organ. AL includes former designations of primary amyloidosis and myelomaassociated amyloidosis.
Treatment usually mirrors the management of multiple myeloma (ie, chemotherapy).
Selected patients have received benefit from high-dose melphalan and autologous stemcell transplantation, with reports of prolonged survival in recent studies. Alternative
therapeutic approaches include thalidomide, lenalidomide, iododoxorubicin, etanercept,
and rituximab.[11] Iododoxorubicin, a molecule that binds to and solubilizes amyloid
fibrils, is undergoing clinical study. For more information, see Amyloidosis,
Immunoglobulin-Related.

Heavy chain amyloidosis

In a few cases, immunoglobulin chain amyloidosis fibrils contain only heavy chain
sequences rather than light chain sequences, and the disease is termed heavy chain
amyloidosis (AH) rather than AL. Electron microscopy may be helpful in the detection of
small deposits and in the differentiation of amyloid from other types of renal fibrillar
deposits.[12] For more information, see Amyloidosis, Immunoglobulin-Related.

Transthyretin amyloidosis
The precursor protein is the normal- or mutant-sequence TTR, a transport protein
synthesized in the liver and choroid plexus. TTR is a tetramer of 4 identical subunits of
127 amino acids each. Normal-sequence TTR forms amyloid deposits in the cardiac
ventricles of elderly people (ie, >70 y); this disease was also termed senile cardiac
amyloidosis. The prevalence of TTR cardiac amyloidosis increases progressively with
age, affecting 25% or more of persons older than 90 years. Normal-sequence ATTR can
be an incidental autopsy finding or can cause clinical symptoms (eg, heart failure,
arrhythmias).
Point mutations in TTR increase the tendency of TTR to form amyloid. Amyloidogenic
TTR mutations are inherited as an autosomal-dominant disease with variable penetrance.
More than 100 amyloidogenic TTR mutations are known.[13] The most prevalent TTR
mutations include TTR Val30Met (common in Portugal, Japan, and Sweden), and TTR
Val122Ile (carried by 3.9% of African Americans). Amyloidogenic TTR mutations cause
deposits primarily in the peripheral nerves, heart, gastrointestinal tract, and vitreous.

Mutant-sequence amyloidogenic TTR is treated with liver transplantation or supportive

care. Liver transplantation should be performed in Val30Met-positive patients as early as
possible.[13] For normal-sequence amyloidogenic TTR, the treatment is supportive care.
For details, see Amyloidosis, Transthyretin-Related.

Beta2 -microglobulin amyloidosis

The precursor protein is a normal beta2 -microglobulin (2 M), which is the light chain
component of the major histocompatibility complex. In the clinical setting, 2 M is
associated with dialysis and, rarely, renal failure in the absence of dialysis. 2 M is
normally catabolized in the kidney.
In patients with renal failure, the protein accumulates in the serum. Conventional dialysis
membranes do not remove 2 M; therefore, serum levels in patients on hemodialysis can
vault to 30-60 times the reference range. Traut et al (2007) reported that patients using
polyamide high-flux membranes had lower 2 M concentrations than patients on low-flux
dialyzers.[14] They postulated that the difference was mediated by an increase in 2 M
mRNA, lower concentrations of 2 M released from the blood cells, and/or better 2 M
clearance in patients treated with high-flux dialyzers.[14]
Musculoskeletal involvement is common and is characterized by deposits in the carpal
ligaments, synovium, and bone, resulting in carpal tunnel syndrome, destructive
arthropathy, bone cysts, and fractures. Other organs involved include the heart,
gastrointestinal tract, liver, lungs, prostate, adrenals, and tongue.
Treatment includes renal transplantation, which may arrest amyloid progression. For
details, see Amyloidosis, Beta2M (Dialysis-Related).

Cryopyrin-associated periodic syndromeassociated amyloidosis

Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and
neonatal-onset multisystem inflammatory disease (NOMID) are all types of CAPS.
These disorders are typically associated with heterozygous mutations in the NLRP3
(CIAS1) gene, which encodes the cryopyrin (NALP3) protein, and are inherited in an
autosomal-dominant manner.[15] The inflammation in CAPS is driven by excessive release
of IL-1.[16] IL-1 release is normally regulated by an intracellular protein complex known
as the inflammasome, which maps to a gene sequence called NLRP3. Mutations in
NLRP3 may cause an aberrant cryopyrin protein inside the inflammasome, leading to the
release of too much IL-1 and subsequent multisystem inflammation.
Patients with CAPS have chronically elevated levels of acute-phase reactants, especially
serum amyloid A (SAA) and high-sensitivity C-reactive protein (hsCRP), due to
increased IL-1 levels.[17, 18, 19] With elevated SAA combined with multisystem cytokine
dysregulation, multisystemic amyloid deposition can be severe, with the most feared

complication including renal failure. By blocking the action of IL-1 or down-regulating

its production, inflammation and therefore amyloid deposition can be reduced.[20]
In a recent randomized double-blind CAPS therapy trial, a novel soluble decoy receptor
called rilonacept was shown to provide rapid and profound symptom improvement in
addition to measures of inflammation such as hsCRP and SAA levels.[20] In the second
part of the study, continued treatment with rilonacept maintained improvements, and
discontinuation worsened disease activity.[20]

Muckle-Wells syndrome
MWS is another autoinflammatory syndrome secondary to a mutation in CIAS gene
encoding cryopyrin, a component of the inflammasome that regulates the processing of
IL-1. The IL-1 receptor antagonist anakinra has been shown to improve the signs and
symptoms in MWS by decreasing serum CRP and SAA levels and cytokines such as IL6, IL-8, IL-12, and IL-1. In some cases, it improved sensory deafness, as well as the
laboratory values for markers of inflammation MWS.[21]

Hereditary Renal Amyloidoses

Hereditary amyloidoses encompass a group of conditions that each are related to
mutations in a specific protein. The most common form is TTR amyloidosis (usually
neuropathic), but nonneuropathic amyloidoses likely result from abnormalities in
lysozyme, fibrinogen, alpha-chain, or apolipoprotein A-I and A-II.[22] Consider these
diseases when a renal biopsy demonstrates amyloid deposition and when they are likely
diagnoses (rather than AL or AA) because the family history suggests an autosomaldominant disease. Again, the definitive diagnosis is made using immunohistologic
staining of the biopsy material with antibodies specific for the candidate amyloid
precursor proteins. A clinical correlation is required to diagnose amyloid types, even if a
hereditary form is detected by amyloid protein typing.[23] For details, see Amyloidosis,
Familial Renal.
Apolipoprotein AI amyloidosis (apoAI) is an autosomal-dominant amyloidosis caused by
point mutations in the apoAI gene. Usually, this amyloidosis is a prominent renal amyloid
but can also form in many locations. ApoAI (likely of normal sequence) is the fibril
precursor in localized amyloid plaques in the aortae of elderly people. ApoAI can
manifest either as a nonhereditary form with wild-type protein deposits in atherosclerotic
plaques or as a hereditary form due to germline mutations in the apoA1 gene.[24]
Currently, more than 50 apoAI variants are known, and 13 are associated with
amyloidosis.[24] As more gene locations are found, the clinical phenotypes are slowly
being elucidated.
Fibrinogen amyloidosis (AFib) is an autosomal-dominant amyloidosis caused by point
mutations in the fibrinogen alpha chain gene. If DNA sequences indicate a mutant
amyloid precursor protein, protein analysis of the deposits must provide the definitive
evidence in laboratories with sophisticated methods.[23]

Lysozyme amyloidosis (ALys) is an autosomal-dominant amyloidosis caused by point

mutations in the lysozyme gene.
Apolipoprotein AII amyloidosis (AapoAII) is an autosomal-dominant amyloidosis caused
by point mutations in the apoAII gene. The 2 kindreds described with this disorder have
each carried a point mutation in the stop codon, leading to production of an abnormally
long protein.

Central Nervous System Amyloidoses and Other Localized

Amyloidoses
Central Nervous System Amyloidoses
Beta protein amyloid
The amyloid beta precursor protein (AbPP), which is a transmembrane glycoprotein, is
the precursor protein in beta protein amyloid (Ab). Three distinct clinical settings are as
follows:
1. Alzheimer disease has a normal-sequence protein, except in some cases of
familial Alzheimer disease, in which mutant beta protein is inherited in an
autosomal-dominant manner.
2. Down syndrome has a normal-sequence protein that forms amyloids in most
patients by the fifth decade of life.
3. Hereditary cerebral hemorrhage with amyloidosis (HCHWA), Dutch type, is
inherited in an autosomal-dominant manner. The beta protein contains a point
mutation. These patients typically present with cerebral hemorrhage followed by
dementia.
The accumulation of amyloid- peptide (A) in the brain, both in the form of plaques in
the cerebral cortex and in blood vessels as cerebral amyloid angiopathy (CAA), causes
progressive cognitive decline. Recently, experimental models and human clinical trials
have shown that accumulation of A plaques can be reversed by immunotherapy. A
immunization results in solubilization of plaque A42, which, at least in part, exits the
brain via the perivascular pathway, causing a transient increase in the severity of CAA.
The extent to which these vascular alterations following A immunization in Alzheimer
disease are reflected in changes in cognitive function remains to be determined.[25]
Prion protein amyloidosis
The precursor protein in prion protein amyloidosis (APrP) is a prion protein, which is a
plasma membrane glycoprotein. The etiology is either infectious (ie, kuru, transmissible
spongiform encephalitis [TSE]) or genetic (ie, Creutzfeldt-Jakob disease [CJD],
Gerstmann-Strussler-Scheinker [GSS] syndrome, fatal familial insomnia [FFI]). The
infectious prion protein is a homologous protein encoded by a host chromosomal gene
that induces a conformational change in a native protease-sensitive protein, increasing the

content of beta-pleated sheets. The accumulation of these beta-pleated sheets renders the
protein protease-resistant and therefore amyloidogenic.[26] Patients with TSE, CJD, GSS,
and FFI carry autosomal-dominant amyloidogenic mutations in the prion protein gene;
therefore, the amyloidosis forms even in the absence of an infectious trigger.
Similar infectious animal disorders include scrapie in sheep and goats and bovine
spongiform encephalitis (ie, mad cow disease).
Cystatin C amyloidosis
The precursor protein in cystatin C amyloidosis (ACys) is cystatin C, which is a cysteine
protease inhibitor that contains a point mutation. This condition is clinically termed
HCHWA, Icelandic type.
ACys is autosomal dominant. The clinical presentation includes multiple strokes and
mental status changes beginning in the second or third decade of life. Many patients die
by age 40 years. This disease is documented in a 7-generation pedigree in northwest
Iceland. The pathogenesis is one of mutant cystatin that is widely distributed in tissues,
but fibrils form only in the cerebral vessels; therefore, local conditions must play a role in
fibril formation.
Nonamyloid beta cerebral amyloidosis (chromosome 13 dementias)
Two syndromes (British and Danish familial dementia) that share many aspects of
clinical Alzheimer disease have been identified. Findings include the presence of
neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid
angiopathy, and amyloid-associated proteins. Both conditions have been linked to
specific mutations on chromosome 13; they cause abnormally long protein products
(ABri and ADan) that ultimately result in different amyloid fibrils.

Other Localized Amyloidoses

Gelsolin amyloidosis
The precursor protein in gelsolin amyloidosis (AGel) is the actin-modulating protein
gelsolin. Amyloid fibrils include a gelsolin fragment that contains a point mutation. Two
amyloidogenic gelsolin mutations are described. One example is Asp187Asn, which is
endemic in southeast Finland.
Clinical characteristics include slowly progressive cranial neuropathies, distal peripheral
neuropathy, and lattice corneal dystrophy.
Atrial natriuretic factor amyloidosis
The precursor protein is atrial natriuretic factor (ANF), a hormone that controls salt and
water homeostasis; it is synthesized by the cardiac atria. Amyloid deposits are localized

to the cardiac atria. This condition is highly prevalent in elderly people and is of
generally little clinical significance. Atrial natriuretic factor amyloidosis (AANF) is most
common in patients with long-standing congestive heart failure, presumably because of
persistent ANF production. No relation exists to the amyloidoses that involve the cardiac
ventricles (ie, AL, ATTR).
Keratoepithelin amyloidosis and lactoferrin amyloidosis
Point mutations occur in a gene termed BIGH3, which encodes keratoepithelin and leads
to autosomal-dominant corneal dystrophies characterized by the accumulation of corneal
amyloid. Some BIGH3 mutations cause amyloid deposits, and others cause nonfibrillar
corneal deposits. Another protein, lactoferrin, is also reported as the major fibril protein
in familial subepithelial corneal amyloidosis. The relationship between keratoepithelin
and lactoferrin in familial corneal amyloidosis is not yet clear.
Calcitonin amyloid
In calcitonin amyloid (ACal), the precursor protein is calcitonin, a calcium regulatory
hormone synthesized by the thyroid. Patients with medullary carcinoma of the thyroid
may develop localized amyloid deposition in the tumors, consisting of normal-sequence
procalcitonin (ACal). The presumed pathogenesis is increased local calcitonin
production, leading to a sufficiently high local concentration of the peptide and causing
polymerization and fibril formation.
Islet amyloid polypeptide amyloidosis
In islet amyloid polypeptide amyloidosis (AIAPP), the precursor protein is an islet
amyloid polypeptide (IAPP), also known as amylin. IAPP is a protein secreted by the
islet beta cells that are stored with insulin in the secretory granules and released in
concert with insulin. Normally, IAPP modulates insulin activity in skeletal muscle. IAPP
amyloid is found in insulinomas and in the pancreas of many patients with diabetes
mellitus type 2.
Prolactin amyloid
In prolactin amyloid (Apro), prolactin or prolactin fragments are found in the pituitary
amyloid. This condition is often observed in elderly people and has also been reported in
an amyloidoma in a patient with a prolactin-producing pituitary tumor.
Keratin amyloid
Some forms of cutaneous amyloid react with antikeratin antibodies. The identity of the
fibrils is not chemically confirmed in keratin amyloid (Aker).
Medin amyloid

Aortic medial amyloid occurs in most people older than 60 years. Medin amyloid
(AMed) is derived from a proteolytic fragment of lactadherin, a glycoprotein expressed
by mammary epithelium.

Nonfibrillar Components of Amyloid

All types of amyloid deposits contain not only the major fibrillar component (solubility in
water, buffers of low ionic strength) but also nonfibrillar components that are soluble in
conventional ionic strength buffers. The role of the minor components in amyloid
deposition is not clear. These components do not appear to be absolutely required for
fibril formation, but they may enhance fibril formation or stabilize formed fibrils.
The nonfibrillar components, contained in all types of amyloid, include the following:

Pentagonal component
o Pentagonal (P) component comprises approximately 5% of the total
protein in amyloid deposits. This component is derived from the
circulating SAP component, which behaves as an acute-phase reactant.
The P component is one of the pentraxin group of proteins, with homology
to C-reactive protein. In experimental animals, amyloid deposition is
slowed without the P component.
o Radiolabeled material homes to amyloid deposits; therefore, this
component can be used in amyloid scans to localize and quantify
amyloidosis and to monitor therapy response. Radiolabeled P component
scanning has proven clinically useful in England, where the technology
was developed, but it is available in only a few centers worldwide.
Apolipoprotein E
o ApoE is found in all types of amyloid deposits.
o One allele, ApoE4, increases the risk for beta protein deposition, which is
associated with Alzheimer disease. ApoE4 as a risk factor for other forms
of amyloidosis is controversial.
o The role of apoE in amyloid formation is not known.
Glycosaminoglycans
o GAGs are heteropolysaccharides composed of long unbranched
polysaccharides that contain a repeating disaccharide unit. These
proteoglycans are basement membrane components intimately associated
with all types of tissue amyloid deposits. Amyloidotic organs contain
increased amounts of GAGs, which may be tightly bound to amyloid
fibrils. Heparan sulfate and dermatan sulfate are the GAGs most often
associated with amyloidosis.
o Heparan sulfate and dermatan sulfate have an unknown role in
amyloidogenesis. Studies of AA and AL amyloid have shown marked
restriction of the heterogeneity of the GAG chains, suggesting that
particular subclasses of heparan and dermatan sulfates are involved.

Compounds that bind to heparan sulfate proteoglycans (eg, anionic

sulfonates) decrease fibril deposition in murine models of AA and have
been suggested as potential therapeutic agents.
Other components found in some types of amyloid include complement
components, proteases, and membrane constituents.
o

Mechanisms of Amyloid Formation

Amyloid protein structures
In all forms of amyloidosis, the cell secretes the precursor protein in a soluble form that
becomes insoluble at some tissue site, compromising organ function. All the amyloid
precursor proteins are relatively small (ie, molecular weights 4000-25,000) and do not
share any amino acid sequence homology. The secondary protein structures of most
soluble precursor proteins (except for SAA and chromosomal prion protein [Prpc]) have
substantial beta pleated sheet structure, while extensive beta sheet structure occurs in all
of the deposited fibrils.
In some cases, hereditary abnormalities (primarily point mutations) in the precursor
proteins are always present (eg, lysozyme, fibrinogen, cystatin C, gelsolin). In other
cases, fibrils form from normal-sequence molecules (eg, AL, 2 M). In other cases,
normal-sequence proteins can form amyloid, but mutations underlying inflammatory
milieu accelerate the process (eg, TTR, beta protein precursor, CAPS).

Deposition location
In localized amyloidoses, the deposits form close to the precursor synthesis site; however,
in systemic amyloidoses, the deposits may form either locally or at a distance from the
precursor-producing cells. Amyloid deposits primarily are extracellular, but reports exist
of fibrillar structures within macrophages and plasma cells.

Proteolysis and protein fragments

In some types of amyloidosis (eg, always in AA, often in AL, ATTR), the amyloid
precursors undergo proteolysis, which may enhance folding into an amyloidogenic
structural intermediate. Also, some of the amyloidoses may have a normal proteolytic
process that is disturbed, yielding a high concentration of an amyloidogenic intermediate.
For example, it was shown that the mast cells of allergic responses may also participate in
the development of secondary or amyloid AA in chronic inflammatory conditions. Mast
cells hasten the partial degradation of the SAA protein that can produce highly
amyloidogenic N-terminal fragments of SAA.[27] However, factors that lead to different
organ tropisms for the different amyloidoses are still largely unknown.
Whether the proteolysis occurs before or after tissue deposition is unclear in patients in
whom protein fragments are observed in tissue deposits. In some types of amyloid (eg,
AL, A, ATTR), nonfibrillar forms of the same molecules can accumulate before fibril

formation; thus, nonfibrillar deposits, in some cases, may represent intermediate

deposition.

Approach To Diagnosing Amyloidosis

Pathologic diagnosis (Congo red staining and
immunohistochemistry)
Immunocytochemical studies for amyloid should include stains for Congo Red apple
green birefringence, hematoxylin and eosin staining (H&E) stains for amorphous
material, kappa and lambda light chains, beta-amyloid A4 protein, TTR, beta 2microglobulin, cystatin C, gelsolin, and immunoreactivity with antiamyloid AA antibody.
[28]

Amyloidosis is diagnosed when Congo redbinding material is demonstrated in a biopsy

specimen. Because different types of amyloidosis require different approaches to
treatment, determining only that a patient has a diagnosis of amyloidosis is no longer
adequate. A clinical situation may suggest the type of amyloidosis, but the diagnosis
generally must be confirmed by immunostaining a biopsy specimen. Antibodies against
the major amyloid fibril precursors are commercially available. For example, AL, ATTR,
and A2 M can present as carpal tunnel syndrome or gastrointestinal amyloidosis, but
each has a different etiology and requires a different treatment approach.
Similarly, determining whether the amyloid is of the AL or ATTR type is often difficult in
patients with cardiac amyloidosis because the clinical picture is usually similar. Without
immunostaining to identify the type of deposited protein, an incorrect diagnosis can lead
to ineffective and, perhaps, harmful treatment. Be wary of drawing diagnostic
conclusions from indirect tests (eg, monoclonal serum proteins) because the results of
these presumptive diagnostic tests can be misleading; for example, monoclonal serum
immunoglobulins are common in patients older than 70 years, but the most common form
of cardiac amyloidosis is derived from TTR.

Diagnosis by subcutaneous fat aspiration

For many years, rectal biopsy was the first procedure of choice. An important clinical
advance was the recognition that the capillaries in the subcutaneous fat are often involved
in patients with systemic amyloidosis and can often provide sufficient tissue for the
diagnosis of amyloid, immunostaining, and, in some cases, amino acid sequence analysis;
thus, biopsy of the organ with the most severe clinical involvement is often unnecessary.
For example, in cardiac amyloidosis, the definitive diagnosis of the type of amyloid can
be made using an endomyocardial biopsy specimen, with Congo red and immunologic
staining of the tissue sample. Alternatively, when noninvasive testing suggests cardiac
amyloidosis, a specific diagnosis is often made by studying a subcutaneous fat aspiration
instead of endomyocardial biopsy, thereby avoiding an invasive procedure.

Organ biopsies
When the subcutaneous fat aspiration biopsy does not provide information to reach a firm
diagnosis, biopsy samples can be collected from other organs. In addition, an advantage
to performing a biopsy of an involved organ (eg, kidney, heart) is that it definitively
establishes a cause-and-effect relationship between the organ dysfunction and amyloid
deposition.
It is important to recognize that not all biopsy sites offer the same sensitivity. The best
sites to biopsy are the abdominal fat pad and rectal mucosa (approaching 90% sensitivity
for fat pad and 73%-84% for rectal mucosa).[29] Other sites that are often sampled but
have poor sensitivity for the diagnosis of amyloid include the salivary glands, skin,
tongue, gingiva, stomach, and bone marrow.

Amyloid Arthropathy
RA and other autoimmune diseases (juvenile RA, spondyloarthropathies,
autoinflammatory syndromes) can predispose to the deposition of amyloid fibrils.[30]
Amyloidosis is actually a common cause of death in patients with ankylosing spondylitis.
Amyloid deposition in inflammatory syndromes is amplified by the underlying
inflammatory state, significantly increasing morbidity and mortality, especially in the
case of renal amyloidosis.[31] However, autopsy study shows that amyloid arthropathy in
RA is often undiagnosed in patients with long-standing severe RA.[32]
Amyloid arthropathy is typically seen in the shoulders, knees, wrists, and elbows,
especially because these joints are more easily aspirated to make tissue available for
Congo Red and immunostaining. Amyloid arthropathy can actually mimic classic RA but
usually lacks the intense distal synovitis and affects the hips and shoulder more than
peripheral joints.[29] Synovial fluid found to contain amyloid fibrils, although not
particularly inflammatory, with white blood cell counts on average less than 2000/L,
contains marked synovial villi hypertrophy. The classic "shoulder-pad" sign denotes endstage amyloid deposits in the shoulder synovium and periarticular structures.
Another articular structure commonly affected by amyloid deposition is the carpal tunnel.
Carpal tunnel syndrome can be the presenting of sign of primary or secondary forms of
amyloid, as only minimal deposits are required to impair nerve conduction. The diagnosis
can be made with biopsy at the time of carpal tunnel release surgery or other joint
procedures. In a pathology review of 124 patients undergoing carpal tunnel release
without the previous diagnosis or clinical signs of amyloidosis, 82% had amyloid
deposition. At 10-year follow up, only two patients had systemic amyloidosis diagnosed
after amyloid was discovered in their tenosynovium.[33]
Radiography can show irregularly shaped hyperlucencies, subchondral cysts, and
erosions that correspond with low intensity signals on both T1 and T2 MRIs.[34]
Ultrasonographic investigations may also show lucencies, soft-tissue changes, increased
thickness of tendons, and joint effusions with echogenic zones.[35]

Up to 5% of patients with long-standing RA can develop systemic amyloidosis that

usually presents as nephrotic syndrome.[29] Genetic studies can predict certain haplotypes
that can increase the risk of developing amyloidosis 7-fold.[31] This increasing
understanding of haplotypes and proteomics will hopefully lead to more specific
therapies.[36]
Interestingly, with the advent of newer, more effective therapies for inflammatory
arthritis, the incidence of amyloidosis secondary to RA and other rheumatic conditions
has recently decreased from 5% to less than 1%.[29]
NEW TOPIC

Primary Systemic Amyloidosis

Author: Judit Nyirady, MD, MBA; Chief Editor: Dirk M Elston, MD

Updated: Oct 11, 2012 Background

Systemic amyloidosis can be classified as follows: (1) primary systemic amyloidosis
(PSA), usually with no evidence of preceding or coexisting disease, paraproteinemia, or
plasma-cell dyscrasia; (2) amyloidosis associated with multiple myeloma; or (3)
secondary systemic amyloidosis with evidence of coexisting previous chronic
inflammatory or infectious conditions.
Primary systemic amyloidosis involves mainly mesenchymal elements, and cutaneous
findings are observed in 30-40% of patients. Secondary systemic amyloidosis does not
involve the skin, whereas localized amyloidosis does.
Primary systemic amyloidosis involves the deposition of insoluble monoclonal
immunoglobulin (Ig) light (L) chains or L-chain fragments in various tissues, including
smooth and striated muscles, connective tissues, blood vessel walls, and peripheral
nerves.[1] The amyloid of primary systemic amyloidosis is made by plasma cells in the
bone marrow. These L-chains are secreted into the serum. Unlike the normal L-chain and
the usual form seen in patients with myeloma, these L-chains are unique in that they
undergo partial lysosomal proteolysis within macrophages, and they are extracellularly
deposited as insoluble amyloid filaments attached to a polysaccharide. Sometimes,
instead of an intact L-chain, this amyloid has the amino-terminal fragment of an L-chain.
In 1838, Mathias Schleiden (a German botanist) coined the term amyloid to describe the
normal amylaceous constituent of plants. In 1854, Rudolf Virchow used the term
amyloid. Virchow described its reaction with iodine and sulfuric acid, which, at the time,
was a marker for starch; thus, the term amyloid or starchlike is used. Virchow adopted the
term to describe abnormal extracellular material that is seen in the liver during autopsy.

Some 70 years after Virchow's description, Divry and associates recognized that the
amyloid deposits showed apple-green birefringence when specimens stained with Congo
red were viewed under polarized light. This observation remains the sine qua non of the
diagnosis of amyloidosis.[2]
In 1959, with the use of electron microscopy, Cohen and Calkins first recognized that all
forms of amyloidosis demonstrated a nonbranching fibrillar structure. Electron
microscopy remains the most sensitive method for recognizing the disorder.[3]

Pathophysiology
The final pathway in the development of amyloidosis is the production of amyloid fibrils
in the extracellular matrix. The process by which precursor proteins produce fibrils
appears to be multifactorial and differs among the various types of amyloidosis.
The fibrils in primary systemic amyloidosis are composed of Ig L-chain material (protein
amyloid L) consisting of intact L-chains, L-chain fragments (particularly the variable
amino-terminal region), or both. Amyloid deposition occurs as a result of plasma-cell
dyscrasia.
The diagnosis depends on the demonstration of amyloid deposits in tissue. The organs
most commonly involved are the kidneys or heart, either individually or together.[4]
Autonomic and sensory neuropathies are relatively common features.
About 30-40% of patients with primary systemic amyloidosis have cutaneous findings.
Mucocutaneous involvement provides early evidence of the existence of an underlying
plasma-cell dyscrasia. Petechiae, purpura, and ecchymoses that occur spontaneously or
after minor trauma are the most common skin signs and are found in about 15-20% of
patients.[5] The most characteristic skin lesions consist of papules, nodules, and plaques
that are waxy, smooth, and shiny.[6] Scalp involvement may be evident with hair loss.
Mucocutaneous changes in the oral cavity include localized rubbery papules, petechiae,
and ecchymoses. Xerostomia may result from the infiltration of the salivary glands.
Macroglossia is reported in 19% of patients with primary systemic amyloidosis.
Primary systemic amyloidosis accounts for 7% of nonhematological malignancies,[7] but
few cases of gastric carcinoma in patients with primary amyloidosis have been described.
Although acute pseudoobstruction is an uncommon clinical manifestation of amyloidosis,
the coexistence of both gastrointestinal hemorrhage and pseudoobstruction of the small
intestine should alert the clinician to a diagnosis of gastrointestinal amyloidosis.

Epidemiology
Frequency

United States
Precisely defining the epidemiologic characteristics of amyloidosis is difficult because
the disease is often undiagnosed or misdiagnosed. The age-adjusted incidence of primary
systemic amyloidosis and secondary systemic amyloidosis is estimated to be 5.1-12.8
cases per million person-years, which means that approximately 1275-3200 new cases
occur annually in the United States. In a large series of 236 cases of systemic
amyloidosis, Kyle and Bayrd reported that 56% were primary cases and 26% were
multiple myeloma cases.[8]

Mortality/Morbidity
In the report by Skinner et al, the overall survival of all patients was 8.4 months from
their entry into the study. In the group receiving only colchicine and the group treated
with melphalan, prednisone, and colchicine, the survival was 6.7 and 12.2 months,
respectively (P = .087). The cardiac subgroup of both treatment groups had poor survival,
and the renal subgroup had the longest survival.[9]
In another trial, Kyle and Greipp reported the effectiveness of combined melphalan and
prednisone therapy compared with placebo therapy.[10] The overall survival rates for the 2
groups were not substantially different, although the nephrotic syndrome improved in a
number of individuals receiving the active medications.
In a prospective observational study involving 206 consecutive patients with biopsyproven systemic light-chain amyloidosis, Buss et al found that reduced left ventricular
longitudinal function independently predicted survival and offered incremental
prognostic information beyond that offered by standard clinical and serological
parameters.[11]

Race
No racial predilection is reported for the development of primary systemic amyloidosis.

Sex
No sexual predilection is reported for primary systemic amyloidosis; however, Kyle and
Greipp reported a slight male dominance in a large series of 182 patients with primary
systemic amyloidosis.[10]

Age
Primary systemic amyloidosis is a disease of adulthood. In reported cases, the mean
patient age of onset is 65 years.

History
The symptoms of a patient with primary systemic amyloidosis (PSA) are rarely helpful in
making the diagnosis because they are often too nonspecific. Therefore, the diagnosis is
often delayed.
Presenting symptoms include the following:

Fatigue
Weight loss
Paresthesias
Hoarseness
Edema

Classically, patients present with symptoms of the following:

Carpal tunnel syndrome

Macroglossia
Mucocutaneous lesions
Hepatomegaly
Edema

The organs most commonly involved are the kidneys or heart, either individually or
together. The patients' symptoms reflect the organ or organs most prominently involved.

Physical
Clinically evident mucocutaneous involvement occurs in 30-40% of patients with
primary systemic amyloidosis, and it provides an early clue to the existence of an
underlying plasma-cell dyscrasia.
Petechiae and ecchymoses are the most common skin findings, because of cutaneous
blood vessel involvement.
The face is most commonly affected; minor trauma sometimes precipitates eyelid and
periorbital purpura (pinch purpura or raccoon eyes sign). Purpuric lesions are found in
flexural regions such as the nasolabial folds, neck, and axillae.
At times, bullae form; these may be hemorrhagic.

The most characteristic skin lesion in primary systemic amyloidosis consists of waxy
papules, nodules, or plaques that may be evident in the eyelids, retroauricular region,
neck, or inguinal and anogenital regions. Plaques may coalesce to form large tumefactive
lesions.
Diffuse infiltrates may resemble infiltrates of scleroderma or myxedema.
Scalp involvement may appear as diffuse or patchy alopecia.[12]
Dystrophic nail changes include brittleness, crumbling, and subungual striation.
The tongue may be infiltrated, resulting in macroglossia. Macroglossia is a classic feature
of primary systemic amyloidosis. The tongue may extrude through gaps between the teeth
to produce unique irregular indentations. The presence of amyloid in the oral cavity is
often revealed by localized, soft, elastic papules.[13, 14]
Amyloid deposition in the smooth and striated muscles, connective tissue, blood vessel
walls, and peripheral nerves may result in myocardial insufficiency, which is the most
common cause of death in this fatal disease.
Cardiac infiltration may cause angina, infarction, arrhythmias, or orthostatic hypotension.
Blood vessel infiltration may lead to claudication of the legs or jaw.
Renal amyloidosis usually manifests as proteinuria, often resulting in nephrotic
syndrome.
Edema is frequently found and may be the result of cardiac failure or nephrotic
syndrome.
Amyloid infiltration of the gastrointestinal tract may result in hemorrhage or
malabsorption. Gut bleeding may also be fatal.
Hepatomegaly occurs in about 50% of patients with primary systemic amyloidosis, but
splenomegaly is present in less than 10% of patients.
Autonomic and sensory neuropathies are relatively common features. Autonomic
neuropathy may result in symptomatic postural hypotension, impotence, and disturbances
in gastrointestinal motility.
Summers and Kendrick reported and association with CREST syndrome (ie, calcinosis,
Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia
syndrome).[15]
Villa et al reported on amyloid goiter.[16]

Causes
Primary systemic amyloidosis is a plasma-cell dyscrasia characterized by an autonomous
proliferation of plasma cells with an overproduction of a monoclonal Ig protein.

Differential Diagnoses

Amyloidosis, Lichen
Amyloidosis, Macular
Amyloidosis, Nodular Localized Cutaneous
Cutis Verticis Gyrata
Mastocytosis
Pseudoxanthoma Elasticum
Scleredema
Sebaceous Hyperplasia
Xanthomas

Laboratory Studies
In a review of 132 primary systemic amyloidosis cases, Kyle and Bayrd reported that
laboratory studies revealed anemia in less than 50% of the cases.[8] The white cell count
was usually within the reference range, and the erythrocyte sedimentation rate was higher
than 50 mm/h in one half of the cases. Hepatic function was abnormal, and the serum
creatinine level was increased in 50% of patients. Proteinuria was present in more than
90% of the cases.
Conventional urine heat testing and electrophoresis of serum and urine samples may fail
to demonstrate small quantities of monoclonal paraprotein or Bence-Jones protein.
Immunoelectrophoresis of serum and concentrated urine samples is essential.

Imaging Studies
Echocardiography is valuable in the evaluation of amyloid heart disease. It usually
reveals a concentrically thickened left ventricle and often a thickened right ventricle, with
a normal-to-small cavity.
Doppler studies are useful and may show abnormal relaxation early in the course of the
disease. Advanced involvement is characterized by restrictive hemodynamics.

Procedures
Biopsy of a cutaneous lesion, if present, has the advantage of safety and a high diagnostic
yield.
Biopsy results in clinically normal skin may be positive in as many as 50% of cases of
primary systemic amyloidosis.

Findings from abdominal fat aspiration are positive in almost 80% of patients.
Rectal biopsy reveals positive findings in about 80% of patients.
If specimens from the biopsy sites are negative for amyloid, tissue should be obtained
from an organ or area with suspected involvement, such as the kidney, liver, heart, or
sural nerve.

Histologic Findings
The best way to identify amyloid is to stain paraffin-embedded sections with alkaline
Congo red and to examine them with polarized light to elicit a green fluorescence.
Routine hematoxylin-eosin staining may show a homogenous, faintly eosinophilic mass
if enough amyloid is present. See the image below.

Amorphous eosinophilic interstitial amyloid observed on a

renal biopsy.
Analysis of a skin biopsy specimen of a papule reveals an amorphous or fissured
eosinophilic mass in the papillary dermis with associated thinning or obliteration of the
rete ridges. Nodules and plaques may demonstrate diffuse amyloid deposition in the
reticular dermis or subcutis. Amyloid depositions are usually not associated with an
inflammatory infiltrate.
The appearance of amyloid infiltration of the blood vessel walls, pilosebaceous units,
arrector pili muscles, and lamina propria of sweat glands and infiltration around
individual fat cells in the subcutis (known as amyloid rings) are characteristic findings.
Amyloid may be deposited in the nail bed of dystrophic nails.

Medical Care
The treatment of primary systemic amyloidosis (PSA) is directed toward the affected
organ and the specific type of the disease. In studies of different regimens of intermittent
oral melphalan and prednisone, Skinner et al and Kyle et al reported that the response
rates were low, with an increased survival from a median of approximately 7-9 months in
patients who did not receive chemotherapy to approximately 12-18 months in those
receiving chemotherapy.[9, 18]

Shimojima et al reported a patient with primary systemic amyloidosis who achieved

partial hematological response after 2 courses of the VAD (vincristine, doxorubicin
[Adriamycin], and dexamethasone) chemotherapy regimen and subsequent high-dose
melphalan followed by autologous peripheral blood stem cell transplantation despite
involvement of multiple organs, including the heart.[19] When amyloidosis-related
dysfunction is seen in multiple organs, intensive chemotherapy might be a possible
therapeutic option, although several modifications in the regimen and careful
management are necessary.
The nephrotic syndrome requires supportive therapy and diuretics, and renal failure can
be successfully treated with dialysis.
Congestive heart failure may respond to diuretics, but larger doses are often required as
the disease progresses. The use of calcium channel blockers, beta-blockers, and digoxin
are contraindicated in cardiac amyloidosis, because they may cause toxicity at therapeutic
levels.
Gastrointestinal involvement and neuropathy are treated symptomatically.

Medication Summary
The treatment of primary systemic amyloidosis is often unsatisfactory. No reliable
method for the accurate assessment of the total amount of amyloid in the body exists.
Investigations are limited to the evaluation of organ function and the measurement of
monoclonal protein levels in the serum and urine.
The similarity between primary systemic amyloidosis and multiple myeloma suggests
that chemotherapy may be useful. Using different regimens of intermittent oral melphalan
and prednisone, 2 groups of investigators[9, 18] confirmed the effectiveness of this therapy
compared with no therapy or therapy with colchicine alone. However, the response rate
was low, with an increased survival from a median of approximately 7-9 months in
patients who did not receive chemotherapy to approximately 12-18 months in those
receiving chemotherapy.
In another trial, Kyle and Greipp reported the effectiveness of combined melphalan and
prednisone therapy compared with placebo therapy.[20] Although the nephrotic syndrome
improved in a number of individuals receiving the active medications, overall survival
rates for the active and placebo groups were not substantially different.
Colchicine has also been used in the treatment of primary systemic amyloidosis.
Colchicine may inhibit amyloid deposition by blocking the formation of amyloidenhancing factors, and it also inhibits the secretion of amyloid from hepatocytes.
Based on encouraging results in myeloma patients, Dispenzieri et al reported results of a
clinical trial of lenalidomide therapy with or without dexamethasone in patients with
primary systemic amyloidosis.[21] As a single agent, lenalidomide had modest activity in

primary systemic amyloidosis. This activity was significantly enhanced when

lenalidomide was used in conjunction with dexamethasone.

Immunosuppressants
Class Summary
These agents inhibit key factors in the immune system that are responsible for
inflammatory responses.
View full drug information

Prednisone (Deltasone, Orasone, Meticorten)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation
by reversing increased capillary permeability and suppressing PMN activity. Stabilizes
lysosomal membranes and suppresses lymphocytes and antibody production.
View full drug information

Dexamethasone (Decadron)
Has many pharmacologic benefits but significant adverse effects. Stabilizes cell and
lysosomal membranes, increases surfactant synthesis, increases serum vitamin A
concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha,
IL-6, IL-2, and IFN-gamma). The inhibition of chemotactic factors and factors that
increase capillary permeability inhibits recruitment of inflammatory cells into affected
areas. Suppresses lymphocyte proliferation through direct cytolysis and inhibits mitosis.
Breaks down granulocyte aggregates, and improves pulmonary microcirculation.
Important chemotherapeutic agent in the treatment of ALL. Used in induction and
reinduction therapy and given as intermittent pulses during continuation therapy.
Adverse effects are hyperglycemia, hypertension, weight loss, GI bleeding or perforation
synthesis, cerebral palsy, adrenal suppression, and death. Most of the adverse effects of
corticosteroids are dose or duration dependent.
Readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are
excreted via the kidneys. Lacks salt-retaining property of hydrocortisone.
Patients can be switched from an IV to PO regimen in a 1:1 ratio.

Antineoplastic agents
Class Summary
These agents inhibit cell growth and proliferation.
View full drug information

Melphalan (Alkeran)
Inhibits mitosis by cross-linking DNA strands.

Uricosuric agents
Class Summary
These agents may inhibit the events involved in the inflammatory response associated
with the disease.
View full drug information

Colchicine
Decreases leukocyte motility and phagocytosis in inflammatory responses.

Immunomodulators
View full drug information

Lenalidomide (Revlimid)
Structurally similar to thalidomide. Elicits immunomodulatory and antiangiogenic
properties. Inhibits proinflammatory cytokine secretion and increases anti-inflammatory
cytokines from peripheral blood mononuclear cells.

Complications
The presence of diffuse skin infiltrates and the loss of scalp hair can be distressing.
Macroglossia may be associated with painful dysphagia.
Cardiac involvement may cause angina, infarction, arrhythmias, or orthostatic
hypotension.[22, 23]

Congestive heart failure or arrhythmias account for death in about 40% of the cases of
primary systemic amyloidosis.
Blood vessel infiltration may lead to claudication of the legs or jaw.
Amyloid infiltration of the gastrointestinal tract may result in hemorrhage that can cause
malabsorption or even death.[24]

Prognosis
The prognosis of primary systemic amyloidosis is generally poor.
Cardiac failure and renal failure are the major causes of death.
The median survival in most reported cases is as long as 14.7 months.
The prognosis depends on the response to therapy and the extent of disease.[25]
The presence of congestive heart failure is associated with a median survival of 7.7
months.
NEW TOPIC

AA (Inflammatory) Amyloidosis

Author: Richa Dhawan, MD; Chief Editor: Herbert S Diamond, MD

Updated: Aug 23, 2011Background

Amyloidosis comprises of a heterogeneous group of diseases in which normally soluble
plasma proteins are deposited in the extracellular space in an abnormal, insoluble,
fibrillar form.
Amyloid A (AA) amyloidosis is the most common form of systemic amyloidosis
worldwide. It is characterized by extracellular tissue deposition of fibrils that are
composed of fragments of serum amyloid A (SAA) protein, a major acute-phase reactant
protein, produced predominantly by hepatocytes. AA amyloidosis occurs in the course of
a chronic inflammatory disease of either infectious or noninfectious etiology, hereditary
periodic fevers, and with certain neoplasms such as Hodgkin disease and renal cell
carcinoma.
In developing countries, the most common instigator of AA amyloidosis is chronic
infection; in industrialized societies, rheumatic diseases, such as rheumatoid arthritis
(RA), are the usual stimuli. The United States is a major exception to this in that

immunoglobulin-related amyloid light chain type (AL) of amyloidosis is more frequent

than AA as the cause of systemic amyloid deposition.
In AA amyloidosis, the kidney, liver, and spleen are the major sites of involvement. It
becomes clinically overt mainly when renal damage occurs, manifesting either as
proteinuria, nephrotic syndrome, or derangement in renal function.
The tissue fibril consists of a 7500-dalton cleavage product of the SAA protein, which is
an acute phase reactant, and like C-reactive protein, is synthesized by hepatocytes under
the transcriptional regulation of cytokines including interleukin (IL)-1, IL-6 and tumor
necrosis factor (TNF).[1] Under the influence of the inflammatory cytokine IL-6, hepatic
transcription of the messenger ribonucleic acid (mRNA) for SAA may increase 1000-fold
when exposed to an inflammatory stimulus.
Intact circulating SAA (molecular weight 12,500 dalton) is complexed with high-density
lipoproteins (HDL). During the course of inflammation, the apolipoprotein SAA
(apoSAA) apparently displaces apolipoprotein A1 (apoA1) from the HDL particles and
facilitates HDL-cholesterol uptake by macrophages.
Several lines of evidence have indicated that the conversion of SAA into amyloid fibrils
occurs through its specific interaction with heparan sulphate, a ubiquitously expressed
glycosaminoglycan component of the extracellular matrix. SAA specifically binds to
heparan sulfate (HS) glycosaminoglycan, a common constituent of all types of amyloid
deposits that has been shown to facilitate conformational transition of a precursor to betapleated sheet structure.[2]
The protein has also been shown to be chemotactic for neutrophils, and it stimulates
degranulation, phagocytosis, and cytokine release in these cells.
Until relatively recently, the erythrocyte sedimentation rate (ESR) and the serum Creactive protein (CRP) level were used to monitor inflammation clinically. Current data
suggest that, under some circumstances, changes in SAA may be a better measure.
Increases in both CRP and SAA have been associated with active atherosclerotic
coronary artery disease and cited as evidence for the inflammatory nature of that disease
process. SAA also has been used to monitor the dissemination of malignancy.
For information on other types of amyloidosis, see the article Amyloidosis, Overview in
eMedicines Rheumatology volume.

Pathophysiology
Chronic or acute, recurrent, substantial elevations of SAA are necessary but not sufficient
for the development of amyloidosis. The median plasma concentration of SAA in healthy
persons is 3 mg/L, but the concentration can increase to more than 2000 mg/L during the
acute-phase response. Many individuals with long-standing inflammatory disease,
although severely compromised by their primary condition, clearly do not develop tissue

amyloid deposition. What determines any patient's risk for the development of this
complication of inflammation is not known. Therapy, genetic factors, and environmental
factors have all been proposed as possible contributors to the response of the primary
disease.

Genes and proteins involved:

Three protein isoforms of SAA are noted (ie, SAA 1, 2, 4). Each isoform is encoded by
its own gene in a cluster on band 11p15.1 that also includes a pseudogene (SAA3P).
SAA1 has 3 alleles (SAA1.1, SAA1.3, SAA1.5), defined by amino acid substitutions at
positions 52 and 57 of the molecule.[3]
The frequency of these alleles varies between populations and may be associated with the
occurrence of AA amyloidosis in diseases such as rheumatoid arthritis. Also, it may have
a role in determining the level of SAA in blood, clearance, susceptibility to proteolytic
cleavage, severity of disease, and response to treatment. Seventy-six percent of
Caucasians have SAA1.1, whereas only 5% have SAA1.3. In the Japanese population,
the 3 alleles occur at approximately the same rate. Patients with a 1.1/1.1 genotype have a
3-fold to 7-fold increased risk of amyloidosis. But overall, the actual significance of the
SAA genotype remains undefined.[2]
Cellular and extracellular tissue factors :
Mononuclear phagocytes might play a role in degradation of SAA and initiation of
development of AA amyloidosis.
Polymorphisms of the mannose-binding lectin 2(MBL-2) gene leading to decreased levels
of functional MBL have been related to defective macrophage function. This suggests
that genetic background may affect the ability of mononuclear phagocytes to effectively
process and degrade SAA proteins. Additional tissue factors, such as enzymes found in
the extracellular matrix, are likely to be involved in the proteolytic processing of SAA.
Matrix metalloproteinases (MMPs) are involved in generation of SAA N-terminal
fragments. In vitro studies confirmed that human SAAs and AA amyloid fibrils are
susceptible to proteolytic cleavage by MMPs, generating fragments of different sizes.
Studies have demonstrated that susceptibility to MMP-1 degradation is highly dependent
on SAA1 genotype.
The factors responsible for determining the site of deposition in any form of amyloidosis
have not been identified. AA fibrils have been generated in tissue cultures by incubating
SAA with macrophages. Deposits are frequently found in tissues with large numbers of
phagocytic cells, notably the liver and spleen, but other affected organs, such as the
kidneys, do not have the same cellular composition. Some data, derived from analysis of
renal biopsy specimens, have suggested that glycoxidative modification of proteins,
probably the AA protein itself, may also play a role in AA deposition in kidneys.

Epidemiology
Frequency

United States
The absolute prevalence of AA amyloidosis is difficult to ascertain because it depends on
both the occurrence of predisposing inflammatory disorders and the proportion of
individuals with those conditions who develop tissue amyloid deposition. The diseases in
which AA amyloidosis has been reported are noted below, as are the frequencies (when
such data are available). AA amyloidosis is far less common in the United States than in
other countries, even in the setting of the same inflammatory disease. The variation in the
occurrence of amyloid in a particular disease in different geographic locales may reflect
genetic background, differences in treatment of the primary disease, or factors that are not
currently understood.

International
As in the United States, the frequency of AA amyloidosis is determined by the prevalence
of the associated diseases, as well as the incidence of amyloid deposition in those
conditions. For instance, in some Middle Eastern countries, the prevalence of familial
Mediterranean fever (FMF) is higher than anywhere else in the world. The frequency of
renal amyloidosis in some populations with untreated FMF is almost 100%. In those
countries, amyloidosis represents a significant proportion of all renal disease.
Most available data to approximate the epidemiology of AA amyloidosis are derived from
autopsies. The overall autopsy incidence of AA amyloidosis in western nations ranges
from 0.50-0.86%.[4]
Currently, rheumatic diseases such as rheumatoid arthritis (RA), ankylosing spondylitis
(AS), psoriatic arthritis, and juvenile idiopathic arthritis are the most frequent causes
(70%) of AA amyloidosis. The reported prevalence of amyloidosis in RA varies with the
diagnostic procedure used (that is, autopsy, kidney biopsy or subcutaneous fat aspiration),
the clinical status (preclinical or symptomatic disease), and the type of study (case series
or population-based study).
A study from Finland of the autopsy records of 1,666 patients with RA revealed a
prevalence of amyloidosis of 5.8%, while a 10-year study of 1,000 patients with RA
showed that 3.1% died of amyloidosis.
The most common cause of renal involvement in ankylosing spondylitis is AA
amyloidosis (62%), followed by IgA nephropathy (30%). Although its prevalence might
be in decline, renal AA amyloidosis is a serious complication of AS, with a median
survival time after onset of dialysis of 2.37 years, and with a 5-year survival rate of only
30%.

The prevalence of the asymptomatic phase of AA amyloidosis in RA can range between

0.5% and 14%.
Autopsy studies from the Netherlands have suggested a minimal prevalence of
amyloidosis of approximately 1 per 75,000 population. Because 30-40% of amyloidosis
cases in Western Europe is of the AL type, the estimated prevalence of AA amyloidosis is
1 per 100,000 population. Both the duration and severity of the inflammatory disease
correlate with the frequency of amyloidosis as a complication.
The occurrence of multiple alleles encoding the predominant fibril precursor raised the
issue of whether each allele had the same propensity to form amyloid. If an
amyloidogenic allele were more common in a particular population, then the frequency of
amyloidosis in inflammatory disease would be expected to be higher.
Three studies have indicated that a particular inherited form of SAA1 is associated with
an increased frequency of amyloidosis in the course of a single inflammatory disease. In
Japanese people, in whom the SAA 1.5 allele is far more common than in whites (37.4%
vs 5.3%), the 1.5 allele is enriched among patients with RA and amyloidosis. Individuals
with RA and a single 1.5 gene have twice the risk for developing amyloid as those with
no 1.5 alleles. People who are homozygous for the 1.5 allele have a relative risk of 4.48
compared with those with RA who lack any 1.5 alleles. The mechanism of the association
may reside in the fact that the SAA 1.5 allele is associated with higher SAA levels in
Japanese patients. The duration of the inflammatory disease prior to the development of
amyloidosis appeared to be inversely related to the dose of the allele.
In the United Kingdom, heterozygosity or homozygosity for the SAA 1.1 allele is
associated with a greater risk for amyloidosis in whites with juvenile chronic arthritis;
however, in patients with adult RA, the increase was not statistically significant.

Mortality/Morbidity
In some cases, usually of infectious origin, the clinical consequences of amyloid
deposition may dissipate with reduction or disappearance of the tissue deposits if the
inflammatory disease can be suppressed totally or eliminated. If treatment of the primary
disease is unsuccessful, death of organ failure secondary to the amyloid deposition is the
rule. In patients treated at centers in the United States, the United Kingdom, and Europe
from 1956-1992, renal failure or sepsis was the mode of exitus in one half to three
quarters of AA amyloidosis cases, with a median survival of 24-36 months. Series that are
more current show a longer survival, which is based largely on the increased availability
of renal replacement therapy.
The progression of amyloidosis is related to the production and concentration of the
circulating amyloidogenic precursor protein. The concentration of the acute phase protein
SAA during follow-up correlates with deterioration of renal function, amyloid burden,
and mortality in AA amyloidosis.

In a study of 374 patients with AA amyloidosis who were followed for 15 years, the
median survival after diagnosis of amyloidosis in those with a sustained acute phase
response was 133 months. As per this study, the risk of death was 17.7 times as high
among patients with SAA concentrations in the highest eighth, or octile, (155 mg/L) as
among those with concentrations in the lowest octile (< 4 mg/L).
In general, amyloidosis shortened the median life span 7.7 years, and survival strongly
depended on controlling the underlying inflammatory process. Amyloid deposits
regressed in 60% of patients who had a median SAA concentration of less than 10 mg/L,
and survival among these patients was superior to survival among those in whom
amyloid deposits did not regress. Sustained increased concentration of SAA is the most
significant risk factor in AA amyloidosis, whereas reduction of SAA concentration
improves survival and is associated with arrest or even regression of amyloid deposits.[5, 6,
7]

As per the Finnish Registry for Kidney Diseases, 502 patients with amyloidosis were
identified entering RRT from 1987-2002. Eighty percent of these patients had
amyloidosis associated with an underlying rheumatic disease. The 5-year survival rates
among patients with the RA, AS, and juvenile idiopathic arthritis were 18%, 30%, and
27%, respectively.[8]
Cardiac amyloidosis appears to be a predictor of worse outcome with a 5-year survival of
31% versus 63% for patients without cardiac involvement in a retrospective series of 42
patients from Japan.[9]
The degree of renal involvement is important, with patients who have elevated creatinine
levels doing worse compared with patients with a normal creatinine. The pattern of renal
involvement is also important. Specifically, glomerular involvement with amyloid and
fibrosis appear to have clinical course characterized by deteriorating renal function
compared to patients with other types of renal involvement. Generally, however the
median survival is over 5 years.[10]
In a multicentric retrospective survey to assess the graft and patient survival in 59 renal
recipients with AA amyloidosis, the recurrence rate of AA amyloidosis nephropathy was
estimated at 14%. There was significant decrease in the 5-year and 10-year survival of
patients in the AA amyloidosis group compared with the control group. Also, AA
amyloidosis transplanted patients exhibited a high proportion of infectious complications
after transplantation.[11]

Race
Very few appropriately controlled data address the question of racial prevalence of AA
amyloidosis, other than observations suggesting that an increased frequency of AA
amyloidosis occurs in the course of RA, which is related to variation in the distribution of
particularly amyloidogenic SAA1 alleles among different ethnic groups. Within a single
medical center in California, autopsies of patients of similar economic status with

different ethnic origins displayed differences in the frequency of AA amyloidosis. In that

series, AA amyloidosis was more common in Hispanic patients of Mexican origin than in
either whites or African Americans.

Sex
In the United States, AA amyloidosis is more common in females, reflecting the fact that
the major predisposing disease, RA, is predominantly a disorder of younger women and
middle-aged men; hence, women are apt to have the disease for a longer period than men.

Despite the statistical female predominance in terms of overall numbers of AA

amyloidosis cases, males seem to have an earlier average age of onset.
FMF is more common in males than in females (male-to-female ratio, 60:40), but
the frequency of renal amyloidosis in people who are affected appears to be
similar.

Age
The age of onset of amyloidosis is related to the age of onset of the inflammatory disease,
its severity, and the duration of the disease within the constraints imposed by the alleles
of SAA carried by the patient. Thus, in the course of juvenile rheumatoid arthritis (JRA),
amyloidosis occurs in teenagers. When it is a consequence of adult RA, it develops in late
middle age. In the course of inadequately treated FMF, the renal amyloidosis is also of
relatively early onset.

History
The most common presentation of amyloid A (AA) amyloidosis is renal. Renal
involvement is found in as many as 90% of patients. Thus, symptoms reflect the
appearance of proteinuria, progressive development of renal insufficiency, or nephrotic
syndrome.

Weakness, weight loss, and peripheral edema are the most common symptoms.
In patients with active RA, some of these symptoms may be incorrectly attributed
to progression of the inflammatory disease or to adverse effects of drugs. But the
development of proteinuria in patients with RA should always raise the suspicion
of AA amyloidosis.
The amyloid deposits occur in the spleen and liver. However, even a significant
splenic and hepatic load may remain asymptomatic for long periods. Splenic
involvement might be suspected if HowellJolly bodies are found in a peripheral
blood smear of a nonsplenectomized patient, or by frequent episodes of
infections.
Rarely, evidence of bowel involvement dominates the presentation. GI
involvement may lead to motility disorders and pseudo-obstruction. Amyloid
accumulations in the small intestine can cause generalized malabsorption. The

weakened bowel wall can rupture, leading to peritonitis. Blood vessel wall and
tissue amyloid predispose to bleeding.
Again, in patients with inflammatory joint disease, the GI symptoms can also be
secondary to treatment, particularly with nonsteroidal anti-inflammatory drugs.
Goiter has also been reported as a possible feature of symptomatic AA
amyloidosis.
Cardiac AA deposits may be revealed with echocardiography in about 10% of
patients. Clinical evidence of cardiac involvement occurs in as many as 50% of
patients with AL amyloidosis compared with less than 5% with AA amyloidosis.
Amyloid accumulation in the heart may be suggested by by decreased voltage in
the electrocardiogram limb leads, pseudoinfarction pattern in form of Q-waves in
the anterior chest leads, and by thickening of the left ventricular wall
disproportionate to the degree of current or prior hypertension. The hypomotile
and pathological heart wall and failing heart predispose to mural thrombosis and
embolic complications. Such right-sided heart involvement is a major prognostic
determinant in AL amyloidosis, but uncommon in AA amyloidosis. Amyloid in
the conduction pathways can lead to high-grade blocks.[12]
In contrast to AL amyloidosis and other amyloidoses, congestive heart failure,
peripheral neuropathy, or carpal tunnel syndrome occasionally occurs during the
course of AA amyloidosis, but they are rarely, if ever, a presenting manifestation.
In patients with FMF, the history of periodic fever, arthritis, serositis, and the
presence of the same disorder in other family members are characteristic. Some
instances have been reported in which febrile episodes are not apparent, and renal
amyloid is the first manifestation of disease.
In patients with atrial myxoma or renal carcinoma, the appearance of symptoms
consistent with nephrotic syndrome or renal failure due to amyloidosis may be the
first evidence of the primary neoplastic disease.
In general, the appearance of symptoms suggesting renal disease in a patient with
chronic infectious or noninfectious inflammation should raise a warning flag with
respect to the presence of AA amyloidosis as a complication.
Rarely, a more specific symptom, such as abdominal fullness or right upper
quadrant discomfort (reflecting hepatomegaly), might bring the patient to the
physician.

Physical

Patients with amyloid renal disease are commonly hypertensive, although whether
the hypertension is associated with the renal amyloidosis or is a coincidental
finding is not always clear.
Sallow complexion and peripheral edema are the main physical findings in
individuals with either renal failure or nephrotic syndrome.
The purpura and macroglossia observed in AL amyloidosis are not features of AA
amyloidosis, nor is the orthostatic hypotension associated with AL amyloidosis or
the familial amyloidoses, unless gastrointestinal bleeding or other forms of
hypovolemia associated with renal dysfunction are present.
The major physical findings may be those associated with the primary
inflammatory disease, notably deforming arthritis.

The appearance of hepatosplenomegaly in a patient with ongoing inflammation

should prompt investigation for amyloidosis, although some patients with severe
RA develop splenomegaly with subsequent Felty syndrome (splenomegaly and
neutropenia or pancytopenia in the course of RA). These patients with Felty
syndrome generally have normal renal function, although they might have a renal
disease other than AA deposition.

Causes

Chronic infectious diseases, including tuberculosis, leprosy, bronchiectasis,

chronic osteomyelitis, and chronic pyelonephritis, have been associated with AA
amyloidosis. The precise frequencies are difficult to ascertain, but they may be as
high as 10% in some chronic suppurative disorders (eg, osteomyelitis).
The overall incidence in autopsies in western countries is estimated at 0.5-0.86%,
where the most frequent underlying diseases are RA (23-51%), juvenile idiopathic
arthritis (7-48%), and AS (0-12%).[5, 13]
RA is the most common rheumatic cause of AA amyloidosis. However, most
patients with RA do not have development of AA amyloidosis. Prolonged duration
of disease, continuous disease activity, and inadequate treatment are risk factors
for AA amyloidosis. Renal failure due to amyloid deposition usually occurs in the
fifth decade of life. In living patients with RA, the incidence of AA found in
biopsies ranges from 7-29%.
In industrialized countries, chronic noninfectious inflammatory diseases are more
commonly the cause of AA amyloidosis. In RA, the incidence is 5-26%, being
found more often on autopsy than biopsy. The frequency of AA amyloidosis may
be lower in patients treated earlier and more aggressively. Other inflammatory
disorders associated with AA amyloidosis include the following:
o Inflammatory bowel disease (0.4-2%)
o Behet syndrome in Turkey (1-2%)
o Reactive arthritis in adults (0.3%)
o Psoriatic arthritis (3-13%)
The most common cause of renal involvement in ankylosing spondylitis is AA
amyloidosis (62%), followed by IgA nephropathy (30%).[1]
AA amyloidosis is a rare complication of inflammatory bowel disease and occurs
more commonly in Crohn disease and in males. The reason that Crohn disease is
more readily complicated by AA amyloidosis than ulcerative colitis is not known
but may be secondary to greater degree of sustained inflammation in association
with the former and, in particular, the suppurative features of Crohn disease such
as abscesses and fistulae may be risk factors.[14]
Chronic juvenile arthritis seems to be a special case, with a large geographic
variance (7-48%) in the incidence of AA amyloidosis depending on whether the
analysis was performed in the United States (low) or Eastern Europe (high).
In the 1980s, a high frequency of renal AA amyloidosis was observed among
subcutaneous drug abusers in some cities in the United States. Whether this was
related to the drug or to some contaminating substance that elicited chronic
inflammation when injected subcutaneously is not clear.

FMF is characterized by recurrent attacks of fever, arthritis, pleuritis, peritonitis,

or erysipelas like erythema lasting 2448 hours. FMF begins in childhood and
usually affects persons of Mediterranean origin. AA amyloidosis develops in upto
one-quarter of patients with FMF. Renal AA amyloidosis is virtually a universal
complication of FMF in some populations if the patients are not compliant with
colchicine prophylaxis. Other hereditary fever syndromes, such as tumor necrosis
factor receptorassociated periodic syndrome (TRAPS), chronic infantile
neurologic cutaneous articular syndrome (CINCA), Muckle-Wells syndrome, and
hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), may be
complicated by AA amyloidosis.
Among tumors, hypernephroma has been associated with AA amyloidosis. More
recently, Castleman disease (angiofollicular lymph node hyperplasia) has been
recognized as a cause of amyloidosis. Resection of the tumor can lead to the
regression of clinical signs of amyloid nephropathy.[15]
Among other noninfectious chronic inflammatory diseases, AA amyloidosis has
been reported in systemic lupus erythematosus, polymyositis, and polymyalgia
rheumatica and has been observed in temporal artery biopsy samples of such
patients. AA amyloidosis has also been noted in patients with gout, pseudogout,
and some cases of apparently noninflammatory sarcoidosis.
Because SAA production is mediated through inflammatory cytokines, primarily
IL-6, AA deposition has been noted in other disorders associated with increased
IL-6 production. Occasionally, patients with atrial myxomas, renal cell
carcinomas, Hodgkin disease, hairy cell leukemia, and carcinomas of the lung and
stomach have been found to have renal AA amyloidosis, presumably because of
production of the cytokine by the tumor cells. Paradoxically, some patients with
agammaglobulinemia also have developed AA amyloidosis, demonstrating the
dissociation between cytokine production and the synthesis of its normal
downstream effector molecules, immunoglobulins.
Few case reports have described patients with cyclic neutropenia developing AA
amyloidosis.
As many as 6% of patients with AA amyloidosis have no clinically overt
inflammatory disease.

Differential Diagnoses

Amyloidosis, Familial Renal

Amyloidosis, Immunoglobulin-Related
Glomerulonephritis, Membranous
Renal Vein Thrombosis

Laboratory Studies

The overwhelming factor in diagnosing amyloid A (AA) amyloidosis is

considering the possibility that it is present. The development of proteinuria in
any individual with chronic inflammatory disease or any of the associated
conditions listed in Causes should prompt a search for tissue AA deposition, most
commonly in the kidney.

No specific tests for AA amyloidosis exist.

o While the SAA precursor is usually elevated, prolonged elevation does not
necessarily indicate tissue deposition because many patients with
inflammatory disease have very high levels of SAA without developing
amyloidosis.
o Serum immunoglobulins should be evaluated because the presence of a
monoclonal serum or urine protein suggests AL amyloidosis as a more
likely diagnosis.
o Patients with AA amyloidosis tend to show polyclonal
hypergammaglobulinemia, reflecting their underlying inflammatory
condition.
Evaluate the parameters of renal function to monitor the course of the nephrotic
syndrome or renal failure.
o Occasionally, patients show renal tubular acidosis as an early
manifestation of renal involvement.
o Deterioration of a patient with the nephrotic syndrome may indicate
progression of the amyloid renal disease, but consider the possibility of
renal vein thrombosis because this complication can be observed in
nephrotic syndrome due to any cause.
o A serum creatinine level greater than 2 mg/dL and/or a serum albumin
level less than 2.5 g/dL have been associated with diminished survival
rates, including renal survival.

Imaging Studies

Avoid intravenous pyelography in patients with suspected amyloidosis because

dye exposure has been associated with more frequent renal failure in individuals
with substantial proteinuria.
Ultrasonography is useful in establishing renal size; however, kidneys may be
large, small, or normal size in patients with renal amyloidosis.
CT scanning may be useful because technetium occasionally binds to soft-tissue
amyloid deposits. This was originally reported as an incidental finding. However,
CT scanning does not yield great sensitivity, and reports concerning the
specificity of CT scanning have varied considerably. If results are positive, CT
scanning can be used to monitor gross progression of the deposition in a given
organ.
MRI may have a role in amyloidosis diagnosis in the future, but, currently, no
formal studies have reported its use in a large series of patients.
Radiolabeled P-component gamma scanning has been used in centers in London
and France to demonstrate the total body burden of amyloid and its disappearance
after successful treatment of the primary disease. This test has been most useful in
AA amyloidosis because the major sites of deposition, ie, liver, kidneys, spleen,
and adrenal glands, are readily accessible to the imaging agent.

Other Tests

In the 10% of cases of AA amyloidosis in showing cardiac involvement,

conventional parameters of cardiac dysfunction, measured using
electrocardiography, echocardiography, and cardiac catheterization with
endomyocardial biopsy, provide the appropriate diagnostic information and tissue
for the demonstration of AA (or other amyloid) deposition in the myocardium or
coronary vessels.

Procedures
The choice of tissue specimen
For the detection of amyloid, biopsy of a clinically affected organ is the most sensitive
method and may also detect concomitant pathologies. However, such a biopsy is invasive
and carries the risk of complications, in particular bleeding. Thus, if amyloidosis is
clinically suspected, a less invasive procedure may be desirable. In the early 1970s,
Westermark and Stenkvist demonstrated that amyloid can be detected in subcutaneous
fat. During the decades, subcutaneous fat pad biopsy, obtained via fine-needle aspiration,
being safe, cheap, and rapid, has been introduced as a screening test for the detection of
amyloidosis.[16]
The tissue with the highest yield, particularly in the presence of proteinuria or renal
failure, is the kidney. Technically adequate samples have a diagnostic yield close to
100%.
Rectal biopsy is more useful than subcutaneous fat aspiration in AA amyloidosis. It has
been found to produce positive results (assuming that submucosa is included in the
biopsy specimen) in 80-85% of patients ultimately found to have tissue amyloid at a
clinically relevant site. Samples from either the subcutaneous fat aspirate or the rectal
biopsy can be stained as conventional tissue biopsies to determine the presence and
nature of the amyloid precursor. Occasionally, patients have positive results on
subcutaneous fat aspirates in the presence of a negative result on rectal biopsy, while
others may have deposits in the rectal tissue and not in the aspirate. Use of both
procedures may increase the yield to 90%. Abdominal subcutaneous fat biopsy results are
not very sensitive in AA amyloidosis caused by FMF and in dialysis-related amyloidosis.
The results are usually negative, probably because beta2-microglobulin does not
accumulate in this tissue.
Series from individual centers have shown that the labial gland or gastric mucosal
biopsies can also be high-yield procedures, but these have not been used widely for
amyloidosis, and their general utility remains to be definitively established.
In the past, liver biopsy was a common procedure in the investigation of AA amyloidosis.
Several reports of fatal liver rupture or bleeding, as well as the availability of sampling
procedures with little or no morbidity and mortality, have resulted in its decreased use.

Detection of amyloid
Congo red stain continues to be the criterion standard for detection of amyloid deposits.
In AL and AA amyloidosis, Congo red staining of aspirated subcutaneous abdominal fat
has a sensitivity of 70-90% for the diagnosis. Kidney, heart, or liver samples have also
been used for Congo red staining, but biopsy of rectal mucosa, skin, or subcutaneous fat
is often sufficient, except in the cases of FMF, when it is rarely, if ever, positive.
The tissue is stained with an alkaline solution of Congo red, and examined it under
polarized light, where positive (green) birefringence is detectable in the presence of
amyloidosis of any type. The nature of the fibril precursor can be established by
immunohistochemical staining with antibodies specific for the major amyloid precursors
(AA, immunoglobulin L chains of or type, antitransthyretin). In AA amyloidosis, only
the AA is positive. The amyloid nature of the deposit can by confirmed by staining with
an antiserum specific for serum amyloid P-component (SAP).
Once histological diagnosis of amyloidosis has been established, the amyloid type should
be defined based on immunohistochemical analysis and genetic testing. Immunoelectron
microscopy characterizes the amyloid deposits by co-localizing the specific proteins with
the fibrils and can be performed on abdominal fat samples.

Histologic Findings
Infiltrated tissues show homogeneous eosinophilic staining with hematoxylin and eosin.
The earliest deposits are usually vascular. In the kidney, early deposits may be mesangial,
but, late in the course, entire glomeruli may be obliterated. Distinguishing these from
glomerulosclerosis and from other causes is difficult prior to Congo red staining. Congo
red binding by itself may be observed in other states, particularly in collagen-rich tissues,
but the green birefringence is characteristic on examination with polarized light and the
amyloid nature of the deposit can be demonstrated by observing the characteristic beta
pleated sheet on electron microscopy. The nature of the precursor can be established with
certainty using antisera specific for various amyloid precursors. In this case, staining with
anti-AA serum is positive, as described above.

Staging
NMedical Care
At present, the major therapeutic strategy in amyloid A (AA) amyloidosis is treatment of
the primary inflammatory disease in order to reduce the circulating levels of the amyloid
precursor protein SAA. Intensive treatment that lowers SAA levels to less than 10 mg/L
may halt disease progression and induce a slow progressive recovery of renal function.
Accounts exist of the disappearance of the amyloid deposits associated with tuberculosis
or chronically infected burns with appropriate treatment of the infection. Similarly, case
reports exist of the disappearance of amyloid deposition associated with chronic
inflammatory bowel disease after resection of the affected section of bowel.

Data from a randomized prospective series of patients with juvenile chronic arthritis who
were treated with chlorambucil or cyclophosphamide show that the occurrence of
amyloidosis is markedly reduced.[17] The tradeoff for the aggressive use of alkylating
agents is an increased incidence of leukemia.
Treatment with TNF- inhibitors and IL-1 inhibitors has proved effective in controlling
the progression of renal amyloid in patients with inflammatory arthritides and hereditary
periodic fevers. The application of these agents possibly achieve similar therapeutic
effects without the additional risk, thus lowering the incidence of amyloidosis without
increasing mortality.
The rationale for using TNF inhibitors in secondary amyloidosis comes from the fact that
these medications lower serum IL-6, which is an important mediator of the acute phase
inflammatory response. By reducing IL-6, synthesis of acute-phase proteins is reduced,
systemic inflammation suppressed, and SAA levels are lowered leading to reduction of
amyloid deposits.[18]
Biologic agents such a Tocilizumab (anti-IL6 receptor antibody) used in juvenile
idiopathic arthritis, and Infliximab, an anti TNF antibody, have been used to successfully
reduce inflammation and thereby induce SAA reduction in AA amyloidosis.[19]
A case report described combination therapy with steroids, methotrexate and intravenous
hyperalimentation benefiting GI symptoms in a patient with RA and intestinal AA
amyloidosis.[20]
Castelman disease, a rare IL-6 secreting tumor, can sometimes be completely excised. In
those cases where surgery is not feasible or curative, evidence suggests benefit with antiIL-6 therapies.[15]
The use of colchicine (0.6 mg tid) by patients with FMF has been shown to reduce or
eliminate the febrile episodes and to prevent the appearance of renal amyloidosis. The
mechanism of action is not clear, although the elimination of AA deposition is likely
mediated through the suppression of the inflammatory response and SAA production,
rather than having a primary effect on amyloidogenesis.
Based on observations of people with FMF and mice with experimental AA amyloidosis,
individual patients with the nephrotic syndrome secondary to renal AA amyloidosis in the
course of inflammatory bowel disease, ankylosing spondylitis, and psoriatic arthritis were
treated with colchicine and had clinical pictures consistent with the resolution of the
nephrotic syndrome.
Although none of these reports contained follow-up renal biopsies, the clinical
information supports the conclusion; however, many unreported instances in which
colchicine has been used unsuccessfully in similar circumstances also are likely to exist.
The only attempt at a randomized prospective trial of colchicine has been carried out in
AL disease, and it showed no effect on that process.

Anakinra, a recombinant form of IL-1 receptor antagonist, has shown favorable effects on
dermatologic and rheumatic manifestations in patients with MuckleWells syndrome and
familial cold autoinflammatory syndrome. This treatment also resulted in the resolution
of AA amyloidosis in these patients.[21]
The following are new approaches to the treatment of AA amyloidosis that are currently
undergoing clinical trials:

A lowmolecular-weight sulfonated molecule has been developed that interferes

with fibril formation and deposition of amyloid by inhibiting interaction of SAA
with glycosaminoglycans. In experimentally induced murine AA amyloidosis, this
drug (NC-503) has been shown to reduce the amount of amyloid deposits.
Dimerization of human SAP molecules in vivo with a palindromic compound
(CPHPC) triggers very rapid clearance of the complexed protein by the liver,
depleting SAP from the circulation within a few hours of drug administration.
A case report describes severe protein-losing enteropathy with intractable diarrhea
due to systemic AA amyloidosis successfully treated with corticosteroids and
octreotide.[22]
A single patient with AA amyloidosis secondary to Hodgkin disease was
administered 4'-iodo-4'deoxydoxorubicin as antitumor therapy (see the treatment
section in Amyloidosis, Immunoglobulin-Related); this patient has been reported
to show a reduction in proteinuria and the liver amyloid burden on biopsy. The
response was not complete and the resolution on liver biopsy may have been the
result of sampling differentially infiltrated portions of tissue; nonetheless, the
result is potentially exciting.[23]
A more experimentally and theoretically based approach uses the observation that
anionic sulphonates interfere with the deposition of AA fibrils in a murine model
of inflammatory amyloidosis. Little or no toxicity was shown in the preclinical
testing.
The plasma glycoprotein serum amyloid P component (SAP) is a universal
constituent of all types of amyloid plaques, and potentiates the amyloidogenic
process. A study by Bodin and colleagues tested a two-step therapeutic strategy
for amyloidosis that targeted SAP by first pharmacologically depleting circulating
levels of SAP with the bivalent crosslinker CPHPC, and then subsequently
administering anti-human-SAP antibodies. In mice transgenic for human SAP, an
experimental model of systemic AA amyloidosis, this treatment regimen produced
almost complete regression of hepatic and splenic amyloid deposits 4 weeks after
anti-SAP treatment. These strikingly successful results strongly support the
concept that amyloid deposition is reversible, and the initiation of clinical trials in
humans will be of great interest.[24]
Interactions between heparan-sulfate and dermatan-sulfate glycosaminoglycan
(GAG)-containing proteoglycans and the misfolded amyloid precursor protein are
also considered important for amyloidogenesis and the stabilization of amyloid.
This insight has been used in a clinical trial to destabilize amyloid deposits with
eprodisate, a negatively charged, sulfonated GAG analog, which binds to GAGbinding sites of the amyloid fibrils.[25]

Experiments have shown that a number of agents appear to retard AA amyloidosis

in animal models. These include fenofibrate, FK506, and lovastatin, inhibition of
interactions between SAA and the receptor for advanced glycation end-products
(RAGE).[26, 27]
A study demonstrated the efficacy of pegylated INF-alpha once a week in FMF in
the induction of a durable disease remission and the almost complete reversal of
secondary renal AA amyloidosis.[28]
Six percent of the patients in whom the underlying inflammatory disease cannot
be identified are a serious management challenge, and the therapy in these cases
has to be empirical-guided by frequent assays of SAA.
In patients with AA amyloidosis who were treated before 1990, the major cause of
death was renal failure, generally accounting for 35-70% of mortality, with
infection responsible for an additional 10-20%. The mean survival was 2-4 years,
with the degree of renal insufficiency present at the time of diagnosis correlating
with longevity. In a series of patients with AA amyloidosis presenting from 19851999, the median survival was 53 months, and the median renal survival (time
alive and independent of renal replacement) was 18 months.[29] Because of the
increased availability of renal replacement, renal failure was the cause of death in
only 12.5% of people, and infection became dominant (42%). Nonetheless, the
results of dialysis in patients with renal amyloid and an underlying inflammatory
disease are worse than the results in those undergoing dialysis for other chronic
renal diseases.

Surgical Care
Renal transplantation is an option in these patients, with some successes reported;
however, data suggest that patients who have amyloidosis do not have as favorable a
prognosis as patients transplanted for other forms of renal failure. Nonetheless, results
have been improving, and transplantation is a reasonable option, particularly if the
primary inflammatory disease has been treated successfully.

Consultations

Because AA amyloidosis is usually a complication of a primary chronic infectious

or inflammatory disease, consultations with specialists in infectious diseases
concerning antibiotics, surgical resection, and other diagnostic and therapeutic
modalities are appropriate.
o Consult a rheumatologist with regard to newer modes of antiinflammatory treatment before assuming that the patient will inevitably
follow a downhill course.
o Nephrologic and surgical management of the chronic renal failure also
requires a coordinated team approach for an optimal outcome.
o Cardiac complications at the time of transplantation seem to be more
common in patients with amyloidosis than in those with other forms of
renal failure.

Diet
No specific dietary recommendations for patients with amyloid disease exist.

Patients with chronic renal failure should be managed by a nutritionist who has
experience with such patients, maintaining appropriate levels of sodium and
protein intake.
Occasionally, patients have significant gastrointestinal symptomatology, and
attention should be paid to maintaining caloric intake with minimal
gastrointestinal distress.

Activity
Encourage as much activity as the patient can tolerate in order to maintain muscle mass
and a positive outlook.

Medication Summary
No specific therapeutic agents are recommended for the treatment of amyloid A (AA)
amyloidosis. Therapy for the underlying inflammatory disorders should be as aggressive
as possible.

Anti-inflammatory agents
Class Summary
Colchicine is a disaggregator of microtubules, not a member of any of the traditional
categories of anti-inflammatory agents.
View full drug information

Colchicine
Decreases leukocyte motility and phagocytosis in inflammatory responses. Effective in
the treatment of acute gout, pseudogout, and the prophylaxis of acute febrile episodes of
FMF. The latter effect probably is responsible for the reduced frequency of renal
amyloidosis when treatment is adequate.

Further Inpatient Care

Inpatient care may be necessary for intercurrent infections or deterioration in

renal function, requiring acute dialysis or the initiation of chronic dialysis.

Further Outpatient Care

Monitor renal function to assess progress and the ultimate need for dialysis or
transplantation.

Inpatient & Outpatient Medications

Use medications effective in the treatment of the primary inflammatory diseases

to completely suppress the inflammatory process, if possible.
Colchicine may be administered concurrently with these agents, although no
controlled studies indicate that it is effective in amyloid A (AA) amyloidosis,
other than in cases associated with FMF.

Transfer

Diminishing renal function demands management by an experienced

nephrologist, with particular emphasis placed on the need for dialysis and the
availability of transplantation.

Deterrence/Prevention

The use of colchicine prophylaxis in FMF has been previously mentioned, as has
the need for aggressive anti-inflammatory treatment for the predisposing
inflammatory disorders (see Treatment).
The recent introduction of anti-inflammatory biological agents for the treatment
of rheumatologic disorders may decrease the current rate of appearance of tissue
AA deposition.

Complications

The major consequence of renal amyloidosis is complete renal failure. Because it

occurs in the natural course of AA amyloidosis, it may not be considered a
complication but certainly requires aggressive management, with transplantation
or maintenance with dialysis.

Prognosis

The prognosis of the AA amyloidosis, regardless of the prognosis of the primary

disease, has generally been associated with the degree of renal compromise
present at the time of diagnosis, ie, poor prognosis is associated with a serum
creatinine level greater than 2 mg/dL or a serum albumin level of less than 2.5
g/dL. Mean survival is 2-3 years.
More recent studies in which patients had access to renal replacement therapy
suggest improved survival to more than 4 years. In the latter cases, infection was
the major cause of death. With improved aggressive anti-infectious treatment,
further enhanced survival likely is possible, even without specific treatment that
allows resorption of the deposited fibrils or inhibits further deposition.
The idea has been suggested that, even with fibril resorption and no further
deposition, residual tissue damage will persist or fibrillar material will

redistribute, primarily to the kidney. At present, these speculations remain to be

tested.

Patient Education

Inform patients about the natural course of AA amyloidosis and the fact that
aggressive anti-inflammatory management could prevent ultimate organ failure.
Preparing the patient for either renal transplant or dialysis is the major educational
goal. Clearly, the manner in which this is presented depends on the relationship
between the physician and the patient and the physician's assessment of the
patient's emotional needs.

NEW TOPIC

Dialysis-Related Beta-2m Amyloidosis

Author: Anita Basu, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN

Updated: Aug 2, 2012 Background

Beta-2 microglobulin (beta-2m) amyloidosis is a disabling condition that affects patients
undergoing long-term hemodialysis (HD) or continuous ambulatory peritoneal dialysis
(CAPD).[1, 2] Case reports involving patients with near end-stage renal disease also exist.
The condition does not affect individuals with normal or mildly reduced renal function or
patients with a functioning renal transplant. Beta-2m amyloidosis evolves predictably
over time and is rare in the first few years of HD. (See Etiology.)
Beta-2m is a major constituent of amyloid fibrils.[3] It has been shown that, through
accumulation, it invades synovial membranes and osteoarticular sites. As a result, it
causes destructive osteoarthropathies, such as carpal tunnel syndrome, flexor
tenosynovitis, subchondral bone cysts, and erosions, as well as pathologic fractures. (See
Etiology, Prognosis, and Presentation.)
Visceral involvement has been found in different organs, such as the gastrointestinal (GI)
tract, heart, and tongue, but overt manifestations are rare. (See Presentation and Workup.)

Complications
The most severe complication involves beta-2m amyloid deposits destroying
paravertebral ligaments and intervertebral discs, which can result in paraplegia. Cardiac
involvement, with subsequent fatal arrhythmias, and massive GI bleeding have been
described. (See Prognosis, Presentation, Treatment, and Medication.)

Etiology
Beta-2m is a glycosylated polypeptide with a molecular weight of 11,800 dalton. It makes
up the beta chain of the human leukocyte antigen (HLA) class I molecule and has the
prominent beta-pleated structure that is characteristic of amyloid fibrils.
Beta-2m is present on the surface of most nucleated cells and in most biologic fluids,
including urine and synovial fluid. It circulates as an unbound monomer distributed in the
extracellular space and polymerizes to form amyloid deposits in a variety of tissues. Two
or 3 conformational isomers of beta-2m are recognized in human serum by capillary
electrophoresis.[4]
In the normally functioning kidney, beta-2m is cleared by glomerular filtration and is
catabolized in the proximal tubules. Reference range serum levels are 1.5-3 mg/L. In
renal failure, impaired renal catabolism causes an increase in synthesis and release of
beta-2m, and levels can rise 10- to 60-fold. Retention and accumulation of this type of
amyloid protein is presumed to be the main pathogenic process underlying beta-2m
amyloidosis.
There is also some suggestion that the dialysis process itself may stimulate beta-2m
synthesis, by activation of complements and cytokine production. However, it is unlikely
that this is a significant mechanism of dialysis-related amyloidosis (DRA), since the
disease is also seen in patients on CAPD and people who have never been on dialysis.

Role of dialysis in amyloidogenesis

Retention of amyloidogenic protein remains a key factor in patients on dialysis. Several
factors affecting retention have been implicated, including the following:

Type of dialysis membrane

Prolonged uremic state and/or decreased diuresis
Elevated levels of cytokines
Advanced glycation end products
Dialysate

Type of dialysis membrane

The healthy kidney can eliminate endogenous end products of metabolism, as well as
exogenous toxins that are both large and small molecular weight substances. Cuprophan
and cellulose acetate membranes previously used in conventional HD have small pores
and cannot clear substances with molecular weights higher than 200 dalton. This makes
them impermeable to beta-2m, elevating the proteins serum levels. The newer cellulose
triacetate dialyzers and the high-flux synthetic dialyzers remove molecules with a higher
molecular weight and do a better job of removing beta-2m.

High cut-off, high-flux dialysis and online hemodiafiltration have been shown to be
superior to previously used HD membranes in the removal of beta-2m, possibly
decreasing beta-2 amyloidosis.
Beta-2m amyloidosis has also been described in patients receiving long-term CAPD,
despite the permeability characteristics of the peritoneal membrane. Clearance of middle
molecules is better, however, making CAPD a more biocompatible mode of treatment.
Nonetheless, data are conflicting. Some report the prevalence of beta-2m amyloidosis in
patients on long-term CAPD as comparable to the prevalence in patients on HD. Other
data show that plasma levels of beta-2m are lower in patients on CAPD, suggesting that
accumulation of amyloid may occur more slowly. Some of this may also be related to
residual renal function. Results of long-term studies are needed.
Prolonged uremic state and/or decreased diuresis
Membranes with poor biocompatibility cannot completely explain increases in beta-2m,
because several reports note individuals who were treated exclusively by CAPD. Cases
have also been described in patients with chronic renal failure who have not yet started
dialysis. Inadequate diuresis and prolonged uremia are suggested contributing factors.
Elevated levels of cytokines
Dialysis is an inflammatory stimulus, inducing cytokine production and complement
activation. The released cytokines, including interleukin 1 (IL-1), tumor necrosis factoralpha (TNF-alpha), and interleukin 6 (IL-6), are thought to stimulate the synthesis and
release of beta-2m by macrophages and/or augment the expression of HLA class I
antigens, increasing beta-2m expression.
Advanced glycation end products
Following the identification of advanced glycation end products (AGEs) in beta-2m
amyloid deposits, the role of AGE has been the focus of much research.[5]
AGEs make up a heterogeneous group of compounds formed by nonenzymatic glycation
and oxidative reactions between reducing sugars, lipids, and protein amino groups.
HD and peritoneal dialysis are ineffective in removing these lowmolecular weight
compounds from circulation.
As AGE-modified beta-2m accumulates, chemotaxis is enhanced, stimulating
macrophages to release proinflammatory cytokines, as well as interfering with collagen
synthesis. It has been suggested that the interaction of AGE-modified beta-2m with
mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory
arthropathy of DRA, is mediated by the receptor for AGEs, or RAGE.

RAGEs are central binding sites for AGEs formed in vivo.[6] AGE beta-2m/MP/RAGE
interaction likely contributes to the initiation of an inflammatory response in amyloid
deposits of patients on long-term HD. This inflammatory response may ultimately lead to
bone and joint destruction.
Oxidation of beta-2m may enhance amyloid deposition. Studies suggest that increased
oxidative stress during HD and exposure of beta-2m to hydroxyl radicals stimulate the
autoxidation of unstable molecules, leading to augmented AGE production.
Dialysate
Acetate and/or bacterial lipopolysaccharide (endotoxin) may enter the blood via the
dialyzer and stimulate the release of cytokines, inducing beta-2m production.

Epidemiology
The incidence of DRA in the United States is not known; however, past studies have
suggested an incidence of greater than 95% in patients who have been on dialysis for
more than 15 years.
Some European studies have suggested that DRA can be seen in as many as 20% of
patients after 2-4 years of HD and in 100% after 13 years of HD. Again, however, the
overall incidence and prevalence of beta-2m amyloidosis are not clear. Moreover, most
studies have focused on HD-associated amyloidosis and were performed before high-flux
dialyzer use became commonplace.
There is some mention in the literature that the incidence and prevalence of beta-2m
amyloidosis are less in CAPD than in HD (because of residual renal function). Other
studies, however, suggest that there is no significant difference in incidence or
prevalence.

Prognosis
The prognosis of beta-2m amyloidosis depends on the duration of dialysis, the age of the
patient, the age of the patient at the start of dialysis, and the type of dialysis membrane
that is being used. Ultimately, residual renal function is probably the best determinant of
beta-2m levels in HD patients and may supersede enhanced convective clearance by
hemodiafiltration.[7]

Morbidity and mortality

Patients receiving long-term dialysis can experience disabling musculoskeletal
complications.[8] For individuals who are able to undergo renal transplantation,
progression of the disease can be halted, but regression is unlikely. Rarely, submucosal
bowel deposits have resulted in massive GI bleeding.

Case reports also exist of severe pulmonary hypertension and heart failure due to beta-2m
amyloid deposits in the interstitium and/or vasculature of the cardiovascular system.
Studies in Japan have suggested that most patients with carpal tunnel syndrome
associated with beta-2m amyloid deposits have undergone HD for 10 years or more. In
one study, up to 50% of patients developed this complication after 20 years, and the
percentage was even higher after 25 years.

History
Clinical manifestations of beta-2m amyloidosis almost never appear before a patient has
undergone 5 years of dialysis therapy. Unlike other types of amyloids, beta-2m amyloid is
confined largely to osteoarticular sites.[9]
Patients often present with a characteristic triad of carpal tunnel syndrome, shoulder pain,
and flexor tenosynovitis in the hands. The rate of surgery for osteoarticular disorders,
such as carpal tunnel syndrome, destructive spondyloarthropathy (DSA), and joint
arthropathy, which may show the presence of DRA, is very high.[10]
Visceral deposits are rare, occur after 10 or more years of dialysis, and tend not to cause
symptoms in most cases.

Osteoarticular manifestations

Osteoarticular manifestations can include the following:

Carpal tunnel syndrome
Flexor tenosynovitis
Scapulohumeral arthropathy
Spondyloarthropathy
Lytic bone lesions
Bone cysts
Pathologic fractures - Caused by amyloid deposition within joints, intervertebral
discs, and tendon sheaths[9]
Musculoskeletal deformities

Carpal tunnel syndrome

This syndrome is the most common presenting feature. It usually is bilateral and
progressive.[11] Patients report numbness, paresthesias, pain, and swelling in the region of
the distal median nerve. Pain usually is worse during dialysis and at night. Progression to
contraction of the hand and atrophy of the muscles can occur. However, it is important to
remember that not all cases of carpal tunnel syndrome in dialysis patients are amyloid
related; the syndrome may arise from other causes, such as ischemia.
Flexor tenosynovitis

This disorder is often referred to as trigger finger or trigger thumb. Patients can flex the
finger, but with reextension, the patient may feel a painful snap that refers to the dorsum
of the hand.
Scapulohumeral arthropathy
Amyloid may deposit in and around the rotator cuff, resulting in shoulder pain that
becomes worse when the patient is in the supine position. Patients often report difficulty
dressing.
Spondyloarthropathy
The cervical spine is most often affected, and patients often present with neck and back
pain. DSA is a major cause of hospital admissions in long-term dialysis patients,
especially in patients who have undergone dialysis for 30 years or more.
Bone cysts
Thin-walled bone cysts are common and are most frequently found in the carpal bones.
They are also observed in the femoral heads, humerus, patella, acetabulum, and spine.
Patients may experience stiffness and/or pain over the affected area.
Fractures can develop in bones weakened by bone cysts. The femoral neck is most
commonly involved. Patients may experience a sudden onset of leg pain while walking.

Systemic manifestations
Systemic manifestations are rare, and patients with systemic involvement generally are
asymptomatic. Most individuals with systemic manifestations have undergone dialysis
for longer than 10-15 years.
If systemic involvement does occur, small, localized deposits are observed around blood
vessels and in the mucosa of the GI tract, heart, lungs, and genitourinary tract. In rare
cases, fatal GI hemorrhages, cardiac arrhythmias, and renal vein thromboses have
occurred.
GI involvement
Macroglossia, dysphagia, small bowel ischemia, malabsorption, and pseudo-obstruction
can occur because of subepithelial, submucosal, and blood vessel amyloid deposits.[12]
Cardiovascular involvement
Myocardial, pericardial, and cardiac valves may be involved. Beta-2m amyloid deposits
have also been identified in small pulmonary arteries and veins.

Genitourinary tract involvement

Renal and bladder calculi containing beta-2m deposits and causing obstruction have been
described. Beta-2m amyloid has also been identified in the prostate and the female
reproductive tract.

Physical Examination
Systemic involvement is rare in beta-2m amyloidosis. Osteoarticular involvement can
include the following:

Carpal tunnel syndrome - Patients experience weakness and atrophy of the thenar
muscle, along with decreased strength in abduction, opposition, and flexion of the
thumb
Flexor tenosynovitis - Amyloid deposits may result in prominence of the tendons
of the hands on extension; patients often experience decreased digital mobility
and soft-tissue swelling over flexor tendon sheaths
Scapulohumeral arthropathy - Deposits in and around the rotator cuff may cause
soft-tissue thickening around the shoulder, referred to as the shoulder pad sign;
the patient's capacity to abduct or internally rotate the arm is limited
Spondyloarthropathy - Paravertebral ligaments and intervertebral discs may be
destroyed or dislocated, resulting in spinal cord impingement or paraplegia; the
cervical spine is most often affected, and patients often present with neck and
back pain
Bone cysts - Cysts grow in size and number in the wrist, humeral head, hip, and
patella; as cysts enlarge, soft-tissue swelling and swollen joints, with subsequent
spontaneous tendon rupture and pathologic fracture, may occur (cysts do not
regress with renal transplantation)

Diagnostic Considerations
Secondary hyperparathyroidism
Secondary hyperparathyroidism is the most common bone disease found in patients with
end-stage renal disease. Bone erosions, tendon ruptures, and osteosclerosis can be the
source of bone pain or polyarthralgias.
Renal osteodystrophy
DRA bone lesions differ from renal osteodystrophy in that in DRA, the presence of the
amyloid deposits interferes with normal bone-tissue dynamics, while in renal
osteodystrophy, the abnormality is in the underlying metabolic process itself, causing
bone turnover to be either increased or decreased.
In the case of pathologic fractures in patients on dialysis, it is essential that DRA be
distinguished from renal osteodystrophy, because there are implications for healing.

Aluminum overload
Patients with end-stage renal disease sometimes receive aluminum-containing antacids to
control serum phosphate levels. Absorbed aluminum can be toxic to osteoblasts, leading
to the development of osteomalacia.
Dupuytren contracture
Dupuytren contracture is a type of palmar fasciitis observed in people with chronic
alcoholism or chronic diabetes.
Other forms of amyloidosis
Types of amyloidosis to consider in the differential diagnosis of beta-2m amyloidosis
include the following:

Familial renal amyloidosis

Immunoglobulin-related amyloidosis
Transthyretin-related amyloidosis

Approach Considerations
The diagnosis of beta-2m amyloidosis is established primarily by its clinical appearance
on tissue or bone biopsy.
Obtaining a biopsy of the affected bone or synovium, followed by routine hematoxylin
and eosin staining, reveals homogeneous eosinophilic material. Amyloid deposits are
positive for Congo red staining, showing green birefringence of the amyloid fibrils under
polarized light. Specific immunostaining of amyloid deposits by monoclonal anti beta2m antibody confirms the diagnosis of beta-2m amyloidosis.
Antisera to amyloid beta-2m are taken up by the Congo redpositive areas, but are not
taken up in other types of amyloidosis.

Blood tests
The reference range of the serum concentration of beta-2m is 1.5-3 mg/L, while in
amyloidosis, serum levels can be elevated to values of 50-100 mg/L. Beta-2m levels
correlate with elevated serum creatinine levels and are inversely related to the glomerular
filtration rate. Hematologic findings frequently reveal a normochromic, normocytic
anemia.

Electron microscopy
Typically, 8-10 nm wide, nonbranching, curvilinear fibrils are observed in beta-2m
amyloidosis.

Imaging Studies
Radiography
Radiologic lesions typically present prior to the onset of pain. Joint erosions (usually
involving large joints), lytic and cystic bone lesions (typically juxta-articular), pathologic
fractures (most commonly involving the femoral head), spondyloarthropathies (usually
involving the cervical area), and vertebral compression fractures may be observed.
However, conventional radiography may underestimate the extent of the disease.[13]

CT scanning
Computed tomography (CT) scans reveal amyloid deposits of intermediate attenuation.
CT scans can also be used to identify pseudotumors and pseudocystic areas in the juxtaarticular bone. Moreover, CT scanning is the best method for detecting small areas of
osteolysis in cortical bone or osseous erosion, and it may be helpful in the assessment of
the distribution and extent of destructive changes.[13]

MRI
Magnetic resonance imaging (MRI) shows characteristic long T1 and short T2 relaxation
times, resulting in low to intermediate signal intensity. MRI is helpful in differentiating
destructive spondyloarthropathies from inflammatory processes and infections. In
evaluating amyloidosis, MRI may provide considerably more information than that
obtained from conventional radiographic, CT scan, and sonographic studies.[13]

Ultrasonography
Ultrasonography is useful in the detection of tendon thickness. Rotator cuff thickness
greater than 8mm, thickening of joint capsules (especially of the hip and knee), and
retention of synovial fluid may be observed.

Scintigraphy
Scintigraphy in the diagnosis of beta-2m amyloidosis employs radiolabeled P-component
scans, including iodine-123 (123 I) serum amyloid P, iodohippurate sodium (131 I) beta-2m,
and the more natural111 I beta-2m.
The cells surrounding the amyloid deposit take up the circulating tracer, making
scintigraphy a useful means of evaluating the total body burden of amyloid. This method
has primarily been used in Europe and is not available in North America for diagnosing
beta-2m amyloidosis.

Biopsy
The criterion standard for diagnosis is histologic identification using Congo red and
immunohistochemical staining of biopsy specimens or centrifuged synovial fluid
sediments. Puncture biopsies are obtained from cystic bone lesions and intra-articularly in
synovia. In contrast to other types of amyloidosis, rectal biopsy and subcutaneous fat
aspiration are of little value in diagnosing beta-2m amyloidosis. The most common site
from which biopsies are obtained is the sternoclavicular joint.

Approach Considerations
At present, no adequate treatment of beta-2m amyloidosis exists. Medical therapy is
limited to symptomatic approaches to ameliorating joint pain and inflammation.
Conservative treatment includes physical and occupational therapy. Wrist splints, cervical
collars, lumbar corsets, knee braces, and immobilization for spondyloarthropathies often
are helpful.
The treatment of joint pain includes the use of nonsteroidal anti-inflammatory drugs
(NSAIDs), intra-articular injections of prednisolone, 10% hydrocortisone cream, and, in
severe cases, low-dose oral prednisone.

Surgery
Surgical interventionincluding carpal tunnel release with surgical decompression of the
median nerve or release of the transverse carpal ligaments under endoscopic
visualization, flexor tenosynovectomy or percutaneous first annular pulley release, spinal
stabilization or laminectomy, or total joint replacementmay be effective in alleviating
pain and restoring function.
Unfortunately, orthopedic interventions have high failure rates in DRA compared with
rates in the general population. If, during the course of a surgery, beta-2m amyloidosis is
suspected, then a biopsy should be performed at that time.

Consultations
Involve rheumatologic, surgical, and transplant consultants early.

Follow-up
A nephrologist should care for patients with beta-2m amyloidosis on an ongoing basis.

Renal Transplantation
Renal transplantation is the treatment of choice for beta-2m amyloidosis. It lowers the
blood concentration of beta-2m to the reference range, halting the progression of the
disease.

Osteoarticular symptoms, such as joint pain, swelling, and stiffness, disappear within the
first week after transplantation. Cystic lesions usually remain unchanged, and regression
of amyloid deposits probably does not occur.
Transplantation is not an option for all patients. Some patients on long-term dialysis will
have undergone unsuccessful renal transplantation before they first developed beta-2m
amyloidosis; in certain other cases, patients are not suitable candidates.

Prevention
Although preventive measures are hard to assess, possible ways of preventing, or at least
decreasing, the incidence of DRA are the use of a high-flux dialyzer, online
hemodiafiltration,[14] ultrapure dialysate,[15] and adsorbent columns.[16]
Based on guidelines from the Disease Outcomes Quality Initiative (DOQI), there are no
indications for the routine monitoring of beta-2m.[17]

High-flux dialyzers
High-flux biocompatible polyacrylonitrile and polysulfone membranes have increased
middle molecule removal and have thereby enhanced beta-2m removal during HD and
hemofiltration.

Online hemodiafiltration
Online hemodiafiltration has been associated with maximal removal of beta-2m.[14]

Ultrapure dialysate preparations

The use of ultrapure, sterile, and apyrogenic dialysate may aid in decreasing stimulation
and in releasing cytokines. It also may decrease plasma levels of acute-phase proteins.[15]

Direct hemoperfusion-type adsorption column (Lixelle)

This was developed to selectively eliminate beta-2m from the circulating blood of
patients with DRA. Lixelle treatments reduce the circulating levels of beta-2m and
inflammatory cytokines, thereby improving the symptoms of patients with DRA. While
this therapy has been used and studied in Japan, it is not currently employed in the United
States.[16, 18]

Laser therapy
Studies examining the use of laser-beam irradiation to destroy amyloid fibrils of beta-2m
fragments have been performed in Japan. This technique has implications for the
prevention of amyloid fibril deposition and for the destruction of preformed amyloid
deposits.[19]

Medication Summary
No medical treatment presently exists to reverse or alter the course of beta-2 amyloidosis.
Low-dose steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are symptomatic
approaches to ameliorating joint pain and inflammation. Medications used include the
following:

Prednisone - Immunosuppressive agent

Triamcinolone - Immunosuppressive agent
Capsaicin topical -Topical analgesic
Ibuprofen -NSAID
Sulindac NSAID

Immunosuppressants
Class Summary
Used to suppress the inflammatory process.
View full drug information

Prednisone
Prednisone may decrease inflammation by reversing increased capillary permeability and
suppressing polymorphonuclear (PMN) leukocyte activity. It is used only in severe cases
of joint pain and immobility.
View full drug information

Triamcinolone (Aristospan)
Triamcinolone decreases inflammation by suppressing the migration of PMN leukocytes
and reducing capillary permeability. The drug decreases autoimmune reactions, possibly
by suppressing key components of the immune system.

Analgesics, Topical
Class Summary
Topical analgesics penetrate deep for temporary relief of minor, arthritis-associated aches
and pains of muscles and joints.
View full drug information

Capsaicin topical (Capzasin-P, Salonpas-Hot, Zostrix)

Capsaicin is derived from plants of the Solanaceae family. It may render skin and joints
insensitive to pain by depleting substance P in peripheral sensory neurons.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Class Summary
These agents have analgesic, anti-inflammatory properties and antipyretic activities.
Their mechanism of action is not known but may inhibit cyclo-oxygenase activity and
prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of
leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil
aggregation, and various cell membrane functions.
View full drug information

Ibuprofen (Advil, Ultraprin, I-Prin, Motrin IB)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits
inflammatory reactions and pain by decreasing prostaglandin synthesis.
View full drug information

Sulindac (Clinoril)
Sulindac decreases the activity of cyclo-oxygenase and, in turn, inhibits prostaglandin
synthesis. Its action results in the decreased formation of inflammatory mediators.
View full drug information

Naproxen (Anaprox, Aleve, Naprosyn, Naprelan)

Naproxen is used for the relief of mild to moderate pain. It inhibits inflammatory
reactions and pain by decreasing the activity of the enzyme cyclo-oxygenase (COX),
which results in prostaglandin synthesis.
View full drug information

Meloxicam (Mobic)

Meloxicam decreases COX activity, and this, in turn, inhibits prostaglandin synthesis.
These effects decrease the formation of inflammatory mediators.
View full drug information

Ketoprofen
Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages
are indicated initially in small patients, elderly patients, and patients with renal or liver
disease. Doses higher than 75 mg do not increase the therapeutic effects. Administer high
doses with caution, and closely observe the patient's response.
View full drug information

Flurbiprofen
Flurbiprofen may inhibit COX, thereby, in turn, inhibiting prostaglandin biosynthesis.
These effects may result in analgesic, antipyretic, and anti-inflammatory activities.