REVIEWS

Pathophysiology and treatment of systemic

amyloidosis
Julian D. Gillmore and Philip N. Hawkins
Abstract | Amyloid is an abnormal extracellular fibrillar protein deposit in the tissues. In humans, more than 25
different proteins can adopt a fibrillar conformation in vivo that results in the pathognomonic tinctorial property
of amyloid (that is, green birefringence when an affected tissue specimen is stained with Congo red dye and
viewed by microscopy under cross‑polarized light). Amyloid deposition is associated with disturbance of organ
function and causes a wide variety of clinical syndromes that are classified according to the respective fibril
protein precursor. Systemic amyloidosis, in which amyloid deposits are widespread and typically accumulate
gradually, continues to be fatal and is responsible for about one in 1,500 deaths per year in the UK. Advances
in our understanding of the pathogenesis of systemic amyloidosis have resulted in the identification of new
therapeutic targets, and several drugs with novel mechanisms of action are currently under development.
Meanwhile, an increased awareness of amyloidosis coupled with enhancements to existing diagnostic
techniques and therapeutic strategies have already resulted in better outcomes for patients with the disease.

Gillmore, J. D. & Hawkins, P. N. Nat. Rev. Nephrol. advance online publication 27 August 2013; doi:10.1038/nrneph.2013.171

Introduction
Amyloidosis is a generic term for a group of diseases fold. The misfolded protein or peptide then assembles
that are caused by the misfolding and extracellular accu- with like proteins or peptides in a highly ordered fashion
mulation of various proteins. These misfolded proteins to form fibrils that accumulate in the interstitial space.2
form fibrillar deposits that produce pathognomonic The deposition of amyloid ultimately results in tissue
green birefringence when stained with Congo red dye damage and organ dysfunction (Figure 1).
and viewed under cross-polarized light using micros- The propensity for proteins to form amyloid fibrils
copy.1 The process of amyloid formation and deposition in vivo can be enhanced by several factors: a patho-
causes progressive organ dysfunction. Amyloidosis is logic and sustained increase in the concentration of
remarkably diverse and can be hereditary or acquired, the protein (for example, acute phase reactant serum
localized or systemic, and lethal or an incidental finding. amyloid A protein [SAA] in chronic inflammatory
So far, 27 different human proteins with amyloidogenic diseases and β2-microglobulin in end-stage renal
potential in vivo have been identified; ~15 of these pro- disease [ESRD]); the presence of an inherently un­stable
teins cause systemic amyloidosis.1 The classification of amyloido­genic protein with an increased propensity
amyloid is based on the fibril protein, and the various for misfolding and aggregation (for example, acquired
amyloidogenic proteins give rise to distinct but fre- proteins in monoclonal immunoglobulin light chain-
quently overlapping clinical syndromes. The kidneys associated [AL] amyloidosis or inherited proteins in
are frequently involved in systemic amyloidosis (Table 1) the hereditary amyloidoses), proteolytic remodelling
and, without treatment, the disease is usually fatal. of a protein (for example, cleavage of integral mem-
Current management of amyloidosis is dependent brane protein 2B and gelsolin by the protease furin,
upon identifying the fibril protein and reducing its and release of amyloid‑β peptides by secretases) and
abundance. Such a reduction can sometimes result in advancing age (for example, wild-type transthyretin
regression of amyloid deposits, prevention or recovery and apolipoprotein A‑I have intrinsic amyloidogenic National Amyloidosis
of organ failure and improved patient survival. In this properties and are associated with age-related amyloid Centre, Centre for
Review, we outline amyloid pathophysiology and discuss deposition). Although a combination of these factors Amyloidosis and Acute
Phase Proteins,
current and future therapeutic strategies for the various often determines the amyloidogenic potential of a par- Division of Medicine,
systemic amyloidosis syndromes. ticular protein, they are not sufficient to account for the University College
London, Royal Free
occurrence, timing, distribution or effects of amyloid Hospital Campus,
Aetiology and pathogenesis deposition in vivo. Environmental and genetic factors Rowland Hill Street,
Amyloid formation occurs when a protein or peptide that have not yet been identified must be involved in London NW3 2PF, UK
(J. D. Gillmore,
loses—or fails to acquire—its physiologic, functional amyloidogenesis, as only a minority of patients with P. N. Hawkins).
long-lasting inflammation and persistent elevation
Correspondence to:
Competing interests of SAA concentration develop AA amyloidosis3 and, J. D. Gillmore
The authors declare no competing interests. similarly, the disease-associated Val30Met variant of j.gillmore@ucl.ac.uk

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Key points structure.5,6 More recently, refined structural studies

of amyloid fibrils using solid-state nuclear magnetic
■■ More than 25 different human proteins can misfold to form amyloid fibrils
resonance spectro­s copy and microcrystals of small
in vivo; ~15 of these misfolded proteins cause systemic amyloidosis, which is
usually fatal amyloid-like peptides by X‑ray diffraction analysis have
■■ Diagnosis of amyloidosis relies on a high index of clinical suspicion and requires revealed a degree of structural variation between fibrils
histological confirmation by staining of tissue specimens with Congo red dye composed of different proteins.7,8
■■ Identification of amyloid should prompt a series of investigations to identify the
amyloid fibril protein and associated organ involvement and dysfunction Common constituents of amyloid deposits
■■ Therapies to enhance clearance of amyloid are in development; current A circulating glycoprotein of the pentraxin family,
treatment involves reducing the supply of the amyloid fibril precursor protein to
serum amyloid P‑component (SAP), is bound by all
slow or halt new amyloid formation
■■ Amyloidotic organ dysfunction may gradually improve when amyloid formation
types of amyloid fibril via a specific calcium-dependent
is slowed or halted, and supporting organ function while waiting for clinical interaction that partially protects amyloid fibrils from
improvement is a crucial aspect of management proteolytic degradation.9 The universal presence of SAP
■■ Advances in understanding of the molecular mechanisms involved in amyloid in amyloid deposits is the basis for imaging amyloidotic
formation have led to the identification of several new therapeutic targets, and organs using radioiodine-labelled SAP scintigraphy,
new therapeutic approaches are now in development and underscores SAP as a therapeutic target.10 Various
proteoglycans are also common to all amyloid deposits.
The role of heparan sulphate in the genesis of amyloid
Table 1 | Systemic amyloidoses commonly associated with kidney involvement
deposits was demonstrated in a transgenic experimental
Type Fibril precursor Clinical syndrome model in which fragmentation of heparan sulphate by
AL Monoclonal Systemic AL amyloidosis associated with clonal heparanase resulted in resistance to the induction of AA
immunoglobulin dyscrasia or myeloma
amyloidosis.11 Heparan sulphate accelerates the transi-
light chain V region Primary renal presentation in ~50% and renal
fragments involvement in ~75% of patients tion of SAA from the native state into the amyloido­
Multiple other organs frequently involved genic partially folded state 12 and also accelerates the
AA Normal serum Secondary amyloidosis, reactive to chronic inflammation formation of fibrils by amyloidogenic immunoglobulin
amyloid A protein Primary renal presentation among >95% of patients light chains,13,14 SAA,15 transthyretin16 and amyloid‑β
Liver and gastrointestinal dysfunction in advanced protein,17 through selective binding to a basic motif.
disease
Other common elements found in amyloid deposits
ALECT2 Leukocyte Sporadic amyloidosis include components of the extracellular matrix, such
chemotactic factor 2 Most common in Mexican Americans, North Africans
as laminin, nidogen‑1 (also known as entactin) and
and South Asians
Primary renal presentation in all patients type IV collagen, and chaperone proteins, such as
Other organ function remains intact apolipo­protein E and clusterin.18
AApoAI Variant Hereditary amyloidosis
apolipoprotein A‑I Primary renal presentation is common, dependent Kinetics of fibril formation
upon mutation In vitro studies have shown that amyloid fibril formation
Liver and cardiac involvement are common
often proceeds through a process of nucleated growth
AApoAII Variant Hereditary amyloidosis that is reminiscent of crystallization. Starting from a
apolipoprotein A‑II Primary renal presentation is typical
solution of monomeric proteins, an initial lag phase
ALys Variant lysozyme Hereditary amyloidosis occurs, but once a critical nucleus has been generated
Primary renal presentation is common
Liver involvement almost universal
fibril formation commences and proceeds with very fast
kinetics; additional amyloidogenic precursor protein
AFib Variant fibrinogen Hereditary amyloidosis
Aα‑chain Primary renal presentation in all patients
in its aggregation-prone, presumably partly unfolded,
Extra-renal manifestations are rare conformation is rapidly incorporated into the growing
AGel Variant gelsolin Hereditary amyloidosis
fibrils.7 These kinetics have clinical implications; fibril
Primary renal presentation is rare formation is far more rapid than the natural clearance of
Cranial neuropathic and ocular presentation is typical amyloid and even after an optimal response to therapy
ATTR Variant transthyretin Hereditary amyloidosis at least some traces of amyloid are likely to remain in
Kidney involvement and/or dysfunction is unusual until the tissues. Following a disease relapse, these traces of
the late stages of disease amyloid may act as ‘seeds’ and trigger rapid reaccumula-
Cardiac and/or neuropathic presentation is typical
tion of amyloid deposits.19 The clinical relevance of these
in vitro findings are highlighted in cases of AA amyloid-
transthyretin shows significant variation in penetrance osis in which renal function declines rapidly in associa-
and clinical presentation between different ethnic tion with a short burst of inflammation characterized by
groups and geographic areas.4 elevated SAA levels, despite a previous gradual improve-
ment in proteinuria resulting from prolonged control of
Amyloid structure SAA production.
Electron microscopy and X‑ray diffraction analyses
have shown that amyloid deposits are composed of Organ tropism
rigid, nonbranching fibrils with an average dia­meter Although amyloid deposition may occur in almost any
of 7.5–10 nm and a cross‑β-sheet supersecondary organ, specific amyloidogenic proteins tend to deposit

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 REVIEWS

predominantly in particular organs: for example, in the siRNA, antisense

Extracellular Protease
oligonucleotides
kidney in AA, fibrinogen Aα chain-associated (AFib) chaperones inhibitors
and leukocyte chemotactic factor 2‑­a ssociated
(ALECT2) amyloidosis; in the peripheral nerves in
Proteolysis
trans­t hyretin-associated (ATTR) amyloidosis; and
in the joints and bones in β2-microglobulin-associated
(Aβ 2 M) amyloid­o sis. The basis of organ tropism mRNA
Misfolded protein
remains unclear but factors that influence the site of
amyloid deposition may include local protein concen-
trations, interactions with collagen, 20 tissue-specific Small molecule drugs
Protein synthesis
glycosamino­g lycans, pH, specific local proteolytic
enzymes or cellular receptors. In AL amyloidosis, some
evidence suggests that the particular physicochemical
GAG
characteristics of certain subclasses of immunoglobu- Oligomers GAGs mimetics
lin light chains substantially determine the type and
location of organ dysfunction.21–23

Mechanisms of tissue damage CPHPC and mAb

Although the mechanisms of tissue damage in amyloid­ Anti-amyloid mAb
Iododoxorubicin
osis have not been fully elucidated, the presence of large Doxycycline
amounts of amyloid in the interstitium has been shown
to disrupt tissue architecture and interfere with the
physiologic function of affected organs. 24 Some evi-
SAP
dence suggests that prefibrillar oligomeric species may
be toxic. For example, prefibrillar oligomers of trans­
thyretin,25,26 amyloid‑β protein, 27–29 immunoglobulin
light chains,30–32 and prion protein33 have been shown CPHPC
Organ dysfunction Amyloid deposits
to adversely affect cell function in vitro and/or in vivo.
Thus, organ damage may have a multifactorial aetiol- Figure 1 | New approaches to amyloidosis therapy. Synthesis of amyloid proteins
ogy, which probably varies between types of amyloid can be inhibited using siRNA or antisense oligonucleotides. Small molecule drugs
and individual patients, particularly in AL amyloidosis, that stabilize amyloid proteins in vitro and are thought to prevent their auto-
aggregation in vivo, and compounds that inhibit the binding of GAGs to amyloid
the most idiosyncratic type. The best clinical evidence
fibrils are also being evaluated in clinical trials. Depletion of SAP from amyloid
for toxic oligomers is seen in cardiac AL amyloidosis, in deposits using the small palindromic drug CPHPC may enhance amyloid clearance
which the serum concentration of the amino terminal or slow amyloid formation in vivo. Elimination of amyloid deposits can be greatly
fragment of N‑terminal probrain natriuretic peptide accelerated by macrophage activation and opsonisation following administration
(NT-proBNP), a powerful marker of cardiac dysfunc- of complement-activating mAbs that bind to amyloid. Amyloid fibrils may be further
tion, may decrease substantially and very rapidly when disrupted using drugs such as iododoxorubicin and doxycycline, which are
the supply of amyloidogenic light chains is suppressed currently being tested in clinical trials. Abbreviations: GAG, glycosaminoglycan;
mAb, monoclonal antibody; mRNA, messenger RNA; SAP, serum amyloid P
following chemotherapy, despite no apparent early
component; siRNA, short interfering RNA. Permission obtained from the American
reduction in myocardial amyloid load.34 Society of Clinical Oncology © Merlini, G. et al. J. Clin. Oncol. 29, 1924–1933
(2011). All rights reserved.
Epidemiology
Systemic amyloidosis is a rare disease that accounts
for approximately 1 in 1,500 deaths per year in the reported prevalence in patients with chronic arthritides
UK and presumably also in other developed coun- is 3–6%.43–45 The incidence of AA amyloidosis seems to
tries.35 Amyloidosis can occur in children (most often be lower in the USA than in Europe46,47 and seems to be
AA amyloidosis as a complication of chronic inflamma- declining worldwide but the reasons for these trends are
tory disease) but is predominantly a disease of mid-to- unknown.48–50 The duration of latency between onset of
late life. Renal amyloidosis is identified in ~4% of adult inflammation and diagnosis of AA amyloidosis can vary
renal biopsy samples36 and accounts for ~1.6% of patients from less than a year to many decades, with a median of
starting dialysis.37 approximately 17 years.51
The age-adjusted incidence of AL amyloidosis in the Aβ 2M amyloidosis usually occurs in patients who
US and in the UK is estimated to be 5.1–12.8 cases per have been on dialysis for more than 6–10 years and, very
million persons per year.35 The disease develops in about occasionally, in individuals with longstanding severe
2% of individuals with monoclonal B‑cell dyscrasias.38 chronic kidney disease (CKD) not on dialysis. The inci-
The clonal cell burden is usually small39–41 and progres- dence of this disease seems to be decreasing, possibly
sion of the underlying monoclonal gammopathy to overt due to increasing use of dialysis membranes with larger
myeloma is rare.42 pore sizes.52
AA amyloidosis may complicate almost any long- In the UK, the prevalence of hereditary non-­
standing inflammatory condition (Box 1) and the neuropathic systemic amyloidoses (AFib amyloidosis,

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Box 1 | Conditions that can underlie AA amyloidosis* Clinical features

Systemic AL amyloidosis
Chronic inflammatory arthritides The clinical features of AL amyloidosis are protean as
■■ Rheumatoid arthritis
any organ other than the central nervous system can be
■■ Juvenile inflammatory arthritis
■■ Ankylosing spondylitis
directly involved (Table 2).56 Renal dysfunction is present
■■ Psoriatic arthropathy in more than 60% of patients and causes proteinuric
■■ Reiter’s syndrome renal failure in the context of normal or low blood pres-
■■ Adult Still’s disease sure. Up to 50% of patients present with CKD stage 1 or 2
Vasculitides and 16% present with CKD stage 5.57 Cardiac and hepatic
■■ Polyarteritis nodosa involvement is also common.
■■ Takayasu’s arteritis
■■ Behçet’s disease Systemic AA amyloidosis
■■ Systemic lupus erythematosis The predominant clinical manifestations of AA amyloid­
■■ Giant cell arteritis and polymyalgia rheumatica
osis are renal and more than 97% of patients with this
Chronic infections disease present with proteinuric kidney dysfunction; just
■■ Bronchiectasis
over 50% of patients have nephrotic syndrome and ~10%
■■ Chronic cutaneous ulcers
■■ Chronic pyelonephritis have ESRD at diagnosis.51 More than 40% of patients
■■ Chronic osteomyelitis with AA amyloidosis eventually progress to ESRD.51 The
■■ Subacute bacterial endocarditis spleen is almost always infiltrated and the adrenal glands
■■ Leprosy are involved in more than one-third of cases although
■■ Tuberculosis clinical hypoadrenalism is rare.51 Hepatosplenomegaly
■■ Whipple’s disease owing to amyloid infiltration is seen at presentation
Inflammatory bowel disease in 9% of patients whereas liver failure is exceptionally
■■ Crohn’s disease rare.51 Gastrointestinal malabsorption occurs only in very
■■ Ulcerative colitis
advanced disease and cardiac amyloidosis is present in 2%
Inherited periodic fever syndromes of patients (but only in those with advanced disease).51
■■ Familial mediterranean fever
■■ Cryopyrin-associated periodic syndrome
■■ TNF-receptor-associated periodic syndrome
Dialysis-related amyloidosis
■■ Mevalonate kinase deficiency Levels of β2-microglobulin are increased in patients
Neoplasia
on dialysis because this protein is too large to easily
■■ Hodgkin’s disease cross the dialysis filter. In dialysis-related amyloidosis,
■■ Renal cell carcinoma β2-microglobulin is preferentially deposited in articular
■■ Adenocarcinoma of the lung, gut or urogenital tract and periarticular structures and the clinical manifesta-
■■ Basal cell carcinoma tions are largely confined to the locomotor system.58
■■ Hairy cell leukaemia The first clinical manifestation is normally carpal tunnel
■■ Castleman’s disease syndrome, which is usually followed by the develop-
■■ Hepatic adenoma
ment of amyloid arthropathy that particularly affects
Other the shoulders, knees, wrists and the small joints of the
■■ Intravenous and subcutaneous drug abuse
hand, and results in swelling, chronic tenosynovitis and
■■ Cystic fibrosis
■■ Kartagener’s syndrome occasionally haemarthroses. Spondyloarthropathies
■■ Epidermolysis bullosa and cervical cord compression are also symptoms
■■ Hypogammaglobulinaemia of dialysis-related amyloidosis. The deposition of
■■ Cyclic neutropaenia β2‑microglobulin within the periarticular bone results
■■ Common variable immunodeficiency in the appearance of subchondral erosions and cysts,
■■ Hyperimmunoglobulin M syndrome which can contribute to pathological fractures, par-
■■ SAPHO syndrome
ticularly of the femoral neck, cervical vertebrae and
*This list is not exhaustive. Abbreviations: SAPHO, synovitis, acne,
pustulosis, hyperostosis, osteitis; TNF, tumour necrosis factor.
scaphoid. Although β2‑microglobulin amyloidosis is a
systemic form of amyloid, manifestations outside the
musculoskeletal systemic are rare. However, congestive
apolipoprotein A‑I-associated [AApoA1] amyloidosis cardiac failure, gastrointestinal bleeding, perforation and
and lysozyme-associated [ALys] amyloidosis), which pseudo-obstruction, and the presence of visceral amyloid
typically present with renal dysfunction, seems to be in deposits, have all been reported.59,60
the order of 1.5 cases per million population.35
LECT2 has been identified as a new amyloid fibril Hereditary systemic amyloidoses
protein.53 Data from a US study suggest that ALECT2 The hereditary systemic amyloidoses—ALys amyloid­
amyloidosis might account for up to 2.5% of amyloid­ osis, AApoA1 amyloidosis, AFib amyloidosis, and
otic renal biopsy samples. 54,55 For reasons that are apolipoprotein A-II-associated (AApoA2) amyloidosis—
unclear, ALECT2 amyloidosis seems to predominantly usually present with renal dysfunction in association with
affect individuals of Hispanic, North African, Indian or involvement of various other organ systems.61–64 A patient
Pakistani ancestry. with renal apolipoprotein A-IV-associated amyloidosis

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Table 2 | Organ involvement in systemic AL amyloidosis

Organ system Clinical manifestations Outcomes
Nonspecific Many patients present with nonspecific symptoms such as fatigue and No data
weight loss132
Renal Renal dysfunction is present in >60% of patients and causes proteinuric Isolated renal involvement is associated with favourable overall
renal failure in the context of normal or low blood pressure survival
<50% of patients present with CKD stage 1 or 2 and 16% present with ~10% of surviving patients eventually require dialysis57
CKD stage 557
Nephrotic-range proteinuria is a typical finding
Cardiac Cardiac involvement is present in ~75% of patients at presentation and Cardiac involvement is a major determinant of outcome
approximately one-third of these patients present with congestive heart Cardiac biomarkers provide a quantitative assessment of
failure133 cardiac damage (troponin I or T) and wall strain (BNP,
NT‑proBNP) and are important predictors of outcome
Patients can be classified into three prognostic stages using the
cutoffs of 0.055 μg/l for high sensitivity troponin T and 332 ng/l
for NT‑proBNP134
Median survival among patients with stage I, stage II and
stage III disease was 26.4 months, 10.5 months and
3.5 months, respectively
Hepatic Hepatic amyloid is present in ~50% of patients135 Hyperbilirubinaemia is unusual but is associated with poor
Despite substantial hepatomegaly, liver function is often well preserved outcomes (median survival 4 months)135
with modest increase in ALP and GGT levels
Gastrointestinal Gut involvement may cause motility disturbances (often secondary to No data
autonomic neuropathy), malabsorption, perforation, haemorrhage or
obstruction
Peripheral Painful sensory polyneuropathy with early loss of temperature sensation No data
neuropathic followed by motor deficits is present in 10–20% of patients24
Carpal tunnel syndrome is present in 20% of patients24
Autonomic Autonomic neuropathy leading to orthostatic hypotension, impotence and Poor prognosis in patients with severe autonomic neuropathy
neuropathic gastrointestinal disturbances at diagnosis
Soft tissue Macroglossia occurs in 10% of patients24 and is pathognomonic of AL No data
amyloidosis
Skin Skin involvement is common and usually takes the form of bruising either Little influence on prognosis
spontaneously or after minor trauma
Haematological An acquired bleeding diathesis may be associated with deficiency of Occasional spontaneous organ rupture and fatal bleeds have
factor X and factor IX, or with increased fibrinolysis been reported
Musculoskeletal Articular amyloid is rare and may superficially resemble acute polyarticular Little influence on prognosis
arthritis or asymmetrical arthritis affecting the hip or shoulder
Infiltration of the glenohumeral joint and surrounding soft tissues
occasionally produces the characteristic ‘shoulder pad’ sign
Abbreviations: ALP, alkaline phosphatase; BNP, brain natriuretic peptide; CKD, chronic kidney disease; GGT, γ-gluteryl transferase; NT‑proBNP, N‑terminal proBNP.

characterized by gradually progressive renal dysfunction proteinuria tends to be low grade and hypertension is well
and amyloid deposits limited to the renal medulla has recognised. Although splenic and adrenal amyloid depos-
also been reported.65 This patient had no family history its are evident on SAP imaging, from a clinical perspective
of amyloidosis. Using DNA analysis, the investigators ALECT2 amyloidosis is mainly a renal disease.
identified three sequence variants representing common
polymorphisms of the apolipo­protein A-IV gene, but the Investigations
clinical significance of this finding remains uncertain. The diagnosis of amyloidosis relies on a high index
Patients with gelsolin-­associated (AGel) amyloidosis typ- of clinical suspicion. Unfortunately, the disease is fre-
ically present with cranial neuropathy, whereas patients quently asymptomatic until a fairly late stage and can
with ATTR amyloid­osis present with neuropathy and then present with highly variable or nonspecific symp-
cardiomyopathy, although renal amyloid deposits, which toms. Amyloidosis should be suspected in any patient
are occasionally associated with ESRD, may be present.66 with the following symptoms: nondiabetic albumin­
Hereditary Aβ2M amyloidosis, causing progressive bowel uria, nonischaemic cardio­myopathy (particularly if
dysfunction with extensive visceral amyloid deposits, has an echocardiogram suggests concentric hypertrophy),
been reported in a French family.67 increased levels of NT‑proBNP in the absence of primary
heart or renal disease, hepatomegaly or increased levels
ALECT2 amyloidosis of alkaline phosphatase without biliary tract dilatation,
The majority of patients with ALECT2 amyloidosis peripheral and/or autonomic neuro­pathy, unexplained
present in their 6th or 7th decades with slowly progres- facial or neck purpura or macroglossia. Any patient with
sive renal impairment.55 In patients with this disease, suspected amyloidosis should undergo a biopsy to look

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Box 2 | Investigation of patients with amyloid deposits Congo red staining of amyloid produces pathognomonic
green birefringence when viewed under cross-polarized
Determining the amyloid type light, whereas negatively stained electron microscopy
■■ Clinical presentation—macroglossia, periorbital bruising and/or jaw
shows rigid, nonbranching fibrils 8‑15 nm in diameter,
claudication strongly suggest AL amyloidosis; amyloid cardiomyopathy and/or
neuropathy suggest AL or ATTR amyloidosis
composed of twisted protofibrils of indeterminate length.
■■ Family history—suggests hereditary amyloidosis The individual amyloid fibril protein can often be
■■ Biochemical evaluation—evidence of clonal dyscrasia (abnormal sFLC ratio, identified by immunohistochemistry, although this
presence of BJPs and/or paraprotein) suggests AL amyloidosis; evidence of a technique has limited sensitivity in AL and hereditary
chronic acute phase response suggests AA amyloidosis amyloidosis (70–80%).71 Proteomic analysis using mass
■■ Immunohistochemistry—negative staining excludes AA amyloidosis; 70–90% spectrometry is a discriminating and sophisticated tech-
sensitivity in AL and hereditary amyloidoses nique for amyloid fibril typing that is gradually being
■■ Mass spectrometry—currently used in research but is likely to become the gold
adopted in the clinic.72,73
standard
■■ Genetic sequencing—frequently required when immunohistochemistry and/or
mass spectrometry is nondiagnostic Imaging
Determining organ involvement SAP scintigraphy
■■ Clinical history and examination—examine for macroglossia, carpal tunnel All types of amyloid deposits bind SAP and in the UK,
syndrome, postural hypotension and ecchymoses, assess Eastern Cooperative radiolabelled SAP scintigraphy has been used for the
Oncology Group performance status and perform 6 min walk test diagnosis and quantitative monitoring of amyloidosis
■■ SAP scintigraphy—to determine visceral organ involvement and whole body since 1988.74 This safe, noninvasive method provides
amyloid load and to monitor progression information on the presence, distribution and amount
■■ Cardiac evaluation—echocardiography, MRI, 99Tc‑3,3-diphosphono‑1,2-
of visceral amyloid deposits, and serial scans can be used
propanodicarboxylic acid scintigraphy and biomarker analyses
to monitor disease progression and responses to therapy.
■■ Organ function tests—quantification of proteinuria and renal, liver and
autonomic function Unfortunately SAP scintigraphy is not informative about
Characterizing the underlying disease
amyloid deposition in the moving heart and has not been
AL amyloidosis developed commercially.
■■ Bone marrow biopsy—cytogenetic and flow cytometric analysis
■■ Serum immunoelectrophoresis—monitor paraprotein levels Cardiac imaging
■■ Urine immunoelectrophoresis—quantify and monitor 24 h levels of BJPs The classical two-dimensional Doppler echocardio-
■■ sFLC assay—monitor sFLC levels during therapy and throughout disease course graphic appearance of cardiac amyloidosis is of con-
■■ Skeletal survey—to detect lytic lesions centric biventricular wall thickening with a restrictive
■■ Lymph node biopsy, CT and PET scanning—use when indicated (that is, in patients
filling pattern. Echocardiography remains the first-line
with absence of plasma cell dyscrasia, suspected lymphoma, or IgM paraprotein)
AA amyloidosis
imaging modality in most patients with symptoms of
■■ Identify clinical syndrome—rheumatoid arthritis, juvenile inflammatory arthritis, heart failure. To avoid missing a diagnosis of amyloid­
chronic infection or hereditary periodic fever osis, it is important to appreciate that amyloid typically
■■ Serological assays—monitor levels of autoantibodies, C‑reactive protein and causes diastolic dysfunction with well-preserved con-
serum amyloid A tractility until a fairly late stage of disease.75 An electro-
■■ Genetic sequencing of periodic fever genes—MEFV, TNFRSF1A and MVK cardiogram of a patient with amyloidosis might show
Abbreviations: BJP, Bence Jones proteins (immunoglobulin light chains found in the urine); small voltages and pathological ‘Q’ waves (that is, a
SAP, serum amyloid P‑component; sFLC, serum free light chain.
pseudo-infarct pattern).
Cardiac magnetic resonance imaging (CMR) provides
for the presence of amyloid deposits and a positive result functional and morphological information on cardiac
should prompt a series of investigations to identify the amyloid in a similar way to echocardiography, although
amyloid fibril protein and associated organ involvement the latter is superior for evaluating and quantifying dia­
and dysfunction (Box 2). stolic abnormalities.76 CMR is, however, advantageous
for myocardial tissue characterization. CMR imaging of
Histology amyloidotic myocardium without contrast can be used
Histological confirmation is required for a diagnosis of to identify subtle T1 and T2 abnormalities,77,78 but the
amyloidosis (Figure 2).68 Amyloid deposits may be iden- use of extravascular contrast agents based on chelated
tified in biopsy samples from malfunctioning organs (for gadolinium is helpful for diagnosis. The appearance of
example, in biopsy samples from the kidney, heart, liver subendocardial late gadolinium enhancement is highly
or nerves in patients with nephrotic syndrome, cardio- characteristic of cardiac amyloid79 and correlates with
myopathy, a liver function test abnormality or peripheral patient prognosis.80 CMR is especially useful in patients
neuropathy, respectively) or in screening biopsy samples with LV thickening and/or hypertrophy because it can
if systemic amyloidosis is suspected. Subcutaneous fat, be used to differentiate LV thickening and/or hyper-
rectal and labial salivary gland biopsy samples contain trophy resulting from amyloidosis from that resulting
some amyloid in 60–80% of patients with systemic from hypertension, which may not be possible using
amyloid­osis.69 Concerns exist that the risk of haemor- routine echocardiography.79 The presence of trans­
rhagic complications after organ biopsies might be thyretin amyloid deposits in the heart can be detected
increased in patients with amyloidosis but firm evidence using 99Tc‑3,3-diphosphono‑1,2-propanodicarboxylic
of this increased risk is lacking.70 As mentioned above, acid (Tc-DPD) scintigraphy.81

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DNA analysis a b
Hereditary amyloidoses are rare and often overlooked
diseases. Although all types of hereditary amyloidoses
are dominantly inherited, the penetrance and expres-
sivity are highly variable and many patients have no
obvious family history. DNA analysis is mandatory in
all patients with systemic amyloidosis whose fibril type
cannot be confirmed by immunohistochemistry or
mass spectro-metry. Mutations that encode a number
of amyloidogenic protein variants are known to cause
hereditary amyloidosis and both new variants and new Figure 2 | Amyloid deposits in a renal biopsy sample. Sections of a renal biopsy
amyloido­genic proteins are identified periodically.82 sample were stained with Congo red dye and viewed at ×10 magnification.
a | Amorphous deposits of eosinophilic material are visible within the glomeruli.
b | Pathognomonic green birefringence of amyloid deposits are visible when viewed
Characterization of the underlying disease under cross-polarized light.
In patients with AL amyloidosis, the associated clonal
immunocyte dyscrasia must be characterized in detail
using techniques such as bone marrow examination, as difference in level of involved and uninvolved FLC
skeletal survey, serum and urine electrophoresis and [dFLC] <40 mg/l) are associated with the best clinical
immunofixation, and serum free light chain (FLC) assay outcomes.87,88 A partial haematologic response (defined
(Box 2).83 An attempt to characterize the underlying as decrease in dFLC >50% but not meeting criteria for CR
inflammatory disease should also be made in all patients or VGPR) can also be beneficial89 but is no longer con-
with AA amyloidosis although, intriguingly, the exact sidered sufficient in many patients with AL amyloid­osis.88
cause of excessive SAA production remains unclear in A new paradigm for the treatment of AL amyloidosis has
up to 10% of these patients.51 been proposed in which the underlying haematologic dis-
order and the end-organ damage should be monitored
Treatment and outcomes using FLC assays and cardiac biomarkers, respectively, to
Relentless accumulation of amyloid is almost always optimize therapy and minimize toxicity.90
associated with a progressive decline in the function of Treatment regimens for AL amyloidosis are gener-
the affected organ. Conversely, a decrease in the quan- ally administered by haematologists and were adapted
tity of amyloid within an organ may result in functional from regimens that were developed for the treatment
improvement, although many affected organs are beyond of multiple myeloma, although most patients with AL
recovery at diagnosis. Although therapies aimed at amyloid­o sis have a low-grade plasma cell dyscrasia
enhancing amyloid clearance are in development, current and small clonal burden. Treatment for AL amyloid­
treatment of all types of amyloid centres on reducing the osis is highly individualized and is based on age,
supply of the amyloid fibril precursor protein in order cardiac staging, and regimen toxicities.83 Outcomes in
to reduce new amyloid formation. This strategy often patients with AL amyloid­osis have improved following
results in measurable regression of amyloid, although the introduction of effective chemotherapy regimens.
this invariably occurs slowly. Nonetheless, amyloidotic For example, among 600 consecutive patients with AL
organ dysfunction may gradually improve when amyloid amyloidosis referred to the UK National Amyloidosis
formation is slowed or halted,84 and measures to support
organ function whilst waiting for clinical improvement
Box 3 | Haematologic response in AL amyloidosis86,88
is a crucial aspect of patient management. Treatment of
amyloidosis, therefore, requires precise identification Complete response
of the amyloid fibril protein in every patient, and early ■■ Normalization of FLC levels and ratio of κ and λ FLC
diagnosis is the key to effective therapy. ■■ Negative serum and urine immunofixation
Very good partial response
Systemic AL amyloidosis ■■ Decrease in dFLC to <40 mg/l
The immediate goals of therapy for systemic amyloidosis Partial response
are to rapidly eliminate production of amyloidogenic light ■■ >50% decrease in dFLC
chains using chemotherapy whilst minimizing treatment No response
■■ ≤50% decrease in dFLC
toxicity and supporting target organ function. Effective
management of AL amyloidosis requires a multidisciplin­ Progression
■■ From a complete response—any detectable
ary approach and consensus criteria for haematologic
monoclonal protein or abnormal FLC ratio
and organ responses in AL amyloidosis have been pub- (amyloidogenic FLC levels must double)
lished (Box 3 and Table 3).85,86 Achieving a haematologic ■■ From a partial response—≥50% increase in serum M
response in AL amyloidosis translates into improved protein levels to >0.5 g/dl or ≥50% increase in urine M
overall survival and complete haematologic responses protein levels to >200  mg per day (a visible peak must
(CR; defined as a normal ratio of κ to λ FLC in the serum be present) or ≥50% increase in FLC levels to >100  mg/l
and negative serum and urine immunofixation) and very Abbreviations: dFLC, difference in levels of involved and
uninvolved free light chains; FLC, free light chain.
good partial haematologic responses (VGPR; defined

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REVIEWS

Table 3 | Organ responses and progression in AL amyloidosis86

Organ Response Progression
Heart >30% and >300 ng/l decrease in NT‑proBNP levels in patients with >30% and >300 ng/l increase in NT‑proBNP levels
NT‑proBNP levels ≥650 ng/l at baseline or ≥2-class decrease in NYHA or ≥33% increase in cardiac troponin levels
class in patients with NYHA class 3 or 4 at baseline or ≥10% decrease in ejection fraction
Kidney >50% (≥0.5 g per day) decrease in 24 h urine protein levels in patients with ≥50% (≥1 g per day) increase in 24 h urine protein levels
urine protein levels >0.5 g per day at baseline without ≥25% increase in or ≥25% increase in serum creatinine levels
serum creatinine levels or decrease in creatinine clearance from baseline or ≥25% decrease in creatinine clearance from baseline
Liver ≥50% decrease in alkaline phosphatase levels and/or ≥2 cm decrease in ≥50% increase in alkaline phosphatase levels from the
liver size (assessed by radiography) lowest recorded value
Peripheral Improvement in electromyogram nerve conduction velocity (such a Progressive neuropathy by electromyography or nerve
nervous system response is rare) conduction velocity
Abbreviations: NT‑proBNP, N‑terminal probrain natriuretic peptide; NYHA, New York Heart Association.

Centre, median survival increased from 23 months in with autologous stem cell transplantation, a renal
those diagnosed between 1990 and 1995 to 40 months response was seen in 15 of the 21 (71%) patients who
in those diagnosed between 1996 and 2001 (P <0.0001; achieved a complete haematological response. 95 The
our unpublished observations). procedure was, however, associated with renal toxicity, as
Currently, the treatment regimens that are most evidenced by an acute doubling of serum creatinine levels
widely used to treat AL amyloidosis include combina- in 15 patients; this decline in renal function persisted in
tions that contain bortezomib (cyclophosphamide, bort- only three patients.
ezomib and dexamethasone), melphalan (melphalan
and dexametha­sone), thalidomide (cyclophosphamide, Reactive systemic AA amyloidosis
thalidomide and dexamethasone) and lenalidomide In AA amyloidosis, the aim of treatment is to suppress
(lenalidome and dexamethasone). High-dose melphalan the underlying inflammatory disease as completely as
in combination with autologous stem cell transplanta- possible in terms of SAA production. Choice of therapy
tion is associated with excellent clinical outcomes,91,92 depends on the underlying disease and should be
but rigorous selection of suitable patients is required guided by frequent measurements of SAA concentra-
owing to the excessive risk of treatment-related mor- tion or C-reactive protein concentration if SAA assays
tality in certain individuals with AL amyloidosis, par- are un­available.84 Most patients with AA amyloid­osis
ticularly those with substantial cardiac or autonomic complicating inflammatory arthritis can be treated
nerve involvement.93 effectively with the many biologic agents that are now
available, such as cytokine inhibitors and anti‑CD20
AL amyloidosis with renal involvement antibodies. Historically, alkylating agents such as
Close communication between haematologists and chlor­ambucil or cyclophosphamide proved very effec-
nephrologists is crucial during chemotherapy for renal tive in many patients with AA amyloidosis, and these
AL amyloidosis. Patient survival is strongly influenced less-­targeted agents may still have a therapeutic role.96
by the degree of haematologic response and the presence A multi­disciplinary approach involving the nephrologist
of cardiac amyloidosis, but not by the degree of renal and rheumatologist is beneficial.
dysfunction at presentation.57 SAA concentration is a strong predictor of survival
In two studies that included a total of 1,068 patients and renal outcome in patients with AA amyloidosis.
with AL amyloidosis, the median survival in patients who Persistent complete suppression of inflammation in
presented with renal disease was 2–3 years.57,94 More association with normal SAA levels (that is, <4 mg/l)
than 40% of patients with a renal presentation eventu- is associated with an almost 18-fold lower risk of death
ally required dialysis and one-quarter of patients who than are SAA levels ≥155 mg/l.51 Two large case series, one
presented with potentially salvageable renal function from Italy 97 and another from the UK,51 demonstrated
(defined as baseline creatinine clearance >20 ml/min57 or median survival from diagnosis of AA amyloidosis of
baseline creatinine level <5 mg/dl94) progressed to ESRD 79–137 months. Approximately 40% of patients with
during a median of 12 months. One of these studies systemic AA amyloid­osis will eventually require renal
reported that during a median follow-up of 24 months, replacement therapy, with a median time to dialysis from
renal function deteriorated in almost 55% of patients and diagnosis of 78 months.51
improved in approximately one-third of patients. 57
Achieving a >90% FLC response to chemotherapy within Dialysis-related amyloidosis
6 months of presentation was associated with an almost The only effective treatment for dialysis-related amyloid­
fourfold increase in renal response (P <0.001) and a 68% osis is successful renal transplantation. Serum levels of
reduction in risk of renal progression (P <0.001).57 β2-microglobulin decrease rapidly following transplan-
In a study of 65 patients with AL amyloidosis who tation and this decrease is usually accompanied by a
received high-dose melphalan therapy in combination very rapid improvement in symptoms,98 presumably

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 REVIEWS

reflecting either an effect of anti-rejection therapy, ces- Kidneys

sation of new amyloid formation and/or the removal Nephrotic syndrome owing to amyloid generally requires
of an unknown contributing factor that is associated treatment with high-dose loop diuretics and resistant
with dialysis treatment. In contrast to the symptoms of cases may require addition of thiazide and/or potassium-­
dialysis-related amyloidosis, radiological bone cysts heal sparing diuretics. Salt and, in many cases, fluid restric-
slowly, and amyloid can be detected histologically many tion may be advisable and infusions of salt-poor human
years after renal transplantation.98 Greater removal of albumin can be helpful in patients who have difficulty
β2-microglobulin is attained in patients undergoing high- maintaining intravascular volume. Standard drug-­
flux haemodiafiltration than in those receiving conven- mediated nephroprotection using angiotensin-­converting-
tional dialysis; in the long term, the former group may be enzyme (ACE) inhibitors and angiotensin-receptor
less prone to dialysis-related amyloidosis.99 blockers may be beneficial but the effects of these drugs
in patients with renal amyloidosis have not been system-
Hereditary systemic amyloidosis atically determined and caution is advised in patients with
Hereditary non-neuropathic systemic amyloidoses, par- pre-existing hypotension.
ticularly ALys and ApoAI amyloidosis, tend to have very The outcomes of patients with AL amyloidosis on
indolent courses over several decades. In patients with long-term dialysis are improving but their survival is
these diseases, kidney transplantation for ESRD is often reduced compared with that of age-matched non­diabetic
highly successful and graft survival for decades has been patients with other diseases.57,94 In the UK, patients with
reported.61,100 By contrast, in patients with AFib amyloid­ AL amyloidosis who commenced dialysis after 2002 had
osis, reaccumulation of amyloid causes renal graft loss a median survival of 43.6 months,57 whereas historical
after a median of ~7 years.64 As fibrinogen is synthesised data from the USA102 and Italy 103 reported a median
solely in the liver, combined hepatorenal transplanta- survival in such patients of <12 months. Outcomes of
tion offers the possibility of ‘surgical gene therapy’ and dialysis in patients with other types of amyloid are more
complete protection from recurrent amyloidosis, but favourable. 97,104 For example, in AA amyloidosis the
this procedure is associated with a substantial risk of median survival of patients on dialysis was reported to
transplant-­related mortality.64 be 69 months.105
ATTR amyloidosis (familial amyloid polyneuro­ Although less than 10% of patients with ESRD resulting
pathy, hereditary amyloid cardiomyopathy and senile from AL amyloidosis receive a donor kidney, long-term
systemic amyloidosis) is typically fatal over the course renal allograft survival, rejection rates and survival among
of 5‑15 years as amyloid deposits gradually accumulate carefully selected patients are comparable with those in
within the heart and nerves. A small molecule drug, other systemic diseases.57,106 In a few patients, renal trans-
tafamidis, which stabilizes circulating transthyretin in plantation has been followed by autologous stem cell
its normal conformation, has been developed for the transplantation; however, the outcomes were mixed and
treatment of ATTR amyloidosis. A placebo-controlled a number of acute renal allograft failures were reported.107
trial in 125 patients with early-stage familial amyloid In selected patients with AA amyloidosis, 5-year and
polyneuropathy associated with the Val30Met variant 10-year graft survivals of 74% and 68%, respectively, have
of transthyretin suggested that tafamidis therapy might been reported.105 These encouraging data have prompted
slow progression of the disease.101 The drug has now use of living donor renal transplantation in patients with
been approved by the European Medicines Agency for AL amyloidosis.108,109 Most patients with amyloidosis,
treatment of grade 1 neuropathy in familial amyloid regardless of amyloid type, have a functioning graft until
polyneuro­pathy, but wider experience of the therapy is death,57,110 despite the frequent histological presence of
required to define its clinical role. amyloid deposits in the renal allograft.100,111

ALECT2 amyloidosis Heart

ALECT2 amyloidosis has a very slow natural history and Clinical benefit with standard heart failure medications
renal function may be preserved for many years from in patients with cardiac amyloidosis remains unproven
diagnosis. There is no specific treatment for the condi- and agents such as digoxin and calcium antagonists may
tion other than general renoprotective measures such as adversely affect prognosis.112 Hypotension may be pre-
blood pressure control. cipitated by ACE inhibitors and these drugs should be
used with caution or avoided in patients with cardiac
Preservation and replacement of organ function amyloidosis. Amiodarone is used by some physicians to
Organs that are infiltrated by amyloid may fail reduce the risk of sudden cardiac death in patients with
acutely, often without obvious reason. Attention amyloidosis and cardiomyopathy but again, evidence for
must, therefore, be paid to salt and water balance, a beneficial effect of this intervention is lacking.113 The
maintenance of the circulating blood volume and role of β‑blockers in patients with cardiac amyloidosis
prompt treatment of sepsis to reduce the risk of acute also remains uncertain.114 Diuretics continue to be the
organ failure. Potentially nephrotoxic drugs, elective mainstay of symptomatic therapy but should be used
surgery and general anaesthesia are best avoided in with close monitoring in amyloid cardiomyopathy as the
patients with systemic amyloidosis unless compelling resulting restrictive physiology means that high filling
indications exist. pressures may be required to maintain cardiac output.

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 9

© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS

α‑2A adrenergic receptor-agonists such as midodrine An approach that involves using the small molecule
can improve postural hypotension in patients with palindromic drug CPHPC to deplete SAP from the
cardiac amyloidosis. The efficacy of implantable cardiac circulation and then uses complement-activating anti-
defib­r illators in patients with cardiac amyloidosis bodies to bind the remaining SAP in amyloid deposits
remains controversial.115,116 and promote their clearance by macrophages has been
In highly selected younger patients with isolated irre- validated experimentally in animal models and is now
versible cardiac failure, heart transplantation offers a pos- being evaluated in phase I clinical trials in patients with
sibility of long-term survival and has been performed in systemic amyloidosis.10,127,128 Other antibody therapies
a small number of individuals. 100,117–119 The scarcity of aimed at promoting clearance of amyloid deposits are
donor hearts, the high transplant-related mortality, and also being investigated.129
the risk of amyloid deposition in the graft make rigorous Finally, small molecules that might interfere with
patient selection mandatory. In patients with AL amyloid­ amyloid fibril structure to prevent aggregation or
osis, chemotherapy is required after cardiac transplanta- promote clearance, such as iododoxorubicin130 and
tion to prevent amyloid deposition in the graft and/or doxycycline,131 are under investigation in patients with
disease progression in other organ systems.120 amyloidosis. In the near future, amyloid diseases will
probably be treated using a combination of approaches
Novel therapies and perspectives that reduce the production of protein precursors, prevent
Advances in understanding of the molecular mechanisms aggregation of fibrils, and promote the clearance of
involved in amyloid formation and tissue damage have led established amyloid deposits.
to the identification of several new therapeutic targets, and
several novel therapeutic approaches are now in develop- Conclusions
ment (Figure 1). One such approach is to inhibit the pro- Current therapy for systemic amyloidosis involves
duction of amyloidogenic precursor proteins using small attempting to reduce the plasma concentration of the
interfering RNAs121 or antisense oligonucleotides.122,123 respective amyloid fibril precursor protein to slow or halt
Phase I and II trials of these agents are now underway new amyloid formation. This strategy, in combination
in patients with ATTR amyloidosis.124 Tafamidis and with supportive management of amyloidotic organs, can
diflunisal­—agents that stabilize circulating trans­thyretin prolong life expectancy, but many patients fail to derive
and inhibit its conversion into amyloid fibrils—are clinical benefit and die as a result of amyloid-related
also being tested in patients with ATTR amyloidosis.125 organ failure. Advances in understanding of the mecha-
Tafamidis has already been approved by the European nisms of amyloid formation and elimination in vivo have
Medicines Agency for the treatment of patients with resulted in the identification of novel therapeutic targets;
grade 1 neuropathy in familial amyloid polyneuropathy. small molecule drugs that interfere with fibrillogenesis
Another novel approach is to inhibit fibril forma- by stabilizing fibril precursors are now in clinical use.
tion by preventing the binding of misfolded proteins Immunotherapy for amyloidosis also shows great promise
to matrix components that promote auto-aggregation, and has reached the clinical setting. These new therapeu-
such as glycosaminoglycans. The glycosaminoglycan tic strategies could potentially be effective in treating the
mimetic eprodisate, which inhibits the association of wide spectrum of amyloid-associated diseases.
glycosamino­glycans with AA fibril proteins, is currently
being evaluated in a phase III clinical trial in patients
Review criteria
with AA amyloidosis.126
SAP is an attractive therapeutic target as it binds The PubMed database was searched for full-text articles
to all types of amyloid fibrils and protects them from using the search terms “amyloid”, and “amyloidosis”.
proteolytic cleavage. Depletion of SAP might enhance Relevant abstracts from recent International Amyloidosis
Symposia were also identified.
amyloid clearance or slow amyloid formation in vivo.

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inhibition of amyloidogenesis. Proc. Natl Acad. AL amyloidosis is associated with high clonal Acknowledgements
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