Seminar

Systemic amyloidosis
Ashutosh D Wechalekar, Julian D Gillmore, Philip N Hawkins

Tissue deposition of protein fibrils causes a group of rare diseases called systemic amyloidoses. This Seminar focuses Published Online
on changes in their epidemiology, the current approach to diagnosis, and advances in treatment. Systemic light chain December 21, 2015
http://dx.doi.org/10.1016/
(AL) amyloidosis is the most common of these conditions, but wild-type transthyretin cardiac amyloidosis (ATTRwt) S0140-6736(15)01274-X
is increasingly being diagnosed. Typing of amyloid fibrils, a critical determinant of therapy, has improved with the
National Amyloidosis Centre,
wide availability of laser capture and mass spectrometry from fixed histological tissue sections. Specific and accurate University College London
evaluation of cardiac amyloidosis is now possible using cardiac magnetic resonance imaging and cardiac repurposing (Royal Free Campus), London,
of bone scintigraphy tracers. Survival in AL amyloidosis has improved markedly as novel chemotherapy agents have UK (A D Wechalekar FRCPath;
J D Gillmore FRCP;
become available, but challenges remain in advanced disease. Early diagnosis, a key to better outcomes, still remains P N Hawkins FMedSci)
elusive. Broadening the amyloid-specific therapeutic landscape to include RNA inhibitors, fibril formation stabilisers
Correspondence to:
and inhibitors, and immunotherapeutic targeting of amyloid deposits holds promise to transform outcomes in Dr Ashutosh D Wechalekar,
systemic amyloidoses. National Amyloidosis Centre,
University College London l
(Royal Free Campus), Rowland
Introduction AL amyloidosis as three to five  cases per million
Hill Street, London NW3 2PF, UK
The amyloidoses are a rare group of diseases that result population.5 Death certificates from the UK indicate a.wechalekar@ucl.ac.uk
from extracellular deposition of amyloid, a fibrillar that amyloidosis has an incidence of about one per
material derived from various precursor proteins that 100 000 population and is the cause of death in 0·58 per
self-assemble with highly ordered abnormal cross 1000 individuals.6 Analysis of Swedish hospital discharge
β-sheet conformation.1,2 Deposition of amyloid can and outpatient registers found an incidence of 8·29 per
occur in the presence of an abnormal protein (eg, million person-years for non-hereditary amyloidosis and
hereditary amyloidosis and acquired systemic 3·2 per million person-years for AL amyloidosis.7 Table 1
immunoglobulin light chain [AL] amyloidosis), in shows the frequency of different amyloid types among
association with prolonged excess abundance of a 5100 individuals with amyloidosis or amyloidogenic
normal protein (eg, reactive systemic [AA] amyloidosis mutations assessed at the National Amyloidosis Centre
and β2-microglobulin [β2M] dialysis-related amyloidosis), (NAC) in the UK from 1987 to 2012.9
and, for reasons unknown, accompanying the ageing Patterns of referral to the NAC have changed
process (eg, wild-type transthyretin amyloidosis substantially over the past two decades.9 The frequency of
[ATTRwt; or senile systemic amyloidosis] and atrial AL amyloidosis, as a proportion of total referrals every
natriuretic peptide amyloidosis). year, has essentially remained stable over the decades
More than 30 proteins have been identified to form (67% of all cases). Conversely, a remarkable progressive
amyloid in man,3 but recent use of mass spectrometry to decrease has been seen in the proportion of patients
identify amyloid suggests that many more proteins referred with AA amyloidosis—from 32% of all cases
might be amyloidogenic.4 The most frequent type of during 1987–95 to 6·8% during 2009–12—which probably
amyloidosis in high-income countries is AL amyloidosis. reflects improvement of treatment of inflammatory
The availability of new technologies has improved arthropathies with biological drugs. Referral of patients
diagnosis and enabled accurate fibril typing and better with wild-type TTR amyloidosis (ATTRwt)-related
risk stratification. Outcomes have improved, at least in cardiomyopathy has increased greatly—from fewer than
AL amyloidosis, and several novel therapies are on the ten (0·2%) cases during 1988–99 to more than 100 (6·4%)
horizon for various types of amyloidosis, including cases in 2009–12, which probably reflects the increasing
antibody-based therapy and RNA inhibition strategies.
However, management of patients with advanced organ
involvement at diagnosis remains a major challenge, Search strategy and selection criteria
with nearly a third of all patients with AL amyloidosis A literature search was performed between 1990 and 2014
still dying within a few months of diagnosis. Early using PubMed and Web of Science with the search terms
diagnosis of amyloidosis remains an elusive goal that “amyloidosis” or “amyloid*” and each of “systemic
requires education of both physicians and patients. amyloidosis“, “AL“, “AA“, “ATTR“, “AFib“, “AApoA1”, ”ALys”,
This Seminar reviews progress in the field over the ”Aβ2M”, ”ALect2”, ”epidemiology”, ”imaging”, ”diagnosis”,
past decade. “treatment“, “chemotherapy”, ”stem cell transplantation”, and
“outcome”. We also reviewed conference abstracts of the
Epidemiology of amyloidosis international amyloidosis workshops in Rome 2010 and
Few epidemiological data have been published for Groningen 2012, the Annual Meeting of the American Society
amyloidosis. The first population-based study of AL of Hematology, 2010–2012, and the International Myeloma
amyloidosis was done in Olmsted County, MN, USA, Workshops 2011 and 2013.
and was published in 1992. It reported the incidence of

www.thelancet.com Published online December 21, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01274-X 1

 Seminar

Acquired or Patients seen Underlying Precursor protein Organ involvement Treatment Treatment
hereditary at UK-NAC disorder target
(%; n=5100)
Heart Kidneys Liver PN Other
(AN)
AL Acquired 4067 (68%) Plasma cell Monoclonal +++ +++ ++ +(+) Soft tissue Chemotherapy or dFLC <40 mg/L
dyscrasia immunoglobulin gastrointestinal ASCT
light chain
AA Acquired 633 (12%) Inflammatory SAA –/+ (late) +++ +(late) – Gastrointestinal Suppression of SAA <4 mg/L
disorders (RA, JIA, (late) inflammation
IVDU, FPS)
ATTR Acquired 168 (3·2%) ·· Wild-type TTR +++ – – – Carpal tunnel Supportive Optimum control
syndrome of heart failure
Hereditary 339 (6·6%) Mutations in TTR Abnormal TTR ++ – – +++ (+++) – Liver transplant Optimum control
gene (younger patients of congestive
with heart failure and
V30M-related symptoms of
ATTR), diflunisal, PN/AN
(doxycycline/
TUDCA)
Supportive
AFib Hereditary 87 (1·7%) Mutations in Abnormal – +++ –/+ – – Supportive, organ Preserve renal
fibrinogen fibrinogen transplant function
α-chain gene
ALect2 Acquired 16 (0·3%) Uncertain Lect2 – +++ ++ – – Supportive Preserve renal
function
AApoA1 Hereditary 40 (0·8%) Mutations in Abnormal ApoA1 + ++ ++ +/−(–) Testis Supportive, organ Preserve renal
apolipoprotein A1 transplant function
gene
ALys Hereditary 17 (0·3%) Mutations in Abnormal – + ++ – Gastrointestinal Supportive ··
lysozyme gene lysozyme or skin
AGel Hereditary 4 (0·1%) Mutations in Abnormal gelsolin – -/+ – ++(–) – Supportive ··
gelsolin gene cranial
Aβ2M Acquired or 93 (1·8%) Long-term dialysis Aβ2M – – – – (+*) Carpal tunnel Supportive, renal ··
hereditary syndrome, transplant
arthropathy

Aβ2M=β2-microglobulin-related. AFib=fibrinogen A α-chain. AGel=gelsolin amyloid. AL=amyloid light chain. ALect2=leucocyte cell–derived chemotaxin 2. ALys=lysozyme amyloid. AN=autonomic neuropathy.
ASCT=autologous stem cell transplant. ATTR=amyloid transthyretin. dFLC=difference between involved and uninvolved free light chain. FPS=familial periodic fever syndromes. IVDU=intravenous drug abuse.
JIA=juvenile inflammatory arthritis. PN=peripheral neuropathy. RA=rheumatoid arthritis. SAA=serum amyloid A. TTR=transthyretin. TUDCA=tauro-ursodeoxycholic acid. UK-NAC=UK National Amyloidosis
Centre. *AN only in familial Aβ2M amyloidosis.8 + indicates relative frequency: +++ very common, ++ common; + less common; –/+ rare; – not applicable or does not occur in this condition. (drug)=undergoing
clinical trials. AA=amyloid A. AApoA1= apolipoprotein A1 amyloid.

Table 1: Characteristics of the common types of amyloidosis

contribution of cardiac MRI to diagnosis. The true
incidence of ATTRwt amyloidosis in elderly people
remains unknown, but cardiac amyloid deposits of this
type have been reported at autopsy in a quarter of
individuals older than 80 years.10 Amyloidosis of the
recently described leucocyte chemotactic factor-2 (ALect2)
type11 now seems to be the third most common cause of
acquired renal amyloidosis, occurring predominantly in
patients from South Asia, North Africa, the Middle East,
and Mexico.12–14
The epidemiology of hereditary amyloidosis is poorly
studied, other than familial amyloid polyneuropathy
(ATTR-FAP), which results from mutations in TTR and
occurs with a frequency of less than 1:100 000 in Europe.
The frequency of TTR mutations is high in some
populations. For example, the Val30Met variant of TTR
has a prevalence of 1:538 in northern Portugal15 and 4%
in northern Sweden,16 but penetrance differs markedly
between the two countries—80% in Portugal compared
with 11% in Sweden17—for reasons that are as yet
unclear. In County Donegal in northwest Ireland, the
Thr60Ala variant of TTR has a population prevalence of
1·1%.18 The Val122Ile variant, which is carried by 3–4%
of the African American population, is associated with
late-onset amyloid cardiomyopathy,19 but the disease
penetrance seems to be very low. The population
frequency of other familial amyloidoses remains
unknown. Apolipoprotein A1 (ApoA1) amyloidosis
accounted for 0·8% of all cases of amyloidosis seen at
the NAC, but the population incidence is unknown.
Amyloid fibrils
All amyloid deposits are composed of protein fibrils
that have a remarkably similar structure, with a
diameter of 7–13 nm and a common core structure
consisting of anti-parallel β-strands (less commonly,

2 www.thelancet.com Published online December 21, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01274-X


parallel β-strands) that form sheets.20–23 All amyloid
deposits also contain several minor non-fibrillary
constituents, including glycosaminoglycans (GAGs)
and serum amyloid P component (SAP).24,25 The specific,
highly ordered ultrastructure of amyloid fibrils accounts
for their characteristic property of binding Congo
red dye in a spatial manner that produces green
birefringence when viewed under cross-polarised light.
This birefringence remains the histological gold
standard for confirming the presence of amyloid in
tissue samples. The universal presence of common
non-fibrillary constituents within amyloid deposits is
the basis for specific imaging (SAP scintigraphy) and
novel therapeutic approaches (targeting GAGs26 or
amyloid-associated SAP27).
Clinical features of amyloidosis
The potential for amyloid deposits to affect almost any
organ system means that the clinical features of systemic
amyloidosis are diverse, and they are rarely specific to
one type of amyloidosis, which leads to difficulties and
delays in diagnosis. Table 1 details features of the
common types of amyloidosis. Clinical features that are
virtually pathognomonic of AL amyloidosis include a
combination of macroglossia and periorbital purpura
(figure 1), but these occur in less than a third of all cases.
Isolated periorbital purpura is occasionally seen in other
types of amyloidosis.
Cardiac involvement is the leading cause of morbidity
and mortality in amyloidosis.28 It occurs in about 50% of
patients with AL amyloidosis,29 is a dominant feature in
patients with wild-type and variant ATTR amyloidosis
(although it is rare in patients with Val30Met-associated
disease30), and can be a prominent feature in hereditary
AApoA1 amyloidosis, but it is very rare in AA
amyloidosis.31 Amyloid deposition in the heart typically
presents as restrictive cardiomyopathy, often with
disproportionate signs of right ventricular failure
(oedema, raised jugular venous pressure, and
congestive hepatomegaly), while low cardiac output and
hypotension are features of advanced disease. Patients
with AL amyloidosis are often more symptomatic than
patients with other types of amyloidosis given an
apparently similar degree of amyloid deposition in the
heart, which supports in-vitro evidence of myocardial
cell toxicity of amyloidogenic light chains in this
subtype.32,33
The kidneys are the organs most commonly involved in
AL, AA, fibrinogen A α-chain (AFib), ALect2, and AApoA1
amyloidoses. Albuminuria, which often progresses to
nephrotic syndrome, is typical, but renal dysfunction
might remain asymptomatic until it is very advanced.
AFib amyloidosis, which results from mutations in the
fibrinogen A α chain gene, is the most common hereditary
renal amyloidosis in the UK.34 Proteinuria or renal
dysfunction is a characteristic feature of AA amyloidosis,
and clinical presentation without renal involvement is
www.thelancet.com Published online December 21, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01274-X
Seminar
exceptionally rare.31 The hallmark of hereditary AApoA1
and lysozyme (ALys) amyloidosis is involvement of the
kidneys and liver, which is very slowly progressive,
sometimes over decades.35
Neuropathy is a feature of AL amyloidosis and some
hereditary types of ATTR and AApoA1 amyloidosis.
Amyloid peripheral neuropathy is predominantly
axonal and involves both the small and large fibres. It
begins with loss of the small fibre-mediated sensations
of heat or cold, can be painful,36 and can be difficult
to differentiate from the more common chronic
inflammatory demyelinating polyneuropathy. Auto-
nomic neuropathy causes impotence as an early
symptom in men, which is followed by postural
hypotension, early satiety, and diarrhoea or constipation
(or both). Other than amyloidosis and severe diabetic
neuropathy, diseases that cause a combination of
progressive sensory motor peripheral neuropathy and
autonomic neuropathy are rare. Cranial neuropathy
occurs in hereditary gelsolin (AGel) amyloidosis in
association with corneal lattice dystrophy and cutis
laxa. About a fifth of all patients with systemic AL
amyloidosis have peripheral neuropathy at presentation,
but isolated neuropathy in the absence of other organ
involvement is uncommon in AL amyloidosis.
Involvement of soft tissues, apart from carpal tunnel
syndrome, is almost unique to AL amyloidosis.
Macroglossia, muscular pseudohypertrophy, enlargement
of the salivary glands, and submandibular soft-tissue
infiltration are common. Carpal tunnel syndrome is a
common early symptom in wild-type and hereditary
ATTR amyloidosis, and deposition of wild-type TTR
amyloid is found in about a third of elderly people
undergoing carpal tunnel decompression.37 A history of
carpal tunnel syndrome predating unexplained symptoms
of heart failure in elderly patients should prompt
suspicion of cardiac ATTR amyloidosis.
Localised AL amyloidosis is associated with in-situ
production of amyloidogenic light chains by clonal
B cells in the affected tissue. Common sites include the
respiratory tract, bladder, eyelids, and skin. This form of
amyloidosis is an indolent disease that almost never
evolves systemically, but it can nevertheless have serious
consequences (ie, the mass lesion can occupy space in a
critical area of the body). Local surgical measures to
control symptoms are usually appropriate, and radio-
therapy can have a role in selected cases.38
Diagnosis
A stepwise approach to diagnosis and staging of
amyloidosis is critical and involves confirmation of
amyloid deposition, identification of fibril type,
assessment of the underlying amyloidogenic disorder,
and evaluation of the extent and severity of amyloidotic
organ involvement. Serum cardiac biomarkers are an
important validated method for risk stratification and
staging in AL amyloidosis.39
3
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Clinical features raising suspicion of amyloidosis

• Peri-orbital purpura
• Macroglossia (A)
• Nail dystrophy (B)
• Monoclonal protein and diastolic heart failure with preserved apical systolic
function and “bulls-eye” on 2D strain imaging (C), thick-walled heart with
low-voltage ECG, monoclonal protein and albuminuria, peripheral and
autonomic neuropathy, and family history

A B C

Baseline tests of organ function Confirmation of diagnosis

• Serum creatinine • Tissue biopsy or abdominal fat
• eGFR aspiration for Congo red stain
• 24 h proteinuria • Fibril typing with IHC, IEM,
• FBC or LCMS
• Liver function tests
• Clotting
• ECG
• NT-proBNP
• Troponin T/I

Suspected AL amyloidosis Cardiac investigations Suspected hereditary amyloidosis Where available (to determine and
• Serum and urine SPE/IFE • Echocardiogram • Appropriate genetic sequencing track whole body amyloid load):
123
• Serum FLC For selected cases: I-SAP scintigraphy
• Bone marrow • Cardiac MRI
aspiration/biopsy • 99mTcDPD/pyrophosphate scan
• Skeletal imaging

Figure 1: Clinical features raising suspicion of amyloidosis and diagnostic approach for a patient with suspected systemic amyloidosis
¹²³I-SAP=123-iodine-labelled serum amyloid P component. 2D=two dimensional. ⁹⁹mTc-DPD=99m-technetium-labelled 3,3-diphosphono-1,2-propanodicarboxylic
acid. AL=amyloid light-chain. ECG=electrocardiography. eGFR=estimated glomerular filtration rate. FBC=full blood count. FLC=free light-chain.
IEM=immunoelectronmicroscopy. IFE=immunofixation electrophoresis. IHC=immunohistochemistry. LCMS=laser capture microscopy followed by mass spectrometry.
MRI=magnetic resonance imaging. NT-proBNP=N-terminal pro-brain natriuretic peptide. SPE=serum protein electrophoresis.

Advanced and irreversible organ dysfunction has often
ensued by the time a clinical diagnosis of amyloidosis is
made, so keeping a high index of suspicion is important
for early diagnosis. Specific combinations of symptoms
should trigger suspicion for a diagnosis of amyloidosis,
such as nephrotic syndrome and heart failure; peripheral
and autonomic neuropathy; thick-walled heart failure
with normal or low-voltage electrocardiogram; recurrent
carpal tunnel syndrome; a combination of carpal tunnel
syndrome and heart failure in elderly people; and
appropriate family history (figure 1). Regular testing for
the N-terminal of the prohormone brain natriuretic
peptide (NT-proBNP) and urine sampling for albuminuria
in patients with monoclonal gammopathy of uncertain
significance (MGUS) with abnormal free light chain ratio
of lambda:kappa free light chains should be part of
standard practice, as an abnormality of either may herald
development of amyloidosis.
Histological demonstration of amyloid deposits and
confirmation of fibril type
Demonstration of characteristic green birefringence
under cross-polarised light following Congo red staining
of biopsied tissue remains the gold standard for
confirming deposition of amyloid (figure 2). Novel
fluorescent dyes, such as conjugated polymer
pentameric formic thiophene acetic acid (pFTAA), show
promise for identifying (figure 2) and typing amyloid

4 www.thelancet.com Published online December 21, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01274-X

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deposits.40,41 Biopsy of an organ in which amyloid is Congo red stain (bright field) Immunohistochemistry (anti-SAA antibody)
suspected is the most common approach, but there is a
risk of bleeding, so biopsy should be considered only if
other methods do not reveal amyloid deposits.
Microscopic amyloid deposits are very widespread in
systemic forms of the disease, and abdominal fat
aspiration is a simple and innocuous high-yield
alternative to target organ biopsy. A negative fat aspirate
does not exclude amyloidosis, and biopsy of rectal or
labial salivary glands are alternatives with reasonable
diagnostic sensitivity.42
Confirmation of the type of amyloid fibril is crucial,
since this will guide therapy. Immunohistochemistry
remains the most widely available method for fibril
typing.43 Its diagnostic value is very high in AA
amyloidosis (figure 2) and in most cases of ATTR
amyloidosis, but the results are not definitive in many
patients with AL amyloidosis (appendix). Immuno-
electron microscopy with gold-labelled anti-fibril protein
antibodies is very sensitive but of limited availability.44
Congo red stain (cross polarised light) pTFAA stain (fluorescent microscopy)
The proteomic method of mass spectrometric analysis
of amyloidotic material (appendix) is the new gold
standard for fibril typing.18,19 This method involves laser
microdissection and capture of Congo red-stained
deposits from a fixed tissue section using a laser capture
microscope or the direct use of fat aspirate samples
followed by tryptic digestion and tandem mass
spectrometry. Computer algorithms then match the
peptides to a protein reference database. This is
technically challenging and requires validation in each
laboratory before ‘routine’ clinical use. Gene sequencing
must be performed when there is any suspicion of
hereditary amyloidosis. An online database provides an
updated list of amyloidogenic mutations and an outline
of associated phenotypes in hereditary amyloidosis.

Assessment of the underlying disorder

Assessment or identification of the underlying disorder
is the next step in patients with AL and AA amyloidosis.
A combination of serum and urine testing with
immunofixation electrophoresis (IFE) and measurement
of free light chain (FLC) in serum is required to detect
the often very subtle monoclonal protein underlying AL
amyloidosis45 and will be informative in more than
95% of cases.46 By contrast with the light chain isotype
in MGUS and myeloma, AL fibrils are four times more
often lambda than kappa light chains. The amount of
plasma cell infiltrate in the bone marrow is usually very
modest (median 10%).47,48 Genetic studies of bone
marrow plasma cells and investigations to rule out
myeloma, including bone imaging, should be done
at baseline.49 In patients with AA amyloidosis,
investigations are needed to identify the underlying
inflammatory disorder, including sequencing of the
genes that cause familial periodic fever syndromes
in the 10–20% in whom the cause of AA amyloidosis
is obscure.
Figure 2: Congo red staining of tissue biopsy, the gold standard for confirming amyloid deposition
Top and bottom left panels show Congo red staining (top, bright field) and typical apple green birefringence
(bottom) under cross-polarised light in a patient with AA amyloidosis. Diagnosis was confirmed by
immunohistochemical staining by antibodies to serum amyloid A (SAA; top right panel). Bottom right panel
shows bright green fluorescence exhibited by renal amyloid deposits using the novel luminescent conjugated
polymer pentameric formic thiophene acetic acid (pFTAA) in a patient with AL amyloidosis (pFTAA image
reproduced courtesy of Professor Gunella Westermark, Sweden).
Assessing the extent of disease—role of imaging See Online for appendix
Assessment of amyloid-related end-organ damage
informs prognosis, the need for supportive care, and For the database of
formulation of a risk-adapted treatment plan. SAP amyloidogenic mutations see
http:/www.
scintigraphy, the only specific imaging method available, amyloidosismutations.com
enables the amyloid load in the liver, kidneys, spleen,
adrenal glands, bones, and various other sites to be
ascertained and monitored serially (figure 3).50
Scintigraphy with SAP shows that the quantity of amyloid
present in a given organ correlates poorly with the level
of organ dysfunction and that regression of amyloid

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 Seminar
deposits occurs at different rates in different organs
(figure 3). Dual modality ¹²³I-labelled SAP single-photon
emission computerised tomography (SPECT) facilitates
accurate localisation of deposits of amyloid in soft tissue.
This technique is unable to image amyloid in the moving
heart and is only available at the NAC in London and the
University of Groningen in the Netherlands.
Echocardiography, including tissue Doppler and
strain imaging, is important to document baseline
cardiac structure and function.28,51 Echocardiography
shows “pan-cardiac” thickening (increased thickness of
left and right ventricular free walls, septum, valves, and
intra-atrial septum, with dilatation of the atria), which
is rare in other infiltrative cardiomyopathies. A
thick-walled heart on an echocardiogram but with a
normal or low voltage electrocardiogram remains a
diagnostic hallmark of amyloidosis, with high sensitivity
(72–79%) and specificity (91–100%).52 It is noteworthy,
however, that a substantial proportion of patients with
Pre-treatment 3 years after treatment
Figure 3: ¹²³Iodine-labelled serum amyloid P component scintigraphy
Whole body image (A) shows marked uptake in the liver, with attenuation of the normal blood pool signal in a
patient with systemic AL amyloidosis with liver and renal involvement. The patient was treated with combination
chemotherapy and achieved complete clonal response. A scan after 3 years (B) shows near complete regression of
amyloid deposits from the liver, with return of the normal blood pool signal. Uptake is seen in the kidneys (arrows),
which were previously obscured by uptake in the enlarged amyloidotic liver. AL=amyloid light-chain.
6 www.thelancet.com Published online December 21, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01274-X
cardiac ATTR do not have reduced QRS voltages on
electrocardiography but rather have an inappropriately
“normal” voltage on ECG for the degree of left
ventricular wall thickening. Two-dimensional (2D)
strain mapping shows relative preservation of apical
function, which can be an early clue to amyloidosis,
since it gives rise to a “bulls-eye” pattern when the
segmental strain is plotted (figure 1D), which is rare in
other cardiomyopathies.
Cardiac MRI has been an important imaging
development, since it is easily available and has high
specificity for diagnosis of cardiac amyloidosis.53,54
Amyloid cardiomyopathy demonstrates a typical pattern
of late subendocardial or diffuse enhancement after
gadolinium contrast injection (figure 4).39,40 Cardiac MRI
can give accurate anatomical information, including the
wall thickness and left ventricular mass. Equilibrium
contrast MRI (Eq-CMR) uses a low-dose gadolinium
infusion for contrast and allows accurate quantification
of the myocardial interstitial volume fraction, which is
greatly expanded in amyloidosis,55 therefore providing a
novel tool to monitor amyloid load in the heart.
The bone-seeking radionuclide tracers ⁹⁹m-technetium-
3,3-diphosphono-1,2-propanodicarboxylic acid (⁹⁹mTc-DPD)
and ⁹⁹mTc-pyrophosphate (⁹⁹mTc-PYP) also seem to localise
with remarkable sensitivity in cardiac ATTR deposits.56–61
Scans with ⁹⁹mTc-DPD seem to show asymptomatic ATTR
cardiac deposits before any other imaging modality.62
Uptake into other types of cardiac amyloid may occur,
but this is usually minor (figure 4).60 Scintigraphy with
⁹⁹mTc-DPD/PYP may have a role in screening for cardiac
ATTR amyloidosis in elderly patients with cardiac failure
of unclear aetiology and in differentiating cardiac ATTR
from other types of cardiac amyloidosis.
Scintigraphy with ¹²³I-labelled meta-iodobenzyl-
guanidine (¹²³I-mIBG) can provide information on cardiac
autonomic neuropathy, but its place in clinical practice
remains to be established.63,64 PET tracers developed to
image amyloid in the brain of patients with Alzheimer’s
disease have potential value for systemic amyloidosis, and
¹¹C-labelled Pittsburgh Compound-B (¹¹C-PiB)65 and
florbetapir66 have shown promise in imaging cardiac
amyloidosis, particularly the latter (an imaging agent
licensed for Alzheimer’s disease), which might show
different patterns in AL and ATTR amyloidoses.
Risk stratification and staging
The prognosis of patients with amyloidosis is influenced
by the extent of organ damage, especially by cardiac
involvement in those with AL amyloidosis. Risk
stratification in patients with AL amyloidosis is critical for
optimum selection of therapy. Various variables are
powerful clinical indicators of poor outcome, including
poor performance status, severe postural hypotension,
New York Heart Association functional class 3 or higher,
and low systolic blood pressure (SBP; <100 mm Hg).67
Increased concentrations in serum of the cardiac
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A B C

Figure 4: ⁹⁹mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (⁹⁹mTc-DPD) scintigraphy (A, B and C) and cardiac MRI (D)
(A) Scan of a patient with systemic AL amyloidosis with cardiac involvement, showing low-grade cardiac uptake of ⁹⁹mTc DPD in the heart. (B) Scan of a patient with
senile cardiac amyloidosis due to deposition of wild-type variant transthretin amyloid (ATTRwt), showing striking uptake of ⁹⁹mTc-DPD in the heart, with marked
reduction in the bone signal—a pattern characteristic of cardiac TTR amyloidosis. (C) ⁹⁹mTc DPD-gated SPECT image of the patient shown in (B), demonstrating
greater involvement of the septum and base of the heart, with relative sparing of the apex of the left ventricle, which is in keeping with sparing of apical cardiac
function on echocardiography. (D) Cardiac MRI scan of a patient with AL amyloidosis, showing typical subendocardial ring of enhancement after gadolinium contrast
injection. AL=amyloid light-chain. ATTRwt=wild-type variant transthretin amyloid. SPECT=single-photon emission computed tomography. TTR=transthyretin.

biomarkers NT-proBNP (>332 ng/l), cardiac troponin-T
(cTNT) and cardiac troponin-I (cTNI) (cTNT
>0·035 ng/mL, cTnI >0·1 ng/mL, or high-sensitivity
troponin >0·077 ng/mL)68 provide the basis of the
well-validated Mayo Clinic staging system.39 Those in
whom both biomarkers are abnormal (stage III) have
median survival of 7–8 months.39,68,69 Patients with
NT-proBNP >8500 ng/L (especially in the presence of SBP
<100 mm Hg) had median survival of 3 months in a
historical series70 and can be called stage IIIb. Patients with
higher concentrations of FLC at diagnosis also have
poorer outcomes,71,72 as do patients with bone marrow
plasmacytosis greater than 10% at presentation.73 A staging
system for renal involvement in AL has been published.74
Management
Principles of treatment
A reduction in the supply of precursor proteins for amyloid
fibril underpins all current treatment for amyloidosis,
although this is not yet possible for some types. Various
drugs can be very effective in AL and AA amyloidoses but
are often poorly tolerated because of impaired organ
function. Orthotropic liver transplantation to remove or
diminish the hepatic source of genetically variant
amyloidogenic proteins has a role in selected patients with
hereditary ATTR, AApoAI, and AFib amyloidoses.
Assessment of response in patients with amyloidosis
comprises dual evaluation of a treatment’s suppression
of supply of amyloid precursor protein and its effects on
the function of the affected amyloidotic organs, which is
substantially dependent on the former. Concentrations
of SAA lower than 4 mg/L are associated with best
outcomes in AA amyloidosis. Consensus criteria to
define haematological and organ responses (which are
strong predictors of survival) in AL amyloidosis have
been published.75,76 Patients who achieve a complete
response (no detectable monoclonal immunoglobulin
[M] band in serum or urine by immunofixation and
normal serum free light chains) or very good partial
response (dFLC <40 mg/:) have the best outcomes.76 A
partial response—that is, a reduction of 50% or more in
concentrations of aberrant FLC—is no longer considered

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 Seminar
100 2008–12 median not reached; estimated 4 year OS 50%
2004–07 median 2·2 years; estimated 4 year OS 38%
2001–03 median 1·7 years; estimated 4 year OS 34%
1996–2000 median 1·4 years; estimated 4 year OS 28%
≤1995 median 1·5 years; estimated 4 year OS 28%
80
60
Survival (%)
40
20
0
0 5 10 15
Time (years)
Figure 5: Kaplan–Meier survival curve showing improvement over time in overall survival of patients with
systemic AL amyloidosis seen at the National Amyloidosis Centre in the UK (n=3486)
Estimated 4-year survival has improved from 28% for patients diagnosed in the early part of the past decade to
nearly 50% for patients diagnosed in the past four years (log rank p values: p=0·008 for 2008–12 vs 2004–07;
p=0·03 for 2004–07 vs 2001–03; p=0·29 for 2001–03 vs 1996–2000; p=0·64 for 1996–2000 vs up to 1995). This
improvement in survival coincides with the availability of novel agents such as thalidomide and bortezomib for the
treatment of AL amyloidosis. However, over the past two decades, no improvement has been seen in early
mortality in the first few months after diagnosis of AL amyloidosis. AL=amyloid light chain. OS=overall survival.
satisfactory in many patients.76 A decrease in serum
levels of NT-proBNP of 30% or 300 ng/L is a robust
measure of cardiac response and a powerful guide to
adequacy of treatment in AL amyloidosis.68
Supportive care, with multidisciplinary involvement, is
crucial to control symptoms, maintain organ function,
and manage treatment toxic effects. Supportive measures
include meticulous control of blood pressure in patients
with renal amyloidosis, strict fluid management in those
with cardiac amyloidosis (including judicious use of
diuretics and avoidance of angiotensin-converting
enzyme inhibitors in patients with low blood pressure),
use of α-agonists such as midodrine in patients with
autonomic neuropathy that is causing severe postural
hypotension, and adequate nutritional support.
Treatment of AL amyloidosis
Treatment of AL amyloidosis comprises chemotherapy
that targets the underlying clonal plasma cell dyscrasia,
with the aim of rapidly reducing production of
amyloidogenic light chains to limit progressive damage
to amyloidotic organs.75 The plasma cell dyscrasias that
underlie AL amyloidosis can range from benign MGUS
(which does not otherwise need treatment) to frankly
malignant plasma cell proliferation (eg multiple
myeloma). Most patients with AL amyloidosis have
plasma cell dyscrasia at the MGUS end of the spectrum,
but 10–15% have truly comorbid multiple myeloma.
Over the past decade, the remarkable progress in drugs
for multiple myeloma, which have been adapted for AL
amyloidosis, has translated into improved treatments for
8 www.thelancet.com Published online December 21, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01274-X
patients with AL amyloidosis.77 The reduced functional
reserve of amyloidotic organs and poor performance
status results in much greater treatment toxicity in AL
amyloidosis, so a risk-adapted approach to treatment is
critical. Frequent assessments of haematological
response are needed, with a view to changing treatment
rapidly (as early as three cycles). Median survival in
patients with AL amyloidosis has nearly doubled over
the past decade, but nearly one-quarter of all patients
still die of disease-related complications within a few
months of diagnosis (figure 5). With successful
treatment, such as autologous stem cell transplant
(ASCT),78 outcomes in AL amyloidosis are superior to
those in myeloma,78 presumably because of the smaller
clonal burden79 and the lack of high-risk cytogenetics in
AL amyloidosis.80 Table 2 details treatment regimens and
outcomes for AL amyloidosis.
Patients with AL amyloidosis can be classified as at low,
intermediate, or high risk. Low-risk patients are those
with excellent performance status; NT-proBNP lower
than 5000 ng/mL; cTNT lower than 0·06 ng/mL, no
significant pleural effusions, autonomic neuropathy, or
amyloid-related gastrointestinal bleeding; and good renal
function. Such patients, who represent about 15–20%
of all cases, are potential candidates for high-dose
melphalan followed by ASCT.94–96 Although a small
randomised trial failed to prove superiority of ASCT over
chemotherapy,86 data from various non-randomised
studies show excellent clonal response rates—that is,
very good partial light chain responses (VGPR) in 56% of
patients,97 44% of whom achieved a complete clonal
response98 that translated to improvement in organ
function in three-quarters of such patients, progression
free survival (PFS) longer than 8 years (an endpoint
not yet reported with a non-transplant approach), and
median overall survival longer than 10 years.87 Autologous
stem cell transplantation can be undertaken safely given
strict selection of patients, particularly using cardiac
biomarkers with recent treatment-related mortality lower
than 10%.94,95 A strategy in which bortezomib is used for
induction or consolidation seems to achieve the desired
VGPR target in >90% of treated patients.99,100 Although
early response rates of this order are now possible using
combinations of novel drugs, long-term outcomes
remain to be proven.87 Autologous stem cell trans-
plantation is best undertaken in centres with experience
in amyloidosis.
Most patients with AL amyloidosis are at intermediate
risk and are treated with combination chemotherapy
regimens. The wide choice of treatment regimens
without randomised data comparing their efficacy
makes selection of the best treatment for these patients
difficult; with different paths followed in different
countries it is crucial to enrol patients with this rare
disease into clinical trials. Regimens such as oral
melphalan with dexamethasone (MDex) and a
risk-adapted strategy involving a combination of
 Seminar

Number of Response (%) Median progression- Median overall

patients free survival (years*) survival (years)
Clonal, % of Organ
responders (%
with complete
response)
Standard chemotherapy
Oral melphalan–dexamethasone81,82 46 67% (33%) 48% 3·8 5·1
Cyclophosphamide–thalidomide–dexamethasone83 75 74% (21%) 27% 1·7 3·4
Bortezomib84 70 69% (38%) 29% At 12 months: 75% 84%
Lenalidomide–dexamethasone85 22 41% (–) 23% 1·6 ··
ASCT
ASCT86 37 67% (41%) 45% 2·7 1·8
ASCT87 421 ·· (43%) 53% 3·4 8·4
Risk-adapted ASCT (followed by bortezomib consolidation)88 40 79% (58%) 70% At 2 years: 69% At 2 years: 82%
Novel chemotherapy combinations
Cyclophosphamide–bortezomib–dexamethasone89 43 81% (65%) 46% At 2 years: 53% At 2 years: 98%
Cyclophosphamide–lenalidomide–dexamethasone90 35 60% (11%) 31% 2·4 3·1
Melphalan–lenalidomide–dexamethasone91 26 58% (23%) 50% At 2 years: 54% At 2 years: 81%
Pomalidomide–dexamethasone92 33 48% (3%) 15% 1·2 2·3
Ixazomib93 16 42% (8%) ·· ·· ··

*Unless otherwise specified. ··=data not available. ASCT=autologous stem cell transplant.

Table 2: Treatment regimens for patients with AL amyloidosis

cyclophosphamide, thalidomide, and dexamethasone
(CTDa) were accepted as the standard of care for AL
amyloidosis81 and are associated with haematological
responses in 65–75% patients within 3–4 months of
treatment.81,83 Proteasome inhibitors are a new class of
drugs for myeloma,101 and the plasma cells of patients
with AL amyloidosis seem to show exquisite sensitivity
to them.102 The use of bortezomib—the first such agent
in clinical practice—as a single agent or augmented by
dexamethasone produces high clonal response
rates in patients with AL as initial treatment and after
relapse.103–105 A combination of bortezomib with
cyclophosphamide and dexamethasone (CyBorD) gives
very high response rates >90% for patients treated
upfront, with 60% achieving complete response or
VGPR.89,106 This treatment therefore offers the hope of
very rapid and deep clonal responses and improvements
in function of organs, including the heart, and it is the
front-line treatment of choice in most intermediate-risk
patients. An international randomised phase 3 trial is
comparing the addition of bortezomib to standard
MDex, and results of studies with newer proteasome
inhibitors such as ixazomib (which is administered
orally) and carfilzomib (which has reduced neurotoxic
effects) are awaited with interest.
Lenalidomide and pomalidomide are newer immuno-
modulatory agents with better toxicity profiles than
thalidomide. Good responses are reported with both
agents,85,92,107 especially when combined with alkylators,91,108,109
but complete responses are lower than those reported
with bortezomib-based therapies. Lenalidomide and
pomalidomide are useful for patients with relapsed or
refractory disease after previous proteasome inhibitors and
for those presenting with neuropathic disease.
No particular regimen has yet been shown to be
superior or to reduce early cardiac deaths in very
high-risk (stage IIIb) patients.70 The need for a rapid
response often leads to selection of a bortezomib-based
regimen, but improvements in outcomes with
bortezomib in this patient population remain to be
proven.110 Chemotherapy should be started at low
doses, and the patient should be kept under very close
monitoring (especially cardiac monitoring) because of
the high risk of destabilising organ function with drug
toxic effects. Improved outcomes in this subset are a
major unmet medical need.
Treatment of AA amyloidosis
Reduction of the SAA production with treatment of
the underlying inflammatory disorder is the key to
management of AA amyloidosis.31 Choice of therapy
depends on the nature of the underlying problem.
Antimicrobial therapy is needed for patients with AA
amyloidosis in whom infection is the main problem—
for example, bronchiectasis or tuberculosis. Colchicine
is a highly effective treatment for familial Mediterranean
fever.111,112 Biological therapies, predominantly tumour
necrosis factor (TNF) inhibitors such as etanercept,
infliximab and adalumimab, have improved outcomes
in patients with rheumatological disorders.113,114
Interleukin-1 blockade with anakinra or canakinumab
is highly effective in auto-inflammatory disorders,

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 Seminar
including TNF-related periodic fever syndrome
(TRAPS)115,116 and cryopyrin-associated periodic fever
syndromes (CAPS).117,118 Patients with AA amyloidosis in
whom the underlying inflammatory disorder cannot be
characterised might also respond to specific inhibition
of interleukin (IL) 1 or IL-6.
Glycosaminoglycans are a universal constituent of all
amyloid deposits, and inhibition of the interaction
between GAGs and amyloid fibrils is a promising
approach to treatment of AA amyloidosis. Eprodisate—a
negatively charged, sulphonated molecule of low
molecular weight (with structural similarities to heparan
sulphate)119—is hypothesised to inhibit formation of AA
amyloid fibrils by interfering with their interaction with
GAGs.120 In a phase 3, placebo-controlled trial in patients
with AA amyloidosis,25 eprodisate was associated with
half the risk of reduced creatinine clearance; another trial
is underway to confirm these findings.
Treatment of hereditary amyloidosis
Treatment of patients with hereditary amyloidosis
remains unsatisfactory. The main approach is organ
transplantation to replace a failing amyloidotic organ.
When the liver is the major source of the precursor
protein, this also may be transplanted in order to replace
the mutant amyloidogenic protein with the normal
non-amyloidogenic protein.121
Organ transplantation for hereditary amyloidosis
Fibrinogen, TTR, and ApoA-I are synthesised mainly
in the liver. Hence, liver transplantation has a role in
patients with amyloidosis resulting from mutations in
the respective genes. Although organ transplantation can
be a lifesaving procedure in patients with hereditary
amyloidosis, careful selection and counselling of patients
are important. Procedure-related morbidity can be high
due to amyloidotic organ damage; additional risks
are associated with long-term immunosuppression,
including secondary malignancies and renal impairment.
Liver transplantation is the treatment of choice in
younger patients with hereditary ATTR amyloidosis
associated with the Val30Met variant and early in the
disease course.122 Liver transplantation can be beneficial
in some patients with other TTR mutations, but the near
universal presence of cardiac amyloid deposits in such
patients has proved very problematic, as wild-type TTR
can still be deposited as amyloid on the pre-existing
template of amyloid already present in the heart.123
Curiously, although the liver is the site of production of
TTR, amyloid deposition in patients with ATTR
amyloidosis does not occur in the liver itself. The liver is
healthy, and healthy livers from patients with hereditary
ATTR amyloidosis thus have been used as domino grafts
for patients with other types of liver disease,124 although
recipients can develop acquired ATTR amyloidosis.125–127
Cardiac disease is the dominant clinical feature in
patients with ATTRwt and V122I-related ATTR
10 www.thelancet.com Published online December 21, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01274-X
amyloidosis, and highly selected younger patients have
been reported to do very well after cardiac
transplantation.128,129
Hereditary AFib is predominantly a renal disease34 and
outcomes after renal transplantation are reasonably
good, with median graft survival of about 6 years, limited
by recurrent renal deposition of amyloid.34 Liver
transplantation at the same time as kidney transplantation
has been shown to eliminate the amyloidogenic variant
and prevent further deposition of amyloid,130 but the
procedure-related mortality is high and long-term
benefits are yet to be shown.131
Patients with AApoAI amyloidosis have a variable
disease phenotype depending on the specific mutation.132,133
Reported long-term outcomes of liver, kidney, and heart
transplantation have been remarkably good134 despite
recurrent deposition of amyloid.
Novel therapies for transthyretin amyloidosis
Several very promising therapies are in development for
ATTR amyloidosis. In-vitro studies indicate that the
amyloidogenic misfolding of TTR can be inhibited by
compounds that bind TTR in the plasma to maintain its
normal soluble native tetrameric structure. Tafamidis, a
novel TTR stabiliser, has been developed specifically to
treat ATTR amyloidosis.135 In a small phase 3 trial,
neuropathic disease in patients with Val30Met-related
ATTR amyloidosis progressed at a slower rate over
18 months with tafamidis than with placebo,136 leading to
marketing approval of the drug by the European Medicines
Agency. Other stabiliser drugs are also in development.137
Diflunisal, a non-steroidal anti-inflammatory drug,
stabilised transthyretin in vitro,138,139 reduced the rate of
neurological progression, and preserved quality of life at
2 years compared with placebo.140 Diflunisal is a cheaper
and, on the basis of limited data, an apparently equally
efficacious alternative to tafamidis for the treatment of
neuropathic ATTR amyloidosis. In-vitro data suggest that
doxycycline and tauro-ursodeoxycholic acid (TUDCA)
may interfere with the process of TTR fibrillogenesis,
with a phase 2 trial in Italy reporting stable disease over
18 months among patients with ATTR-FAP amyloidosis
treated with a combination of these drugs. In a slowly
progressive disease with limited recovery of function,
assessment of the real value of any of these agents remains
challenging, and no study has yet compared either of
these strategies.
Transthyretin is almost exclusively synthesised by the
liver, which is the anatomical site most efficiently
targeted by novel RNA-inhibiting therapies. Two such
approaches are now in clinical development: small
interfering RNA therapy and anti-sense oligonucleotide
therapy.141 Both approaches seem to be highly effective,
reducing levels of ATTR by >80% in healthy volunteers
and patients with ATTR amyloidosis, without major toxic
effects,142 and thus hold great promise for patients with
ATTR amyloidosis.

Enhancing regression by immunotherapeutic
targeting
Interest is growing in developing therapeutic antibodies
to target amyloid deposits directly. A chimeric antibody,
Mu11–1F4, reacts with many AL fibrils;143,144 its localisation
has been studied in patients with PET imaging145 and it
is now in phase 1 clinical trials. Another monoclonal
antibody, mAb2A4, binds AL/AA fibrils and human AL
amyloid extracts,146 leading to regression of amyloid in
mouse models of AA and AL amyloidosis. This antibody
has been further developed as NEOD001 and has
recently completed phase 1 trials in systemic amyloidosis
in the USA, showing promising improvement in cardiac
biomarkers and proteinuira.
Serum amyloid P component binds to all amyloid fibrils
in vitro and protects them from degradation by phagocytic
cells and proteolytic enzymes.147 We have developed
R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]
pyrrolidine-2-carboxylic acid (CPHPC, or GSK2315698), a
drug that cross-links pairs of SAP molecules in vivo148 and
triggers their prompt and virtually complete clearance
from the blood. Clinical studies indicate that GSK2315698
is well tolerated and safe and causes rapid and sustained
depletion of circulating SAP,149 but it leads only to gradual
depletion of SAP from amyloid deposits. However,
antibodies to SAP can then target the SAP remaining on
amyloid deposits, and as SAP is a universal component of
amyloid deposits, these antibodies will target all types
of amyloid fibril proteins. In a mouse model of AA
amyloidosis, they produced rapid clearance of amyloid
deposits by macrophage- and complement-mediated
mechanisms.27 Early results of a phase 1 trial using the
combined approach of GSK2315698 and GSK2398852, a
monoclonal antibody to SAP, appear to show promising
results with marked and rapid reduction in liver amyloid
deposits, but data on efficacy in cardiac and renal disease
are awaited.150
In summary, amyloidosis is not as rare as perceived,
should be suspected early by clinicians of all specialties,
and is very treatable, with newer therapies holding
promise of rapid organ recovery and better survival.
Contributors
ADW designed the paper, performed the literature search, and wrote the
paper. JDG and PNH designed and wrote the paper.
Declaration of interests
ADW has received honoraria from Janssen-Cilag and Celgene. JDG and
PNH declare no competing interests.
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