The New England Journal of Medicine
Review Articles
Medical Progress
T HE S YSTEMIC A MYLOIDOSES
RODNEY H. FALK, M.D., RAYMOND L. COMENZO, M.D.,
AND MARTHA SKINNER, M.D.
A
MYLOIDOSIS is not a single disease but a
term for diseases that share a common fea-
ture: the extracellular deposition of patho-
logic insoluble fibrillar proteins in organs and tis-
sues. In the mid-19th century, Virchow adopted the
botanical term “amyloid,” meaning starch or cellu-
lose, to describe abnormal extracellular material seen
in the liver at autopsy.1 Subsequently, amyloid was
found to stain with Congo red, appearing red mi-
croscopically in normal light but apple green when
viewed in polarized light.2,3 Almost a century after
Virchow’s observations, the fibrillar nature of amy-
loid was described with the use of electron micros-
copy and the characteristic beta-pleated–sheet con-
figuration, now believed to be responsible for the
typical staining properties, was identified.4-6
A major development was the recognition that
amyloid fibrils in primary amyloidosis are fragments
of immunoglobulin light chains.7 Subsequently, it
was determined that different proteins made up the
amyloid fibrils in reactive (secondary) amyloidosis
and familial amyloidosis,8,9 opening the way to spe-
cific therapies designed to target the source of fibril-
precursor production.
In this article, we describe the classification, epi-
demiology, pathogenesis, clinical features, diagnosis,
and prognosis of amyloidosis, particularly the two
types most common in the United States — im-
munoglobulin-light-chain–related (AL) and familial
transthyretin-associated (ATTR). Advances in treat-
ment, particularly those of the past five years, are de-
scribed.
From the Amyloid Treatment and Research Program (R.H.F., R.L.C.,
M.S.), Department of Medicine, and the Transfusion Medicine Program
(R.L.C.), Department of Pathology and Laboratory Medicine, Boston
Medical Center, Boston University School of Medicine, Boston. Address
reprint requests to Dr. Falk at the Section of Cardiology, Boston Medical
Center, D 8, E. Newton St. Campus, 1 Boston Medical Center Pl., Boston,
MA 02118.
©1997, Massachusetts Medical Society.
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CLASSIFICATION AND EPIDEMIOLOGY
The modern classification of amyloidosis is based
on the nature of the precursor plasma proteins that
form the fibril deposits.10 These plasma proteins are
diverse and unrelated, but all produce amyloid de-
posits with a common beta-fibrillar structure. Sever-
al of the specific proteins and their amyloid classifi-
cations are listed in Table 1.
The epidemiology of amyloidosis is difficult to de-
fine precisely, since the disease is often undiagnosed
or misdiagnosed and selection bias potentially makes
data from tertiary referral centers unrepresentative.
The age-adjusted incidence of AL amyloidosis is es-
timated to be 5.1 to 12.8 per million person-years,
which means that there are approximately 1275 to
3200 new cases annually in the United States.11 The
incidence of ATTR amyloidosis is unknown, but it
is less common than AL amyloidosis, with the num-
ber of diagnosed cases in referral centers represent-
ing 10 to 20 percent of the number of cases of AL
amyloidosis. A possible exception may be the recent-
ly described variant-sequence transthyretin associat-
ed with late-onset cardiac amyloidosis in blacks,12,13
caused by the substitution of isoleucine for valine in
codon 122 of the transthyretin gene (Ile 122).
PATHOGENESIS
The final pathway in the development of amyloi-
dosis is the production of amyloid fibrils in the ex-
tracellular matrix. The process by which precursor
proteins produce fibrils appears to be multifactorial
and to differ among the various types of amyloid. In
AL amyloidosis, the demonstration that substitutions
of particular amino acids at specific positions in the
light-chain variable region occur at significantly high-
er frequencies than in nonamyloid immunoglobulins
has led to the suggestion that these replacements de-
stabilize light chains, increasing the likelihood of fi-
brillogenesis.14,15
A similar situation may exist in ATTR amyloidosis.
Normal transthyretin is a tetrameric protein with
four identical subunits.16 Inherently unstable variant
monomers, produced by the substitution of amino
acids, may allow the protein to precipitate when pro-
voked by physical or chemical stimuli, such as the lo-
cal surface pH, electric field, and hydration forces on
cellular surfaces.17 Such stimuli may be responsible
for the deposition of amyloid in both AL and ATTR
amyloidosis and may explain the organ specificity of
amyloid deposits.
An intriguing role for aging has been postulated in
the formation of amyloid fibrils, since patients with
 M E D I CA L P RO G R E S S

TABLE 1. CHARACTERISTICS OF THE SYSTEMIC AMYLOIDOSES.*

TYPE FIBRIL COMPOSITION PRECURSOR PROTEIN CLINICAL FEATURES LABORATORY STUDIES FOR DIAGNOSIS

AL (primary) Monoclonal immuno- l or k light chains (ratio Cardiomyopathy, hepatomegaly, pro- Immunofixation electrophoresis of
globulin light chains of l to k, 3:1) teinuria, macroglossia, orthostasis, urine and serum, bone marrow bi-
autonomic and peripheral neurop- opsy with immunohistochemical
athy, ecchymoses staining for l and k light chains
ATTR (familial) Transthyretin Abnormal transthyretin Midlife onset of peripheral and auto- Serum isoelectric focusing for abnor-
(50 identified) nomic neuropathy, cardiomyopa- mal transthyretin or DNA-based
thy, vitreous opacities test for mutant transthyretin gene
AA (secondary) Amyloid A protein Amyloid A protein Underlying inflammatory disorder, Elevated concentrations of serum
hepatosplenomegaly, proteinuria, amyloid A protein, immunohisto-
renal insufficiency, orthostasis chemical staining of tissue speci-
men for AA protein
Other familial types Genetic studies at special centers
AApoA-I Apolipoprotein A-I Apo A-I Polyneuropathy, nephropathy
AGel Gelsolin Gelsolin Lattice dystrophy of cornea, corneal
neuropathy
AFib Fibrinogen A  Fibrinogen A a Nephropathy, hypertension
ALys Lysozyme Lysozyme Nephropathy, hepatomegaly

*In addition, systemic amyloidosis is associated with hemodialysis and localized forms of amyloidosis are associated with Alzheimer’s disease, type II
diabetes, medullary carcinoma of the thyroid, and atrial amyloid deposition.

variant transthyretin do not have clinically apparent
disease until midlife, despite the lifelong presence of
abnormal transthyretin. Once the symptoms start,
however, disease progression is usually rapid, suggest-
ing an age-related trigger. Further evidence of such a
trigger is that senile cardiac amyloidosis, caused by
the deposition of fibrils derived from normal trans-
thyretin, is exclusively a disease of elderly people.18
A role for the precipitation of amyloid fibrils by
“seeding” has been demonstrated in vivo, suggest-
ing that amyloid begets amyloid.19 This again may
partly explain why extensive amyloid deposition is
sometimes concentrated in certain organs in an in-
dividual patient and does not progress in other parts
of the body. Studies of fibrillogenesis may help ex-
plain the aggressiveness of the disease with some
amyloidogenic precursor proteins and the slow pro-
gression with others. The three most common forms
of amyloidosis — namely AL, ATTR, and amyloid
protein A (AA) — differ entirely in their pathogen-
esis. Although there are overlapping characteristics,
certain clinical features may suggest one form of the
disease or another.
AL Amyloidosis
In AL amyloidosis, a plasma-cell dyscrasia related
to multiple myeloma, clonal plasma cells in the bone
marrow produce immunoglobulins that are amy-
loidogenic.7,20 In affected patients, 5 to 10 percent of
bone marrow plasma cells (normal, 4 percent) have
clonal dominance of a light-chain isotype on immu-
nohistochemical staining and, in addition, produce
urinary free monoclonal light chains (commonly
termed Bence Jones proteins) of the dominant k or
l isotype, usually excreting less than a gram of mon-
oclonal protein per day. When the amyloid-subunit
proteins are submitted to amino acid–sequencing
studies, the main constituent of AL deposits is the
light-chain variable region and less frequently parts
of the constant region or of the whole immunoglob-
ulin.21,22 Why some immunoglobulin light chains
form amyloid and others do not is unknown.
More than 50 monoclonal proteins have been iso-
lated from the urine or tissue deposits of patients
with AL amyloidosis.23 On the basis of clinical expe-
rience at several centers and the published sequences
of AL amyloid proteins, the ratio of k to l light
chains (1:3) is the reverse of that both in the normal
state and in myeloma, in which the ratio is 3:2. In
addition, lVI and kI are the most common light-
chain subgroups in patients with AL amyloidosis.
Since lVI light chains account for less than 5 per-
cent of normal immunoglobulin but are found in a
substantial fraction of AL amyloid proteins, the
claim that all light chains in this subgroup are amy-
loidogenic has been made.21
The genetics of AL amyloidosis are currently being
investigated. Among the known kI light-chain amy-
loid sequences, a preponderance appear to be derived
from one pair of k variable region germ-line genes
(O18–O8 and L18), suggesting that some germ-line
genes or allelic variants may be more prone than oth-
ers to mutations that give rise to amyloidogenic light
chains.23 In addition, the use of molecular genetics
has enabled investigators to detect monoclonal cells
containing the identical clonal immunoglobulin-gene
rearrangement in the patient’s peripheral blood as
found in his or her marrow plasma cells.24

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 The New England Journal of Medicine
Familial Amyloidoses
The familial amyloidoses constitute a group of au-
tosomal dominant diseases in which a mutant pro-
tein forms amyloid fibrils beginning in midlife.25
The most common form is caused by mutant trans-
thyretin (ATTR); however, mutations of apolipopro-
tein A-I, gelsolin, fibrinogen A a, and lysozyme also
lead to amyloidosis.26-29
Transthyretin, a transport protein for thyroxine
and retinol-binding protein, is primarily synthesized
in the liver but is also produced in the choroid plex-
us.30,31 More than 50 different substitutions of single
amino acids in transthyretin cause familial amyloi-
dotic polyneuropathy. The most common are a sub-
stitution of methionine for valine at position 30
(Met 30), which occurs in persons of almost every
racial and ethnic background, and alanine for threo-
nine at position 60 (Ala 60), occurring in persons of
English and Irish ancestry.32-34 Recently, a unique
form of cardiac amyloidosis has been described in
which isoleucine is substituted for valine at position
122 (Ile 122).35-37 The importance of the Ile 122
variant lies in the observation that 3.9 percent of the
black population carry the mutant gene (allele fre-
quency of 0.02).12 Cardiomyopathy due to Ile 122
amyloidosis has been described in homozygous and
heterozygous patients, but its prevalence is unknown
owing to the almost certain fact that it is underdiag-
nosed because of the lack of awareness by physicians.
Although the transthyretin mutations are inherit-
ed in an autosomal dominant fashion, studies of Met
30 have demonstrated that the age of onset appears
to vary according to racial or ethnic group and that
about 10 percent of gene carriers never have symp-
toms.38-40 This observation suggests that other ge-
netic or environmental factors may have a role in the
phenotypic expression of these diseases.
Secondary Amyloidosis
The secondary amyloidoses are due to amyloid
formed from serum amyloid A (SAA), an acute-
phase protein produced in response to inflamma-
tion.41 There are several SAA proteins, and in hu-
mans, AA amyloid deposits consist of fragments of
at least five different molecular forms.42,43 With the
virtual abolition of chronic infectious diseases such as
tuberculosis, osteomyelitis, and bronchiectasis from
the Western Hemisphere, AA amyloidosis is rarely
seen. However, it still occurs in patients with rheu-
matoid arthritis, inflammatory bowel disease, and
untreated familial Mediterranean fever.44
CLINICAL FEATURES
AL Amyloidosis
Since AL amyloidosis has the widest spectrum of
organ involvement, it will be discussed in detail and
contrasted with the presentation of ATTR and AA
amyloidosis. The presenting features of this disease
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are protean. A patient’s symptoms reflect the organ
or organs most prominently involved, although his-
tologic examination will reveal some degree of amy-
loid deposition in virtually every organ system except
the central nervous system. The initial symptoms are
frequently fatigue and weight loss, but the diagnosis
is rarely made until symptoms or signs referable to a
particular organ appear.20
The organs most commonly involved are the kid-
ney and the heart, either individually or together.
Renal amyloidosis usually manifests as proteinuria,
often resulting in the nephrotic syndrome. Massive
proteinuria with profound edema and hypoalbumin-
emia may occur with normal serum creatinine and
blood urea nitrogen concentrations, but evidence of
mild renal dysfunction is frequently found. AL amy-
loidosis rarely presents as progressive renal failure,
and even in the presence of a markedly elevated se-
rum creatinine concentration systemic hypertension
is uncommon.
Cardiac involvement is also a common presenta-
tion. Congestive heart failure, usually rapid in onset
and progressive, may be preceded by asymptomatic
electrocardiographic abnormalities. The characteris-
tic clinical features of heart failure are predominantly
right-sided heart physical signs (markedly elevated
jugular venous pressure, a right-sided third heart
sound, peripheral edema, and hepatomegaly) with
low voltage on the electrocardiogram and, often, a
pattern of myocardial infarction in the absence of
coronary artery disease. This latter pattern may lead
to the incorrect diagnosis of atherosclerotic heart
disease, particularly in the small group of patients in
whom cardiac amyloidosis is associated with typical
angina. Echocardiography usually reveals a concen-
trically thickened left (and often right) ventricle with
a normal-to-small cavity and an ejection fraction
that ranges from low normal to mildly reduced (Fig.
1).45,46 Doppler echocardiography shows evidence of
high left-sided filling pressures (a restrictive filling
pattern) with a small or diminutive mitral A wave
due to a combination of atrial infiltration and re-
striction to diastolic filling.47 In severe cases, atrial
thrombi may be present even in sinus rhythm and
the onset of atrial fibrillation is associated with a
high risk of thromboembolism.48 A clinical clue to
the presence of cardiac amyloidosis is a marked wor-
sening of heart failure after the use of a calcium-
channel blocker, sometimes prescribed in an attempt
to treat diastolic dysfunction.49
In contrast to the absence of central nervous sys-
tem involvement, autonomic and sensory neuropa-
thy are relatively common features. A history of car-
pal tunnel syndrome is frequently elicited and may
precede other features of the disease by a year or
more. Motor neuropathy is rare, and sensory neu-
ropathy usually has a distal to proximal and symmet-
ric pattern. It may at times be painful. In contrast,
 M E D I CA L P RO G R E S S

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

autonomic nervous system dysfunction may be se-

B cardiac failure or the nephrotic syndrome limits the
Figure 1. Echocardiographic and Electrocardiographic Features
in AL Amyloidosis.
Panel A shows a diastolic short-axis view of the left ventricle at
the level of the papillary muscles. The left ventricular cavity is
small, and the walls are concentrically and markedly thickened.
A large pleural effusion is also present. The left ventricle in sys-
tole shows near obliteration of the cavity (Panel B). This ap-
pearance mimics that of hypertensive heart disease or hyper-
trophic cardiomyopathy. Despite the high ejection fraction, the
stroke volume in this patient was relatively low because of the
small left ventricular cavity. Panel C shows an electrocardio-
gram from the patient. Unlike the electrocardiograms of pa-
tients with true ventricular hypertrophy, this shows extremely
low voltage with left-axis deviation and a pseudo-infarct pat-
tern in leads V1 to V4. Panel D shows a four-chamber view from
another patient with AL amyloidosis and severe heart failure,
demonstrating normal-sized right and left ventricular cham-
bers, thick walls, and biatrial enlargement.
vere, resulting in symptomatic postural hypotension,
impotence, and disturbances in gastrointestinal mo-
tility. The coexistence of postural hypotension with
use of angiotensin-converting–enzyme inhibitors or
other vasodilator drugs, which may aggravate the
hypotension. In addition to autonomic involvement
(causing early satiety, constipation, or diarrhea), the
gastrointestinal tract is often infiltrated with amy-
loid, which rarely may be associated with malabsorp-
tion or pseudo-obstruction.50,51 These relatively un-
common symptoms further compound the weight
loss associated with the systemic disease and the ede-
ma associated with renal or cardiac involvement.
Hepatomegaly is common in patients with AL
amyloidosis.52 In the presence of heart failure it may
be difficult to differentiate infiltration from passive
congestion, but the presence of massive, irregular, or
hard hepatomegaly suggests the former, particularly
if the serum alkaline phosphatase concentration is
elevated. In contrast to hepatomegaly, splenomegaly
is rare, occurring in about 5 percent of cases. Splenic
dysfunction (hyposplenism), identified by the pres-
ence of Howell–Jolly bodies in the peripheral blood
smear, is a common finding, occurring in 24 percent
of cases.53

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 The New England Journal of Medicine

Other organs are less commonly involved. Vascu-

lar infiltration results in easy bruising, which is typ-
ified by the “raccoon-eyes” sign of spontaneous per-
iorbital purpura, sometimes provoked by minimal
trauma such as sneezing or rubbing the eyes (Fig.
2A). Major bleeding in amyloidosis is rare and,
when present, should prompt an evaluation of clot-
ting factors, particularly for inhibitors of thrombin
or for factor X deficiency, which may be caused by
binding of calcium-dependent clotting factors to
amyloid.54,55
Macroglossia, a classic feature of amyloidosis that
occurs in about 20 percent of patients, is character-
ized by enlargement and stiffening of the tongue.
The tongue is frequently rimmed by the indentation A
of teeth (Fig 2B).56 Submandibular swelling (Fig.
2C) is common with enlargement of the tongue and
may be large enough to produce respiratory obstruc-
tion and sleep apnea. Infiltration of soft tissue by
amyloid may occur elsewhere, resulting in the “shoul-
der-pad sign” (Fig. 2D), nail dystrophy (Fig. 2E), or
rarely, alopecia (Fig. 2F). Taste disturbance is com-
mon even in the absence of macroglossia, and subtle
infiltration of the vocal cords may produce a hoarse
or weak voice.57
Pulmonary amyloidosis rarely causes symptoms,
despite the fact that it is commonly found at autop-
sy.58,59 Dyspnea, though usually due to congestive
heart failure, may infrequently be due to widespread
pulmonary amyloidosis associated with a reticulo-
nodular pattern on the chest x-ray film and impaired
diffusion of carbon monoxide. In patients with heart
failure, unexpectedly large pleural effusions, particu-
larly ones that rapidly reaccumulate after thoracen-
tesis, suggest pleural amyloidosis as a contributing
factor. However, pleural amyloid rarely results in ef-
fusions in the absence of heart failure.
Infiltration of the adrenal glands may result in hy-
poadrenalism, which may go unrecognized because
the associated hypotension and hyponatremia are at-
tributed to autonomic dysfunction and heart fail-
ure.60 The assessment of adrenal function is impor-
tant in patients with these findings. The thyroid
gland may also be infiltrated, and 10 to 20 percent
of patients have hypothyroidism.
ATTR Amyloidosis D
The clinical picture in ATTR amyloidosis differs
somewhat from that of AL amyloidosis. Although
certain clinical features favor one or the other diag-
nosis, the overlap is sufficient to make a diagnosis
solely on clinical grounds inaccurate. The manifes- symptoms, characterized by diarrhea and weight
tations of ATTR amyloidosis tend to be the same loss, may be prominent and reflect autonomic dys-
for each specific mutation, although peripheral sen- function.
sorimotor and autonomic neuropathy is a prominent The pattern of myocardial involvement in ATTR
common feature in most patients, renal disease is amyloidosis differs from that of AL amyloidosis and
much less prevalent than in AL amyloidosis, and varies according to the specific transthyretin muta-
macroglossia does not occur.25,38 Gastrointestinal tion responsible for the disease. In the transthyretin

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 M E D I CA L P RO G R E S S

B C

E F

Figure 2. Clinical Features of Amyloidosis.

All patients had AL amyloidosis. Panel A shows ecchymoses around the eyes with a characteristic absence of soft-tissue swelling.
Panel B shows an enlarged tongue (macroglossia) with prominent indentations caused by the teeth. Panels C and D show soft-
tissue deposits of amyloid in the submandibular glands and synovial tissues, the “shoulder-pad sign.” Panel E shows nail dystro-
phy, and Panel F, total alopecia of the scalp.

Met 30 variant, the commonest mutation, the
echocardiogram usually is normal, although the elec-
trocardiogram may show evidence of conduction
system disease in the form of sinus-node dysfunc-
tion, bundle-branch block, or atrioventricular block.
As the disease progresses, cardiac pacing is often re-
quired. Patients with the transthyretin Ala 60 variant
and several other mutations have myocardial infiltra-
tion that is indistinguishable from that caused by AL
amyloidosis on echocardiography. However, heart
failure is less common and the prognosis is better
than for patients with cardiac disease and AL amy-
loidosis despite the similarity of the echocardio-
graphic findings. This may reflect a difference in the
pattern of histologic deposition of amyloid fibrils in
ATTR and AL amyloidosis or other, currently unrec-
ognized factors. The diagnosis of ATTR amyloidosis
is often missed, and a family history of an unknown
neurologic disease or such entities as motor neuron
disease is often obtained in preceding generations.
Careful questioning may reveal a consistent pattern
of symptoms compatible with the presence of famil-
ial amyloidosis.
AA Amyloidosis
AA (secondary) amyloidosis presents as renal dis-
ease in most patients with hepatomegaly, spleno-
megaly, or both, occurring as the presenting feature
in about 10 percent of patients.61 Cardiac involve-
ment is rare, and even if detected by echocardiogra-
phy, it almost never results in heart failure.62 As in
ATTR amyloidosis, macroglossia is not a feature of
AA amyloidosis.
DIAGNOSIS
The diagnosis of amyloidosis is based on a clinical
suspicion and established by a tissue biopsy. Usually
biopsy of an involved organ will confirm the diagno-

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 The New England Journal of Medicine
sis. When clinical suspicion is high and no biopsy has
yet been obtained, the simplest procedure is to ob-
tain a sample of subcutaneous abdominal fat.63,64 A
fat aspirate stained with Congo red will be positive
in 85 percent of patients with AL amyloidosis (Fig.
3A and 3B), although experience is required to avoid
overstaining of the tissue.
After a positive biopsy result is obtained, the type
of amyloidosis must be determined. Since AL amy-
loidosis is the most common type, a search for clonal
plasma-cell dyscrasia is the first step. Monoclonal
immunoglobulins or light chains are detected in 90
percent of patients with AL amyloidosis by means of
immunofixation electrophoresis of serum or urine
(Fig. 3C), a more sensitive technique than simple
protein electrophoresis. Patients with apparent AL
amyloidosis who do not have monoclonal light chains
can pose a diagnostic problem. In most of these pa-
tients, a clonal dominance of plasma cells will be
identified by immunohistochemical staining of a
bone marrow–biopsy specimen (Fig. 3D) or by oth-
er cellular studies that use labeled antibodies specific
for human light chains. In rare cases, studies of gene
rearrangements may be used.
If there is no evidence of a plasma-cell dyscrasia,
consideration should be given to another form of
amyloidosis. Although a family history of amyloido-
sis or unexplained progressive neuropathy strongly
suggests familial ATTR amyloidosis, a variant trans-
thyretin should be sought in all patients who do not
have a plasma-cell dyscrasia. Transthyretin can be
identified by isoelectric focusing of the serum,
which will separate variant and wild-type transthy-
retin (Fig. 3E).65 The finding of a variant transthy-
retin should prompt specific genetic testing to iden-
tify the site of the mutation (Fig. 3F).25
It is important to verify that the patient has a plas-
ma-cell dyscrasia before aggressive treatment is un-
dertaken. If none can be detected, however, AL amy-
loidosis may still be present and should be suspected
if the patient has macroglossia with the involvement
of other, typical organ systems and no variant trans-
thyretin in the serum. In such cases, referral to a cen-
ter specializing in the diagnosis of amyloidosis is rec-
ommended.
Senile cardiac amyloidosis due to the deposition
of amyloid formed from normal transthyretin is
characterized by a clinical picture of amyloidosis of
the heart in the absence of a mutant transthyretin or
immunoglobulin abnormalities.18 Staining of a fat
aspirate is often negative, and a cardiac-biopsy spec-
imen that stains positively with antibody to normal
transthyretin confirms the diagnosis.66
AA amyloidosis is suspected in patients with renal
amyloid and a chronic inflammatory condition in
whom AL and ATTR amyloidosis have been ruled
out. Confirmation can be made by immunohisto-
chemical staining for AA protein.67
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IMAGING TECHNIQUES
Evaluation of the extent of amyloid deposition is
desirable, since it can help determine the response to
treatment. Technetium Tc 99m pyrophosphate binds
avidly to many types of amyloid and was a popular
imaging agent for cardiac amyloidosis.68 However,
quantitative assessment is not possible with this
agent, and strongly positive images usually only oc-
cur in patients with severe disease, in whom echo-
cardiography is generally diagnostic. Preliminary re-
sults suggest that technetium-labeled aprotinin may
be more sensitive for imaging amyloid deposits than
technetium Tc 99m pyrophosphate.69
Quantitative scintigraphy can be performed with
iodine-123–labeled serum amyloid P component, a
technique effective for the assessment of AL, ATTR,
and AA amyloidosis.70 Serial studies have demon-
strated that both disease progression and regression
correlate with the degree of uptake of the serum
amyloid P component, but this test is currently not
widely available.
PROGNOSIS
The prognosis of the amyloidoses varies, but it is
generally poor if the disease is untreated. Patients
with AL amyloidosis have the worst prognosis, with
a median survival of one to two years.20 Patients with
ATTR amyloidosis may survive up to 15 years, and
the prognosis for patients with AA amyloidosis is
Figure 3. Diagnostic Algorithm for Amyloidosis.
A biopsy of tissue that shows amyloid deposits on Congo-red
staining is the first step. If there is no family history of amyloido-
sis, the next step is to examine the patient for a plasma-cell dys-
crasia by immunofixation electrophoresis of the serum and urine
(Beckman Instruments, Fullerton, Calif.) and by a bone marrow
biopsy with immunohistochemical staining of plasma cells for
k and l light chains. If these are negative, the next step is to look
for a mutant transthyretin (TTR) protein in serum, a mutant TTR
gene in genomic DNA, or both, even if there is no family history
of amyloidosis. Panel A shows an abdominal-fat aspirate stained
with Congo red (amyloid deposits appear red) and viewed mi-
croscopically in normal light (100), and Panel B shows the
specimen under polarized light, demonstrating green birefrin-
gence of the amyloid deposits in the connective tissue surround-
ing the fat cells (100). Immunofixation electrophoresis of se-
rum shows a free l light chain (Panel C). A bone marrow–biopsy
specimen stained with antibody to l light chain shows preferen-
tial staining of plasma cells as well as staining of an amyloid de-
posit around a blood vessel (Panel D, 400). In Panel E, isoelec-
tric focusing of serum samples shows bands of both variant and
wild-type TTR protein (arrow) from a patient with ATTR (lane 2)
and a single band of wild-type TTR in normal subjects (lanes 1
and 3). Panel F shows a restriction-fragment–length polymor-
phism (RFLP) of DNA from amplified exon 2 of TTR after diges-
tion with the restriction enzyme NsiI and polyacrylamide-gel
electrophoresis. There are extra fragments of 4.9 and 1.5 kb in
samples from patients with ATTR and the transthyretin Met 30
alleles (lanes 1 and 3) rather than the expected fragments of 6.4
and 3.2 kb (lane 2). Lane 4 shows the gel markers.
 M E D I CA L P RO G R E S S

A B

Consider AL amyloidosis
(plasma-cell dyscrasia)

C D

IgG IgA IgM k l

Immunofixation electrophoresis Bone marrow biopsy

If either positive If both negative

kb 1 2 3 4
AL Consider mutant TTR protein or gene
F
1 2 3
E

6.4 —

4.9 —

3.2 —

1.5 —

Isoelectric focusing RFLP of DNA

If either positive If both negative

ATTR amyloidosis Consider secondary, senile, and

rarer types of hereditary amyloidosis

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Copyright © 1997 Massachusetts Medical Society. All rights reserved.
 The New England Journal of Medicine
often affected greatly by the underlying chronic dis-
ease. For patients with AL amyloidosis, the progno-
sis varies depending on the extent of organ involve-
ment. Symptomatic heart involvement is associated
with a median survival of 6 months, whereas median
survival is 21 months when the kidney is the major
organ involved. Multisystem involvement, especially
if the heart and bowel are affected, is a very poor
prognostic sign.56
The prognosis in ATTR amyloidosis varies with
the specific mutation and the time of diagnosis. In
general, transthyretin mutations associated with a
younger age at the onset of disease (20 to 30 years)
involve more rapidly progressing neuropathy and
cardiomyopathy and, thus, a shorter survival. Usual-
ly, the age at onset and the duration of disease fol-
low the same pattern in all affected members of a
family. The time of diagnosis may be very late in the
course of disease for some patients who are not
aware of the familial nature of their symptoms. This
is more common in patients in whom the disease be-
comes apparent at an older age; such patients may
have had ancestors who died before symptoms de-
veloped or in whom the disease was misdiagnosed as
another neurologic disorder.
TREATMENT
The treatment of amyloidosis is directed both to-
ward the affected organ and to the specific type of
the disease.71 The nephrotic syndrome requires gen-
eral supportive and diuretic therapy, and renal failure
can be successfully treated by dialysis. Congestive
heart failure may initially respond to diuretics, but
increasing doses are often required as cardiac disease
progresses or renal function worsens. Calcium-chan-
nel blockers and beta-blockers are contraindicated in
cardiac amyloidosis, as is digoxin, which may cause
toxicity at “therapeutic” levels.49,72 A pacemaker may
be required in patients with symptomatic bradycar-
dia, particularly those with ATTR amyloidosis, and
in our experience, pacemakers are usually effective
without excessively high pacing thresholds. Neuropa-
thy and gastrointestinal involvement are treated symp-
tomatically. Gastromotility agents may be of some
benefit. Vigorous treatment or removal of the in-
flammatory source in AA amyloidosis may halt pro-
gression. In familial Mediterranean fever, a genetic
disorder associated with a high incidence of AA amy-
loidosis, therapy with colchicine specifically treats
the underlying disease and prevents amyloidosis.73,74
It was this observation that led to the widespread
use of colchicine in all forms of amyloidosis, but ev-
idence of its efficacy for AL, ATTR, or senile amy-
loidosis is unconvincing.
AL Amyloidosis
The similarity between AL amyloidosis and mul-
tiple myeloma suggested that chemotherapy may be
906  Se p te m b e r 2 5 , 1 9 9 7
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Copyright © 1997 Massachusetts Medical Society. All rights reserved.
a useful treatment. Two major trials, which used
slightly different regimens of intermittent oral mel-
phalan and prednisone, have confirmed the efficacy
of this therapy over no therapy or therapy with col-
chicine alone.56,75 However, the response rate is low,
with an increase in survival from a median of approx-
imately 6 months in patients who did not receive
chemotherapy to approximately 12 months in those
receiving chemotherapy. Patients must live long
enough to receive several cycles of melphalan before
a survival benefit occurs. Since patients with cardiac
amyloidosis have a very short survival, few receive
sufficient therapy to influence survival. Several case
reports have documented prolonged survival and
resolution of heart failure or proteinuria in individ-
ual patients receiving oral chemotherapy.76,77 In these
cases evidence of an active plasma-cell dyscrasia has
generally disappeared despite evidence of persistent
amyloid in the affected tissues.
Treatment with high-dose intravenous melphalan
(200 mg per square meter of body-surface area)
with autologous-blood stem-cell support results in
complete remission of the plasma-cell dyscrasia, de-
fined as a disappearance of monoclonal light chains
or immunoglobulins from serum and urine, and
normalization of the number of plasma cells in bone
marrow and the ratio of l to k light chains, in 65
percent of patients with adequate pretreatment per-
formance status and preserved left ventricular func-
tion.78,79 Substantial improvements in amyloid-relat-
ed organ disease have been documented for more
than three quarters of patients with hepatic, gastro-
intestinal, and neural involvement. More than 50
percent of patients with amyloid-related disease that
is predominantly renal or cardiac also respond to
dose-intensive therapy with reduced proteinuria and
a stable or improved performance status. Remission
of both the plasma-cell dyscrasia and clinical symp-
toms and signs of amyloidosis can occur with this
approach.80,81 The durability of remission remains to
be determined, as does the impact of this approach
on the resorption of amyloid deposits and survival.
Nevertheless, these results indicate that high-dose
melphalan can be given safely to selected patients. A
limitation is the age and poor health of many pa-
tients with advanced AL amyloidosis, for whom the
therapy is excessively toxic.
In the small proportion of patients (less than 10
percent) with AL amyloidosis that is limited clinical-
ly to the heart, death is sudden or due to rapidly
progressive heart failure. Cardiac transplantation has
been performed in a few such patients, but progres-
sion in other organs or recurrence in the transplant-
ed heart has lessened enthusiasm for this therapy.82
However, the induction of remission by intensive
chemotherapy after organ transplantation has been
performed is an attractive possibility that is currently
under consideration.83,84
 M E D I CA L P RO G R E S S
A serendipitous finding of clinical improvement in
amyloid-related symptoms in a patient with AL amy-
loidosis who was receiving chemotherapy with the
iodinated anthracycline 4-iodo-4-deoxydoxorubi-
cin prompted evaluation in seven additional patients
with AL amyloidosis.85 Five of the eight patients had
apparent clinical benefit, including a decrease in di-
arrhea and skin infiltration. In vitro studies showed
avid binding to amyloid fibrils. No reduction in cir-
culating light chains could be documented, and it
was postulated that the drug may act by binding to
amyloid fibrils, thus blocking the deposition of new
amyloid.86
ATTR Amyloidosis
The recognition that transthyretin was predomi-
nantly synthesized in the liver led to liver transplan-
tation as a therapy for this disease.87,88 Liver trans-
plantation resulted in the disappearance of mutant
transthyretin from the blood and improvement in
the degree of neuropathy.89-91 It is now considered
the definitive therapy. Several hundred patients with
ATTR amyloidosis have undergone liver transplanta-
tion during the past five years, and the long-term
outcome is being evaluated.92,93 The precise timing
of liver transplantation in a patient known to carry
an ATTR mutant gene requires careful thought.
Transplantation before the onset of symptoms is not
appropriate, but once symptoms occur they may
progress relatively rapidly. Knowledge of the precise
mutation and its phenotypic manifestation in the
patient’s family or racial or ethnic group may help
determine optimal timing. In a few patients with se-
vere symptomatic cardiac involvement, combined
liver and heart transplantation from a single donor
has been performed.94
CONCLUSIONS
In the past few years advances in molecular biolo-
gy, immunology, and chemotherapeutic techniques
have combined to vastly improve our understanding
of the amyloidoses. Surgical cure of transthyretin-
associated amyloidosis has become accepted therapy,
and advances in the treatment of AL amyloidosis
suggest that intensive chemotherapy may produce
disease remission and dramatic clinical improvement
in selected patients. Unfortunately, the rarity and
rapid progression of this disease often delay diagno-
sis until multiorgan involvement limits the ability to
treat. An increased awareness of the clinical features
of amyloidosis on the part of physicians is critical for
early diagnosis and may enable patients to obtain
timely access to new therapies for this otherwise uni-
formly fatal disease.
Supported by grants from the National Institutes of Health (AR 20613,
AR 40414) and the Food and Drug Administration (FD-R-001346), the
Arthritis Foundation, and the Amyloid Research and Sue Sellors Finley
Cardiac Amyloid Research Funds.
Downloaded from www.nejm.org at BETH ISRAEL HOSP on October 05, 2003.
Copyright © 1997 Massachusetts Medical Society. All rights reserved.
We are indebted to the Amyloid Program Clinical and Research
Team — Peter Bergethon, John Berk, Alan Cohen, Lawreen Con-
nors, Laura Dember, Simon Dubrey, Thomas Ericsson, Kathleen
Finn, David Lewis, Johann Reisinger, Diane Sarnacki, Robert
Simms, James Skare, David Strehlow, Evan Vosburgh, and Mary
Walsh — for many helpful discussions.
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