Joint Bone Spine 2002 ; 69 : 538-45

2002 ditions scientifiques et mdicales Elsevier SAS. All rights reserved

S1297319X02004499/DIS

REVIEW

Diagnostic tools for amyloidosis

Eric Hachulla1*, Gilles Grateau2
1
Internal medicine department, Centre hospitalier rgional et universitaire, Hpital Claude Huriez, 59037, Lille cedex,
France; 2Internal medicine department, Htel Dieu, 1 place du Parvis Notre Dame, 75181, Paris cedex 04, France

(Submitted for publication April 25, 2002; accepted in revised form July 3, 2002)

Summary Demonstration of amyloid deposits in biopsy specimens is the only means of confirming the
diagnosis of amyloidosis. In experienced hands, nonsurgical biopsies of the rectal mucosa or, preferably,
of the abdominal fat pad or labial salivary glands provide the diagnosis in 80 to 85% of cases. Immunolabeling studies help to determine the histological type of amyloidosis but are not performed routinely in
everyday practice. In patients with a family history of amyloidosis, studies of the genome and amyloid
protein can identify the protein variants capable of causing systemic amyloidosis. Once the diagnosis of
amyloidosis is established, the extent of systemic involvement with amyloid should be evaluated by
performing renal and hepatic function tests, a proteinuria assay, and an echocardiogram. Scintigraphy with
radiolabeled serum amyloid P (SAP) component is a rapid and specific investigation that provides a map of
the amyloid deposits. Deposits are usually seen in the liver and spleen. SAP component scintigraphy can
provide support for the diagnosis of amyloidosis in patients with negative histological studies. Tissue
retention of radioactivity predicts survival. Joint Bone Spine 2002 ; 69 : 538-45. 2002 ditions
scientifiques et mdicales Elsevier SAS
amyloidosis / diagnosis / SAP component scintigraphy

The diagnosis of amyloidosis remains dependent on

histological studies of biopsy specimens. Because the
presentation is pleomorphic, months or years often
elapse before the diagnosis is established. Once the
diagnosis is made, tests to determine the type of amyloid are in order to guide treatment decisions. Finally,
the location and extent of the amyloid deposits must be
determined by investigations of target organs. Cardiac
involvement predicts a mean survival of less than 9
months [1], a fact that should be taken into account
when making treatment decisions.

* Correspondence and reprints.

E-mail address: ehachulla@chru-lille.fr (E. Hachulla).

HISTOLOGICAL DIAGNOSIS
Histological examination of biopsy specimens stained
with Congo red is the only method for establishing the
diagnosis of amyloidosis. The amyloid deposits are
often in a perivascular distribution with some degree of
heterogeneity. They range from massive to subtle and
may be lacking in tissue biopsies from compromised
organs such as the kidney [2]. Amyloid deposits may be
overlooked by a cursory or nonoriented examination.
Although biopsies can be obtained from compromised
organs such as the liver, heart, or kidneys, the blood
vessel fragility associated with amyloid deposition carries a risk of bleeding [3]. The skin is more readily
accessible, but specific skin lesions occur mainly in
primary AL amyloidosis. Because amyloidosis is a sys-

Diagnostic tools for amyloidosis

temic disease, routine biopsies from nonsymptomatic

sites can be positive for amyloid deposits. The most
commonly biopsied sites are the rectal mucosa, abdominal fat pad, and labial salivary glands.
Rectal biopsy
Rectal biopsy was the most widely used diagnostic tool
in the 1960s. Deep fragments including the submucosa, where the amyloid predominates, are obtained
during a rectoscopic examination [4]. The sensitivity of
rectal mucosa biopsy ranges from 7585% [5]. The
gastrointestinal tract is involved at multiple levels, and
studies suggest that biopsies from the upper gastrointestinal tract may be similar in diagnostic yield to rectal
mucosa biopsies [6].
Abdominal fat pad aspiration or biopsy
Examination of abdominal fat was developed as a diagnostic tool in the 1970s [7]. Variants of this technique
include needle aspiration, Tru-Cut needle biopsy, and
surgical knife biopsy. Aspiration is done using an 18- to
23-gauge needle. Two to five aspirations are performed
[8, 9]. Sensitivity has ranged across studies from
5575%, with lower values, however, in b2-microglobulin amyloidosis [10]. In a study of 73 patients with
suspected AA or AL amyloidosis, Duston et al. [11]
found that abdominal fat pad aspiration had a sensitivity of 57%, a specificity of 100%, and a negative
diagnostic value of 77%. Whatever the technique used,
optimal performance requires close collaboration
between a clinician and a pathologist familiar with the
clinical and histological pitfalls encountered in amyloidosis, particularly the possibility of false-positive tests
[12].
Labial salivary gland biopsy
Labial salivary gland biopsy is superior over gingival
biopsy, which lacks sensitivity. Delgado and Mosqueda
compared the diagnostic yields of gingival biopsy and
labial salivary gland biopsy in 19 patients with amyloidosis revealed by sicca syndrome [13]. In this preliminary study of patients known to have amyloidosis,
labial salivary gland biopsy was 100% sensitive, as
compared to only 16% for gingival biopsy. In a study of
patients with AA or AL amyloidosis, we found that
labial salivary gland biopsy had a sensitivity of about
86% [14] (figure 1). This technique is also effective in
diagnosing the hereditary transthyretin amyloidoses

539

[15]. Sensitivity is lower, however, for the diagnosis of

b2-microglobulin amyloidosis (about 50% according
to unpublished data).
Other biopsy sites
Biopsy of the kidney or liver is sensitive when laboratory tests show dysfunction of the biopsied organ.
Life-threatening bleeding can occur, however, so that
these procedures should be reserved for patients in
whom abdominal fat pad aspiration/biopsy and/or
labial salivary gland biopsy fail to establish the diagnosis. For instance, we use labial salivary gland biopsy as
the first-line investigation when proteinuria or nephrotic syndrome develops in a patient with long-standing
rheumatoid arthritis. Demonstration of amyloid obviates the need for renal biopsy. Endomyocardial biopsy
in patients with cardiac involvement can cause complications. Peripheral nerve biopsies vary in their diagnostic yield and can result in residual dysesthesia. Finally,
amyloid is visible in the bone marrow in 5060% of
patients with primary amyloidosis [2].
Whatever the biopsy site, staining with Congo red is
the histological technique of reference. Under polarized
light, binding of Congo red to amyloid produces a
specific green-yellow birefringence. Thioflavin staining
is less specific but can detect smaller deposits.
Determining the type of amyloid
The molecular nature of the amyloid governs the treatment options. The three main types of amyloidosis
AA, AL, and transthyretin can produce similar symptoms, making determination of the type of amyloid
particularly important. Although AA amyloidosis typically occurs as a complication of long-standing amyloidosis, patients older than 65 years often have a
monoclonal component, raising the possibility of primary amyloidosis. Some cases of transthyretin amyloidosis are delayed and sporadic, and the cardiac and
neurological manifestations can simulate AL amyloidosis. Transthyretin amyloidosis can occur as a senile
disease, a variant in which chemotherapy is ineffective.
Thus, knowledge of the type of amyloid is a prerequisite to optimal treatment.
Potassium permanganate can provide orientation to
the type of amyloid. Permanganate-sensitive deposits
stained with Congo red lose their birefingence after
oxidation with potassium permanganate [16]. This pattern occurs with AA amyloid and b2 microglobulin
amyloid. In contrast, AL amyloid and TTR amyloid are

540

E. Hachulla, G. Grateau

Figure 1. Amyloid deposits in a labial salivary gland biopsy: positive Congo red stain (Prof. A. Janin).

permanganate-resistant. The results of potassium permanganate oxidation are usually concordant with those
of immunohistochemical studies. However, the findings can be difficult to interpret and merely divide cases
of amyloidosis into two heterogeneous groups. The
potassium permanganate test was chiefly useful for
distinguishing between AA and AL amyloidosis. It has
been superseded by immunohistochemical techniques,
which consist mainly of immunofluorescence and
immunoenzymatic studies.
Immunohistochemistry studies the ability of amyloid
deposits to bind antibodies directed against most of the
amyloid molecules identified to date. In patients with
systemic amyloidosis, studies with antibodies to AA
and to the immunoglobulin light chains j and k are
usually sufficient, as they identify the vast majority of
amyloid deposits composed of AA fibrils or immunoglobulin light chains. Use of frozen specimens considerably increases the reliability and reproducibility of
labeling with antibodies to immunoglobulin light
chains [17]. Deposition of b2 microglobulin amyloid

occurs only in patients receiving chronic renal replacement therapy. In the hereditary amyloidoses, in contrast, the protean nature of the clinical manifestations
requires use of a broad range of anti-amyloid protein
antibodies, in particular to guard against a mistaken
diagnosis of AL amyloidosis.
Several TTR variants can be detected in serum specimens using mass spectrometry or sophisticated electrophoresis techniques [18, 19]. Purification of the amyloid
protein present in the deposits is not performed on a
routine basis.
A family history of amyloidosis should be looked for
routinely. Involvement of the peripheral nerves, kidneys, heart, skin, or eyes is particularly suggestive of
hereditary amyloidosis. Transmission of the hereditary
amyloidoses occurs on an autosomal dominant basis
(table I).
Nearly 60 transthyretin mutations have been identified, some in single families [21]. Transthyretin amyloidosis is the most common hereditary form.
Transthyretin is a chain of 127 amino acids produced

541

Diagnostic tools for amyloidosis

Table I. Systemic amyloidoses inherited on an autosomal dominant basis [20].
Protein

Mutation

Organs involved

Geographic origin

Transthyretin

Met30 and more than 60 other

mutations
Asn187 Tyr 187
Gly26Arg
Leu60Arg
Trp50Arg
Del/Ins(6071)
Deletion(7072)
Leu90Pro
Arg173Pro

nerves, heart, eyes, kidneys,

gastrointestinal tract, other organs
cranial nerves, skin, kidneys
nerves, kidneys
kidneys
kidneys
kidneys, liver
liver
kidneys, liver, spleen
skin, heart
skin, heart

Portugal, Sweden, Japan, and

numerous other countries
Finland mainly; Denmark
USA, United Kingdom
United Kingdom
United Kingdom
United Kingdom, USA

Stop 78 Ser
Arg554Leu
Glu526Val
4904delG
4897delT
Ile56Thr
Asp67His
Trp64Arg

Kidneys
kidneys
kidneys, liver
kidneys, heart
kidneys
kidneys, liver
kidneys
kidneys, salivary glands

Gelsolin
Apolipoprotein A1

Apolipoprotein AII
Fibrinogen Aa

Lysozyme

by the liver. It becomes capable of forming amyloid

fibrils when it has a single amino acid substitution
related to a mutation in a single base in the corresponding gene. Met30 is the most common mutation. Transthyretin mutations can be detected by examination of
a sample of peripheral blood. The vast majority of
transthyretin variants are produced by point mutations
readily identified by standard techniques. The genetic
diagnosis establishes the presence of a gene mutation,
not of amyloidosis: the penetrance of these mutations is
often variable, so that some individuals who carry a
potentially amyloidogenic mutation remain free of amyloidosis throughout their lifetime.
The other variants of hereditary amyloidosis usually
cause renal disease (lysozyme, fibrinogen, apolipoproteins AI and AII) or predominant cardiac or hepatic
involvement. At present, these forms are probably
underdiagnosed.
DETERMINING THE SITES AND EXTENT
OF INVOLVEMENT
Once the diagnosis of amyloidosis is established, simple
investigations should be performed as clinically indicated. These investigations are listed in (table II).
Echocardiography is the best test for diagnosing cardiac involvement. The changes are those of restrictive
cardiomyopathy with concentric ventricular hypertrophy predominating in the interventricular septum and

Spain
South Africa
France
USA
USA
Mexico, USA, France, Africa
USA, Canada
USA
France
United Kingdom
United Kingdom
France

posterior wall of the left ventricle. Ventricular contractility is reduced. There is no dilatation. Absence of valve
disease or arterial hypertension and a hyper-refractile
granular sparkling appearance strongly suggest cardiac
amyloidosis to the experienced examiner [22]. Diffuse
granularity is 87% sensitive and 81% specific for the
diagnosis of cardiac amyloidosis [23]. When this abnormality is lacking, the contrast between the ventricular
hypertrophy and the low-voltage ECG trace is indirect
evidence of amyloidosis.
In a patient with histologically documented amyloidosis, identification of a mutation in the transthyretin
gene establishes the diagnosis of transthyretin amyloidosis, which usually requires liver transplantation if
permitted by the patients clinical condition. In contrast, identification of a transthyretin mutation in a
family member does not necessarily indicate amyloidosis: the penetrance of these mutations is variable, and
about 1 in 3 individuals with the Met30 mutation
remain free of amyloidosis throughout their lifetime.
SAP COMPONENT SCINTIGRAPHY: A DIAGNOSTIC
AND PROGNOSTIC TOOL
Amyloid deposits are composed of fibrillar proteins
with an antiparallel b-pleat secondary structure. The
current classification of amyloidoses rests on the marked
heterogeneity in the peptide subunit [24]. In addition
to the fibrillar protein, amyloid deposits contain a large

542

E. Hachulla, G. Grateau

Table II. Determining the site and extent of histologically documented amyloidosis.
Organ

Investigations
Performed routinely

Performed as clinically indicated

kidneys
heart
gastrointestinal tract
liver
spleen
nerves
respiratory system

proteinuria serum creatinine, ultrasonogram

chest X-ray electrocardiogram echocardiography
serum protein electrophoresis
liver enzymes
ultrasonogram blood cell counts

chest X-ray

endocrine glands
eyes
hemostasis

ACTH test TSH

funduscopy
PT, X factor

amount of the glycosaminoglycans heparan sulfate and

dermatane sulfate, which are noncovalently bound to
the fibrils. The pathophysiological role of these glycosaminoglycans in amyloidosis is incompletely understood, but experimental data support active involvement
in the fibrillar transformation of some amyloid precursors. The SAP component, which is consistently found
in amyloid deposits [25], is a glycoprotein normally
present in the bloodstream. SAP is highly stable and
resistant to proteases.
Development of the SAP component scintigraphy
technique
The SAP component binds to amyloid fibrils via a
calcium-dependent mechanism and contributes to the
stability of amyloid deposits in vivo. This unique property of the SAP component was put to use by Hawkins
et al. [26-28] for developing a scintigraphic technique
capable of detecting amyloid deposits anywhere in the
body. Studies in animals and humans have shown that
hot spots seen after injection of radiolabeled SAP component are specific for amyloid deposits [25, 29, 30]. In
the animal studies, immunohistochemistry was used to
correlate hot spots with amyloid deposits at the same
organ sites. The earliest studies were conducted in mice
and involved gamma camera detection of hot spots in
vivo [29, 30]. Studies in humans were conducted subsequently. Although the definitive diagnosis of amyloidosis continues to depend on histological examination
of biopsy specimens [14], radiolabeled SAP component
scintigraphy is both sensitive and specific for detecting
amyloid deposits.

renal vein Doppler ultrasound

99m
Tc pyrophosphate scan 24-hour Holter
gastrointestinal endoscopy esophageal manometry
ultrasonogram
Howell-Jolly bodies in blood smears
EMG
blood gas analysis bronchoscopy computed tomography
of the chest

slit-lamp examination

Validation of SAP component scintigraphy

as a diagnostic tool
Radiolabeled SAP component scintigraphy is a rapid
and highly specific method for detecting amyloid deposits in vivo. The intensity of the uptake by involved
organs depends directly on the amount of amyloid and
consequently provides information on the amyloid load
[30, 31]. Scintigraphic imaging has 100% and 90%
sensitivity for systemic AA and systemic AL amyloidosis, respectively. Sensitivity is consistently 100% when
scintigraphic imaging is combined with evaluation of
24-hour radioactivity retention in the body tissues (calculated as the radioactivity given intravenously minus
the radioactivity recovered in the 24-hour urine collection and the radioactivity present within the vasculature) [31]. Increased uptake by the liver and spleen is
seen in virtually every case (figure 2). Conversely, in our
experience, hot spots in the kidneys and joints were
fairly uncommon, although in some cases presence of
amyloid had been demonstrated histologically at these
sites. Neither Hawkins et al. nor our group has demonstrated radiolabeled SAP component binding by the
myocardium. Given these limitations of SAP component scintigraphy for evaluating organ involvement by
systemic amyloidosis, a 24-hour proteinuria assay and
an echocardiogram should be performed also. Tissue
retention of radioactivity was greater than 30% in all
the patients with histologically documented systemic
amyloidosis studied by our group, as compared to less
than 24% in all the controls. Furthermore, some
patients with clinically silent amyloidosis confirmed by
labial salivary gland biopsies had very high tissue reten-

Diagnostic tools for amyloidosis

543

Figure 2. 123I-labeled SAP component scintigraphy

showing hepatic and splenic uptake in a patient with
secondary AL amyloidosis (Prof. X. Marchandise).

tion values [14]. Thus, similar to labial salivary gland

biopsy, SAP component scintigraphy may be useful as a
detection tool in patients at high risk for, or suspected
of, systemic amyloidosis, such as individuals with
myeloma or an apparently benign monoclonal component with a suggestive clinical or laboratory test abnormality (e.g., neuropathy or proteinuria). Furthermore,
similar to labial salivary gland biopsy, SAP component
scintigraphy is valuable for establishing a diagnosis of
focal amyloidosis [32], thus assisting in the choice
between local and systemic treatment.

component scintigraphy can be used to identify patients

with heavy amyloid loads. Demonstration of a high
level of tissue retention can prompt a change in treatment (autograft, chemotherapy or thalidomide in AL

Prognostic information provided by SAP

component scintigraphy
Tissue retention after 24 hours was less than 24% in
our controls and strictly greater than 30% in all our
patients with histologically documented systemic amyloidosis. We prospectively evaluated 24 patients with
histologically documented systemic AL amyloidosis
[31]. Median follow-up was 13 months (range, 147).
We found that patients whose 24-hour tissue retention
was greater than 50% had a mean survival of only 11.3
months, as compared to 24.5 months for patients with
a value no greater than 50% (figure 3). Thus, SAP

Figure 3. Survival curve in patients with systemic A amyloidosis

according to the 24-hour tissue retention of radioactivity (>50% or
<50%).

544

E. Hachulla, G. Grateau

amyloidosis). This marker will be useful in randomized

studies designed to evaluate new treatments for amyloidosis of any type.
Contribution of SAP component scintigraphy
to disease monitoring and treatment evaluation
The amyloid load seems to increase relentlessly over
time. However, SAP component uptake by organs can
decrease in response to a reduction in the fibril precursor, providing evidence for dynamic turnover of amyloid deposits [33]. A decrease in deposits at some sites
(e.g., the liver) and an increase at other sites (e.g., the
spleen) has been described. This evidence that mobilization of amyloid can occur is a source of considerable
hope for the patients. We monitored 12 patients with
systemic AL amyloidosis for 4 to 31 months (median,
10 months) [31]. Tissue retention of radioactivity
remained unchanged in four patients, diminished significantly under chemotherapy in two patients, and
increased significantly in six patients, of whom four
experienced worsening of their clinical manifestations.
Radiolabeled SAP component scintigraphy and, above
all, determination of tissue radioactivity retention after
24 hours will make an essential contribution to the
evaluation of new treatments, alongside tests for organ
dysfunction (e.g., 24-hour proteinuria and echocardiography). Until now, survival was the main efficacy
criterion. Tissue radioactivity retention should provide
information on treatment efficacy as early as the sixth
month.
Radiolabeled SAP component scintigraphy is emerging as a noninvasive technique for detecting, localizing
and quantitating amyloid deposits in vivo. Together
with labial salivary gland biopsy, radiolabeled SAP component scintigraphy can distinguish between focal and
systemic forms of amyloidosis. The investigation can be
performed repeatedly in a given patient to monitor the
course of the disease and the efficacy of treatments. SAP
component may prove useful in the future as a vector
for therapeutic substances. An application for orphan
drug status has been submitted to the European Drug
Agency.
CONCLUSION
Skin lesion biopsy, labial salivary gland biopsy, and
abdominal fat pad aspiration or biopsy are the three
techniques of reference for the histological diagnosis of
systemic amyloidosis. Determination of the type of
amyloid relies on immunohistochemical studies,

although false positives and false negatives occur with

antibodies to light chains. Genetic testing is useful in
patients with a positive family history, chiefly to look
for a mutation in the transthyretin gene. In difficult
cases, the type of amyloid is determined on a set of
converging clinical, histological, immunohistochemical, and genetic data.
When evaluating the location and extent of amyloid
deposits, echocardiography performed by an experienced examiner is the most sensitive and specific investigation for detecting cardiac amyloidosis. Prompt
licensing of SAP component would allow wider use of
radiolabeled SAP component scintigraphy as a tool for
establishing the diagnosis, evaluating the extent, and
predicting the outcome of systemic amyloidoses.
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