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REVIEW
Immunoglobulin Light-Chain
Amyloidosis: Clinical Presentations
and Diagnostic Approach
YI L. HWA, DNP,1 TERESA FOGAREN, MSN, AGNP-C, 2 ALLISON SAMS, AGPCNP-BC, 3
DOUGLAS V. FALLER, MD, PhD,4 DAWN M. STULL, PharmD, BCOP, 5
SARA THUENEMANN, RN, MSN, DHSc,6 and LISA MENDELSON, MSN, AGPCNP-BC7
From 1Division of Hematology, Mayo Clinic,
Rochester, Minnesota; 2Division of HematologyOncology, Tufts Medical Center, Boston, Massachusetts; 3Division of Hematology-Oncology,
Outpatient Multiple Myeloma Service, Memorial
Sloan-Kettering Cancer Center, New York City,
New York; 4Millennium Pharmaceuticals, Inc.,
Cambridge, Massachusetts, a wholly owned
subsidiary of Takeda Pharmaceutical Company
Limited; 5
Millennium Pharmaceuticals, Inc., Cambridge,
Massachusetts, a wholly owned subsidiary
of Takeda Pharmaceutical Company Limited;
6
Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda
Pharmaceutical Company Limited; 7Amyloidosis
Center, Boston University School of Medicine,
Boston, Massachusetts.
Authors’ disclosures of conflicts of interest are
found at the end of this article.
Correspondence to: Yi L. Hwa, DNP, Division of
Hematology, Mayo Clinic, 200 First Street SW,
Rochester, MN 55905. E-mail: hwa.yi@mayo.edu
https://doi.org/10.6004/jadpro.2019.10.5.5
© 2019 Harborside™
J Adv Pract Oncol 2019;10(5):470–481
Abstract
Systemic immunoglobulin light-chain (AL) amyloidosis is a rare disorder arising from a plasma cell clone that produces misfolded immunoglobulin light chains, which are deposited in various tissues and organs
as amyloid fibrils. Signs and symptoms are typically vague and overlap
with those arising from other common diseases; consequently, diagnosis of AL amyloidosis is challenging for clinicians. Substantial delays
between onset of symptoms and diagnosis are common, and result
in poorer outcomes, particularly in patients with cardiac AL amyloidosis and others who develop advanced organ dysfunction. With the
need to identify AL amyloidosis as early as possible, it is important for
health-care practitioners, including advanced practice clinicians and
nurses, to be aware of the hallmark presenting signs and symptoms,
as well as the latest practice for evaluation and diagnosis. Increased
awareness of signs and symptoms associated with AL amyloidosis,
particularly relating to the most frequently involved organs, the heart
and kidneys, represents an opportunity for achieving earlier diagnosis.
Here we review these issues in AL amyloidosis, summarize the key presenting symptoms that clinicians need to be alert to, and discuss the
latest diagnostic tests, with the aim of expediting patient identification
and diagnosis with the goal of improving patient outcomes.
S
ystemic
immunoglobulin
light-chain (AL) amyloidosis is caused by plasma cell
clones in the bone marrow
(median 7%–10% marrow infiltration) that produce insoluble, misfolded immunoglobulin light chain
proteins, which are deposited in varJ Adv Pract Oncol
470
ious tissues and organs as amyloid
fibrils leading to progressive organ
dysfunction (Gertz, 2016; Grogan,
Dispenzieri, & Gertz, 2017; Kastritis
& Dimopoulos, 2016). This systemic
disease is a rare disorder, with an
estimated annual incidence of 6 to
10 per million person-years in the
AdvancedPractitioner.com
IMMUNOGLOBULIN LIGHT-CHAIN AMYLOIDOSIS
United Kingdom and United States (Banypersad,
Moon, Whelan, Hawkins, & Wechalekar, 2012; Comenzo, 2007a, 2007b; Merlini & Palladini, 2008).
The actual number of patients with this disorder
may be higher due to underdiagnosis, with a recent real-world epidemiological study estimating
an incidence of up to 14 per million person-years
in the United States (Quock, Yan, Chang, Guthrie,
& Broder, 2018). AL amyloidosis is a disease that
occurs in adults and is predominantly seen in the
sixth decade of life (median age at diagnosis being
estimated as 60–63 years); however, amyloidosis
has been diagnosed in patients as young as 40 and
is more prevalent in male patients (Abeykoon et
al., 2017; Comenzo, 2007a, 2007b; Merlini & Palladini, 2008). There are approximately 30 different
types of amyloidogenic proteins that may cause
systemic or localized disease (Sipe et al., 2014),
and AL amyloidosis is one of the most common
forms of systemic disease (Palladini & Merlini,
2016). Signs and symptoms of AL amyloidosis are
dependent on the involved organs and severity of
organ damage. Initial symptoms are nonspecific,
vary widely, and often overlap with those arising
from other common diseases (Gertz, 2016; Grogan
et al., 2017; Lousada, Comenzo, Landau, Guthrie,
& Merlini, 2015; Palladini & Merlini, 2016). Consequently, the diagnosis of this rare condition represents a challenge for clinicians.
Data from a patient experience survey by the
Amyloidosis Research Consortium, which included 533 patients with amyloidosis (72% AL),
showed that 37% of patients did not receive their
definitive diagnosis of amyloidosis until ≥ 1 year
from the initial onset of symptoms, with 32% requiring visits to ≥ 5 physicians before establishing
the diagnosis of amyloidosis, and 34% of patients
were diagnosed by hematology/oncology specialists (Lousada et al., 2015). Other reports have also
noted substantial delays in the diagnosis of AL amyloidosis (McCausland et al., 2018; Muchtar et al.,
2016) associated with the challenges of nonspecific symptoms and misdiagnosis. In a longitudinal, noninterventional study of community-based
patients with AL amyloidosis, patients reported
an average of 3 years from symptom onset to diagnosis (McCausland et al., 2018).
These delays in diagnosis have a significant impact on patients as treatment outcomes are poorer
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in patients who experience a delay in diagnosis
compared with those who achieve early diagnosis
(Grogan et al., 2017). This review highlights the
need for early recognition of clinical presentations
and diagnostic approach for systemic AL amyloidosis specifically, summarizing the key presenting
symptoms that clinicians need to be alert to, and
discussion of the latest diagnostic tests, with the aim
of expediting symptom identification and diagnosis.
THE IMPORTANCE OF EARLY
DIAGNOSIS OF AL AMYLOIDOSIS
Establishing an early diagnosis of AL amyloidosis
is important because it enables treatment to be
started early in the disease course, with the aim of
reducing the burden of the free light-chain (FLC)
producing plasma cell clone, thereby preventing
further organ damage (Merlini & Palladini, 2012).
A high percentage of bone marrow plasma cells
and baseline FLC burden at diagnosis predict poor
survival, and a reduction in FLC with therapy is associated with improved outcomes (Dispenzieri et
al., 2006; Kourelis et al., 2013; Kumar et al., 2010;
Lachmann et al., 2003). The spectrum and severity
of organ involvement also have a great impact on
prognosis and survival (Kyle, Greipp, & O’Fallon,
1986). Although autologous peripheral blood stem
cell transplantation (ASCT) is an effective therapy
for AL amyloidosis, with a 10-year survival rate of
43% (Sidiqi et al., 2018), the majority of patients
are ineligible for this aggressive treatment due to
significant organ dysfunction or comorbidities.
Frequency of Common Organ Involvement
Multisystem organ involvement is the hallmark of
AL amyloidosis. In a single-center series, Merlini
and Palladini reported that 68% of patients had more
than one organ involved at diagnosis (Merlini & Palladini, 2008). The criteria defining organ involvement in AL amyloidosis, in addition to evidence of
amyloid deposits from organ or alternate-site biopsy, are summarized in Table 1 (Gertz et al., 2005;
National Comprehensive Cancer Network, 2018).
The most commonly involved organs are the
kidney and the heart, either individually or together (Grogan et al., 2017). In various reports of
patient series or clinical studies, 48% to 80% of patients had renal involvement (Jun et al., 2013; Kyle
et al., 1997; Merlini & Palladini, 2008; Michael et
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HWA et al.
Table 1. Criteria Defining Organ Involvement in AL Amyloidosis
Organ
Criteria
Kidney
24-hour urine protein > 0.5 g/day, predominantly albumin
Heart
Mean left ventricular wall thickness (septum and posterior wall) > 12 mm in the absence of
hypertension or other possible causes of left ventricular hypertrophy; low voltage on 12-lead
electrocardiography; elevated (> 332 ng/L) concentration of NT-proBNP in the absence of renal
failure or atrial fibrillation (BNP concentration may also be used)
Liver
Total liver span > 15 cm in the absence of heart failure or alkaline phosphatase > 1.5 times the
institutional upper limit of normal
Nervous system
Peripheral: clinical evidence of symmetric lower extremity sensorimotor peripheral neuropathy
Autonomic: gastric-emptying disorder, pseudo-obstruction, voiding dysfunction not related to direct
organ infiltration
Gastrointestinal
tract
Direct biopsy verification with symptoms
Lung
Direct biopsy verification with symptoms; interstitial radiographic pattern
Soft tissue
Tongue enlargement (macroglossia); arthropathy (shoulder-pad sign); claudication, presumed
vascular amyloid; skin involvement; enlarged lymph nodes; carpal tunnel syndrome; myopathy by
biopsy or pseudohypertropy
Note. AL = systematic immunoglobin light-chain; NT-proBNP = N-terminal pro-brain natriuretic peptide;
BNP = B-type natriuretic peptide.
Adapted with permission from Gertz, MA, et al. Am J Hematol. 79 (2005) 319-28. © John Wiley and Sons.
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Systemic
Light Chain Amyloidosis V.1.2019. © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN
Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written
permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.
The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.
al., 2010; Skinner et al., 2004; Vesole et al., 2006),
and 21% to 70% had cardiac involvement (Jun
et al., 2013; Kyle et al., 1997; Merlini & Palladini,
2008; Michael et al., 2010; Skinner et al., 2004; Vesole et al., 2006). Recent data suggested that 80%
of patients were estimated to have dominant cardiac amyloid, and two thirds had dominant renal
amyloid at diagnosis (Milani, Merlini, & Palladini,
2018). In patients with cardiac AL amyloidosis,
advanced cardiac dysfunction is estimated to result in up to 30% of patients dying within 90 days
of diagnosis (Grogan et al., 2017; Palladini & Merlini, 2016), and AL amyloidosis patients with high
FLC burden are likely to have more severe cardiac
involvement (Kumar et al., 2010).
Other commonly involved organs are liver and
nerve systems. Approximately 16% to 22% of AL
amyloidosis patients have liver involvement, manifesting as hepatomegaly and elevation of alkaline
phosphatase at diagnosis (Gertz, 2018; Merlini &
Palladini, 2012; Merlini, Wechalekar, & Palladini,
2013), although in the presence of heart failure,
the clinical differentiation of amyloid infiltration from venous congestion may not be possible
J Adv Pract Oncol
(Guidelines Working Group of UK Myeloma Forum & British Committee for Standards in Haematology British Society for Haematology, 2004).
Nervous system involvement (peripheral or autonomic) is present in 14% to 20% of patients, with
20% presenting with peripheral neuropathy (Benson & Kincaid, 2007; Merlini & Palladini, 2012).
PRESENTING SIGNS AND SYMPTOMS
The most critical step to early and correct diagnosis is to suspect AL amyloidosis on the basis of the
clinical manifestations (Kastritis & Dimopoulos,
2016). A formal diagnosis of AL amyloidosis is not
usually made until signs or symptoms referable to
a particular organ appear (Falk, Comenzo, & Skinner, 1997; Grogan et al., 2017; Guidelines Working
Group of UK Myeloma Forum & British Committee for Standards in Haematology British Society
for Haematology, 2004; National Comprehensive
Cancer Network, 2018). It is therefore important
for advanced practice clinicians and nurses to be
aware of the multiple signs and symptoms that
could give rise to clinical suspicion of AL amyloidosis. Increased awareness of the potential for
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IMMUNOGLOBULIN LIGHT-CHAIN AMYLOIDOSIS
certain signs and symptoms to be associated with
AL amyloidosis, particularly relating to the most
frequently involved organs (heart and kidneys),
represents an opportunity for achieving earlier diagnosis (Lousada et al., 2015).
The initial presentation of AL amyloidosis can
be subtle and nonspecific, and usually depends on
the organ(s) involved (Comenzo et al., 2012; Falk et
al., 1997; Muchtar et al., 2017b; National Comprehensive Cancer Network, 2018), such as shortness
of breath, weakness, orthopnea, polyneuropathy,
swelling of the ankles and legs, and macroglossia (Jun et al., 2013; Lousada et al., 2015; Merlini
et al., 2013); in a retrospective analysis of Korean
patients with AL amyloidosis, pitting edema was
the most common initial presentation, occurring
in 26% of patients (Jun et al., 2013).
Cardiac involvement is common in AL amyloidosis, with cardiac amyloidosis a diagnostic
consideration in patients presenting with nondilated or restrictive cardiomyopathy with preserved ejection fraction (Carrizales-Sepulveda,
Ordaz-Farias, Vera-Pineda, Benavides-Gonzalez,
& Flores-Ramirez, 2017; Flodrova et al., 2018).
Other signs include low-voltage QRS and pseudo
infarct patterns on electrocardiogram, orthostatic
hypotension associated with low cardiac output,
left ventricular hypertrophy with increased interventricular septal diameter > 12 mm, and/or diastolic dysfunction, and late gadolinium enhancement on cardiac MRI. Other symptoms include
shortness of breath, edema, atypical chest pain
from small vessel disease, ascites, and syncope
(Carrizales-Sepulveda et al., 2017; Guidelines
Working Group of UK Myeloma Forum & British
Committee for Standards in Haematology British
Society for Haematology, 2004; Merlini & Palladini, 2012; Wechalekar et al., 2013).
Renal involvement is also common in AL amyloidosis and a diagnosis should be considered in
patients presenting with nephrotic syndrome
with or without renal insufficiency (Guidelines
Working Group of UK Myeloma Forum & British
Committee for Standards in Haematology British
Society for Haematology, 2004). Symptoms potentially associated with AL amyloidosis with renal
involvement can include ankle swelling, dizziness
due to orthostatic hypotension, frothy urine from
proteinuria, peripheral edema, mild renal impairAdvancedPractitioner.com
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ment, and hypercholesterolaemia in patients with
nephrotic syndrome (Guidelines Working Group
of UK Myeloma Forum & British Committee for
Standards in Haematology British Society for
Haematology, 2004). It is important to note that
nephrotic range proteinuria can occur with normal renal function.
Peripheral neuropathy could be a sign of peripheral nervous system involvement in AL amyloidosis (Benson & Kincaid, 2007). Specific symptoms
associated with sensory neuropathy may include
paresthesia, numbness, and muscle weakness due
to co-occurring myopathy. Additionally, postural
hypotension, impotence, dry mouth and eyes, and
disturbed gastrointestinal (GI) motility may be associated with autonomic neuropathy in AL amyloidosis patients with nervous system involvement
(Guidelines Working Group of UK Myeloma Forum & British Committee for Standards in Haematology British Society for Haematology, 2004; Merlini & Palladini, 2012; Muchtar et al., 2017b).
Specific GI involvement may be associated
with a range of presenting symptoms including
weight loss, nausea, diarrhea, disturbed GI motility, and GI bleeding (Cowan et al., 2013; Guidelines
Working Group of UK Myeloma Forum & British
Committee for Standards in Haematology British Society for Haematology, 2004; Iida, Yamano,
& Nakase, 2018). AL amyloidosis with hepatic involvement—another commonly involved organ
site—should be considered for patients presenting
with unexplained hepatomegaly with normal imaging or isolated elevated alkaline phosphatase in
the absence of transaminitis (Guidelines Working
Group of UK Myeloma Forum & British Committee for Standards in Haematology British Society
for Haematology, 2004). Macroglossia, which is
highly indicative of AL amyloidosis, submandibular and cervical gland enlargement, and carpal
tunnel syndrome are indicative of soft tissue involvement (Merlini & Palladini, 2012).
Rare Presentations
Various other symptoms, reflecting the involvement of other organ systems, may be present; indeed, any organ other than the brain can be involved in AL amyloidosis (Guidelines Working
Group of UK Myeloma Forum & British Committee for Standards in Haematology British Society
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HWA et al.
for Haematology, 2004). Approximately 15% of
patients have soft tissue involvement at presentation (Milani et al., 2018). Less common signs and
symptoms that could indicate AL amyloidosis include: skin and soft-tissue thickening, painful seronegative arthropathy, bone involvement, hoarse
voice, hypoadrenalism, hypothyroidism, lymphadenopathy, and pulmonary infiltration (Guidelines Working Group of UK Myeloma Forum &
British Committee for Standards in Haematology
British Society for Haematology, 2004). Myopathy is a rare presentation, often misdiagnosed, and
serum creatine kinase levels have been shown to
be an unreliable biomarker (Muchtar et al., 2016).
While uncommon, ocular manifestations of amyloidosis have been reported, as a result of involvement of various organ systems. The deposition of
amyloid fibrils has been documented in the conjunctiva, temporal artery, extraocular muscle, trabecular meshwork, and cranial nerves (Reynolds
et al., 2017). Reports of temporal artery biopsies
performed to confirm a diagnosis of suspected
giant cell arteritis (Ghinai et al., 2017; Kanaan,
Lorenzi, Thampy, Pandit, & Dayan, 2017) and to
determine the cause of bilateral sequential optic
neuropathy (Kanaan et al., 2017) have revealed
amyloid deposits confirming a diagnosis of AL
amyloidosis in these patients.
DIAGNOSTIC STRATEGIES TO
CONFIRM AL AMYLOIDOSIS
A number of diagnostic workup algorithms are
available in order to guide clinicians through the
process of establishing a clear diagnosis of AL
amyloidosis (Gertz, 2018; National Comprehensive Cancer Network, 2018; Palladini & Merlini,
2016); a recently published algorithm by Gertz is
reproduced in Figure 1. If AL amyloidosis is suspected based on the presenting signs and symptoms, patients undergo an initial workup to detect
the presence of amyloid deposits and to evaluate
organ function (Table 2). First, an assessment for
the underlying plasma cell dyscrasia is performed
by serum and urine protein electrophoresis and
immunofixation, and the immunoglobulin FLC
assay for κ and λ immunoglobulin light chains
(Merlini & Palladini, 2008; Palladini et al., 2017).
If the screening tests are positive, subcutaneous
fat aspiration and bone marrow biopsy are then
J Adv Pract Oncol
carried out to determine the presence of amyloid
by characteristic Congo red staining (Dispenzieri
et al., 2015; Fernandez de Larrea et al., 2015; Milani et al., 2018). Other histological staining such
as Thioflavin stains may be used; however, Congo
red staining is generally the most accepted and
considered the standard for detection of amyloid
(Dispenzieri et al., 2015). Bone marrow evaluation
may determine the presence of plasma cell dyscrasia, the percentage of plasma cells, and plasma
cell genetics by fluorescence in situ hybridization
(Gertz, 2018). The salivary gland is used as an alternative site for biopsy if the abdominal fat aspirate is negative, with a sensitivity of 58% (Foli
et al., 2011). If fat aspirate and bone marrow are
both negative but clinical suspicion for amyloid
remains high, then a tissue biopsy of the organs
thought to be involved (heart, liver, kidney, nerve,
etc.) is collected (Gertz, 2018) and stained with
Congo red. Although all biopsies carry a risk of
bleeding, liver biopsies should be carried out with
caution due to the increased risk of hemorrhage
(Palladini & Merlini, 2016).
Once the diagnosis of amyloidosis has been
made, the type of amyloidosis that is present must
be determined. When stained using Congo red, the
amyloid deposits produce a pathognomonic redgreen birefringence under cross-polarized light microscopy (Comenzo, 2007a; Falk et al., 1997; Merlini & Bellotti, 2003). However, Congo red staining
and fluorescent birefringence alone do not distinguish AL amyloidogenic protein from other forms
of amyloidosis such as transthyretin (TTR), hereditary apolipoprotein AI, or acquired amyloid A (AA)
amyloidosis due to chronic inflammation; typing
of the amyloid deposits is therefore mandatory to
confirm a diagnosis of AL amyloidosis. The most
commonly available techniques to classify amyloid
deposits are IHC and IF; however, these tests can
be misleading when classifying amyloid deposits
(Gertz, 2018). A more reliable amyloid typing technique is the mass spectrometry–based proteomic
analysis (Gertz, 2018). Although more expensive
and available to a limited number of specialized
medical centers, mass spectrometry is the current
gold standard for determining the type of amyloidosis (Gertz, 2018). Early referral of the patient to a
center of excellence where accurate amyloid typing
can be done is crucial to confirm the diagnosis.
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IMMUNOGLOBULIN LIGHT-CHAIN AMYLOIDOSIS
Suspect amyloidosis
• Nephrotic range proteinuria
• Heart failure preserved ejection fraction
• Nondiabetic neuropathy (carpal tunnel 50%)
• Hepatomegaly, diarrhea
• Atypical MGUS or smoldering myeloma
Serum immunofixation; immunoglobulin FLCs
Add cardiac Pyp scan if heart symptoms
+Ig
–Ig
Fat aspirate; bone marrow
Possible lip biopsy for
Congo red
+
–
Mass spectrometry of deposit
Localized
skin
larynx
bladder
↓Index of ↑Index of Polyp or
suspicion suspicion GI ulcer
Amyloid
excluded
in 85%
Stop
–
AL
Organ biopsy
+
Diagnosis
excluded
TTR
Systemic
↓
Staging
and FLC
NT-proBNP
Troponin
Proceed
with mass
spectroscopy
Light chain amyloid
unlikely
if Pyp scan +
wt TTR
Screen
amyloid very
for familial
–
likely
amyloid
+
Genetic
counseling
Figure 1. Diagnostic algorithm for AL amyloidosis. Reproduced with permission from Gertz MA. Blood
Cancer J. 8 (2018) 44. http://creativecommons.org/licenses/by/4.0/.
AL = amyloid light-chain; MGUS = monoclonal gammopathy of undetermined significance;
FLC = free light-chain; Pyp = technetium-99m stannous pyrophosphate; TTR = transthyretin-related;
GI = gastrointestinal; Ig = immunoglobulin; wt = wild type; NT-proBNP = N-terminal pro-brain natriuretic peptide.
DEVELOPMENTS IN TECHNIQUES TO
ASSESS ORGAN INVOLVEMENT
Once the diagnosis and typing of AL amyloidosis are established, additional evaluations may be
conducted to assess the manifestation and extent
of organ involvement. Patients with renal involvement commonly present with increased proteinuria (mainly albuminuria), evolving into nephrotic
syndrome and progressing into renal failure if untreated (Palladini & Merlini, 2016). Twenty-fourhour urinary protein loss and estimated glomerular filtration rate (eGFR) are the standard tests to
evaluate renal involvement (Palladini & Merlini,
2016). The assessment of proteinuria by 24 hour
urine collection can be used to assess organ response and monitor organ progression. The common clinical features of liver involvement can be
assessed using liver function tests to detect abnormal liver enzymes, especially elevated alkaline
phosphatase, and liver imaging using CT, ultrasound, or MRI to evaluate hepatomegaly (PallaAdvancedPractitioner.com
dini & Merlini, 2016). Suspected GI involvement
may warrant endoscopic evaluation with biopsy
to help confirm a diagnosis by using Congo red
staining to detect the presence of amyloid (Iida
et al., 2018). Cardiac involvement of amyloidosis
can be assessed through electrical disturbances
or lowered voltage in limb leads on electrocardiography, while echocardiographic evidence of
increasing wall thickness and abnormality of longitudinal ventricular strain pattern may also highlight AL amyloidosis with cardiac involvement
(Carrizales-Sepulveda et al., 2017; Grogan et al.,
2017). Furthermore, specific biomarkers are used
to establish and stage cardiac AL amyloidosis, including N-terminal pro-brain natriuretic peptide
(NT-proBNP) and cardiac troponin T (cTnT).
Cardiac MRI with gadolinium is now available to
evaluate cardiac amyloidosis, particularly when
echocardiogram findings are inconclusive (Grogan et al., 2017). Cardiac MRI can provide specific
imaging features to detect cardiac involvement by
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HWA et al.
Table 2. Initial Diagnostic Workup of AL Amyloidosis
Step
Test
Aim
Clinical and amyloidrelated assessment
Orthostatic vital signs
Suspecting diagnosis of AL
amyloidosis
History and physical
Chest x-ray
Skeletal survey
Laboratory evaluation
(screening tests)
CBC differential and platelet count
Assessing effect of medication
PT, PTT, factor X (if indicated)
Assessing coagulation deficiency
Serum quantitative immunoglobulins, SPEP and SIFE
Characterizing presence of
plasma cell dyscrasia and κ and λ
immunoglobulin light chains
24-hour urinary total protein, UPEP and UIFE
Serum FLC assay
Serum BUN/creatinine, electrolytes, albumin and
calcium
Assessing renal function
Creatinine clearance
Serum uric acid
Pathologic evaluation
NT-proBNPa, troponin T
Assessing cardiac function
Alkaline phosphatase, liver enzymes, bilirubin
Assessing hepatic function
Bone marrow aspirate and biopsy with
immunohistochemical staining for κ and λ and Congo
red staining for amyloid
Detecting the presence of amyloid
deposit
Plasma cell FISH
Abdominal fat pad aspirate, and involved organ
biopsy as clinically indicated if both fat pad and bone
marrow biopsy are negative (alternative sites include
rectal or minor salivary gland biopsy)
Mass spectrometry
Accurate tissue typing
Note. AL = systematic immunoglobin light-chain; CBC = complete blood cell count; PT = prothrombin time; PTT =
partial thromboplastin time; SPEP = serum protein electrophoresis; SIFE = serum immunofixation electrophoresis; UPEP
= urine protein electrophoresis; UIFE = urine immunofixation electrophoresis; FLC = free-light chain; BUN = blood urea
nitrogen; NT-proBNP = N-terminal pro-brain natriuretic peptide; FISH = fluorescence in-situ hybridization.
a
If NT-ProBNP is not available, BNP can be performed.
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Systemic
Light Chain Amyloidosis V.1.2019. © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN
Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written
permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.
The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.
amyloidosis; however, it does not distinguish the
light chain amyloidosis from non-AL type amyloidoses (Grogan et al., 2017). Cardiac scintigraphy (Gertz, 2018; Palladini & Merlini, 2016) with
technetium-99m (99mTc) stannous pyrophosphate
(PYP) or 99m 3,3 diphosphono-1, 2-propanodicarboxylic acid (DPD) may be helpful to distinguish
AL from transthyretin (ATTR) cardiac amyloidosis and potentially obviate the need for cardiac biopsy (Gertz, 2018; Palladini & Merlini, 2016), particularly in elderly patients with the absence of a
plasma cell dyscrasia (Bokhari et al., 2013; Siddiqi
J Adv Pract Oncol
& Ruberg, 2018). When a monoclonal protein is
present, biopsy to detect amyloid deposit and to
confirm amyloid type is required to establish an
accurate diagnosis (Grogan et al., 2017).
DIFFERENTIAL DIAGNOSES
The differential diagnosis for AL amyloidosis includes systemic non-AL amyloidoses (including
AA and ATTR types), localized light-chain amyloidosis, and other paraprotein-associated diseases including peripheral neuropathy and immunoglobulin deposition diseases (Guidelines Working
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IMMUNOGLOBULIN LIGHT-CHAIN AMYLOIDOSIS
Group of UK Myeloma Forum & British Committee for Standards in Haematology British Society
for Haematology, 2004). Among the numerous
different types of systemic amyloidosis, AL comprises 78% of new cases (Palladini & Merlini,
2016). The mutated transthyretin (ATTRm) and
wild-type transthyretin (ATTRwt) systemic amyloidosis are found in approximately 7% and 6%
to 10% of new cases, respectively. ATTRm is hereditary and is found primarily in the peripheral
and autonomic system (Palladini & Merlini, 2016),
the heart, and the eye; common clinical features
include heart failure and peripheral or autonomic
neuropathy (Grogan et al., 2017). In ATTRwt the
heart is involved in almost all cases, as well as the
ligaments and tenosynovium (Palladini & Merlini, 2016); common clinical presentations include
atrial fibrillation, heart failure with carpal tunnel
syndrome, tendon rupture, and spinal stenosis
(Grogan et al., 2017).
Distinguishing the AL and ATTR subtypes
can be difficult due to the overlapping symptoms
and because patients can have ATTR amyloidosis
and monoclonal gammopathy of undetermined
significance (MGUS; Phull et al., 2018). In some
patients with ATTR, a monoclonal protein component and abnormal FLC have been identified,
which are usually characteristic of AL amyloidosis
(Geller et al., 2017); for such cases, biopsy to confirm the presence of amyloid and accurate typing
for distinguishing the amyloid subtypes are required. While imaging with PYP or DPD can help
to distinguish ATTR from AL amyloidosis, gene
sequencing should be used to determine hereditary components of amyloidosis (Gertz, 2018).
Patients who are already being treated for
multiple myeloma (MM) and patients with MGUS
who are being monitored may also have or may
develop AL amyloidosis (Grogan et al., 2017; Merlini & Palladini, 2012). Approximately 10% to 15%
of patients with MM may develop primary amyloidosis and up to 38% of patients with MM have
been reported to have AL amyloid deposits in the
absence of readily discernible signs or symptoms
(Desikan et al., 1997; Madan et al., 2010; Rajkumar, Gertz, & Kyle, 1998). Due to the clonal nature of all three conditions, patients with MM or
MGUS should be assessed carefully for symptoms
specific to AL amyloidosis in order to establish a
AdvancedPractitioner.com
REVIEW
diagnosis as early as possible (Merlini & Palladini, 2012). Assessment for an abnormal FLC ratio
and for abnormal cardiac or renal parameters can
help begin the diagnostic process prior to symptomatic manifestation of organ involvement in
patients with MGUS (Merlini & Palladini, 2012);
additional “red flags” have been suggested for
early identification of AL amyloidosis with other
organ involvement, such as alkaline phosphatase
elevation, neuropathic pain, and the onset of hypotension (Merlini & Palladini, 2012). In patients
with AL amyloidosis secondary to MM, specific
non-myeloma symptoms require investigation;
for example, one case report in the literature highlighted a female patient with MM who also presented with macroglossia and restricted tongue
movement (Dawoud & Ariyaratnam, 2016). Diagnosis of AL amyloidosis was established by the
identification of amyloid deposits in the oral cavity following a full oral soft-tissue examination
(Dawoud & Ariyaratnam, 2016).
STAGING OF AL AMYLOIDOSIS
Following confirmation of AL amyloidosis, disease stage is determined. The survival outcome
of patients with AL amyloidosis varies greatly
and often depends on the severity of organ involvement, in particular cardiac dysfunction at
diagnosis. Staging of AL amyloidosis at diagnosis
allows prognostic stratification in order to select
the optimal treatment approach in which the intensity is balanced with the patients’ performance
status (Milani et al., 2018). Patients with advanced
cardiac disease with no treatment (Mayo stages
IIIa and IIIb) had a median survival of less than 1
year (Palladini, Milani, & Merlini, 2015). Current
validated staging systems are outlined in Table 3.
The original Mayo Clinic 2004 prognostic staging
system uses serum cTnT (< 0.035 ng/mL) and NTproBNP (< 332 pg/mL) to stratify AL amyloidosis
into three stages (Dispenzieri et al., 2004). The revised Mayo Clinic staging includes the difference
between involved and uninvolved FLC (dFLC) as
prognostic variables, where one point is assigned
for each of dFLC ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL,
or NT-proBNP ≥ 1,800 pg/mL (Kumar et al., 2012).
The European staging system further added systolic blood pressure < 100 mm Hg and NT-proBNP > 8,500 pg/mL to further classify the stage III
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HWA et al.
Table 3. Staging Systems and Associated Prognostic Stage, Risk Factors, and Survival Outcomes for
Patients With AL Amyloidosis
Staging
systems
Median survival, months
Prognostic variables
Stage
Number of
risk factors
Mayo Clinic
2004 AL
amyloidosis
staging
NT-proBNP ≥ 332 ng/L
cTnT ≥ 0.035 ng/mL
(or cTnI ≥ 0.1 ng/mL)
I
II
III
0
1
2
26.4
10.5
3.5
27.2
11.1
4.1
Dispenzieri et
al., 2004
Advanced
cardiac
stage
Mayo 2004 AL
amyloidosis stage III plus
systolic blood pressure
< 100 mm Hg
NT-proBNP > 8,500 ng/L
III (IIIA: NTproBNP <
8,500 ng/L;
IIIB: NT-proBNP
≥ 8,500 ng/L)
0
1
2
26
6
3
IIIA: 17
IIIB: 4.6
Wechalekar et
al., 2013
cTnT model
cTnI model
Reference
5-year OS
Mayo Clinic
2012 AL
amyloidosis
staging
NT-proBNP ≥ 1,800 ng/L
cTnT ≥ 0.025 ng/mL
dFLC ≥ 18 mg/dL
I
II
III
IV
0
1
2
3
94.1
40.3
14
5.8
59%
42%
20%
14%
Kumar et al.,
2012
Note. AL = systemic immunoglobin light-chain; NT-proBNP = N-terminal pro-brain natriuretic peptide;
cTnT = cardiac troponin T; cTnI = cardiac troponin I; dFLC = difference between involved and uninvolved free-light
chain; OS = overall survival.
from the original Mayo 2004 staging system into
stage IIIa and IIIb (Wechalekar et al., 2013).
SENSITIVITY AND DETECTION
RATES OF DIAGNOSTIC TESTS
Serum and urine immunofixation electrophoresis
have been shown to detect a monoclonal component (with λ/κ ratio of 75/25) in 97% of patients,
and FLC measurements have been shown to have
a sensitivity of 76% (Merlini & Palladini, 2008),
while other studies have demonstrated higher detection rates (up to 97%) by FLC assay in AL amyloidosis patients (Bochtler et al., 2008; Morris et
al., 2007). Subcutaneous fat aspirate is the least
invasive and often the first approach, offering 79%
sensitivity in AL amyloidosis (Fernandez de Larrea
et al., 2015). However, target organ biopsy should
be pursued if clinical suspicion remains high and
fat aspirate is negative, as a biopsy sample from a
symptomatic organ has higher sensitivity than that
from the more accessible tissues (Dispenzieri et al.,
2015). Combined with bone marrow biopsy, subcutaneous fat aspirate can demonstrate AL amyloidosis in more than 85% of patients (Gertz, 2018),
while other studies have demonstrated a sensitivity of 98.9% for AL amyloidosis with renal involvement through a combination of skin, fat, and rectal
mucosal biopsies (Li et al., 2017), and of 84% for
AL amyloidosis with cardiac involvement using abJ Adv Pract Oncol
dominal fat pad fine-needle aspiration (Quarta et
al., 2017). Further, a recent analysis showed that the
sensitivity of abdominal fat pad excisional biopsy
could be increased to almost 100% if large enough
biopsies (> 700 mm3) were used (Garcia, Collins, &
Stone, 2018). It has been reported that fat aspirate
is being underused for diagnosis of AL amyloidosis,
and that a substantial proportion of patients could
avoid a more invasive organ biopsy due to the sensitivity and utility of fat pad aspiration for recognizing the disease (Muchtar et al., 2017a).
CONCLUSIONS
Early recognition of signs and symptoms potentially associated with AL amyloidosis is the key to
identification and diagnosis of the disease before
substantial organ damage can occur and is thus
important for improving treatment outcomes and
survival. Advanced practice clinicians and oncology nurses should be aware of the common presenting signs and symptoms that could give rise to
clinical suspicion of AL amyloidosis with specific
organ involvement. They should also be cognizant of the subsequent needs for further diagnostic workup and, if warranted, urgent referral to a
center of excellence. This would ensure an early
diagnosis of AL amyloidosis when therapeutic
treatments are more effective, and subsequently
result in improved prognosis and quality of life of
478
AdvancedPractitioner.com
IMMUNOGLOBULIN LIGHT-CHAIN AMYLOIDOSIS
patients. Patients with AL amyloidosis should ultimately be evaluated by a team of amyloid experts
to help guide the treatment choices. l
Acknowledgment
The authors would like to thank Steve Hill and
Laura Webb of FireKite (an Ashfield Company,
part of UDG Healthcare PLC) for medical writing assistance, which was funded by Millennium Pharmaceuticals, Inc. All editorial procedures complied with Good Publication Practice-3
(GPP3) guidelines (Battisti et al., 2015).
Disclosure
Yi L. Hwa, Teresa Fogaren, Allison Sams, and Lisa
Mendelson have nothing to disclose. Douglas V.
Faller, Dawn M. Stull, and Sara Thuenemann are
employees of Millennium Pharmaceuticals, Inc.,
Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
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