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CHAPTER 108 brain of patients with Alzheimer disease. Amyloid deposits are always
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extracellular and, under the light microscope, appear amorphous and
IMMUNOGLOBULIN pink when seen after standard hematoxylin-and-eosin staining. All
amyloid deposits bind Congo red dye and demonstrate green birefrin-
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LIGHT-CHAIN AMYLOIDOSIS gence under polarized light, and this test remains the standard diag-
nostic procedure required to confirm a diagnosis of amyloidosis. Under
the electron microscope, amyloid consists of rigid, linear, nonbranch-
ing fibrils of 9.5 nm diameter. Historically, amyloid was defined based
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Morie A. Gertz, Taimur Sher, Angela Dispenzieri, and Francis K. Buadi on whether there was a family history (inherited), whether it was the
result of a chronic inflammatory condition (secondary), or whether it
was idiopathic (primary). Today, amyloidosis is classified based on the
protein subunit composition of the deposits. The term “primary amy-
SUMMARY loid” is archaic and should not be used. Instead, such cases should be
called “immunoglobulin light-chain (AL) amyloidosis,” reflecting the
Amyloidosis should be considered in any patient presenting with nephrotic fact that they represent a systemic plasma cell dyscrasia. The subunit
range proteinuria; infiltrative cardiomyopathy or heart failure with preserved classification is important because AA amyloidosis (secondary) can be
ejection fraction; hepatomegaly without specific imaging findings; or periph- the consequence of sustained inflammation but can also be inherited,
eral neuropathy, particularly if a monoclonal protein is present; as well as any as in familial Mediterranean fever. Inherited forms of amyloidosis are
patient with atypical multiple myeloma. generally composed of mutant transthyretin (TTR) but can also be a
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consequence of mutations in apolipoprotein, fibrinogen, and gelsolin.
When a patient is seen with a relevant syndrome, the patient should have Senile systemic amyloidosis, primarily a cardiac disorder, is being
immunofixation of serum and urine proteins and measurement of κ and increasingly recognized, and is caused by deposition of wild-type TTR
λ immunoglobulin free light chains. If all of these tests are normal, it is unlikely as amyloid material in patients older than age 60 years. Table 108–1
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that the patient has immunoglobulin light-chain (AL) amyloidosis. lists the nomenclature of the various forms of amyloidosis. Practicing
If any of the above tests are positive, further investigation for amyloidosis hematologists and oncologists are not likely to see patients with forms
should be undertaken. The diagnostic test of choice is subcutaneous fat aspi- of amyloidosis other than immunoglobulin light-chain (AL) amyloido-
ration; marrow biopsy is the second best procedure. With these two tests, 83 sis. This is the only form that is responsive to chemotherapy and is the
percent of patients will have a positive result when stained with Congo red focus of this chapter; additionally, the term amyloidosis, unless specified
under green birefringence. otherwise, refers to AL amyloidosis.
All patients with biopsy proven amyloidosis should have the deposits ana-
lyzed by laser capture microdissection mass spectroscopy to definitively clas- EPIDEMIOLOGY
sify the exact protein subunit composing the amyloid. This technique does not
distinguish between systemic and localized amyloidosis, however. Amyloidosis is rare, with an incidence of eight per million persons per
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The prognosis in AL amyloidosis is determined by three tests: (1) the year with a median age at diagnosis of 67 years. This makes it one-
N-terminal probrain natriuretic peptide, (2) serum troponin, and (3) the differ- sixth as common as myeloma and twice as common as Waldenström
ence between the involved and uninvolved immunoglobulin free light chains. macroglobulinemia. Conversely, a practicing oncologist should see
These three tests can be combined to stage the patient from stage 1 through approximately one light-chain amyloid patient for every six patients
stage 4. with myeloma in the oncologist’s practice. If this is not the case, there is
a significant likelihood that the disease is going unrecognized.
Treatment of AL amyloidosis involves either standard systemic chemother-
apy or high-dose chemotherapy with autologous stem cell transplantation.
Fit patients who are expected to have low morbidity with transplantation ETIOLOGY AND PATHOGENESIS
should undergo this approach. The majority of patients, however, will not be
candidates for transplantation and should be treated with traditional systemic The fibrils of immunoglobulin light chain amyloid are composed, in
chemotherapy; with the cyclophosphamide, bortezomib, and dexamethasone most patients, of fragments of immunoglobulin light chains. A normal
regimen currently favored by many investigators. immunoglobulin light chain has a molecular weight of approximately
25 kDa, but the immunoglobulin light chains found in amyloid depos-
its usually range from 8 kDa to 15 kDa. The fragment size is impor-
DEFINITION AND HISTORY tant because it usually reflects the deletion of the constant region of the
immunoglobulin light chain, making immunohistochemistry a poor
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Amyloidosis is a heterogeneous group of diseases characterized by tis- technique to identify the fibril type in paraffin-embedded tissues. A
sue infiltration with misfolded protein precursors as amyloid material. fraction of patients have immunoglobulin heavy chain amyloid deposits
For nearly 100 years, amyloid has been defined by its staining proper- where fragments of immunoglobulin G, A, or M heavy chains comprise
ties. Divry and Florkin first used Congo red to detect amyloid in the the basic subunit. Whereas AL amyloidosis represents approximately 62
percent of all amyloid patients, immunoglobulin heavy-chain amyloi-
dosis represents less than 1 percent of all patients. 7
There is clearly something “amyloidogenic” about the immuno-
Acronyms and Abbreviations: CRAB, calcemia, renal insufficiency, anemia, or globulin light chains in patients with AL amyloidosis. Unlike mono-
bone disease; CyBorD, cyclophosphamide, bortezomib, and dexamethasone; MRI, clonal gammopathy and myeloma where the κ:λ ratio is 2:1, in AL
magnetic resonance imaging; NT-ProBNP, N-terminal probrain natriuretic peptide; amyloidosis, the κ:λ ratio is 1:3, suggesting an intrinsic propensity of
TTR, transthyretin. λ light chains to form amyloid. Moreover, the subgroup λ is exclu-
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sively found in patients with AL amyloidosis. When the light chains
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