Page 1611 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 88

IMMUNOGLOBULIN LIGHT CHAIN AMYLOIDOSIS

(PRIMARY AMYLOIDOSIS)

Morie A. Gertz, Francis K. Buadi, Martha Q. Lacy, and Suzanne R. Hayman

Amyloidosis is defined as the clinical syndrome associated with of the deposits, as discussed in the “Clinical Manifestations” section
deposition of amyloid. Amyloid in tissue is defined by its tinctorial below.
properties of a homogeneous, eosinophilic, hyaline material when Familial amyloidosis is, for most patients, caused by an inherited
viewed by hematoxylin and eosin staining. Amyloid stains specifically mutation of transthyretin (TTR). It is difficult to distinguish from
with Congo red, demonstrating a deep pink amorphous composition. light-chain amyloidosis because the clinical manifestations may be
Although Congo red staining is the sine qua non for the diagnosis of quite similar. Other inherited forms of amyloidosis have been associ-
amyloid, many pathology laboratories prefer the use of sulfated ated with apolipoprotein A1 mutations, fibrinogen A α mutations,
Alcian blue or crystal violet for screening. A second requirement is and mutations of gelsolin.
that the Congo red–positive histologic finding must demonstrate Secondary systemic amyloidosis is amyloidosis that is usually a
apple-green birefringence when observed under polarized light. consequence of a sustained inflammatory process. The frequency of
The term amyloid is a misnomer. The term was first used in 1838 symptomatic secondary systemic amyloidosis has been in sharp
by a German botanist because the tissue stained blue with iodine and decline for the past decade. Previously, secondary systemic amyloido-
was incorrectly thought to be starch-like, thus the terminology sis was a consequence of an uncontrolled inflammatory process, typi-
amyloid. In Vienna, Rokitansky believed that the material was not cally inflammatory polyarthropathies such as juvenile rheumatoid
starch but rather of lipid composition and used the term lardaceous arthritis, psoriatic arthritis, or ankylosing spondylitis. Another cause
degeneration for amyloid. Both were incorrect because all forms of was long-standing inflammatory bowel disease. Amyloidosis as a
amyloid appear to be protein-derived. consequence of these inflammatory processes has fallen sharply with
By electron microscopy, amyloid has been shown to be fibrillar in the introduction of biologic agents that function as inhibitors of
origin with an approximate diameter of 9.5 nm and as being linear interleukin-1, interleukin-6, and inhibitors of tumor necrosis factor
nonbranching and comprised of protofilaments (Fig. 88.1). The α (TNF-α). The ability to control these sustained inflammatory
Congo red binding occurs because the protein misfolds from the processes has resulted in the sharp decline in the recognition of sec-
physiologic configuration of the α-helix into a β-pleated sheet, which ondary systemic amyloidosis. Sporadic patients are seen with multiple
is directly responsible for its insolubility and resistance to proteolysis. cutaneous abscesses, usually as a result of subcutaneous injection of
Amyloid is highly resistant to solubilization unless it is subjected to contaminated narcotics. Patients can also be seen with chronic infec-
the harshest denaturation conditions. This insolubility in physiologic tions related to paraplegia or quadriplegia. Rare patients with lifelong
solution likely contributes to amyloid’s ability to disrupt normal bronchiectasis related to cystic fibrosis can develop systemic amyloi-
organ function and leads to the clinical disease amyloidosis, the dosis. There are also forms of inherited secondary amyloidosis
clinical syndrome associated with deposition of amyloid. associated with familial inflammatory syndromes such as familial
Mediterranean fever or mutations of the TNF receptor gene (so-called
TNF receptor–associated periodic syndrome).
EPIDEMIOLOGY

The incidence of immunoglobulin light-chain amyloidosis is esti- PATHOBIOLOGY OF THE DISEASE
mated to be approximately 8 per 1 million per year. It is the cause of
death in 0.58 of 1000 recorded deaths and is responsible for 0.8% In immunoglobulin light-chain amyloidosis, the immunoglobulin
of end-stage renal disease. At Mayo Clinic, amyloid light-chain (AL) fragments have specific thermodynamic instability that causes them
amyloidosis represents 9% of all patients seen with monoclonal gam- to misfold into the insoluble amyloid configuration. The injection of
mopathies. AL amyloidosis represents 60% of all patients seen with immunoglobulin light chains purified from the urine of patients with
amyloidosis. However, hereditary amyloidosis now accounts for 10% multiple myeloma will not produce amyloid when injected into mice.
of patients, localized amyloidosis 8.5% of patients, senile systemic However, when the light chains are extracted from the urine of
amyloidosis 18% of patients, and secondary amyloidosis 2.5% of patients with light-chain amyloidosis and injected into mice, it will
patients. All these forms of amyloidosis have the same tinctorial produce amyloid deposits and organ dysfunction, suggesting that the
properties in histologic section and must be distinguished using other specifics of the immunoglobulin light chain are important in deter-
techniques. mining its propensity to misfold into amyloid. Monoclonal immu-
The cause of the plasma cell dyscrasia that underlies light-chain noglobulin light chains can be converted in vitro to amyloid by in
amyloidosis remains unknown. There does not appear to be a linkage vitro digestion with pepsin. Historically, before it was clearly under-
to any specific occupation or toxic chemical exposure. No environ- stood that amyloidosis was derived from a plasma cell dyscrasia with
mental agents have been linked to the development of amyloidosis. the development of “toxic” immunoglobulin light chains, the term
However, the Veterans Administration in the United States considers primary amyloidosis was used as a consequence of the lack of under-
amyloidosis in a veteran who was exposed to Agent Orange during standing of the pathophysiology. This term should be abandoned,
the Vietnam era to have a service-connected illness. and the term immunoglobulin light-chain amyloidosis or AL amyloidosis
Amyloidosis may be systemic or localized. The localized forms (amyloid light chain) should be used. Many forms of localized
generally do not require any systemic chemotherapy. The distinction amyloidosis are also derived from immunoglobulin light chains, but
is, therefore, important so that patients for whom chemotherapy will there is no evidence of a systemic plasma cell dyscrasia, and systemic
not benefit are not inappropriately subjected to this form of therapy. therapy is contraindicated. Virtually all patients with systemic AL
Localized amyloidosis can be suspected, usually based on the location amyloidosis have a demonstrable clonal plasma cell disorder. In

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