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Chapter 88 Immunoglobulin Light Chain Amyloidosis (Primary Amyloidosis) 1433

Chromosomal aberrations of the plasma cells in amyloidosis have
also been recognized. Interphase fluorescence in situ hybridization
(FISH) has detected a gain of 1q21, predicting a poor overall survival,
and is an independent prognostic factor. Patients with t(11;14) have
a longer median overall survival. Deletion 13q14 and hyperdiploidy
are prognostically neutral.
The pathobiology of organ dysfunction associated with amyloi-
dosis has long been assumed to be caused by the direct effect of
amyloid protein deposition in tissues. However, there is increasing
evidence that the light chains themselves have a toxic effect on tissues
as a soluble mediator. A zebrafish model of human light-chain car-
diotoxicity has demonstrated that injection of light chains results in
impaired cardiac function, pericardial edema, and increased cell
death. Mitogen-activated protein (MAP) kinase activation may
mediate this cardiotoxicity, and p38 MAP kinase inhibition reduces
cell death and improves cardiac function.
Amyloidosis and multiple myeloma both share the presence in the
bone marrow of a clonal population of plasma cells. The number of
plasma cells and the immunoglobulin light chains that they produce
are both important for prognosis. Patients who have an increased
number of plasma cells in the bone marrow with light-chain amyloi-
dosis have a worse prognosis and a shorter overall survival, regardless
of whether they manifest any of the clinical criteria associated with
multiple myeloma, such as hypercalcemia, renal insufficiency, anemia,
or destructive bone lesions. There appears to be no survival difference
between patients who have an elevated plasma cell count in their bone
marrow and whether they have overt symptoms of myeloma. The
therapeutic import of this finding is still being investigated.
Fig. 88.1 ELECTRON MICROGRAPH DEMONSTRATING THE
CLASSIC FIBRILS OF AMYLOID. CLINICAL MANIFESTATIONS

Patient 1
40 AL
Myeloma Patient 1 is a 46-year-old man who, 10 months prior to diagnosis,
MGUS began to develop cramping abdominal pain associated with an unex-
30 plained 45-lb weight loss. Four months later, he began to develop
episodes of orthostatic syncope and was documented to have an
Percentage 20 to 66 mmHg when standing. As a consequence of his abdominal
orthostatic drop in blood pressure from systolic 110 mmHg in supine
cramping, the patient underwent endoscopy and colonoscopy. Biop-
sies were obtained from the duodenum, proximal jejunum, colon, and
rectum, all of which demonstrated amyloid deposits. Subsequently, a
10 bone marrow biopsy was performed that showed 4% clonal plasma
cells. A subcutaneous fat aspirate was positive for amyloid. The plasma
cells showed a CCND1/IgH fusion t(11;14). The patient’s hemoglo-
0 bin level was normal, as were his creatinine, alkaline phosphatase, and
None lgG Free lgG lgA Free lgD lgM Biclonal urinary protein. The patient had a λ free light chain level of 92.8 mg/L,
κ free light chain of 10.9 mg/L, and a ratio of 0.12.
Serum M Protein
Fig. 88.2 DISTRIBUTION OF HEAVY- AND LIGHT-CHAIN
PROTEINS IN MYELOMA, MONOCLONAL GAMMOPATHY OF Comment on Patient 1
UNDETERMINED SIGNIFICANCE, AND AMYLOID LIGHT-CHAIN
AMYLOIDOSIS. AL, Amyloid light chain; Ig, Immunoglobulin; MGUS, This patient presented with amyloid autonomic neuropathy, leading
monoclonal gammopathy of undetermined significance. to gastrointestinal (GI) tract dysmotility and pain as well as ortho-
static hypotension. There was clear-cut evidence of a low-grade
plasma cell dyscrasia. Orthostatic hypotension causing lightheaded-
monoclonal gammopathy of undetermined significance (MGUS) ness is a very nonspecific complaint, and syncope owing to amyloid
and multiple myeloma, two-thirds of the immunoglobulin light orthostatic hypotension is easily overlooked because of its
chains are κ type. In AL amyloidosis, nearly three-fourths of the light infrequency.
chains are of λ origin (Fig. 88.2), suggesting that there is a greater
propensity for λ light chains to misfold into amyloid configuration.
The λ 6 subgroup of light chains is exclusively associated with amyloid Patient 2
deposition. There are also abnormalities in amyloid-associated germ-
line gene use. A preferential use of variable lambda (VL) germline A 61-year-old man with a known immunoglobulin G λ MGUS of
genes is noted for AL κ and AL λ patients. There is a significant 0.6 mg/dL was monitored on an annual basis with no change in the
correlation between the use of V λ 6 germline, 6a, and renal involve- level of the monoclonal protein over a period of 3 years. He developed
ment as well as the λ 3 gene, 3r, with soft tissue AL. Identification of progressive fatigue and shortness of breath. He was evaluated by a
the clonal VL gene in AL has important implications regarding clini- cardiologist, and his echocardiogram showed thickening that was
cal outcome. interpreted to be related to hypertension, with a normal ejection