Light Chain Disease Associated With the Hyperviscosity Syndrome

PARVEZ KHAN, MD, MARK S. ROTH, MD, DAVID F. KEREN, MD, AND KENNETH A. FOON, MD

The hyperviscosity syndrome refers to a group of symptoms and signs related to increased blood viscosity often produced by monoclonal immunoglobulins. It is most frequently associated with Wal- denstrom’s macroglobulinemia and, on occasion, with other immunoglobulins that are capable of form- ing highly polymerized molecules. This article is a report on the first case of pure light chain myeloma associated with the hyperviscosity syndrome. The hyperviscous plasma in this case is secondary to the unusual degree of aggregation of kappa light chain as demonstrated by high-resolution electrophoresis, serum immunofixation, and Sephadex g-200 (Pharmacia, Piscataway, NJ) column chromatography.

Cancer 60:2267-2268, 1987.

HE HYPERVISCOSITY SYNDROME includes a bleed- T ing diathesis, retinopathy, neurologic symptoms, and hypervolemia. This syndrome typically occurs in patients with Waldenstrom’s macroglobulinemia with an incidence of nearly 50%.’ This syndrome rarely occurs in multiple myeloma, having an incidence of 2% to 4% of patients, who usually have IgG or IgA parapro- tein peaks greater than 5 gm/100 ml or at any level if they have a rare IgM myeloma. In this article we de- scribe a patient with pure light chain myeloma and the hyperviscosity syndrome.

Case Report

A 57-year-old man developed sudden swelling of his right elbow in June 1985; approximately 500 ml of blood was aspir- ated. At that time he reported a several-week history of light- headedness, especially when bending over or climbing stairs, dyspnea on exertion, blurred vision, and progressive head- aches. On August 15, 1985 he was seen at the University of Michigan Medical Center in Ann Arbor, Michigan for a repeat episode of spontaneous elbow swelling. A diagnosis of acute olecranon hematoma was made, and he was treated with a soft cast.

One day later he was seen in the medicine clinic with the same symptoms. His medical history was otherwise unremark- able. The results from his examination were normal except for a blood pressure of 170/ 1 10 mmHg, bilateral venous conges- tion with hemorrhages determined by funduscope examina- tion, hemoccult-positive stool, and a right elbow hematoma.

From the Department of Medicine, Division of Hematology and Oncology, and the Department of Pathology, Biochemistry Section, University of Michigan, Ann Arbor, Michigan.

Address for reprints: Kenneth A. Foon, MD, Roswell Park Memo- rial Institute, 666 Elm Street, Buffalo, NY 14263.

Accepted for publication April 28, 1987.

Laboratory studies revealed a hemoglobin of 10. I g/dl, retic- ulocyte count of 2.3%, leukocyte count 6 X 109/1 (60 segs, 4 bands, 30 lymphocytes, 5 monocytes, and 1 eosinophil), and a platelet level of 212 X 109/l. Prothrombin and partial throm- boplastin times were normal, and bleeding time was prolonged to 18 minutes (N < 12 min). Chemistries were normal, but his plasma viscosity was 25.6 as shown by a Wells-Brookfield vis- cometer (normal range, 0.99 to 1.55). He was admitted for an emergency plasmapheresis. Following removal of 3.8 liters of plasma, his viscosity fell to 8.3 and his symptoms of lighthead- edness and blurred vision completely resolved.

A serum protein electrophoresis performed on admission revealed a spike of 1.5 gm/100 ml in the gamma region. This fell to 0.9 gm/100 ml following plasmapheresis. The spike in the gamma region was found to be a kappa light chain with a serum concentration of 2.9 gm/100 ml. A 24-hour urine pro- tein revealed 1.7 g of Bence Jones kappa chain. Quantitative immunoglobulins were IgG, 512 mg/dl (N = 590 to 1581), IgA, 143 mg/dl (N = 24 to 386 mg/dl), IgM, 30 mg/dl (N = 24 to 393 mg/dl). A bone marrow biopsy and aspiration revealed 25% plasma cells with immature plasma cells and plasma- blasts, which is consistent with the diagnosis of multiple my- eloma. High-resolution electrophoresis and serum immuno- fixation2 (Fig. I ) showed large quantities of kappa light chain in the patient’s serum. The band created by this protein was relatively broad. This, together with its failure to migrate from the origin (Fig. 1) when serum was diluted to less than 15 , suggests a high degree of self-aggregation. Sephadex g-200 col- umn chromatography3 indicated that the molecular weight of the aggregated kappa chain was greater than 2,000.000 dal- tons. A bone survey was negative, and the patient was started on chemotherapy with vincristine, melphalan, cyclophospha- mide, and prednisone alternating every 4 weeks with vincris- tine, bleomycin, doxorubicin, and predisone. The patient had an excellent response to chemotherapy, with plasma viscosity ranging between I .45 and 1.9 and no further symptoms hyper- viscosity.

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FIG. I . High-resolution electrophoresis and immunofixation on serum from the patient. The high-resolution electrophoresis shows a broad gamma band with an artifactual clumping and clearing at the origin. This type of finding is often seen in self-aggregating, mono- clonal proteins and in cryoglobulins. The immunofixation of this sam- ple shown below the high-resolution electrophoresis indicates that only antisera to kappa (K) chain reacted with this protein. No reaction was seen with antisera to lambda (L), IgM (M), IgA (A) or IgG (G). The serum was also tested and found negative for IgD and I@.

Discussion

The association of elevated serum viscosity with in- creased gamma globulins was first reported in the 1 9 3 0 ~ ~ It is most frequently associated with IgM macro- globulinemia of Waldenstrom’s and, on occasion, with other immunoglobulins in multiple myeloma, IgA, IgG, and rarely IgE.5-9 IgA paraproteins are commonly asso- ciated with hyperviscosity because of the tendency of IgA molecules to form polymers.* IgG myeloma, espe- cially the IgG, subclass, are commonly associated with symptoms of hyperviscosity at lower protein concentra- tions’’.” due to the tendency of IgG, to form concen- tration and temperature-dependent aggregates. In one report” a patient with hyperviscosity had multiple my- eloma in association with sickle cell anemia. The au- thors attributed the increased viscosity to erythrocyte interaction with the abnormal immunoglobulin. Our

To our knowledge this is the first reported case of hyperviscosity associated with pure light chain my- eloma. Serum protein electrophoresis revealed a spike in the gamma region with the gamma band migrating minimally from the application well. In addition, the high serum viscosity in the face of modestly elevabcd, total serum proteins is indicative of a large and/or highly polymerised molecule. Immunofixation confirmed the existence of a large, monoclonal kappa chain. Sephadex g-200 column chromatography indicated that the mo- lecular weight of the aggregated kappa chain was greater than 2,000,000 daltons. The hyperviscous plasma in this case is most likely secondary to the unusual degree of aggregation of the kappa light chain. The mechanism by which the large polymers cause hyperviscosity is still unknown. In one study’ a strong correlation was found between increased plasma volume and viscosity in mac- roglobulinemia, IgA and IgG myeloma. More recently, the hyperviscosity syndrome has been described in pa- tients with IgA myeloma and minimal polymer forma- tion.’, It is likely that many factors influence intrinsic globulin viscosity, and large polymer formation is only one. Clearly, however, pure light chain myeloma can cause the hyperviscosity syndrome and justify the use of emergency plasmapheresis.

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