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Case Studies Resolving the Baneful and Banal: Bisalbuminemia in an Adult With Waldenström Macroglobulinemia Mark A. Valasek,1 Richard T. Hopley, MD,2 Frank H. Wians Jr., PhD, MT(ASCP), DABCC, FACB2 (1Medical Scientist Training Program and 2Department of Pathology, University of Texas Southwestern Medical Center, Dallas,TX) DOI: 10.1309/LMD51RR5FXHKDHRX Abstract Case reports of bisalbuminemia (patient serum containing albumin A and an albumin variant differing by single amino-acid substitutions) have included different races or ethnic groups and are often reported in association with various pathologic states. Here, we describe a 70-year-old woman with vague symptoms, the most concerning of which was worsening vision with retinal hemorrhages found on exam. During the workup, serum protein electrophoresis was performed demonstrating a prominent monoclonal component (IgM kappa) and bisalbuminemia as an incidental finding. This represents the first reported case in the literature of the coexistence of bisalbuminemia and Waldenström macroglobulinemia. The possibility exists that some endogenous or pharmacologic substances may interact differently with albumin variants as compared with normal albumin; however, the finding of bisalbuminemia did not influence the diagnosis, management, course, or prognosis of this patient’s lymphoma. Clinical History Patient 70-year-old Hispanic female. Chief Complaint The patient was admitted for increased fatigue, chest discomfort, and myalgia. History of Present Illness The patient reported that her fatigue and chest discomfort have been present for 2 years but have become worse over the last 2 months. She also complained of left shoulder pain (occasionally radiating to the left jaw) and generalized myalgia. Review of systems was also positive for weight loss of 14 pounds over the previous year, blurry vision for 4 months, nosebleeds, chest pain with exertion, weakness, and depression. labmedicine.com Past Medical History The patient has a past medical history significant for hypertension. She has had no surgeries. Current Medications Her only medication was ibuprofen at 600 mg PO (3 times daily) for myalgia. She was not taking any medications for her hypertension. Family History Her mother had diabetes and died at 60 years of age. Her father died of unknown causes. Her sister was diagnosed with renal cancer. Her daughter has “liver and uterine cysts.” Social History The patient denied alcohol, tobacco, and illicit/ intravenous drug abuse. She currently lives at home with her son. Physical Examination Findings Exam was significant for mild systolic hypertension, obesity (body mass index of 38.5), and bilateral ankle-level pitting edema. Fundoscopic examination showed retinal exudates and hemorrhages. Principal Laboratory Findings Initial laboratory studies showed pancytopenia with elevated serum total protein and viscosity (Table 1). Results of Additional Diagnostic Procedures Computed tomography (CT) imaging of the abdomen and pelvis showed moderate splenomegaly without lymphadenopathy. Magnetic resonance imaging (MRI) of the spine showed patchy abnormal bone marrow signaling, most prominently involving the T12 vertebra consistent with metastases or myeloma. In addition, ophthalmologic evaluation revealed bilateral retinal hemorrhages. aspirate smear prepared with Wright-Giemsa stain revealed a hypercellular sample (greater than 95% cellularity) with markedly decreased numbers of megakaryocytes, granulocytes, and erythroid precursors, all exhibiting unremarkable morphology. A manual differential showed relative suppression of the myeloid and erythroid lines with a predominance of lymphocytes/plasmacytoid lymphocytes, and plasma cells (57% and 37%, respectively.) Many of the plasma cells showed cytoplasmic accumulation of abundant eosinophilic material, likely representing immunoglobulin. A periodic acid-Schiff (PAS) staining within plasma cells further supported the presence of cytoplasmic immunoglobulin within numerous enlarged plasma cells. By immunohistochemistry, the neoplastic plasma cells were IgM/kappa-restricted (lambda negative), CD79a positive, and CD20 negative, consistent with a monoclonal proliferation of plasma cells. The neoplastic small lymphocytes were CD79a and CD20 positive. Flow cytometric analysis revealed a CD5 (predominantly negative)/CD10 (negative) B-cell lymphoproliferative disorder of predominantly small cells, consistent with lymphoplasmacytic lymphoma. A peripheral blood smear showed a markedly decreased number of erythrocytes with a normocytic and hypochromic anemia. Mild anisopoikilocytosis and mild rouleaux formation were present. Also consistent with the findings within the marrow cavity, platelets and white blood cells were also decreased in number with otherwise unremarkable morphology. No plasma cells or plasmacytoid lymphocytes were identified in the peripheral blood. Protein analysis of serum and urine included serum and urine protein electrophoresis (SPEP/UPEP) and immunofixation electrophoresis (IFE) of serum (Figure 1). A bone marrow biopsy was also performed (Image 1). Both the core biopsy and an December 2008 j Volume 39 Number 12 j LABMEDICINE 723 Case Studies Questions Table 1_Principal Laboratory Findings Test Patient’s Result Ref Range Chemistry Sodium Potassium Chloride Bicarbonate Anion Gap Creatinine BUN Glucose Calcium Phosphorus Magnesium 134 mmol/L 4 mmol/L 103 mmol/L 20 mmol/L 11 mmol/L 0.59 mg/dL 10 mg/dL 120 mg/dL 8.2 mg/dL 3.7 mg/dL 1.6 mEq/L Direct bilirubin <0.1 mg/dL Total bilirubin 0.7 mg/dL ALT 9 Units/L Alk Phos 42 Units/L AST 19 Units/L LD 136 Units/L GGT 11 Units/L CK 41 Units/L CK-MB <1 ng/mL Troponin I <0.1 ng/mL Coagulation PT 12.7 sec INR 1.3 PTT 33.2 sec D-dimer 2.1 mg/L FEU Fibrinogen 267 mg/dL Hematology WBC 1.7 x109/L RBC 2.14 x1012/L Hemoglobin 6.5 g/dL HCT 21.4% MCV 100 femtoliter MCH 30.4 pg MCHC 30.4 g/dL RDW-CV 19.5% Platelet 68 x 109/L MPV 9.9 femtoliter Differential Neutrophils 25% Lymphs 60% Monocytes 14% Myelocytes 1% 135–145 3.6–5.0 98–109 22–31 6.0–16.0 0.60–1.20 7.0–21 65–200 8.4–10.2 2.4–4.5 1.4–1.8 0.0–0.3 0.2–1.3 10.0–40 38–126 13–40 140–271 8.0–78 30–135 0–3 N/A 9.2–12.8 0.9–1.3 23.5–33.5 0.0–3.0 190–400 3.90–10.70 4.01–5.31 12.1–16.1 36.8–48.7 76.2–98.6 24.6–33.4 31.6–35.4 11.5–15.0 174–404 9.4–12.9 36–72 20–51 4.0–11.0 N/A Total protein 11.4 g/dL 6.3–8.2 Albumin 3.71 g/dL 3.90–5.10 Viscosity 4.1 centipoise ≤1.5 1. 2. 3. 4. 5. 6. 7. 8. What is bisalbuminemia? Are there albumin variants that cause disease? What is Waldenström macroglobulinemia? When does hyperviscosity syndrome occur? How is Waldenström macroglobulinemia treated? Is there any known association between these 2 entities? What types of bisalbuminemia are there? Do albumin variants cause significant differential binding of compounds? 9. What other diagnoses should be considered in this case? Possible Answers 1. Bisalbuminemia (also called alloalbuminemia) is a clinically benign condition defined by the presence of differentially migrating albumin variants on agarose gel electrophoresis (AGE). Usually, this is seen as 2 distinct bands on AGE but can sometimes appear as a single widened band. Hereditary forms of bisalbuminemia account for approximately 39% of the sequence polymorphisms known to exist in the albumin gene, and they are generally caused by single point mutations.1 However, because albumin variants are rare, the overall prevalence of bisalbuminemia is low, generally ranging from 1:10,000 to 1:1,000. 2. Are there albumin variants that cause disease? Yes. Twelve mutations have been identified that lead to a rare condition called analbuminemia in which patients have serum albumin concentrations less than 0.1 g/dL. Given the fundamental roles of albumin in maintaining oncotic pressure and transporting lipophilic compounds, it is surprising that this disease results only in mild edema, mild fatigability, and hyperlipidemia. (In many cases the disease is entirely asymptomatic.) It should be noted that albumin mutations can display biochemical evidence of differential binding to lipophilic hormones, ions, or drugs, but it is unclear at present whether or not these represent disease states. It has been discovered that 3 mutations in albumin can cause enhanced binding of thyroid hormones, thereby causing familial dysalbuminemic hyperthyroxinemia and familial dysalbuminemic hypertriiodothyroninemia.2-4 These individuals can have elevated free and total thyroid hormone, but are clinically in a euthyroid state. The only potential clinical concern is confusion with hyperthyroidism or thyroid hormone resistance syndromes, which might lead to unnecessary treatment.5 These particular mutations do not cause bisalbuminemia.1 A B C Image 1_Hypercellular bone marrow consisting of lymphoplasmacytic infiltrate. (A) Bone marrow core biopsy showing predominantly lymphplasmacytoid cells. (B) Clot section showing lymphoplasmacytoid cells with abundant eosinophilic material. (C) Immunohistochemistry of clot section using CD79a, a B-cell/plasma cell marker, showed almost universal staining of cells. 724 LABMEDICINE j Volume 39 Number 12 j December 2008 labmedicine.com Case Studies A B C D Figure 1_Serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE). (A) A quality control sample serum along with sera from 4 patients. Arrows indicate albumin bands and asterisks indicate M-components. Note 2-band albumin pattern for patient 1. (B, C) Quantification of bands for patient 1. (D) Immunofixation showing M-component consists of IgM kappa. Arrow indicates M-component in total protein (Tot) lane and asterisks indicate positive bands for IgM (lane M) and kappa light chain (lane K). 3. Waldenström macroglobulinemia, along with multiple myeloma (MM) and monoclonal gammopathy of uncertain significance (MGUS), is classified as a plasma cell dyscrasia. It is considered a low-grade non-Hodgkin’s lymphoma (specifically, lymphoplasmacytic lymphoma) that leads to secretion of IgM into the blood. In approximately 15% of cases, the elevated levels of circulating IgM can cause hyperviscosity syndrome characterized by neurologic deficits such as blurred vision, headache, dizziness, and altered mental status. On fundoscopic examination, abnormal “sausage” retinal veins or hemorrhages may be seen. Congestive heart failure and/or pulmonary infiltrates are also presentations of a hyperviscous state. IgM can also cause damage by deposition in tissues causing amyloidosis, glomerulopathy, and peripheral neuropathy. In addition, patients can have cytopenias with corresponding symptoms, hepatomegaly, splenomegaly, and lymphadenopathy. 4. Serum is normally approximately 1.8 times more viscous than water; however, hyperviscosity syndrome generally occurs when the plasma viscosity becomes elevated to 5 times that of water. This is reflected in the absolute measurement of viscosity by units of poise (P) at a given temperature. One poise is equal to 1g/ (cm • s), and this patient’s value was given as 4.1 centipoise (cP). Water has a viscosity of 0.89 cP at room temperature and therelabmedicine.com fore the patient’s serum was approximately 4.6 times as viscous as water at room temperature. For comparison, olive oil has a viscosity of 81 cP at room temperature. In this patient, the elevated viscosity was primarily due to increased IgM kappa (Figure 1). 5. Waldenström macroglobulinemia is treated by removing the excess IgM protein (by plasmapheresis) and by inhibiting production of the excess immunoglobulin via chemotherapeutic regimens to target the lymphoplasmacytic cells. Chemotherapies can include either monotherapy with chlorambucil, fludarabine, cladribine, or rituximab, or a combination of agents. Thalidomide and hematopoietic stem cell transplantation (HSCT), as well as additional molecular targets, are currently being investigated.6-9 6. There is no known association between these 2 entities. To the best of our knowledge, this is the first report in the literature of the coexistence of bisalbuminemia and Waldenström macroglobulinemia and there is currently no known pathophysiological relationship between the 2 conditions. The recognition of bisalbuminemia here is likely simply due to the fact that SPEP/UPEP studies are commonly performed on this patient population. The incidence in these patients is expected be similar to that of the general population. December 2008 j Volume 39 Number 12 j LABMEDICINE 725 Case Studies 7. Bisalbuminemia can be either hereditary or acquired. As discussed above, hereditary bisalbuminemia is generally caused by a single point mutation in the albumin gene. Although there is no known causal connection between hereditary bisalbuminemia and disease, bisalbuminemia has been identified in individual patients with diabetes, Alzheimer’s disease, chronic kidney disease, nephrotic syndrome, multiple myeloma, and other diseases. In contrast, acquired transient bisalbuminemia can result from pancreatitis and beta-lactam ingestion.10 8. Do albumin variants cause significant differential binding of lipophilic compounds? Yes. Several albumin variants have been shown to have decreased binding to warfarin, bilirubin, Ni2+, or Cu2+, or increased binding to prostaglandins, thyroid hormones, or fatty acids; however, these have not been implicated in causing disease states. 9. The differential diagnosis of an additional band in the same region as albumin includes the following: the band may represent an artifact of electrophoresis, although bands of this type are usually easily recognized as such (eg, air bubbles, distortions of the gel, overloading, etc). In addition, proteins that normally migrate in the same region of albumin may be elevated and mimic the appearance of bisalbuminemia. These include prealbumin (increased after recent food ingestion), alpha 1 acid glycoprotein (an acute phase reactant), and alpha lipoproteins. However, any unusual band in a serum protein electrophoresis may indeed be a true paraprotein, and a monoclonal gammopathy must be considered, especially since light chains can migrate to abnormal locations. In addition to bisalbuminemia, our patient was also found to have a monoclonal protein (M protein) in the gamma region. Monoclonal gammopathies occur in multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia. If a monoclonal gammopathy is discovered in a patient with no clinical disease, then it is termed monoclonal gammopathy of undetermined significance (MGUS). In our patient, the M protein was determined to be of IgM kappa type consistent with Waldenström macroglobulinemia (Figure 1D). As our patient presented with retinal hemorrhages in the clinical context of a monoclonal gammopathy, the diagnosis of acquired von Willebrand syndrome (AVWS) may also be considered. Acquired von Willebrand syndrome is a rare entity, with approximately 300 cases reported in the literature.11 The presence of an inhibitor to von Willebrand factor (vWF) or the factor VIII/vWF complex has been demonstrated in 15% of reported 726 LABMEDICINE j Volume 39 Number 12 j December 2008 cases, the majority of which were associated with a monoclonal protein which may or may not have specificity for the factor or the complex. It can also exist in the presence of a normal coagulation profile, as in our patient. Patient’s Treatment and Course Due to the concern for the patient’s vision, she was initially treated with plasmapheresis and her serum viscosity decreased from 4.1 to 1.6 cP. She did experience improvement in vision, albeit minimal, possibly due to the chronicity of her ocular symptoms. She was started on a chemotherapeutic regimen (chlorambucil at 0.2mg/kg for 5 days, every 4 weeks). Her monoclonal component subsequently decreased, and her cytopenia improved significantly. She continues to follow up with Hematology/ Oncology on an outpatient basis. LM 1. Minchiotti L, Galliano M, Kragh-Hansen U, et al. Mutations and polymorphisms of the gene of the major human blood protein, serum albumin. Hum Mutat. 2008;29:1007–1016 2. Ruiz M, Rajatanavin R, Young RA, et al. Familial dysalbuminemic hyperthyroxinemia: A syndrome that can be confused with thyrotoxicosis. N Engl J Med. 1982;306:635–639. 3. Petersen CE, Scottolini AG, Cody LR, et al. A point mutation in the human serum albumin gene results in familial dysalbuminaemic hyperthyroxinaemia. J Med Genet. 1994;31:355–359. 4. Sunthornthepvarakul T, Likitmaskul S, Ngowngarmratana S, et al. Familial dysalbuminemic hypertriiodothyroninemia: A new, dominantly inherited albumin defect. J Clin Endocrinol Metab. 1998;83:1448–1454. 5. Heufelder AE, Klee GG, Wynne AG, et al. Familial dysalbuminemic hyperthyroxinemia: Cumulative experience in 29 consecutive patients. Endocr Pract. 1995;1:4–8. 6. Leleu X, Roccaro AM, Moreau AS, et al. Waldenström macroglobulinemia. Cancer Lett. 2008;270:95–107. 7. Treon SP, Hatjiharissi E, Leleu X, et al. Novel agents in the treatment of Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma. 2007;7:S199– S206. 8. Dimopoulos MA, Anagnostopoulos A. Treatment of Waldenström’s macroglobulinemia. Curr Treat Options Oncol. 2007;8:144–153. 9. Burwick N, Roccaro AM, Leleu X, et al. Targeted therapies in Waldenström macroglobulinemia. Curr Opin Investig Drugs. 2008;9:631–637. 10.Faviou E, Nounopoulos C, Dionyssiou-Asteriou A. Bisalbuminemia from a clinical chemist’s viewpoint: A case report and review of the recent literature. Minerva Med. 2006;97:287–293. 11.Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand’s syndrome: A single institution experience. Am J Hematol. 2003;72:243–247. labmedicine.com