Clinical Case Study - Clinical Chemistry

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Franklin EC, Lowenstein J, Bigelow B, Meltzer M. Heavy chain disease—a new ... Lee MT, Parwani A, Humphrey R, Hamilton RG, Myers DI, Detrick B. Gamma .... Center, and 2 Department of Medicine, George Washington University, Wash-.
Clinical Case Study POINTS TO REMEMBER • ␥-HCD is an underdiagnosed and atypical lymphoproliferative process with high variability in the clinical picture; the laboratory often plays a central role in the diagnosis. • ␥-HCD therapy depends on the underlying clinicopathologic features rather than on the presence of the monoclonal protein. • The monoclonal IgG found in ␥-HCD presents no light chains, and the heavy chains are frequently truncated, yielding an abnormal protein with a low molecular weight. • Electrophoresis and immunofixation of proteins from both serum and urine samples are necessary to establish a ␥-HCD diagnosis and should be performed in all cases of lymphoplasma cell proliferative disease, especially if proteinuria or an abnormal SPEP result are present.

examined the femoral biopsy sample and reported the presence of undifferentiated cells of unknown origin. These cells were not of hematologic lineage, and a prostate origin was thus suspected. A computed tomography examination of the chest and pelvis revealed numerous nodules in the lungs, liver, and bones, suggesting metastatic dissemination. Unfortunately, the diagnosis of ␥-HCD had no impact on the clinical course and the treatment of the patient, because his health deteriorated rapidly and he died 3 weeks later.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References 1. Franklin EC, Lowenstein J, Bigelow B, Meltzer M. Heavy chain disease—a new disorder of serum gamma-globulins: report of the first case. Am J Med 1964;37:332–50. 2. Kyle RA, Greipp PR, Banks PM. The diverse picture of gamma heavy-chain disease. Report of seven cases and review of literature. Mayo Clin Proc 1981;56:439 –51. 3. Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA. Gamma-heavy chain disease: review of 23 cases. Medicine (Baltimore) 2003;82:236 –50. 4. Lee MT, Parwani A, Humphrey R, Hamilton RG, Myers DI, Detrick B. Gamma heavy chain disease in a patient with diabetes and chronic renal insufficiency: diagnostic assessment of the heavy chain fragment. J Clin Lab Anal 2008;22: 146 –50. 5. Stramignoni A, Carbonara A, Paolino W, Navone R, Coda R, Leonardo E. G1 heavy chain disease: clinicopathological, ultrastructural and immunochemical study of a new case. J Cancer Res Clin Oncol 1980;96:93–103. 6. Kambham N, Markowitz GS, Appel GB, Kleiner MJ, Aucouturier P, D’Agati VD. Heavy chain deposition disease: the disease spectrum. Am J Kidney Dis 1999;33:954 – 62. 7. Daval S, Tridon A, Mazeron N, Ristori JM, Evrard B. Risk of antigen excess in serum free light chain measurements. Clin Chem 2007;53:1985– 6. 8. Yoo EM, Wims LA, Chan LA, Morrison SL. Human IgG2 can form covalent dimers. J Immunol 2003;170:3134 – 8.

Commentary David F. Keren*

Busser et al. have shared an unusual case featuring a broad, prominent increase in the ␤ region of a urine protein electrophoresis result. The immunofixation electrophoresis (IFE) result identifying the band in serum and urine as containing only ␥ chains with no corresponding light chain secured the diagnosis of ␥– heavy chain disease. The serum protein electrophoresis had been performed by capillary electrophoresis, a technique in which radiocontrast dyes and antibiotics can create

Warde Medical Laboratory, Ann Arbor, MI. * Address correspondence to the author at: Warde Medical Laboratory, 300 W. Textile Rd., Ann Arbor, MI 48108. Fax 734-214-0399; e-mail [email protected]. Received February 16, 2011; accepted February 24, 2011. DOI: 10.1373/clinchem.2011.162669

spikes that mimic an M protein (1–5 ). Such spikes are typically quite discrete, however. Hemoglobin and fibrinogen are other common M protein mimics, but they have characteristic migrations that clinical laboratories usually recognize (6 ). Some M proteins that migrate in the ␤ region of serum can be quite subtle and easily missed. Narayan et al. reported that in electrophoresis systems that produce crisp resolution of the ␤1- and ␤2-globulins, an increase in either of these fractions not explained by an obvious process, such as ␤–␥ bridging, deserves an IFE evaluation (7 ). These investigators reported that of 36 samples with such an increase, 12 had an M protein by IFE. Similarly, Katzmann et al. found M proteins when they reflexed to IFE serum samples that had the following suspicious findings: “fuzzy” bands (54% M proteins), ␤ regions of 1.6 –1.9 g/dL (16 –19 g/L) (10% M proteins), and hypogammaglobulinemia (12% M proteins) (6 ). Clinical Chemistry 57:7 (2011) 951

Clinical Case Study An unusual phenomenon, “phantom light chain,” rarely accounts for an apparent lack of a light chain in some cases of myeloma. This term, coined by Cejka and Kithier and originally described in a case of IgD ␭ myeloma (8 ), has also been reported in a case of IgA ␭ myeloma (9 ). The apparent lack of light chains by IFE may be due to heavy chains cloaking light chain determinants; however, by using other antisera, or a stronger concentration of the antisera, one can demonstrate the light chains (9 ).

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References 1. Arran˜z-Pena ML, Gonza´lez-Sagrado M, Olmos-Linares AM, Ferna´ndez-Garcı´a N, Martı´n-Gil FJ. Interference of iodinated contrast media in serum capillary zone electrophoresis. Clin Chem 2000;46:736 –7. 2. Blessum CR, Khatter N, Alter SC. Technique to remove interference caused by radio-opaque agents in clinical capillary zone electrophoresis. Clin Chem 1999;45:1313. 3. Bossuyt X, Mewis A, Blanckaert N. Interference of radio-opaque agents in clinical capillary zone electrophoresis. Clin Chem 1999;45:129 –31. 4. Bossuyt X, Peetermans WE. Effect of piperacillin-tazobactam on clinical capillary zone electrophoresis of serum proteins. Clin Chem 2002;48:204 –5. 5. Bossuyt X, Verhaegen J, Marien G, Blanckaert N. Effect of sulfamethoxazole on clinical capillary zone electrophoresis of serum proteins. Clin Chem 2003; 49:340 –1. 6. Katzmann JA, Stankowski-Drengler TJ, Kyle RA, Karen SL, Snyder MR, Lust JA, Dispenzieri A. Specificity of serum and urine protein electrophoresis for the diagnosis of monoclonal gammopathies. Clin Chem 2010;56:1899 – 900. 7. Narayan S, Lujan MG, Baskin LB, Devaraj S, Rutherford C, Jialal I. Measurement of ␤1- and ␤2-globulins improves detection of M-spikes on highresolution electrophoresis. Clin Chem 2003;49:676 – 8. 8. Cejka J, Kithier K. IgD myeloma protein with “unreactive” light chain determinants. Clin Chem 1979;25:1495– 8. 9. Su L, Keren DF, Warren JS. Failure of anti-lambda immunofixation reagent mimics alpha heavy-chain disease. Clin Chem 1995;41:121–3.

Commentary Geraldine P. Schechter1,2*

Two monoclonal proteins—a urinary ␬ light chain and a serum ␥ heavy chain without an identifiable light chain—were discovered in this elderly patient. Absence of a light chain is usually due to truncation of the heavy chain, thereby preventing the binding of light chains. The patient’s presentation with anemia, leukopenia, hypoalbuminemia, and albuminuria raises the possibility of myeloma rather than metastatic prostate cancer; however, malignancies associated with monoclonal ␥ heavy chains are usually lymphoproliferative disorders that exhibit adenopathy rather than plasma cell myeloma with lytic bone lesions (1 ). Both M proteins are low in concentration, and these findings may simply reflect a diclonal gammopathy of unknown significance in an elderly individual with an unrelated neoplasm. Monoclonal gammopathy of unknown significance (MGUS) has been found in 7.5% of patients older than 80 years, and diclonal gammopathy occurred in 3% in a population-based study

(2 ). Individuals with MGUS may have small amounts of urinary free light chains without a serum M protein. These uncommon MGUS clones of light chains have the potential to progress to light chain myeloma (3 ). In 9% to 17% of patients with monoclonal ␥ heavy chains, there is no associated pathologic finding, and the truncated protein simply represents a rare type of MGUS (1 ). Alternatively, this patient’s pathologic fracture may be due to hyposecretory multiple myeloma derived from one or both clones. Rare patients with myeloma have exhibited truncated ␥ chains. If so, the relationship of the 2 clones to the malignancy may be determined by immunohistochemical or flow cytometry analysis. A recent report described a myeloma patient in whom all of the malignant plasma cells contained a truncated ␥ chain, whereas a subclone of 30% of the cells also contained light chain (4 ). Heavy ␥ chains may also cause immunoglobulin deposition disease or amyloid fibrils (5, 6 ), which could explain the patient’s albuminuria.

1

Hematology Section, Medical Service, Washington Veterans Affairs Medical Center, and 2 Department of Medicine, George Washington University, Washington, DC. * Address correspondence to the author at: Veterans Affairs Medical Center, 50 Irving St. NW, Washington, DC 20422. Fax 202-518-4300; e-mail [email protected]. Received February 27, 2011; accepted March 10, 2011. DOI: 10.1373/clinchem.2011.162677

952 Clinical Chemistry 57:7 (2011)

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.