Mu Heavy Chain Disease Workup

Anemia, related to bone marrow involvement, is the most common laboratory finding in mu-HCD, followed by thrombocytopenia and lymphocytosis.  Increased urine protein with detection of Bence Jones protein is common, due to production of unpaired monoclonal light chain, but renal complications are infrequent, with cast nephropathy and renal failure reported in a single case. ^[12]  Two patients, including the first reported case, have had amyloidosis with renal impairment. ^[9]

The diagnosis of mu-HCD often can be difficult to establish. Serum protein electrophoresis is often normal or may show a broad monoclonal band.  Diagnosis is confirmed by immunofixation that is positive for anti-mu, but negative for anti-kappa or anti-lambda light chains. ^[8]  Consulting a hematopathologist is appropriate to facilitate an appropriate and adequate workup.

Laboratory studies should include the following:

• Complete blood cell count with differential
• Kidney function studies (ie, blood urea nitrogen [BUN] and creatinine)
• Liver function studies (ie, total protein, albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase)
• Calcium levels
• Beta-2 microglobulin values
• Serum protein electrophoresis (SPEP) and immunofixation
• Urine protein electrophoresis (UPEP) and immunofixation

Serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP) and immunofixation are essential tests. While SPEP is typically normal, immunofixation detects monoclonal mu IgH in polymers of different sizes without an associated light chain. ^[7]  Performing a combination of electrophoretic, immunoelectrophoretic, and immunofixation techniques can help establish the diagnosis.

When developed with specific anti-heavy and anti-light sera, the immunoelectrophoretic pattern reveals a heavy chain–specific band that does not react with either anti-kappa or anti-lambda antisera on immunofixation. IgM M-proteins sometimes do not react with certain anti–light chain (kappa or lambda) sera. In these cases, isolating the monoclonal proteins from the serum, treating them with reducing agents to cleave disulfide bonds, and subjecting them to gel electrophoresis to determine the size of the immunoglobulin heavy chain polypeptide may be necessary to confirm mu-HCD.

More commonly, the proteins are present in smaller amounts and show a heterogeneous pattern on electrophoresis. One study reported a detectable monoclonal spike in 8 of 19 patients, and 3 of 28 patients had a biclonal gammopathy. Immunofixation with a panel of anti-heavy/anti-light antibodies can strongly suggest the diagnosis. ^[11]

Urinary excretion of the mu fragment has been noted in very few patients, presumably because the polymers of the carboxy-terminal mu fragment are too large to be filtered by intact renal glomeruli. Monoclonal light chains have been found in the urine in two thirds of cases. Thus, Bence Jones (free light chain) proteinuria is common in patients with this disorder. Nonetheless, renal complications are infrequent. Immunoglobulin light chains capable of producing amyloid are found in approximately 12% of cases, an incidence that is similar to that observed in patients with multiple myeloma.

Maisnar et al presented a case study in which they used immunofixation electrophoresis, capillary zone electrophoresis with immunotyping, and high-resolution two-dimensional electrophoresis to detect and characterize monoclonal mu-heavy chains in a patient with multiple malignancies. ^[13] The investigators were able to determine the molecular weight of the mu heavy chains; their patient's abnormally high serum protein concentration, 38 g/L, appears to be the highest reported in the literature. ^[13]

Almost all patients should undergo bone marrow aspiration and biopsy. Certain histologic features, as outlined below, may aid in making the diagnosis of mu-HCD.

When mu-HCD is not considered, based on the patient's presentation (as is commonly the case), biopsy of the appropriate involved area (eg, lymph node mass) is required to establish the diagnosis of a lymphoproliferative disorder.

No definitive guidelines are available regarding the extent of imaging studies that should be performed for suspected mu-HCD. Performing a chest radiograph is reasonable, and a skeletal survey is considered essential given the fact that 40% of patients present with osteolytic lesions.

Obtaining computed tomography (CT) scans of the thorax and abdomen is appropriate because hepatosplenomegaly and lymphadenopathy are common. CT scan findings help to objectively quantify disease and are useful for assessing response to therapy.

Marrow involvement is characterized by infiltration with lymphocytes and plasma cells. Cells that often are described as lymphocytic plasmacytes or plasmacytoid lymphocytes are prominent. Although the marrow of almost all patients contains the multivacuolated plasma cells described in the index case, the vacuoles are not universally apparent. The identification of these vacuoles sometimes offers a clue to the diagnosis, which requires confirmation by appropriate electrophoretic and immunoelectrophoretic studies. ^[14]

On immunophenotypic analysis, associated cells lack light chain expression but are positive for the following ^[8] :

• CD19
• CD20
• CD38
• Cytoplasmic IgM
• CD5 (rare)

Given the rarity of mu-HCD, a clinical staging system has not been developed. Accompanying lymphoproliferative disorders such as CLL, non-Hodgkin lymphoma, and multiple myeloma should be appropriately staged.