Mu Heavy Chain Disease

The pathogenesis of mu-HCD is not completely understood. No viruses, chemical, physical, or genetic factors have been identified.[4] Most patients have a concurrent lymphoproliferative disorder resembling chronic lymphocytic leukemia/ small lymphocytic leukemia. There are also single reports of mu-HCD associated with myelodysplastic syndrome, amyloidosis, and diffuse large B cell lymphoma.

In mu-HCD the altered heavy chains contain deletions, insertions, and point mutations that are acquired during the process of somatic hypermutation. These alterations typically result in loss of a large portion of the constant-1 (CH1) domain of the heavy chain, which is responsible for light chain binding. Additionally, this abnormal CH1 domain is unable to bind to the heat-shock protein 78 (hsp78), which would otherwise promote proteosomal degradation of the aberrant, unbound heavy chain. The heavy chain thus bypasses elimination and is secreted into the serum, where it can be detected.[2, 5, 6]

Mu-HCD is the least common of the HCDs. Fewer than 50 cases have been reported in the literature.[7] However, many cases likely have not been reported, especially in the past decade. Given the difficulty in diagnosing this disorder, most reports are from the United States, Western Europe, and Scandinavia.

Mu-HCD is predominantly reported in white men in the 5th or 6th decade of life. However, reports also exist in black and Asian patients, with ages of diagnosis ranging from 15-80 years.

The course of mu-HCD is variable. Survival ranges from a few months to several years, with a median survival of 24 months in well-studied cases.[8] Possible complications include pathologic fracture secondary to osteolytic lesions. Renal insufficiency occasionally is associated with mu-HCD. Etiologies include cast glomerulopathy, nodular glomerulosclerosis, and amyloidosis. Cytopenias requiring transfusion are possible in advanced disease.

The presenting signs and symptoms of mu heavy chain disease (mu-HCD) are generally secondary to the associated hematologic disorder, such as chronic lymphocytic leukemia (CLL), lymphoproliferative disorder, or myeloma. Patients may show evidence of systemic disease, such as weight loss, fever, night sweats, and recurrent infection.[9]

The first reported cases of mu-HCD had a clinical picture consistent with CLL; however, with better diagnostic procedures and increased awareness of the disease, the defining heavy chain protein has been observed in a broader range of clinical settings. Currently, only one third of patients with mu-HCD appear to have CLL. In a review of 150 consecutive patients with CLL, thorough investigation of serum proteins failed to identify a single instance of mu-HCD, which suggests an incidence of less than 1% in this population.[10]

Various clinical presentations of mu-HCD have since been identified, including a presentaiton of monoclonal gammopathy without any identified symptoms of B-cell lymphoma (20%).[11] In 10% of cases, an intact IgM protein is simultaneously detected in the serum. Another 10% of cases were associated with clinical multiple myeloma or plasmacytoma. Mu-HCD is also reported to be associated with systemic amyloidosis in rare instances.[9]

Physical examination findings are variable in patients with mu-HCD, but may include the following:

• Splenomegaly is almost universal.
• Hepatomegaly is noted in 25% of cases.
• Peripheral lymphadenopathy is present in 40% of cases.
• Bone pain from lytic lesions is present in 40% of cases.
• Pallor may be noted if significant anemia is present, which is usually observed only in advanced disease.

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.

Because of the paucity of cases, no standard treatment has been established for mu heavy chain disease (mu-HCD). Currently, the identification of a mu-HCD protein in the serum of an apparently healthy patient should be considered a monoclonal gammopathy of undetermined significance, and the patient should be monitored closely for the development of a symptomatic lymphoproliferative disorder.

Once a lymphoproliferative disorder develops, chemotherapeutic agents are used as appropriate for the patient's disorder, stage, and clinical situation (eg, combinations of proteasome inhibitors, steroids, and immunomodulatory agents for multiple myeloma; purine analogs, alkylating agents, and monoclonal antibodies for chronic lymphocytic leukemia). Successful treatment with fludarabine has been reported in two cases.[15] The details of some of these therapies can be found in Chronic Lymphocytic Leukemia and Multiple Myeloma.

If no overt lymphoproliferative disorder is found, the patient should be evaluated every few months to assess the abnormal protein. Reasonable follow-up intervals are every 3 months in the first year following diagnosis, every 4 months for the next year, and every 6 months thereafter. The patient should be evaluated earlier if symptoms occur. If the patient is symptomatic in any way, then radiologic assessment and other diagnostic procedures for lymphoproliferative disorders are essential.

Surgical care usually is not required, although special circumstances may require surgery (eg, surgery needed to fix a pathologic fracture). Occasionally, consultation with a radiation oncologist may be indicated to reduce risk of pathologic fracture, to treat a pathologic fracture site after surgical correction, or to treat a site of symptomatic bony involvement.