HCDs are rare B-cell lymphoproliferative disorders characterised by the production of a monoclonal immunoglobulin heavy chain with no associated light chains. The heavy chain is typically truncated, and its small size results in low serum concentrations due to rapid renal clearance (Chapter 3) [739]. The three main types are α-, γ- and μ-HCD.

Since HLC assays target junctional epitopes that span the immunoglobulin heavy and light chains (Chapter 9), the monoclonal protein associated with HCD is not recognised by HLC assays. However, in such cases, HLC assays allow quantitation of the polyclonal immunoglobulins.

Kaleta et al. [682] evaluated the use of IgG HLC assays in 15 patients with γ-HCD. By immunofixation electrophoresis, each patient’s serum contained a discrete γ-heavy chain with no associated κ or λ light chains (Figure 34.1A). The concentration of polyclonal IgG (determined by HLC analysis: IgGκ + IgGλ) accounted for 18% of the total IgG (as measured by a total IgG nephelometric assay). This indicated that 82% of the IgG did not have an associated light chain. Subtraction of IgGκ + IgGλ HLC concentrations from total IgG measurements was an indirect measure of the monoclonal heavy chain produced by the tumour [682]. The relationship between the heavy chain concentration determined by this indirect nephelometric measure was compared with that determined by SPE (using scanning densitometry) (Figure 34.1B). The monoclonal protein concentration determined by nephelometry was approximately 2-fold higher than the value determined by SPE. This overestimation of total IgG may be due to the calibrator comparing poorly with the monoclonal heavy chain fragment.

Although no light chains are bound to monoclonal heavy chains, monoclonal sFLCs have been reported [682][739][915]. In a study of 15 patients with γ-HCD, 20% had monoclonal κ sFLCs [682]. This finding was supported by flow cytometry of tumour cells from a patient with γ-HCD plus monoclonal κ sFLCs where the tumour cells were positive for cytoplasmic IgG with κ restriction [740]. This indicated that the tumour was the source of both the monoclonal γ-heavy chain and κ sFLCs. Deighan et al. [915] reported an unusual case study of a multiple myeloma (MM) patient with a triple monoclonal gammopathy: IgGκ, κ sFLCs and γ-heavy chains. The patient was monitored with a combination of electrophoresis, Freelite and Hevylite assays, and enabled the patient’s disease evolution to be fully characterised. The patient was initially diagnosed with IgGκ MGUS, and evolved through to MM with both light chain and γ-heavy chain escape. The authors conclude that the potential for heavy chain escape should be kept in mind when monitoring MM patients.