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Chapter 7

Biological variation studies define the physiological fluctuation of analyte concentrations in a biological fluid around its homeostatic set point [171]. Knowledge of the biological variation of FLCs in serum is useful when interpreting monitoring data for individual patients. Braga et al. [172] studied the biological variation of sFLC measurements in 21 healthy volunteers (12 women and 9 men), measured at the same time on the same day, every 2 weeks over the course of 2 months. λ sFLC concentrations were significantly higher in men than women (p<0.01), whereas no difference was found for κ sFLC concentrations. Intra-individual variances of κ or λ FLCs were similar (8.1% and 7.0%, respectively), and were not different between men and women. By contrast, the inter-individual variance of λ sFLCs was higher than that of κ sFLCs (27.5% vs. 14.1%, respectively), and was higher for men than women (33.0% vs. 22.6%, respectively). The reference change value (RCV) defines the minimum significant difference (p<0.05) between two consecutive measurements in the same individual. In this study the RCV for κ and λ sFLCs was similar: 22.6% and 19.6%, respectively. Similar findings were reported by Hansen et al. [173].

Katzmann et al. [174] studied the long-term biological variation of monoclonal FLCs in 158 patients with clinically stable monoclonal gammopathy. For each patient, at least three serial samples were obtained within a 5 year period. During the study, each patient received no treatment, had no change in clinical diagnosis, and had a <5 g/L change in serum monoclonal immunoglobulin quantification by protein electrophoresis. A total of 52/158 patients had measurable monoclonal sFLCs (defined as iFLC ≥100 mg/L with an abnormal κ/λ sFLC ratio). The total coefficient of variation (CV) for iFLC measurements was 28.4%, which was almost entirely attributable to biological variation (CV=27.8%) and, to a lesser extent, due to inter-assay analytical variation (CV=5.8%). The variation in iFLC was more comparable to that of monoclonal protein quantification by urine protein electrophoresis (Total CV=35.8%) than serum protein electrophoresis (Total CV=8.1%). This is likely to reflect the short serum half-life of FLCs compared with intact immunoglobulins (Chapter 3). The RCV for monoclonal sFLCs was 54.5%. This value is significantly higher than that reported by other smaller studies [172][173] and may reflect differences in the length of patient follow-up (5 years vs. less than a week). Several authors now recommend that biological variation data should be taken into account to update the definitions of sFLC response criteria.