Dear Editor,
Clinical laboratories routinely use hemolysis, icterus, and lipemia indices to identify analytic interferences in serum samples. The lipemia index (L-index) is obtained by diluting a sample with saline solution and measuring absorbance at 660 and 800 nm to detect elevated triglyceride concentrations. However, the L-index can be elevated in samples with normal triglyceride levels. Such false lipemia is frequently associated with monoclonal IgM [1–4]. We developed an algorithm incorporating the L-index to identify patients with high monoclonal IgM concentrations. This study was approved by the Research Ethics Committee of Germans Trias i Pujol University Hospital, Badalona, Spain (PI-25-137). Informed consent was not required because of the retrospective nature of the study and the use of anonymized data.
We retrospectively analyzed data from serum samples with an L-index >0 that underwent serum protein electrophoresis (SPE) and had triglyceride concentrations within the reference range (≤150 mg/dL). For control, we selected samples with an L-index=0 under the same conditions. The dataset included all samples analyzed, after excluding repeated samples from the same patient. Patients with an L-index >0 constituted the pos-L-index group (N=650, mean age=70 yrs), whereas those with an L-index=0 formed the neg-L-index control group (N=647, mean age=64 yrs). Pos-L-index and neg-L-index data were collected from January 2018 to December 2022 and from March 2020 to April 2020, respectively. The L-index was evaluated on a semi-quantitative scale (0–7) using an AU5800 analyzer (Beckman Coulter, Brea, CA, USA). SPE was performed using the CAPILLARYS system (Sebia, Lisses, France). The monoclonal component was confirmed via immunofixation using an Interlab G26 analyzer (Interlab, Rome, Italy).
In the neg-L-index group, 0.8%, 3.9%, and 0.5% of patients showed the presence of monoclonal IgM, IgG, and IgA, respectively. In contrast, the pos-L-index group showed a markedly higher prevalence of monoclonal IgM (39.6%, including 70 patients with a prior positive SPE result for a monoclonal IgM), whereas monoclonal IgG and IgA were detected in 3.0% and 0.8% of patients, respectively. Among patients with an L-index >2, 93.8% exhibited monoclonal IgM (Table 1). In the pos-L-index group, 21 patients presented with a biclonal component involving either different heavy chains or an intact immunoglobulin plus a free monoclonal light chain. Only one case was identified in the neg-L-index group. In the pos-L-index group, 70 of 75 samples without a detectable monoclonal component, but with available total IgM results, exhibited elevated polyclonal IgM levels.
Table 1. Distribution of patients with a monoclonal component based on their lipemia index values.
| Lipemia index | IgM+ (total)* | % IgM+ | Median monoclonal IgM concentration (g/L) (IQR)† | Risk ratio (vs. control)‡ | Monoclonal IgM concentration ≥15 g/L§ |
|---|---|---|---|---|---|
| 7 | 15 (15) | 100.0 | 20.5 (15.7–30.0) | 125.0 | 12 |
| 5 | 23 (24) | 95.8 | 12.0 (10.8–16.0) | 115.0 | 7 |
| 4 | 27 (30) | 90.0 | 9.5 (6.8–13.3) | 112.5 | 5 |
| 3 | 25 (27) | 92.6 | 5.9 (4.7–6.5) | 115.7 | 0 |
| 2 | 59 (75) | 78.7 | 5.3 (3.9–6.3) | 98.3 | 0 |
| 1 | 99 (458) | 21.6 | 3.2 (1–5.5) | 27.0 | 3 |
| 7–1 | 248 (629) | 39.6 | NA | 49.1 | 27 |
| 0 (control) | 5 (646) | 0.8 | 3.7 (1–4.3) | NA | 0 |
| Lipemia index | IgG+ (total) | % IgG+ | Median monoclonal IgG concentration (g/L) (IQR) | Risk ratio (vs. control) | Monoclonal IgG concentration ≥15 g/L |
|---|---|---|---|---|---|
| 7 | 0 (15) | 0 | NA | 0 | 0 |
| 5 | 0 (24) | 0 | NA | 0 | 0 |
| 4 | 0 (30) | 0 | NA | 0 | 0 |
| 3 | 0 (27) | 0 | NA | 0 | 0 |
| 2 | 1 (75) | 1.3 | 13.7 (NA) | 0.3 | 0 |
| 1 | 18 (458) | 3.9 | 6.0 (2.6–10.2) | 1.0 | 1 |
| 7–1 | 19 (629) | 3.0 | NA | 0.8 | 1 |
| 0 (control) | 25 (646) | 3.9 | 6.7 (2.7–10.5) | NA | 5 |
| Lipemia index | IgA+ (total) | % IgA+ | Median monoclonal IgA concentration (g/L) (IQR) | Risk ratio (vs. control) | Monoclonal IgA concentration ≥15 g/L |
|---|---|---|---|---|---|
| 7 | 0 (15) | 0 | NA | 0 | 0 |
| 5 | 0 (24) | 0 | NA | 0 | 0 |
| 4 | 1 (30) | 3.3 | 2.6 (NA) | 6.7 | 0 |
| 3 | 0 (27) | 0 | NA | 0 | 0 |
| 2 | 1 (75) | 1.3 | 32.7 (NA) | 2.7 | 1 |
| 1 | 3 (458) | 0.7 | 6.6 (1–38.2) | 1.3 | 1 |
| 7–1 | 5 (629) | 0.8 | NA | 1.6 | 2 |
| 0 (control) | 3 (646) | 0.5 | 1.0 (1.0–6.2) | NA | 0 |
*IgM+, IgG+, and IgA+ refer to patients presenting with a monoclonal IgM, IgG, or IgA, respectively. The total represents the total number of patients with available data, with or without a monoclonal component.
†When the monoclonal component was not quantifiable, its concentration was set to 1 g/L. No samples with a lipemia index of 6 were detected. Data related to biclonal components involving either different heavy chains or intact immunoglobulin plus free monoclonal light chains are not included.
‡Risk ratio represents the quotient between the percentage of monoclonal components in samples with a positive lipemia index and that in the control group.
§Monoclonal IgM, IgG, and IgA ≥15 g/L represent the number of patients with monoclonal protein concentrations ≥15 g/L.
Abbreviations: IQR, interquartile range; NA, not applicable.
A Mann–Whitney U-test comparing the monoclonal IgM levels in the group with L-index values of 1–3 with those in the group with an L-index of 4–7 revealed a significant difference (P< 0.001), with higher monoclonal IgM concentrations observed in the latter group, distinct from findings reported by Thouault et al. [1] (Table 1). The monoclonal IgM concentration exceeded 15 g/L in 12 patients (80.0%) with an L-index of 7, 7 patients (29.2%) with an L-index of 5, and 5 patients (16.7%) with an L-index of 4 (Table 1). This concentration threshold indicates a stage associated with an increased progression risk from monoclonal gammopathy of undetermined significance (MGUS) [5].
The L-index, a widely accessible laboratory parameter, is a valuable tool for identifying IgM monoclonal gammopathies, potentially reducing diagnostic delays. Early monoclonal IgM detection in asymptomatic individuals facilitates close monitoring and timely intervention before symptom onset [6].
The L-index has been used for detecting monoclonal IgM, with positivity rates of 48–87% or predictive values above 79% [1–4]. However, neither the semi-quantitative application of the L-index [1, 2] nor the distribution of positive cases across lipemia grades [3, 4] was evaluated. The studies involved different analyzers, including the AU5820.
An elevated L-index (4–7) was associated with an increased M protein concentration, a known risk factor for disease progression [6]. Given the limited healthcare resources available for patient follow-up and the high prevalence of MGUS (carrying a low probability of progression to symptomatic disease), an elevated L-index may serve as a cost-effective screening tool to prompt clinicians to order SPE for monoclonal gammopathies [7]. Alternatively, laboratories could report the presence of a probable monoclonal IgM without performing SPE, serving as an initial alert to guide further investigation based on clinical presentation and laboratory findings. We propose a novel diagnostic algorithm for IgM-type monoclonal gammopathies that incorporates an estimated IgM concentration based on the L-index measured by the AU5800 analyzer (Fig. 1). As a limitation, our algorithm requires the evaluation of analyzers from other manufacturers. Although a positive L-index demonstrated good diagnostic accuracy for detecting monoclonal IgM, the prevalence of patients with IgM monoclonal gammopathy that exhibit a positive L-index was not assessed. This work may provide clinical laboratories with practical guidance on how to apply the L-index in the detection of IgM monoclonal gammopathies.
Fig. 1. Diagnostic algorithm for IgM monoclonal gammopathies based on the lipemia (L)-index.
ACKNOWLEDGEMENTS
We thank Yolanda Alba and Marc Morales for their technical support.
Footnotes
AUTHOR CONTRIBUTIONS
Piedra-Aguilera A contributed to data curation and investigation; Piedra-Aguilera A, Fernández-Prendes C, Malumbres-Serrano S, and Morales-Indiano C drafted the original manuscript; all authors contributed to conceptualization and reviewing and editing the manuscript. All authors read and approved the final manuscript.
CONFLICTS OF INTEREST
None declared.
RESEARCH FUNDING
None declared.
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