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Letters |
1
Department of Laboratory Medicine, Azienda Ospedaliera, 35128 Padova, Italy
2
Department of Laboratory Medicine, Hospital of Rovigo, 45100 Rovigo, Italy
3
Department of Medical, and Surgical Sciences, University of Padova, 35128 Padova, Italy
aAuthor for correspondence. Fax 39-049-663-240; e-mail pad08821{at}pd.nettuno.it.
To the Editor:
Cardiac troponins (I and T) represent a major improvement in the biochemical approach to the detection and evaluation of myocardial damage (1)(2). Here, we describe a case in which the measurement of cardiac troponin I (cTnI) gave erroneous clinical information because of interference caused by the presence of a macrocomplex.
The patient, a 78-year-old Caucasian woman with a pacemaker, had a long-standing history of cardiac disease, including a myocardial infarction 1 year before (July 1999), transient ischemic episodes with chest pain, and mitral valve failure. On July 22, 2000, the patient was admitted to the cardiac intensive care unit for an episode of chest pain and dyspnea. On admission, no significant electrocardiographic alterations were found. Biochemical markers were measured on several occasions (e.g., Table 1
). Reference values were according to the manufacturers and confirmed in our population. At admission, cTnI and myoglobin (RxL Dimension; Dade-Behring) were increased (1.0 and 96 µg/L, respectively; reference values <0.05 and <70 µg/L), but creatine kinase MB (CK-MB) was not (2 µg/L; reference value <5 µg/L). The patient was moved from the intensive care unit to a medical department on the 2nd day after admission. cTnI ranged from 0.9 to 1.1 µg/L, myoglobin gradually decreased to within the reference interval, and CK-MB remained within normal limits, ranging from 1.5 to 2.3 µg/L. After July 29 (7th day of admission), a progressive increase was observed in cTnI, with the maximum of 10.2 µg/L observed on August 17 (the 26th day after admission).
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The patient was discharged as the increased cTnI values were not associated with a worsening clinical status. At follow-up, cTnI values were persistently increased (17.4, 19.0, and 18.8 µg/L on the 34th, 39th, and 47th day after initial presentation, respectively), whereas CK-MB and myoglobin were within their reference intervals. On the 74th day after initial presentation (October 4, 2000), cTnI was still increased (4.0 µg/L) but had decreased from the September 7 value. The variations observed were not ascribable to the imprecision of the assay because the CV was <3% at those concentrations. We found no alterations in renal function or in electrocardiographic or clinical findings in relation to the increased cTnI.
The constant increases in cTnI were also confirmed with the Triage System (Biosite Diagnostic; cTnI values, 23.0, 22.8, and 15.6 µg/L; reference value <0.19 µg/L) and the Stratus CS (Dade-Behring; cTnI values, 32.7, 32.5, and 3.8 µg/L; reference value <0.05 µg/L) in several specimens retested on August 30, September 7, and October 4 (Table 1
). Cardiac troponin T (cTnT; Elecsys 2010, third-generation assay; Roche Diagnostics) was positive (0.55 µg/L; reference value <0.01 µg/L) in the first sample collected at admission and negative in the following four samples (Table 1
). The simultaneous increase of both cTnI and cTnT at admission seems to indicate myocardial damage. The discrepancies between biochemical and clinical data were initially ascribed to the presence of heterophilic antibodies, but no differences were found in cTnI concentrations before and after treatment with heterophilic blocking tubes (17.7 vs 17.1 µg/L; Scantibodies Laboratories) (3). Rheumatoid factor, another interference in immunoassays (4), was undetectable (<10.6 kIU/L; BN II; Dade-Behring).
A progressive discrepancy was found between the observed and expected cTnI concentrations in serial dilutions with either the level 1 (0 µg/L) cTnI RxL calibrator or TnI-free human serum (data not shown). An immunoprecipitation procedure (5) was carried out with anti-IgG, IgA, IgM-specific antisera (Dako Ltd). When the patient’s sample of August 30 was treated with an anti-IgG antiserum, a large decrease in the cTnI concentration was obtained (from 19.0 to 3.0 µg/L; 16% recovery in the sample diluted 1:10 (1 mL in 9 mL) with anti-IgG antiserum), whereas treatment with other antisera did not affect the measured cTnI. These results suggest the presence of an immunocomplex involving cTnI and IgG that produces the persistently high cTnI concentrations, probably because of the prolonged half-life of the IgG. Furthermore, when our patient’s immunoglobulins were separated by precipitation with ammonium sulfate (at 55% saturation) and tested against a sample from another myocardial infarction patient (cTnI = 3.1 µg/L) to verify their behavior toward cTnI of different origins, the cTnI concentration of the patient was totally recovered when treated with IgG.
Our findings suggest the possibility that a modified molecule of cTnI (6) induced the immunocomplex formation, differently from most cases of macroenzymes described in the literature (7) in which a modified immunoglobulin molecule (IgG or IgA) was the responsible complexing factor that bound the normal protein. An immunoblotting analysis carried out in 1.5% agarose with the same anti-cTnI antibodies (kindly provided by Dade-Behring) used in the RxL Dimension assay confirmed the presence of a complex characterized by a molecular mass similar to that of apolipoprotein B-100 (
500 kDa).
Our report is not intended to question the role and value of cardiac troponins in the diagnosis of acute coronary syndromes (8), but to underline the need to identify analytical and pathophysiologic situations that could compromise the measurement of cTnI (and, potentially, cTnT).
References
chains) conjugated with lactate dehydrogenase in serum. Clin Chem 1987;33:1085-1086.The following articles in journals at HighWire Press have cited this article:
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  K. B. Wallace, E. Hausner, E. Herman, G. D. Holt, J. T. Macgregor, A. L. Metz, E. Murphy, I.Y. Rosenblum, F. D. Sistare, and M. J. York Serum Troponins as Biomarkers of Drug-Induced Cardiac Toxicity Toxicol Pathol, January 1, 2004; 32(1): 106 - 121. [PDF]
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 T. J. DeMartini and H. S. Loeb Coronary Artery Disease and the Acute Coronary Syndrome Ann Intern Med, December 2, 2003; 139(11): W-82 - W-82. [Full Text] [PDF]
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 S. Eriksson, M. Junikka, P. Laitinen, K. Majamaa-Voltti, H. Alfthan, and K. Pettersson Negative Interference in Cardiac Troponin I Immunoassays from a Frequently Occurring Serum and Plasma Component Clin. Chem., July 1, 2003; 49(7): 1095 - 1104. [Abstract] [Full Text] [PDF]
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