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Letters to the Editor |
1 Department of Pathology, and Laboratory Medicine, and,
2 Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, GA
aAddress correspondence to this author at: F-147, Emory University Hospital, Department of Pathology and Laboratory Medicine, 1364 Clifton Road NE, Atlanta, GA 30322. Fax 404-712-4780; e-mail jritchi{at}emory.edu.
To the Editor:
We describe here the first case of immunoassay interference from human anti-mouse antibodies (HAMAs) induced by a therapeutic anti-idiotypic antibody. A 76-year-old woman was referred to the Emory Endocrinology Clinic in May 2002 for evaluation of abnormal thyroid function tests. Between August 2001 and March 2002, her total triiodothyronine (T3) was 6.62 to >12.32 nmol/L, but her T3 uptake, total thyroxine (T4), free T4, thyroid-stimulating hormone (TSH), and thyroglobulin were within the appropriate reference intervals.
The patient had undergone a partial thyroidectomy in 1987 for toxic goiter and had been stable on thyroxine replacement with thyroid indices within the appropriate reference values since that time. In January 2000, she underwent a colon resection for colon carcinoma and received adjuvant chemotherapy with 5-fluorouracil until August 2000 and an investigational tumor vaccine (CeaVac) from February 2000 until April 2002. CeaVac is a monoclonal antibody generated in BALB/c mice against another antibody that binds to a highly restricted carcinoembryonic antigen (CEA) epitope (i.e., an anti-idiotypic antibody) (1).
Because the patient was clinically euthyroid, thyroid hormone tests were repeated (Table 1
). On the Beckman Coulter ACCESS Immunoassay System (Emory University Hospital Core Laboratory), free T3, total T3, free T4, total T4, T3 uptake, and thyroglobulin were all abnormally high, whereas TSH was low. Only anti-thyroglobulin antibody was within the reference interval. At a reference laboratory, all thyroid test results were normal except total T3, measured by RIA, which was high. Anti-T3 and anti-T4 antibodies were not detected. At another local hospital, results for thyroid assays performed on the Abbott AxSYM were within the reference intervals except for TSH, which was below the reference interval.
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Excess exogenous thyroid hormone ingestion and endogenous production giving rise to these thyroid testing aberrations were considered highly unlikely based on clinical history and evaluation of the patient. Exogenous T3 overdose could account for the high total T3 results detected by RIA and the Beckman Coulter ACCESS, but would fail to explain why total T4 and free T4 were also increased. Likewise, T3 toxicosis was compatible with the assay results from the ACCESS Immunoassay System, but a euthyroid clinical picture was highly inconsistent with this possibility. 5-Fluorouracil administration can increase serum thyroid-binding globulin concentrations, which may in turn increase total T3 and total T4 values (2). However, this theory could not explain the abnormal concentrations of the free hormones.
The possibility of immunoassay interference was next considered. Autoantibodies against thyroglobulin, T3, and T4 have been documented in the setting of hypothyroidism, hyperthyroidism, and goitrous states and may be present in up to 1.8% of the euthyroid general population (3)(4)(5). Tests for these autoantibodies were negative in our patient, however; thus, these autoantibodies were ruled out as a possible cause of the aberrant results. Even when anti-T3 or anti-T4 antibodies are present, they may not necessarily cause analytical interference in immunoassays, as do other autoantibodies (5)(6). On the other hand, anti-animal antibodies are increasingly being recognized as a source of immunoassay interference. Some of these patients do not have well-documented histories of animal antigen exposure (7).
We retested our patient’s serum after treatment with heterophile blocking tubes (Scantibodies Inc.). When 0.5 mL of the patient’s serum was added to the blocking tube, complete corrections of free T4 and thyroglobulin were achieved on the ACCESS. The other thyroid indices, with the exception of total T4, were also partially corrected, although still above the upper limits of their corresponding reference intervals. When 0.25 mL of serum was used (doubling the ratio of blocking reagent to serum), all thyroid indices (except total T4) fell within the reference intervals. Total T4 values, however, remained markedly increased at >377 nmol/L (>29.2 µg/dL).
The investigational tumor vaccine (CeaVac) that our patient received is a monoclonal antibody with antigen binding sites that mimic CEA, thereby inducing an immune response against colon cancer cells producing CEA. As a monoclonal antibody derived from mice, CeaVac therefore has the propensity to induce HAMA formation.
HAMA interference is a potential pitfall for all immunoassays that use animal antibodies (7). In this case, the ACCESS total T4 values failed to correct with the Scantibodies HAMA-blocking reagent. One possible explanation is that the specific HAMA in our patient’s serum was not reactive with the blocking reagent. Alternatively, the HAMA may have been present in an extremely high titer and simply overwhelmed the capacity of the blocking reagent. Further studies would be necessary to clarify the exact mechanism.
With the ever-increasing use of animal monoclonal antibodies as therapeutic agents (8), immunoassay interference of the type described here is now a real concern for the laboratory.
References
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