Analytical interference in the corticotropin immunoassay in patients with adrenal adenomas

Iglesias, Pedro; Cano, Ana García; Jiménez, Lucía; Díez, Juan J.

doi:10.1016/j.endinu.2017.11.003

Cited by 3 publications

(5 citation statements)

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“…In all but one of the ACTH assay interference cases previously reported, the Siemens Immulite platforms were used [3][4][5][7][8][9][10] (Table 3), whereas in the present case, the Roche Diagnostics Elecsys ACTH assay yielded falsely elevated ACTH levels, for the first time to our knowledge. The Siemens Immulite platforms adopt a murine monoclonal anti-ACTH antibody and a rabbit polyclonal antibody that is considered capable of react-ing with unknown interference antibodies [9]. On the other hand, the Elecsys ACTH assay is an electrochemiluminescence method employing two monoclonal antibodies specific for ACTH (9-12) and for ACTH (36-39).…”

Section: Discussionmentioning

confidence: 57%

“…It is extremely rare that falsely high or low ACTH levels by a substance in the specimen interfering with the ACTH measurements are confirmed. There have been only 23 such cases, to our knowledge [3][4][5][6][7][8][9][10] (Table 3). Of the 23 cases, 22 exhibited erroneously elevated ACTH levels.…”

Section: Discussionmentioning

confidence: 99%

“…Of the 23 cases, 22 exhibited erroneously elevated ACTH levels. In some of these reports, the elevated ACTH levels measured on the Immulite platforms were proved to be false, either by pretreatment with heataggregated rabbit IgG, which is known to adsorb assayinterfering heterophilic antibodies [3], or by adoption of different assay platforms [4,[7][8][9][10].…”

Section: Discussionmentioning

confidence: 99%

“…In the field of endocrinology, falsely elevated levels of free thyroxine by anti-reagent or anti-analyte antibodies [1,2] and falsely elevated PRL or TSH levels due to formation of macromolecular complexes (such as "macro-PRL" or "macro-TSH") by anti-analyte antibodies [2] are well known. In the case of ACTH, however, there are extremely few reports only on the Siemens Immulite ACTH and the Abbott Architect ACTH [3][4][5][6][7][8][9][10].…”

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confidence: 99%

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Falsely elevated plasma ACTH levels measured by the Elecsys assay related to heterophilic antibody in a case of secondary adrenocortical insufficiency

et al. 2019

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A 49-year-old woman with membranous nephropathy was referred to our hospital during the tapering of oral prednisolone, because of suspicion of primary adrenal insufficiency based on a plasma ACTH level of 399.1 pg/mL in the Elecsys assay and a serum cortisol level of 3.1 μg/dL. A rapid ACTH stimulation test revealed a suboptimal response, whereas a prolonged ACTH simulation test showed a sufficient increase in her urinary free cortisol. Also, big ACTH was not detected by gel exclusion chromatography. Therefore, we speculated that ACTH levels were falsely elevated due to some interference substances. Pretreatment of her plasma with either polyethylene glycol precipitation or a heterophilic blocking tube substantially reduced her ACTH values. When either the Immulite ACTH II or the TOSOH II ACTH was tried instead of the Elecsys ACTH, her plasma ACTH values turned out to be lower and appropriate for her clinical status. These results indicated that heterophilic antibodies interfered only with the Elecsys ACTH assay presumably by bridging the capture and tracer antibodies. To our knowledge, this is the first case in which the Elecsys ACTH assay yielded falsely elevated results. Regardless of the measurement system used, if there is a discordance between assay results and clinical findings, it should be considered to adopt additional procedures and/or another assay.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Falsely elevated plasma ACTH levels measured by the Elecsys assay related to heterophilic antibody in a case of secondary adrenocortical insufficiency

et al. 2019

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“…Previous studies have illustrated that the interaction between these antibodies and other unknown interference antibodies results in most of the doubtful plasma ACTH elevations analyzed using the ACTH (Immulite). 12 Cisbio ELSA-ACTH assay used at the LEZEN Reference Lab was composed of an ACTH N-terminal and C-terminal specific monoclonal antibody, which were, respectively, coated on the ELSA solid phase and radiolabeled with iodine-125 tracer. The increased specificity of the ELSA-ACTH immunoassay yields more accurate plasma ACTH levels.…”

Section: Discussionmentioning

confidence: 99%

A Pitfall of Falsely Elevated ACTH: A Case Report and Literature Review

Yang

Kuo

Lin

et al. 2022

Journal of Investigative Medicine High Impact Case Reports

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A 35-year-old woman with unintentional weight gain, hyperpigmentation of bilateral palms, and general fatigue was initially suspected of Cushing’s syndrome or adrenal insufficiency based on the isolated elevation of the plasma adrenocorticotropic hormone (ACTH) level (113.0 pg/mL) in the Siemens ACTH Immulite assay (ACTH [Immulite]). However, both of the diagnoses were excluded by screening tests including the overnight dexamethasone suppression test, the 24-hour urinary free cortisol excretion, and the ACTH stimulation test in spite of the consistent elevation of the plasma ACTH levels. We speculated that the existence of the immunoassay interference may be the underlying cause because the plasma ACTH level analyzed by the CIS Bio International ELSA-ACTH immunoassay (ELSA-ACTH) was within the normal range. After reviewing our case and several reported cases of falsely elevated plasma ACTH levels, we conclude that when discrepancy between clinical symptoms and laboratory measurements exists, medical practitioners ought to rely on formal diagnostic criteria rather than misleading laboratory results to avoid misdiagnosis or even unnecessary invasive testing and procedures. In addition, current methods for investigation and elimination of immunoassay interferences should be applied with caution due to variable efficacy and inevitable deviations.

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An Intact ACTH LC-MS/MS Assay as an Arbiter of Clinically Discordant Immunoassay Results

et al. 2019

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BACKGROUND Measurement of plasma adrenocorticotropic hormone (ACTH) is key in the differential diagnosis of hypothalamic-pituitary-adrenal disorders. Two-site sandwich immunoassays dominate clinical testing of ACTH in North America; however, discordant results between manufacturers have been repeatedly reported. To resolve the discrepancy, we developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay for the intended measurand, biologically active intact ACTH (iACTH). METHODS The multiple reaction monitoring LC-MS/MS assay was designed to selectively measure full-length iACTH, as well as ACTH analogs and fragments (i.e., ACTH1–24 and ACTH18–39). Epitope assignment of the Roche Elecsys antibodies was performed by MALDI-TOF mass spectrometry. A method comparison between Roche Elecsys and Siemens Immulite ACTH immunoassays was performed and clinically concordant/discordant results identified. In a subset of these samples, the iACTH concentration was determined using the LC-MS/MS method. RESULTS The lower limit of the measuring interval of the iACTH LC-MS/MS assay was 9 pg/mL (2 pmol/L). The assay was linear from 9 to 1938 pg/mL (2 to 427 pmol/L). Epitope mapping revealed that the Roche capture and detection antibodies bound residues 9–12 and 36–39 of ACTH, respectively. The iACTH LC-MS/MS analysis demonstrated that for discordant results between 2 immunoassays studied, only the Roche results were highly positively correlated with the iACTH concentration. CONCLUSIONS Immunoprecipitation of biologically active ACTH molecules followed by LC-MS/MS analysis enabled selective detection of iACTH and relevant biologically active fragments in plasma. Applied to the investigation of clinically discrepant results, this method can act as an arbiter of the concentration of iACTH present.

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Analytical interference in the corticotropin immunoassay in patients with adrenal adenomas

Cited by 3 publications

References 10 publications

Falsely elevated plasma ACTH levels measured by the Elecsys assay related to heterophilic antibody in a case of secondary adrenocortical insufficiency

Falsely elevated plasma ACTH levels measured by the Elecsys assay related to heterophilic antibody in a case of secondary adrenocortical insufficiency

A Pitfall of Falsely Elevated ACTH: A Case Report and Literature Review

An Intact ACTH LC-MS/MS Assay as an Arbiter of Clinically Discordant Immunoassay Results

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