A possible analytical and clinical role of endogenous antibodies causing discrepant adrenocorticotropic hormone measurement in a case of ectopic Cushing’s syndrome

Abstract

Heterophilic antibodies are well described, but poorly appreciated interferents and is often not a recognized problem affecting most immunoassays. We report a patient presented with ectopic Cushing's syndrome (CS), but repeated plasma adrenocorticotropic hormone (ACTH) concentrations conducted by immunoassay were inappropriately within the reference range and not elevated, most probably as a result of antibody interference. A 36-year-old woman, presented with large gastric neuroendocrine carcinoma and severe ectopic CS, while repeated plasma ACTH concentrations conducted by immunoassay were inappropriately within the reference range. As we expected ACTH concentration to be higher, we performed several tests to evaluate whether there was any assay interference causing falsely lower than expected ACTH results. We measured ACTH using a different immunoassay, assayed the sample in dilution, assayed the sample after being incubated in heterophilic antibody blocking agent tube and performed recovery studies. Tests indicated the presence of interfering compounds, most probably heterophilic antibodies. When clinicians find ACTH concentrations to be lower than expected, we recommend the laboratory investigate antibody interference.

When laboratory tests can mislead even when they appear plausible

“…4 On 8 August 2014, the WHO declared the Ebola outbreak a public health emergency of international concern (PHEIC). 5 The case fatality rate (CFR) for this epidemic was estimated to be between 31% and 74% in the three most affected countries in West Africa, with an average CFR of 48% for hospitalised patients; this is largely consistent with the range of CFRs reported for previous Ebola Zaire (EBOV) outbreaks. [6][7][8][9][10][11] Cases were also diagnosed in Senegal, Nigeria, Mali, USA, UK, Italy and Spain.…”

“…A more realistic general 'guestimate' in practice would be 0.4-1%, which is still high; hence the need for awareness and caution. [1][2][3][4][5][6][7][8][9] Probabilistic reasoning based on Bayesian inference, which takes into account key relevant information such as the rate of analytical inherent error and disease prevalence/incidence, is a concept that can help in identifying potentially false results and quantifying the likelihood of false positive and negative data.…”

“…10,11 The immunoassay used to measure TSH may be assumed to have an excellent diagnostic accuracy of 99.6% and an error rate of ±0.4% (considered among the lowest reported). [1][2][3][4][5][6][7][8][9] This means four false positives or negatives are predicted per thousand in any population sample.…”

“…Unquestioning acceptance at face value may lead to misdiagnosis and mistreatment or unnecessary surgery for unconfirmed disease with consequent iatrogenic morbidity. [1][2][3][4][5][6][7][8][9] A probabilistic rationale based on Bayes' theorem 1 -in which key information, such as (a) the rate of inherent analytical error in a test and (b) the disease prevalence (number of cases per head of ABSTRACT When laboratory tests can mislead even when they appear plausible population) or incidence (rate of new cases over a period of time), is taken into account -can be used to evaluate the likelihood of an erroneous result occurring and its nature, ie false positive or false negative. Essentially, in disorders with low prevalence/incidence and/or when a test is used as a screen with vague or insufficient clinical correlates, erroneous results are likely to be false positives.…”

A Case With Immunoassay Interferences in the Measurement of Multiple Hormones

“…Human antimouse antibody interference in a PTH immunoassay mimicking tertiary hyperparathyroidism resulted in unnecessary parathyroidectomy in a renal transplant patient (18). On the contrary, "nonelevated" ACTH levels in a patient with severe ectopic Cushing syndrome due to a large gastric neuroendocrine tumor is an example for assay interference leading to falsely low levels (19). To the best of our knowledge, no case of assay interference for calcitonin has yet been reported.…”