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A 53-year-old woman was admitted with non-exertional chest pain and elevated cardiac troponin I (cTnI) without dynamic changes of ischaemia on the ECG. She had recently undergone coronary angiography which had shown normal coronary vessels. Repeat angiography on this admission was again unremarkable. Samples of blood were sent for analysis using different troponin assays and demonstrated chronic basal elevation of cTnI while simultaneous assay for troponin T (cTnT) remained normal. Subsequent testing revealed the presence of heterophile antibodies interfering with the troponin I assay leading to a false positive result.
This case demonstrates an example of false positive cardiac troponin elevation due to the presence of heterophile antibodies. Although the prevalence of such interference with troponin assays is unknown, we have seen two such cases in recent months in our cardiac unit. It seems likely that many more cases like this go undetected, and may lead to unnecessary and potentially harmful investigations and treatments. Various strategies exist to avoid this problem. In addition, it should be remembered that the diagnosis of acute coronary syndromes relies on accurate clinical history and interpretation of the ECG and should not be made on the basis of biomarkers alone.
A 53-year-old woman was admitted with non-exertional chest tightness radiating to the left arm. She had a past medical history of depression and hypertension but had no other vascular risk factors. She had had two previous admissions over the past 12 months with similar pains associated with low level elevations of cardiac troponin I (cTnI). Clinical examination was unremarkable. Angiography 1 year previously had demonstrated normal coronary arteries.
Her ECG showed minor fixed T-wave changes in the anterior leads. Peak cTnI was elevated at 0.37 (normal 0–0.069). Echocardiography showed no abnormality.
She was treated as having a troponin-positive non-ST elevation acute coronary syndrome. Anti-ischaemic and secondary preventive therapy was optimised. On the 5th day of her admission an exercise tolerance test was performed. This was deemed low risk and she was therefore discharged home.
An outpatient myocardial perfusion scan was arranged. This showed a small reversible perfusion defect in the territory of the left anterior descending artery. She underwent further coronary angiography which again demonstrated normal coronary arteries.
We subsequently took blood samples from the patient when she was seen in the outpatient department and was asymptomatic. Simultaneous blood samples were sent for measurement of cTnI in our own laboratory and for cardiac troponin T (cTnT) in a different laboratory. This showed that cTnI was chronically elevated, while simultaneous cTnT was normal.
It was therefore demonstrated that the raised cTnI was a false positive result. Further analysis revealed the presence of heterophile antibodies in the patient's blood, causing interference with our cTnI assay.
Cardiac troponins are single chain polypeptides involved in the regulation of cardiac muscle contraction. They are the most sensitive and specific markers of cardiac myocyte damage and are recommended for use in the diagnosis of acute coronary syndromes.1 While only one assay for cTnT is commercially available, there are many different assays for cTnI in use.
Cardiac troponin elevation in the correct clinical context may confirm the diagnosis of acute coronary syndromes, and can also be used to stratify the risk of further adverse cardiac events. Elevated troponin levels may also result from a variety of non-coronary causes of cardiac myocyte necrosis (table 1). In addition, analytical errors may lead to false positive troponin elevations in the absence of myocyte necrosis. These errors may be related to interference with the troponin assay by fibrin,2 alkaline phosphatase,3 haemolysis4 and instrumentation malfunction.
The presence of heterophile antibodies in the serum of the test subject may also lead to a false positive result. These are defined as antibodies with multispecific activity produced against poorly defined antigens. Troponin assays are based on the principle of the two-site ELISA. Heterophile antibodies may bind non-specifically to the Fc-portions of the assay antibodies resulting in spurious troponin elevation.
Heterophile antibody production may be stimulated by exposure to a variety of antigens including transfused blood,5 vaccinations,6 exposure to mice7 and rabbits,8 therapeutic use of mouse monoclonal antibodies,9 and even dietary antigens.10 Autoimmune diseases may also give rise to antibodies with heterophile activity, for example, rheumatoid factor.11
The precise prevalence of heterophile antibodies is unknown, and their interference with troponin assays has traditionally been considered to be rare. However, the prevalence of false positive troponin elevations in routine populations has been found in studies to be as high as 3.1%,12 a proportion of which will be due to the presence of heterophile antibodies. One study of troponin elevations in rheumatoid factor positive subjects demonstrated 11.5% to be false positive results.13
A number of strategies exist to counteract interference from heterophile antibodies. Pooled animal sera may be used to remove anti-animal antibodies, and heterophile blocking agents are available and are incorporated into many of the newer assays.14 Blood may be sent for testing using a different assay on a simultaneous sample. Furthermore, serial samples should be sent in suspected acute coronary syndromes to look for a sequential rise and fall of cardiac biomarkers.
This case demonstrates an example of false positive cardiac troponin elevation due to the presence of heterophile antibodies. Although the prevalence of such interference with troponin assays is unknown, we have seen two such cases in recent months in our cardiac unit. It seems probable that many more cases like this go undetected, and may lead to unnecessary and potentially harmful investigations and treatments. Various strategies exist to avoid this problem. In addition it should be remembered that the diagnosis of acute coronary syndromes relies on accurate clinical history and interpretation of the ECG and should not be made on the basis of biomarkers alone.
Competing interests None.
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