Discussion
Troponin T and troponin I are not exclusively cardiac-specific proteins, but are present in all striated muscle (albeit with different amino acid structures in cardiac and skeletal muscle). In laboratory assays for troponin T and troponin I, antibodies against cardiac troponins are used, and these are regarded as cardiac-specific tests; however, in rare pathological conditions, skeletal muscle may express cardiac troponin isoforms. When there is a dynamic change in troponin levels, myocardial injury is normally suspected (1).
After the initial admission, myopericarditis was considered the most likely cause of the patient's chest pain and elevated troponin T. The condition is characterised by an inflammatory process primarily involving the pericardium, with only mild involvement of the myocardium, presenting with troponin release and/or ST-segment elevation on ECG (2). This is in contrast to perimyocarditis, in which myocardial involvement is more pronounced, resulting in reduced left ventricular function. The gold standard for diagnosis is endomyocardial biopsy, but this is only recommended when there are signs of heart failure. Cardiac MRI is used to detect myocardial inflammation, with a sensitivity of 73–88 % (3), as well as to exclude other diagnoses, while coronary angiography is performed to rule out coronary heart disease. Diagnostic criteria for myopericarditis include elevated troponin and pericarditis, together with at least two of the following: typical chest pain, pericardial friction rub, pericardial effusion and ECG changes. On review of the patient's symptoms and findings, the diagnosis appears to have been based solely on the elevated troponin T level, without other criteria being met.
Macro-troponin is an immune complex consisting of cardiac troponin (troponin T and/or troponin I) bound to endogenous anti-troponin antibodies. The complex will often, but not always, result in elevated measured levels of troponin T and/or troponin I (4–6). The prevalence varies between different populations and assay methods. For example, a large-scale Danish study of a healthy reference population showed a substantially higher proportion of macro-troponin I than macro-troponin T among participants with the highest values (7). Macro-troponin can have a molecular weight of ≥ 150 kDa and is too large to be filtered by the renal glomeruli. Due to reduced elimination, these immune complexes remain in the circulation and can lead to elevated troponin concentrations for a potentially prolonged period (weeks to months) in the absence of acute ongoing myocardial injury (8). The half-life of troponin T will increase from around two hours to weeks, corresponding to the half-life of IgG, thereby resulting in relatively stable and persistently elevated levels. This is consistent with the slow decline in troponin T from day 6 to 14 months in our patient.
Elevated troponin T is a marker of myocardial injury, and numerous investigations were performed, despite a low clinical suspicion of coronary heart disease. Both the elevated troponin T level on admission and the almost threefold increase by day 3 raised suspicion of unresolved myocardial injury or inflammation. The patient also showed no signs of heart failure, including Takotsubo syndrome (9), or arrhythmias that could explain the elevated troponin T. Troponin T levels can be elevated in severe renal failure (10), certain myopathies (11), severe rhabdomyolysis, severe sepsis and following strenuous physical exertion, none of which were suspected in our patient. We also found no definite cardiac source for the elevated troponin T during the two hospital stays.
A retrospective review of the patient's medical record revealed that the patient had experienced pain on palpation of the chest muscles since 2010. These myalgic chest pains are unlikely to explain the elevated and rising troponin levels at the time of the initial admission. In addition, the patient described progressive muscle weakness. This raised the question of whether skeletal muscle could be the source of a selective troponin T release (11). Inclusion body myositis can present with moderately elevated CK and disproportionate troponin T elevation (12). The patient was referred for MRI of the thigh, which showed moderate fatty infiltration without oedema. This does not support the diagnosis and is more likely related to ageing. We therefore found no definitive muscular source either.
In retrospect, CK, CK-MB and myoglobin could have been measured earlier, rather than only after three and twelve months, respectively. It was also unfortunate that the troponin I result sent to the GP was not identified at the time of the subsequent admission, prior to the ward round on day one. This result could have prevented an unnecessary repeat investigation, although it did not have clinical consequences in this case.
Clinicians must be alert to discrepancies between clinical findings and biomarkers in order to avoid patients undergoing repeated, costly and potentially hazardous investigations, such as invasive coronary angiography and contrast-enhanced CT scans. The laboratory should be contacted when troponin results do not fit the clinical picture. Appropriate measures may include repeat analysis of the sample, troubleshooting of the analysis instrument, assessment of possible interferences and use of complementary tests such as troponin I, CK, CK-MB, NT-proBNP and myoglobin in cases of elevated troponin T, as well as investigation for macro-troponin. Although macro-troponin was detected, we did not identify the cause of the troponin T release leading to macro-troponin formation in this patient. Nevertheless, the finding meant that no further investigations were undertaken and that the patient was reassured that she did not have significant cardiac disease.