Jie Gao, PhD, MLS(ASCP)CM, and Floyd Josephat, EdD, MT(ASCP)

The recent joint American and European guidelines on the diagnosis of acute myocardial infarction (AMI) rely heavily upon the measurements of cardiac troponins (cTn), especially troponin T (cTnT) and troponin I (cTnI), which are the most useful cardiac biomarker today.1 However, an increasing number of studies have revealed the cTn elevation is not specific to AMI, and it has been observed in a variety of diseases, such as end-stage renal disease, pulmonary embolism, sepsis, cirrhosis, diabetes mellitus, and so on, regardless of whether the symptoms of acute coronary syndrome (ACS) are present or not. Therefore, it is critical to be aware of pathological conditions that may cause elevated cTn levels in conditions other than AMI. This is also essential to prevent misdiagnoses and can provide an opportunity for laboratory professionals to become actively involved in the diagnostic process as well as to provide accurate results. Below are two examples of disease states or conditions where cTn levels were identified to be elevated.

“[I]t is critical to be aware of pathological conditions that may cause elevated cTn levels in conditions other than AMI.”

End-Stage Renal Disease

End-stage renal disease (ESRD), also called kidney failure, is the advanced stage of chronic kidney disease when kidneys are no longer able to work as they should to meet the body’s needs. A great number of clinical studies have reported the blood levels of cTn increase over time as the chronic kidney disease progresses.2, 3 Fortunately, the elevated levels of cTn in ESRD are divergent from the ones in AMI.

The cTn values in AMI are usually as high as 20-50 times of the upper reference limit. However, modest elevations are found in ESRD patients who were asymptomatic or present with nonspecific ACS symptoms such as dyspnea, fatigue, or nausea.4 In addition, the cTn elevation in ESRD carries important prognostic information.

ESRD patients with elevated blood levels of cTn, particularly cTnT, are closely associated with a high risk of death despite being ACS asymptomatic.5 Several theories have been proposed to explain the mechanisms of cTn release into blood in renal diseases, but additional studies are still needed to clarify the patterns of cTn changes over time in patients with chronic kidney disease, especially in the absence of myocardial ischemia.6

Acute Pulmonary Embolism

Acute pulmonary embolism (APE) is the occlusion of the pulmonary artery by thrombus, fat, air, and other materials. The pulmonary artery obstruction can lead to an acute right ventricle dilatation, which significantly increases the pulmonary vascular resistance, reduces coronary artery perfusion, and eventually causes severe myocardial ischemia and elevated cTn levels.7

Patients with pulmonary emboli may clinically mimic myocardial ischaemia, but the management for them is completely different; therefore, it is critical to differentiate AMI and APE in patients with elevated cTn and ACS related symptoms. From the laboratory perspectives, cTn elevation is found in approximately 40-50 percent of patients with APE.8, 9 Despite the low diagnostic accuracy, the elevation process of cTn in APE is significantly different from the one in AMI.

It has been widely known that in AMI, the blood levels of cTn usually start to elevate from four to six hours after the onset of symptoms and remain high for up to four to seven days (cTnI) or 10 to 14 days (cTnT). By contrast, the increase of cTn in APE may occur from 6-12 hours after the symptomatic occurrence and its retention lasts no longer than three days.10 In addition, the blood levels of cTn in APF are moderately increased compared to AMI cTn elevations, which are at least 20 times higher than the upper reference limits.

It has been well known that elevated cTn levels do not always indicate AMI. A variety of diseases should be considered in the differential diagnosis of patients with cTn elevations, despite whether the acute coronary syndrome related symptoms are present or not. The cTn elevations may not be diagnostic for most of these diseases except AMI, however, its strong prognostic implications have been clearly proven with predictive values of increased risk of mortality and cardiovascular incidents. Therefore, it should be recommended that patients with elevated cTn levels receive more intense follow-ups and guidance on the appropriate approach to treatment.

  1. Thygesen, K.; Alpert, J. S.; Jaffe, A. S.; Chaitman, B. R.; Bax, J. J.; Morrow, D. A.; White, H. D.; Executive Group on behalf of the Joint European Society of Cardiology /American College of Cardiology /American Heart Association /World Heart Federation Task Force for the Universal Definition of Myocardial, I., Fourth Universal Definition of Myocardial Infarction (2018). Circulation 2018, 138 (20), e618-e651.
  2. Chesnaye, N. C.; Szummer, K.; Barany, P.; Heimburger, O.; Magin, H.; Almquist, T.; Uhlin, F.; Dekker, F. W.; Wanner, C.; Jager, K. J.; Evans, M.; dagger, E. S. I.; Investigatorsdagger, E. S., Association Between Renal Function and Troponin T Over Time in Stable Chronic Kidney Disease Patients. J Am Heart Assoc 2019, 8 (21), e013091.
  3. Stacy, S. R.; Suarez-Cuervo, C.; Berger, Z.; Wilson, L. M.; Yeh, H. C.; Bass, E. B.; Michos, E. D., Role of troponin in patients with chronic kidney disease and suspected acute coronary syndrome: a systematic review. Ann Intern Med 2014, 161 (7), 502-12.
  4. Skeik, N.; Patel, D. C., A review of troponins in ischemic heart disease and other conditions. Int J Angiol 2007, 16 (2), 53-8.
  5. Khan, N. A.; Hemmelgarn, B. R.; Tonelli, M.; Thompson, C. R.; Levin, A., Prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease: a meta-analysis. Circulation 2005, 112 (20), 3088-96.
  6. Kanderian, A. S.; Francis, G. S., Cardiac troponins and chronic kidney disease. Kidney Int 2006, 69 (7), 1112-4.
  7. Kilinc, G.; Dogan, O. T.; Berk, S.; Epozturk, K.; Ozsahin, S. L.; Akkurt, I., Significance of serum cardiac troponin I levels in pulmonary embolism. J Thorac Dis 2012, 4 (6), 588-93.
  8. Meyer, T.; Binder, L.; Hruska, N.; Luthe, H.; Buchwald, A. B., Cardiac troponin I elevation in acute pulmonary embolism is associated with right ventricular dysfunction. J Am Coll Cardiol 2000, 36 (5), 1632-6.
  9. Konstantinides, S.; Geibel, A.; Olschewski, M.; Kasper, W.; Hruska, N.; Jackle, S.; Binder, L., Importance of cardiac troponins I and T in risk stratification of patients with acute pulmonary embolism. Circulation 2002, 106 (10), 1263-8.
  10. Muller-Bardorff, M.; Weidtmann, B.; Giannitsis, E.; Kurowski, V.; Katus, H. A., Release kinetics of cardiac troponin T in survivors of confirmed severe pulmonary embolism. Clin Chem 2002, 48 (4), 673-5.

Jie Gao is Assistant Professor in the Clinical Laboratory Sciences Program/Department of Clinical and Diagnostic Sciences at the University of Alabama at Birmingham.

Floyd Josephat is Program Director for Clinical Laboratory Science and Clinical Pathologist Assistant Programs at the University of Alabama at Birmingham.