In this issue of the journal, Dr. Park and his research team present evidence that increased serum cardiac troponin-enzymes (Tn) measured after liver transplant surgery are associated with worse patient and graft outcome.1 The association between increased serum Tn and adverse outcomes after liver transplantation was previously reported by other investigators.2 However, the current study provides more rigorous evidence to support this association by propensity testing of demographic characteristics and other cardiovascular morbidities in patients with and without troponin elevation. This important step improves specificity of the observations by reducing the independent effects other conditions could have on serum Tn.3 The time to detection of Tn elevation was also markedly shortened by use of a high-sensitivity troponin (hs-Tn) assay. Although the findings are interesting, it is not clear how this information will improve clinical care of liver transplant patients receiving deceased or living donor organs.
High-sensitivity troponin assays are clinical biomarkers that are primarily used as predictive analytic tools for the diagnosis and outcome of myocardial infarction.4 They have been widely available throughout the world but were only approved for clinical use in the USA in 2017. Assays are defined as high sensitivity if the coefficient of variation for the upper reference limit is <10% at the 99th percentile in the population of interest.5 This minimizes false-positive results but can reduce diagnostic specificity.6
All biomarkers, including Tn enzyme assays, need well-defined reference parameters for the clinical condition and the population of interest.7 There are no known reference values for unusual populations such as pre- and postoperative transplant recipients. The reference ranges used for diagnosis of myocardial infarction may not have equal predictive value for overall early mortality or graft loss.6 It is also possible that existing reference values may not uniformly apply to all patients with liver disease and could vary with the severity or etiology of illness. Systematic testing is still needed to address gaps in our understanding of how well hs-Tn can be applied to liver transplant patients before they can be used for evaluating patient outcomes.
The study by Park et al assumes a single test result above the upper reference range for hs-TnI in myocardial infarction can predict adverse outcomes in liver transplant recipients. There is some evidence to support this hypothesis as investigators found an association between elevated hs-Tn and early mortality in conditions not caused by myocardial infarction.4 These include heart failure, pulmonary embolus, and renal failure. Elevated Tn in the latter conditions is caused by ischemic injury from myocardial stretching.
However, diagnostic and predictive accuracy are limited when a single test value is used in chronic conditions. In contrast, reference change values, which measure changes in serial results, may perform better in chronic diseases.6 These diseases have ongoing injury patterns that may be best detected by constructing kinetic profiles of enzyme changes. Because the mechanism of injury for increased hs-Tn after liver transplant is still unknown, a kinetic analysis of serial enzyme levels would have been more informative in the current study. This is nicely illustrated by the ability of serial but not single hs-Tn levels to predict early occurrence of adverse cardiovascular events in patients with diabetes.8
Diagnosis is only one use of hs-Tn. Serum levels have been effective in directing the clinical management of patients diagnosed with myocardial infarction. Clinical decision-making is guided by algorithms that triage patients into cost-effective care plans.9 The latter direct hospital admission, interventions and subsequent drug treatment. The practical role of conventional or even hs-Tn assays in liver transplant recipients is unknown.
In this study, 103 of 159 patients had increased hs-TnI, without any adverse outcomes. The low discriminant accuracy of a single hs-Tn to categorize the relative risk of complications in liver transplant recipients makes it difficult to develop meaningful care plans. The performance of hs-Tn in this study was not rigorous enough to support the development of cost-effective clinical care pathways. Further, there are no obvious interventions because a diagnosis or cause of the observation is unknown.
Questions remain about how the association between hs-Tn and outcome can be used to improve the care of transplant recipients. It is possible that posttransplant hs-Tn has limited prognostic utility for risk stratification and intervention. However, Tn assays could play a role in generating evidence-based quality improvement data. To date, there are few sensitive and objective outcomes measures of intraoperative liver transplant care.
The effects of small changes in clinical care are difficult to isolate and measure. This is particularly true during surgery when there are multiple rapid interventions for each patient. Mortality or graft loss, the principal outcome measures provide late and insensitive findings. More effective tools could be developed if the degree of injury directed changes in clinical practice. Combining hs-Tn tests with other predictive biomarkers could improve prognostic performance. Each biomarker can be chosen to improve test performance and reliability. This is a similar approach used in the new biomarker map used for predictive purposes in acute myocardial infarction.10
In summary, the study by Park et al shows us that we can use new sensitive tests, generate sophisticated data and still not know what to do with the findings. The validity and meaning of clinical associations are context specific and even the most sensitive assays lose their predictive power when the application is unclear or context differs from the original reference point. However, these types of studies also open the door to innovative thinking that leads us to viewing observations from a different perspective; an essential aspect for taking the next step in clinical care.
1. Park J, Seung Hwa Lee SH, Han S, et al. Elevated high-sensitivity troponin I during living donor liver transplantation is associated with postoperative adverse outcomes. Transplantation
2. Snipelisky D, Donovan S, Levy M, et al. Cardiac troponin elevation predicts mortality in patients undergoing orthotopic liver transplantation. J Transplant
3. Wu C, Singh A, Collins B, et al. Causes of troponin elevation and associated mortality in young patients. Am J Med
4. Sherwood MW, Kristin Newby L. High sensitivity troponin assays: evidence, indications and rationale use. J Am Heart Assoc
5. Koerbin G, Abhayaratna WP, Potter JM, et al. Effect of population selection on 99th percentile values for a high sensitivity cardiac troponin I and T assays. Clin Biochem
6. Chapman AR, Lee KK, McAllister DA, et al. Association of high-sensitivity cardiac troponin I concentration with cardiac outcomes in patients with suspected acute coronary syndrome. JAMA
7. Thygesen K, Mair J, Giannitsis E, et al. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J
8. Cavender MA, White WB, Jarolim P, et al. Serial measurement of high-sensitivity troponin I and cardiovascular outcomes in patients with type 2 diabetes mellitus in the EXAMINE trial (examination of cardiovascular outcomes with alogliptin versus standard of care). Circulation
9. Morrow DA. Evidence-based algorithms using high-sensitivity cardiac troponin in the emergency department. JAMA Cardiol
10. Schernthaner C, Lichtenauer M, Wernly B, et al. Multibiomarker analysis in patients with acute myocardial infarction. Eur J Clin Invest